Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].[C:23](/[C:25](=[CH:31]\OCC)/[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].[C:35]([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.CC(O)=O>[CH2:29]([O:28][C:26]([C:25]1[C:31]([CH3:35])=[N:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C:13]3[C:3]([CH2:1][CH3:2])=[N:4][N:5]4[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=34)=[CH:20][CH:19]=2)[C:23]=1[NH2:24])=[O:27])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: CCO/C=C(\C#N)C(=O)OCC
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(NN)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)c1N
Temperature: 100 °C
Reaction time: 3 h

Procedure:
[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-hydrazine (15) (1.8 g, 6.1 mmol) was dissolved in 40 ml water/AcOH (1:3), and after addition of (E)-ethyl 2-cyano-3-ethoxyacrylate (1.24 g, 7.3 mmol) and sodium acetate (1.1 g, 13.4 mmol) the reaction mixture was stirred for 3 h at 100° C. Sodium carbonate was added (pH 11). The organic layer was extracted 2 times with EtOAc, washed with water and brine, dried over Na2 SO4 and concentrated. The crude product was purified by chromatography (50-90% EtOAc in cyclohexane).
Reaction SMILES: [CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][CH:2]([CH3:1])[CH2:3]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CNc2ccccc2N1
Product: CC(=O)N1CC(C)Nc2ccccc21

Procedure:
Using the method of Example 15, 3-methyl-1,2,3,4-tetrahydroquinoxaline was reacted with acetic anhydride to provide 1-acetyl-3-methyl-1,2,3,4-tetrahydroquinoxaline.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1>C(Cl)Cl.CCN(C(C)C)C(C)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:14][C:15]1[S:19][C:18](/[CH:20]=[CH:21]/[C:22]([NH:46][O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)=[O:23])=[CH:17][CH:16]=1
Reactant: O=C(O)/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1ccc(CN2CCc3c([nH]c4ccccc34)C2)s1)NOC1CCCCO1
Reaction time: 3 h

Procedure:
A solution of (2E)-3-[5-(1,3,4,9-tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]acrylic acid in DCM (2 mL) and DIEA (0.11 mL) was sequentially treated with HOBT (32 mg), EDCI (64 mg) and NH2OTHP (40 mg). After three hours, the solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with EtOAc. (2E)-3-[5-(1,3,4,9-Tetrahydro-2H-b-carbolin-2-ylmethyl)thien-2-yl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide was obtained as a yellow oil (37 mg), m/e=438 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a solution of 4-aminobenzenemethanamine (1.5 g, 12.3 mmol) in 20 mL CH2Cl2 was added benzylchloroformate (1.57 mL, 11 mmol), followed by triethylamine (Et3N) (1.5 mL, 11 mmol) at room temperature. White percipitates was observed immediately. The reaction was stirred at room temperature for 10 minutes and removed Et3N salt by filtration. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The EtOAc layer was washed with a sat. solution of KHSO4, a sat. solution of NaHCO3, concentrated in vacuo and subjected to a silica-gel column using CHCl3 /CH3OH=25/1 ratio as an eluting solvent to give title compound (43% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:12]>>[OH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:12]
Reactant: ClCc1ccccn1
Reactant: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1OCc1ccccn1
Yield: 27 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]acetamide to give the title compound as a yellow solid in 27% yield; NMR spectrum (DMSO-d6) 2.27 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.20 (s, 2H), 5.49 (t, 1H), 6.98 (d, 1H), 7.14 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H), 7.45 (d, 1H), 7.56 (m, 2H), 7.68 (t, 1H), 7.85 (td, 1H), 8.17 (t, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][S:6][C:5]2([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]2)[O:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.CCOCC>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][CH:3]2[CH2:7][S:6][C:5]3([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]3)[O:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC1CCC2(C1)OC(CO)CS2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)CC1CCC2(C1)OC(COS(=O)(=O)c1ccc(C)cc1)CS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold