Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14]O)[CH:11]=[C:10]([CH3:16])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][Cl:19])[CH:11]=[C:10]([CH3:16])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CO)nc(Nc2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(CCl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 73 %

Procedure:
Phosphorus oxychloride (10 ml) was added to 1.5 g of 2-anilino-4-hydroxymethyl-6-methylpyrimidine and the mixture was heated under reflux for 15 minutes. After completion of the reaction, excessive phosphorus oxychloride was removed by distillation under reduced pressure. After dissolving the residue in dichloromethane, a 10% aqueous solution of sodium hydroxide was gradually added until the solution became alkaline under reflux of dichloromethane. After cooling to room temperature, the organic layer was washed with water, dried over magnesium sulfate and concentrated. The residual solid was recrystallized to obtain 1.2 g (yield: 73%) of 2-anilino-4-chloromethyl-6-methylpyrimidine having a melting point of 100°-101° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([OH:24])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CN.CN(C(ON1N=N[C:42]2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([O:24][CH2:41][CH3:42])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1sc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)sc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylic acid (25b) was dissolved in DMF (10 mL), to it methanamine (1 equiv.) was added followed by the addition of HATU (1.5 equiv.) and DIPEA (4 equiv.) and stirred for 3 h at room temperature. The reaction mixture was concentrated to remove DMF under reduced pressure. The crude material obtained was purified by flash column chromatography using silica gel and MeOH:CHCl3 as eluent. The material obtained was triturated with diethyl ether and hexane to afford ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.32 (d, J=6.40 Hz, 6H), 2.73 (s, 3H), 2.81 (d, J=4.40 Hz, 3H), 3.64-3.69 (m, 1H), 6.13 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.13 (d, J=4.80 Hz, 1H), 8.20 (d, J=7.20 Hz, 1H), 8.37 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.33 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.606 min; LCMS (ES-API), m/z 439.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.323 min; Purity: 96.3%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([OH:9])=O.[NH2:24][CH2:25][C:26]1[C:27]([F:43])=[C:28]([O:33][C:34]2[CH:35]=[C:36]([CH:39]=[C:40]([Cl:42])[CH:41]=2)[C:37]#[N:38])[C:29]([Cl:32])=[CH:30][CH:31]=1>>[Cl:1][C:2]1[N:3]=[C:4]([S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[NH:5][C:6]=1[C:7]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][C:34]2[CH:35]=[C:36]([C:37]#[N:38])[CH:39]=[C:40]([Cl:42])[CH:41]=2)[C:27]=1[F:43])=[O:9]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CN(C)S(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Product: CN(C)S(=O)(=O)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 59.4 %

Procedure:
4-chloro-2-[(dimethylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.12 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.045 g, 0.14 mmol) were employed using a procedure similar to that described herein to provide the title compound (0.039 g, 59%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% formic acid). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54 (s, 1H), 7.34-7.42 (m, 2H), 7.26 (s, 1H), 7.22 (s, 1H), 4.64 (s, 2H), 2.86 (s, 6H). ES-LCMS: m/z 546.1, 547.9, 550.0 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH:25][C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]3=[O:39])=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]2=[O:39])=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:43]([OH:45])([C:42]([F:47])([F:46])[F:41])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CCNC[C@H]1NC(=O)c1ccc(-n2ccccc2=O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cis-4-Benzyloxycarbonylamino-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (22.2 mg, 0.041 mmol) was dissolved in 2 mL of anhydrous CH2Cl2 To this solution was added 2 mL of trifluoroacetic acid (TFA). The mixture was stirred for one hour at rt. The solvent was removed in vacuo to yield cis-{3-[4-(2-Oxo-2H-pyridin-1-yl)-benzoylamino]-piperidin-4-yl}-carbamic acid benzyl ester, CF3COOH salt (42.7 mg) as a viscous oil, which was used without any further purification. Anal. LC/MS (ESI) Shimadzu Phenomenex C18; 4.6×50 mm Luna; flow rate 4 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 4 min; (A=10% MeOH, 90% H2O, 0.1% TFA & B=90% MeOH, 10% H2O, 0.1% TFA); 447.24 (M+H)+, tR=2.15 min.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([O:44][CH3:45])[O:42][CH3:43])[N:36]=2)[OH:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([O:42][CH3:43])[O:44][CH3:45])[N:36]=2)=[O:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