stirred solution of the product of Example O (2.60 g, 10 mmol) in pyridine (30 ml) is added p-toluenesulfonyl chloride (1.91 g, 10 mmol) in portions over 15 minutes. When the addition is completed the reaction is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ether and washed with water, 0.5N aqueous sodium bisulfate solution, 5% aqueous sodium bicarbonate solution and water. The organic layer is dried over sodium sulfate, filtered, and the filtrate is concentrated on a rotary evaporator to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19]C1C=CC(B(O)O)=C(F)C=1>>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[C:2]([F:1])[CH:7]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1ccc(Cl)cc1F
Product: O=C(O)c1csc(-c2ccc(Cl)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (4-chloro-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[N-:19]=[N+:20]=[N-:21].[Na+]>CO.O>[N:19]([CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (2.4 g, 8.71 mmol) in methanol (13 mL) is added sodium azide (1.13 g, 17.4 mmol) in water (10 mL). The mixture is heated to reflux for 3 hrs, cooled to room temperature, majority of the methanol is evaporated, the residue is extracted with ethyl acetate, dried, concentrated and column chromatography on silica gel yields the title compound (2.10 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[O:11]([C:13]1[CH:14]=[C:15]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[S:26](Cl)(=[O:28])=[O:27])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:13]([O:11][CH3:12])[CH:14]=1)(=[O:27])=[O:28]
Reactant: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc(OC)c1OC
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc(OC)c1OC

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 97 mg), NaH (1.4 mmoles, 55 mg), and 2-(3,4,5-trimethoxylbenzyl)-benzo[b]thiophene-3-sulfonyl chloride (0.66 mmoles, 0.27 g) in THF (2 ml) yielded, after flash chromatography using 50% ethyl acetate/haxanes and recrystallization from chloroform and hexanes, 94 mg of a tan solid, m.p. 154-156° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)(Cl)=O.C[N:20]1[CH:25]2[O:26][CH2:27][CH2:28][NH:29][C:24]2=[CH:23][CH:22]=[CH:21]1.O.[CH3:31]N(C)C(=O)C>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:28][CH2:27][O:26][C:25]3[N:20]=[CH:21][C:22]([CH3:31])=[CH:23][C:24]2=3)=[O:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Reactant: CN1C=CC=C2NCCOC21
Reactant: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1cnc2c(c1)N(C(=O)c1ccc(O)c(C(F)(F)F)c1)CCO2
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
4-hydroxy-3-trifluoromethyl-benzoic acid (151 mg, 0.73 mmol) was dissolved in N,N-dimethyl acetamide (2.0 ml) and then cooled to −20° C. Thionyl chloride (0.073 ml, 100 mmol) was added thereto and stirred at −20° C. for 30 minutes. 5-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine dissolved in N,N-dimethyl acetamide (1.0 ml) was added thereto dropwise and then stirred at −20° C. for 20 minutes, and then stirred at room temperature for 15 hours. Water was added thereto and the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting solid residue was recrystallized from dichloromethane to obtain the target compound 69, i.e., (4-hydroxy-3-trifluoromethyl-phenyl)-(7-methyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone, as white solid (176 mg, 78%).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:2].S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[C:1]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:21])=[O:2]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3.67 g, 15.03 mmol, 1 eq) was dissolved in acetone (50 ml) and the solution diluted with water (50 ml). To the reaction mixture was added sulfamic acid (2.04 g, 21.04 mmol, 1.4 eq) and 80% sodium chlorite (1.78 g, 15.8 mmol, 1.05 eq) and allowed to stir for 1 hour at room temperature in an open vessel. Removal of acetone in vacuo yielded crude product as a precipitate in the remaining aqueous solution. The solid was collected, washed with absolute ethanol and dried (3.32 g, 85%). m.p. 173-175° C.