399.7 mg (0.619 mmole) of the compound obtained in step 1 was dissolved in 7 ml of methylene chloride and to the resulting solution was added 890 mg (10.2 mmole) of manganese dioxide. The mixture was stirred for 5 hours at room temperature and the resultant was removed from the solvent and purified with silica gel column chromatography to obtain 370 mg of the title compound (yield 93%).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:29]([C:24]2[N:25]=[C:26]([CH3:28])[O:27][C:23]=2[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)=[O:30])[CH:9]=[N:8]1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=419.22.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cncc(-c3ccc(C#N)c(Cl)c3)c2)cc1
Yield: 44.3 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 4-methyl-benzenesulfonyl chloride (18.3 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-methyl-benzenesulfonamide (14.8 mg, >95% purity, yield: 44.3%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 384 [M+H]+, retention time=2.35 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 7.31-7.36 (m, 2H) 7.64-7.68 (m, 2H) 7.73 (d, J=1.64 Hz, 1H) 7.75 (d, J=2.02 Hz, 1H) 7.99 (d, J=1.52 Hz, 1H) 8.07 (d, J=8.21 Hz, 1H) 8.28 (d, J=2.27 Hz, 1H) 8.62 (d, J=1.77 Hz, 1H) 10.64 (br. s., 1H).
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.Cl.[NH2:13][OH:14]>CO>[N:3]1([CH2:2][N:13]([CH2:2][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[N:4]2)[OH:14])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: OCn1nnc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON(Cn1nnc2ccccc21)Cn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
To a stirred solution of 1-(hydroxymethyl)benzotriazole (44.8 parts) in 375 parts of methanol at room temperature was added 10.4 parts of hydroxylamine hydrochloride. The reaction mixture was stirred at room temperature for about five hours and then placed in a freezer for about six hours. The precipitated white solid was filtered, washed with cold water and dried in vacuo (in presence of phosphorus pentoxide). The dried product, m.p. 175°-7° C. (reported m.p. 173°-4° C.), 24 parts: was identified as N,N-bis (benzotriazol-1-yl methyl) hydroxylamine (54.2% yield) by 1H and 13C NMR spectral analysis.
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1C(=O)[CH2:20][CH2:19][CH2:18]2>>[CH3:11][O:12][C:13]1[CH:22]=[C:17]2[C:16]([CH2:20][CH2:19][CH:18]2[NH2:10])=[CH:15][CH:14]=1
Reactant: NC1CCCc2occc21
Reactant: COc1cccc2c1C(=O)CCC2
Product: COc1ccc2c(c1)C(N)CC2

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 8-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.72, 2.54, 2.74, 2.90, 3.83, 4.34, 6.78, 6.91, 7.13; MS (FAB) m/z (rel. intensity) 164 (MH+, 17), 308 (8), 164 (17), 163 (7), 162 (19), 148 (18), 147 (99), 146 (18), 145 (9), 121 (11), 115 (8). HRMS (FAB) calcd for C10H13NO+H 164.1075, found 164.1071.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5](=[O:24])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=1[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc(Cl)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-chloro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2',5-dichloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone of melting point 147.5°-148.5° C.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH2:40][CH2:41][CH:42]1[CH2:44][CH2:43]1>ClCCl.CN(C=O)C>[CH:42]1([CH2:41][NH:40][CH2:2][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[C:24]([N:26]([CH:28]([CH3:29])[CH3:30])[CH3:27])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[N:5][CH:4]=2)[CH2:44][CH2:43]1