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[N:8]=1.N1C=CC=C[CH:25]=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>ClCCl.CO>[CH:20]([O:19][CH:17]([CH3:6])[CH3:25])([CH3:21])[CH3:22].[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]1[N:8]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:3](=[O:2])[NH:4][C:5]([CH3:23])=[C:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]
Reactant: CCOC(=O)Cl
Reactant: c1ccncc1
Reactant: COC1=NC(c2cccc(Cl)c2Cl)C(C(=O)OC(C)C)=C(C)N1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)OC(C)C
Product: CCOC(=O)N1C(=O)NC(C)=C(C(=O)OC(C)C)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(2,3-dichlorophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (1.2 g., 3.37 mmole) and pyridine (1.0 ml.) in dichloromethane (10 ml.) under argon is cooled to 0° and treated dropwise with ethyl chloroformate (0.4 ml., 4.04 mmole). After the addition is completed, the cooling bath is removed and the reaction is allowed to stir at room temperature for one hour. The solvent is then stripped off to provide a colorless solid. This crude material is dissolved in methanol (12 ml.) and treated with 2N hydrochloric acid (3 ml.). The reaction is allowed to stir at room temperature overnight precipitating a colorless solid. The solvent is evaporated and the residue is dissolved in ethyl acetate. The resulting solution is washed with water, sodium bicarbonate solution, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off and the residue is triturated with isopopyl ether to give 1.12 g. of colorless solid. Recrystallization from dichloromethane--isopropyl ether gives 6-(2,3-dichlorophenyl)-3,6-dihydro-4-methyl-2-oxo-1,5(2H)-pyrimidinedicarboxylic acid, 1-ethyl 5-(1-methylethyl) ester as a colorless solid; m.p. 173°-175°. TLC (silica gel; ethyl acetate: hexanes, 60:40) Rf =0.30.
Reaction SMILES: [CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[NH:4][CH2:5][CH2:6][O:7]2.[C:18](=[O:21])([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:26][N:27]([CH:29]=[O:30])C>>[CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[N:4]([CH2:12][CH2:13][CH2:14][CH2:26][N:27]1[C:29](=[O:30])[C:3]3=[CH:8][CH:9]=[CH:10][CH:11]=[C:2]3[C:18]1=[O:21])[CH2:5][CH2:6][O:7]2
Reactant: CC12OCCNC1Cc1c[nH]c3cccc2c13
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CC12OCCN(CCCCN3C(=O)c4ccccc4C3=O)C1Cc1c[nH]c3cccc2c13
Temperature: 60 °C
Yield: 69 %

Procedure:
To a solution of 4,6,6a,8,9,10a-hexahydro-10a-methylindolo[3,4-gh][1.4]benzoxazine (100 mg, 0.44 mmol) in DMF (5 ml) were added potassium carbonate (303 mg, 2.2 mmol), N-(4=bromobutyl)phthalimido (124 mg, 0.44 mmol) and sodium iodide (0.66 mg, 0.44 mmol). The mixture was heated at 60° C. for 24 hours. After completion of the reaction, the reaction mixture was added to ice water-ethyl acetate. The organic layer was separated, washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (3:2), to afford 130 mg (69%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[N:38])[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[N-:50]=[N+:51]=[N-:52].[Na+].Cl.C([NH+](CC)CC)C.CO.ClCCl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]4[NH:52][N:51]=[N:50][N:38]=4)[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCCCC#N)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCCCc4nnn[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.45 g, 0.67 mmol), sodium azide (0.13 g, 2.04 mmol), and triethylammonium hydrochloride (0.14 g, 1.03 mmol) in N-methylpyrrolidinone (6 mL). Heat to 150° C. After 4 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the aqueous layer three times with ethyl acetate. Adjust the pH of the aqueous layer to about 1 using a 1 M aqueous hydrochloric acid solution. The aqueous layer is again extracted three times with ethyl acetate, and twice with dichloromethane. The aqueous layer is saturated with sodium chloride and again extracted four times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with 20% methanol/dichloromethane to give the title compound: Rf=0.33 (silica gel, 20% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]2([CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=3)[C:20]3[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=3[O:18]2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]2([CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([O:30][CH2:3][CH:2]=[CH2:1])=[C:25]([F:31])[CH:24]=3)[C:20]3[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=3[O:18]2)[CH2:16][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1c(F)cc(C2=CC3(CCN(Cc4ccccc4)CC3)Oc3ccccc32)cc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOc1c(F)cc(C2=CC3(CCN(Cc4ccccc4)CC3)Oc3ccccc32)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Allyl bromide (1.1 mole equiv.) was added dropwise to a mixture of N-benzyl-4-(3,5-difluoro-4-hydroxyphenyl)spiro[2H-1-benzopyran-2,4′-piperidine] (750 mg, 1.79 mmol; prepared according to the procedures outlined in Examples 1 and 42), cesium carbonate (1.1 mole equiv.) and anhydrous N,N-dimethylformamide (15 cm3). After stirring for 2 h at room temperature no starting material remained. The reaction mixture was diluted with ethyl acetate (50 cm3) and treated with water (100 cm3) the aqueous layer was separated and re-extracted with ethyl acetate (2×25 cm3). The combined organic extracts were washed with water (4×100 cm3) before being dried (Na2SO4) and the volatile materials were removed in vacuo to afford the desired material in high purity (60%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=O)[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23].O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[NH2:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[O:12][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:25]=2)[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23]
Reactant: NC(=NO)c1ccncc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)O)c(=O)c1Cl)C2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(Cc3nc(-c4ccncc4)no3)c(=O)c1Cl)C2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
To [5-chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid (80 mg, 0.235 mmol) in dichloromethane (3 mL), N′-hydroxypyridine-4-carboximidamide (38.6 mg, 0.281 mmol) and N,N′-dicyclohexylcarbodiimide (58.2 mg, 0.282 mmol) were added and stirred at room temperature for 18 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure. The resulting oil in toluene (2 mL) was stirred at 110° C. for 5 hours and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4) to give the desired product (78 mg, 75% yield).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]([O:12]CC)=O)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[C:1]([C:5]1[O:9][C:8]([C:10]([NH:16][NH2:17])=[O:12])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ncc(C(C)(C)C)o1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cnc(C(=O)NN)o1
Temperature: 85 °C
Yield: 96.1 %

Procedure:
To a mixture of ethyl 5-tert-butyl-1,3-oxazole-2-carboxylate (28 g, 142 mmol) in ethanol (200 mL) is added hydrazine hydrate (7.1 g, 142 mmol). The reaction mixture is heated at 85° C. for 3 h. The solvent is evaporated and the residue is washed with n-pentane to afford the title compound (25 g, 96%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:21])[C:12]([CH3:20])([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH3:13])=[CH:7][CH:6]=1.C([O:26][CH2:27][CH3:28])(=O)CS.O.C1(C)C=C[C:33]([S:36](O)(=O)=O)=CC=1.[OH-].[Na+]>>[CH3:20][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH3:13])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([S:4][CH2:3][CH2:2][O:1][C:27](=[O:26])[CH2:28][CH2:33][SH:36])=[CH:6][CH:7]=1)=[O:21]
Reactant: CC(C)(C(=O)c1ccc(SCCO)cc1)N1CCOCC1
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(=O)c1ccc(SCCOC(=O)CCS)cc1)N1CCOCC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
5.9 g (19.1 mmol) of 1-[4-(2-hydroxyethylthio)-phenyl]-2-methyl-2-morpholin-4-yl-propan-1-one, 4.2 ml (38.2 mmol) of ethyl thioglycolate, and 4.4 g (22.9 mmol) of p-toluenesulfonic acid monohydrate are mixed and stirred at 100° C. for 24 h. Then the solution is cooled to room temperature and neutralized with 1N NaOH. The crude product is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate -hexane (30:70) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.99 (t, 1H), 2.57 (t, 4H), 3.22-3.30 (m, 4H), 3.70 (t, 4H), 4.36 (t, 2H), 7.34 (d, 2H), 8.51 (d, 2H).