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: NCC1CC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNCC3CC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (210 mg, 0.44 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with aminomethyl-cyclopropane in DMF according to the method described in Example 45. Obtained as a light brown solid (110 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:11]([C:12]([O:14]C)=[O:13])[CH:10]2[C:16]([O:18]C)=[O:17])=[CH:5][CH:4]=1.[Li+].[OH-].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:10]([C:16]([OH:18])=[O:17])[CH:11]2[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)C1C(C(=O)OC)C1c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2C(C(=O)O)C2C(=O)O)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of dimethyl 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate (0.88 g, 3.33 mmol) and LiOH (2M in H2O, 10 mL) in THF (30 mL) was stirred at 55° C. overnight. After cooling to room temperature, the reaction mixture was poured into 1N HCl and extracted with EtOAc (3×). The combined organic extract was dried over MgSO4, filtered, and concentrated to give the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[C:6]([O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]([O:17][CH3:18])=[C:4]([O:19][CH3:20])[CH:3]=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O.O>ClCCl>[CH:13]1([O:12][C:6]2[C:5]([O:17][CH3:18])=[C:4]([O:19][CH3:20])[CH:3]=[C:2]3[C:7]=2[C:8]([OH:10])=[N:23][C:22]([OH:21])=[N:1]3)[CH2:16][CH2:15][CH2:14]1
Reactant: N#C[O-]
Reactant: COC(=O)c1c(N)cc(OC)c(OC)c1OC1CCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2nc(O)nc(O)c2c(OC2CCC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Methyl 6-amino-2-cyclobutyloxy-3,4-dimethoxybenzoate (500 mg, 0.00177 mol) was added to a solution of sodium cyanate (462 mg, 0.00708 mol) and trifluoroacetic acid (0.55 ml, 0.00708 mol) in dichloromethane (15 ml) and the reaction stirred at room temperature for 1 hour. Water (25 ml) was then added and the mixture extracted with dichloromethane (3×25 ml). The combined organic extracts were washed again with water (40 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was suspended in a solution of sodium hydroxide (750 mg) in water (30 ml) and heated to 60° C. for 1 hour. On cooling, the mixture was acidified with concentrated hydrochloric acid, the resulting precipitate filtered and washed with water (20 ml) and diethyl ether (10 ml). Drying under air suction gave the subtitle compound as a solid (300 mg, 58%). 1H-NMR (DMSO-d6): Γ=1.40 (1H, m), 1.67 (1H, m), 2.16 (4H, m), 3.68 (3H, s), 3.83 (3H, s), 4.58 (1H, m), 6.50 (1H, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C[O:9][C:10](=O)[CH2:11][C:12](=[O:15])[CH2:13][CH3:14]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:10](=[O:9])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CCC(=O)CC(=O)OC
Product: CCC(=O)CC(=O)N1CCC(O)CC1

Procedure:
59.0 g (583 mmol) of 4-hydroxypiperidine and 79.7 g (612 mmol) of 3-oxovaleric acid methyl ester were heated for 9 h at 110° C., and the resulting methanol was removed via a distillation bridge. The reaction residue was freed from volatiles on a rotary evaporator, taken up in ethanol, and filtered through 600 ml of strongly acidic ion exchanger (Dowex® HCR-W2), concentrated again and purified by column chromatography (silica gel, eluent's gradient from ethyl acetate to ethanol). The pure product fractions were freed from solvent on a rotary evaporator and yielded 63.6 g (55%) of a viscous, clear, colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4](=[O:9])[C:5]=1[O:6]CC.Br.[NH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:9])[C:3]=1[NH:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[O:16]1
Reactant: CCOc1c(N)c(=O)c1=O
Reactant: NCCn1oc(=O)[nH]c1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(NCCn2oc(=O)[nH]c2=O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione (0.56 g, 4.0 mmol) in ethanol (20 mL) was added to 2-(2-aminoethyl)-1,2,4-oxadiazolidine-3,5-dione hydrobromide (0.90 g, 4.0 mmol) in ethanol (100 mL). The reaction mixture was treated with 1N sodium hydroxide solution (8 mL, 8 mmol) and allowed to stir for 24 hours at room temperature. The resulting precipitate was filtered, dissolved in water and passed through an ion exchange column (AG 50W-X2, 100-200 mesh, H+ form), eluting with water. The eluent was freeze dried yielding the title compound as a cream colored solid, partial hydrate (0.45 g, 45%, mp 225° C. (dec)); IR (KBr, cm-1) 3300, 3140, 1820, 1740, 1720, 1640; MS (+FAB) 242 (MH+); 1H NMR (DMSO, 400 MHz): δ 12.4 (br s, NH), 7.5 (br s, 3 NH), 4.0- 3.5 (m, 4H); 13C NMR (DMSO, 400 MHz): ppm 183.72, 183.63, 170.06, 168.96, 158.17, 152.72, 50.41, 41.68.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[NH:25][C:24](=[O:26])[NH:23][C:22]1=[O:27]>[Cl-].[Li+]>[OH:10][CH:9]([CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:12]=1)[CH2:11][N:23]1[C:22](=[O:27])[C:21]([CH3:28])([CH3:20])[NH:25][C:24]1=[O:26]
Reactant: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Cl-]
Agent: [Li+]
Product: CC1(C)NC(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 1 h
Yield: 79.4 %

Procedure:
25 mg of lithium chloride are added to 5.25 g (0.02 mol) of 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane and 2.56 g (0.02 mol) of 5,5-dimethylhydantoin and the mixture is kept as a melt at 220°-230°C for 60 minutes whilst stirring in a nitrogen atmosphere. After cooling, a glassy residue is obtained, which when recrystallised from toluene/isopropanol gives 6.2 g (78% of theory) of 3-[2-hydroxy-3(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl] -5,5-dimethylhydantoin of melting point 175°-76°C in the form of colourless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14](Br)[CH3:15]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:14][CH3:15])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCBr
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C#N)c1cccc(OC)c1
Yield: 58 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (8.8 g, 60 mmoles), DMF (60 ml), NaH (60%, 2.88 g, 72 mmoles) and ethylbromide (7.85 g, 72 mmoles), and chromatographing with petrolatum/ethyl ether 97:3 as eluent, 6.1 g of the title compound were obtained (yield: 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[CH2:11]([O:13][C:14](=[O:39])[C:15]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([CH3:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH:26]2[CH2:30][NH:29][C:28](=[O:31])[N:27]2[CH3:32])=[CH:19][CH:18]=1)[CH3:12].[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:39])[C:15]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([CH3:33])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH:26]2[CH2:30][N:29]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:28](=[O:31])[N:27]2[CH3:32])=[CH:21][CH:22]=1)[CH3:12]
Reactant: COc1cccc(CBr)c1
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3cccc(OC)c3)C(=O)N2C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxybenzyl bromide (0.024 mL, 0.170 mmol, d=1.436) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.046 g, 0.114 mmol) and sodium hydride (0.011 g, 0.28 mmol, 60% suspension on mineral oil), pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature 48 h, diluted with ethyl acetate, and washed with 1N HCl and water. The organic layer is dried, concentrated, and used in the next step. MS [EI+] 527 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH3:19])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:20][OH:21])[CH2:3]1.S(=O)(=O)(O)O.[Na].C(O)[CH2:29][OH:30]>>[CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH2:19][CH2:29][OH:30])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:20][OH:21])[CH2:3]1
Reactant: OCCO
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CN1C[C@H](CO)C[C@]2(OCCO)c3cccc4[nH]cc(c34)C[C@@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A stirred solution of 10 g of 6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline in 100 ml of ethylen glycol was treated with 7.5 ml of concentrated sulphuric acid at room temperature. After stirring for 3 hour, the solution was poured into ice water then made alkaline with concentrated sodium hydroxyde. The precipitated was collected washed with water, and crystallised from ehanol to provide the title compound in 75% yield, m.p. 201-205° C.
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19](=[O:26])[CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13]1)[CH3:11].[OH-:33].[Na+]>>[C:4]([OH:6])(=[O:5])[C:3]([OH:26])=[O:33].[CH3:11][CH:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19](=[O:26])[CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:17]1)[CH3:9]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: [OH-]
Agent: CC(C)N1CCC(N(C(=O)Cc2cccs2)c2ccccc2)CC1
Agent: [Na+]
Product: O=C(O)C(=O)O

Procedure:
From 6 parts of N-[1-(1-methylethyl)-4-piperidinyl]-N-phenyl-2-thiopheneacetamide (E)-2-butenedioate, the free base is liberated in the conventional manner with a diluted sodium hydroxide solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and dried, yielding 3.2 parts of N-[1-(1-methylethyl)-4-piperidinyl]-N-phenyl-2-thiopheneacetamide ethanedioate; mp. 167.4° C.