Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[N:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(Br)(Br)[Br:26]>>[Br:26][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[N:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1N
Reactant: BrC(Br)Br
Product: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1Br

Procedure:
5-Amino-4-ethoxycarbonyl-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole, was treated with bromoform in a similar manner to Example 11, to give ethyl 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole-4-carboxylate. This was then reduced with zirconium borohydride to give [5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazol-4-yl]methanol, which was oxidised in a similar manner to that described in Example 4, to give 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole-4-carboxaldehyde, which was converted, as described in Example 1, to 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-4-[(2-amino-1,2-dicyanoethenylimino)-methyl]-1H-pyrazole, mp 195°-198°, which was cyclised to give 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-4-(4,5-dicyano-1H-imidazol-2-yl)-1H-pyrazole, m.p. 86°-90°. (Compound 34).
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13][CH3:14].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([CH2:12][S:13][CH3:14])[C:3]=1[NH2:4]
Reactant: Cc1c(F)c(N)cc(F)c1F
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c(F)c(C)c(F)c1F
Reaction time: 0.5 h

Procedure:
To anhydrous dichloromethane (170 ml) are added 2,4,5-trifluoro-3-methylaniline (16.89 g) and dimethyl sulfide (11 ml). Thereto N-chlorosuccinimide (17.2 g) is added gradually below 5° C. After stirring for 30 minutes, triethylamine (21 ml) is added dropwise and the mixture is refluxed over night. After the mixture is cooled and made alkaline with 5% aqueous sodium hydroxide solution, the resultant is extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane : n-hexane =1 : 1) to give 2,4,5-trifluoro-3-methyl-6-methylthiomethylaniline (8.3 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][NH2:21])=[C:16]([CH3:24])[CH:15]=1)[CH:12]=[CH2:13].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH2:11]([C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][NH:21][C:2]2[C:3]3[CH:10]=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[C:16]([CH3:24])[CH:15]=1)[CH:12]=[CH2:13]
Reactant: C=CCc1ccc(OCCN)c(C)c1
Reactant: Clc1ncnc2sccc12
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCc1ccc(OCCNc2ncnc3sccc23)c(C)c1
Yield: 83 %

Procedure:
3.4 g (0.02 mole) of 4-chlorothieno[2,3-d]pyrimidine, 3.8 g (0.02 mole) of 2-(4-allyl-2-methylphenoxy)ethylamine and 2 g (0.02 mole) of triethylamine were dissolved in 50 ml of benzene, and the solution was heated under reflux for 6 hours. At the end of this time, water was added to the reaction mixture, after which it was extracted with benzene. The extract was dried over anhydrous sodium sulphate and the solvent was distilled off, after which the residue was subjected to column chromatography through silica gel, eluted with a 9:1 by volume mixture of benzene and ethyl acetate, to give 5.4 g (yield 83%) of the desired Compound No. 8, in the form of pale yellow crystals melting at 97°-99° C.
Reaction SMILES: C(OC[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)C=C.ClC1C=CC(CN2C3C(=[C:33]([CH2:38][OH:39])C=CC=3)C=C2)=CC=1.C(Br)C=C.[H-].[Na+]>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:10]2[C:11]3[C:7](=[C:6]([CH:38]([OH:39])[CH3:33])[CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)=[CH:21][CH:20]=1
Reactant: OCc1cccc2c1ccn2Cc1ccc(Cl)cc1
Reactant: C=CCOCc1cccc2c1ccn2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: CC(O)c1cccc2c1ccn2Cc1ccc(Cl)cc1

Procedure:
2-[4-[(allyloxy)methyl]-1-(4-chlorobenzyl)-1H-indole, oil (prepared by alkylation of [1-(4-chlorobenzyl)-1H-indol-4-yl]methanol with allyl bromide in DMF in the presence of NaH, at room temperature for 3 h).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[NH:16][C:17]3[C:22]([C:23]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][C:20]([F:28])=[C:19]([CH2:29][CH3:30])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O.[Cu]I>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:17]3[C:22]([C:23]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][C:20]([F:28])=[C:19]([CH2:29][CH3:30])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ncccn1
Reactant: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)NC(C)(C)C)cn3)c(S(C)(=O)=O)c2cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(cc1F)c(S(C)(=O)=O)c(-c1ccc(S(=O)(=O)NC(C)(C)C)cn1)n2-c1ncccn1
Temperature: 110 °C
Yield: 91 %

Procedure:
A mixture of N-tert-butyl-6-(6-ethyl-5-fluoro-3-(methylsulfonyl)-1H-indol-2-yl)pyridine-3-sulfonamide (115 mg, 0.25 mmol), 2-bromopyrimidine (88 mg, 0.55 mmol), CuI (28 mg, 0.15 mmol), K2CO3 (160 mg, 1.15 mmol), and DMF (0.5 mL) was heated at 110° C. for 15 hours. The reaction mixture was diluted in water and extracted into ethyl acetate. The organic layer was washed with water and then with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (40% ethyl acetate in hexanes) yielded N-tert-butyl-6-(6-ethyl-5-fluoro-3-(methylsulfonyl)-1-(pyrimidin-2-yl)-1H-indol-2-yl)pyridine-3-sulfonamide (121 mg, 91%) as a white solid. Melting point: 244-248° C.; MS m/z 532.2 M+H+; 1H NMR (DMSO-d6, 500 MHz): δ 8.82 (d, 1H, J=2 Hz), 8.73 (d, 2H, 5.0 Hz), 8.23 (dd, 1H, J=8.0 Hz, 2 Hz), 8.05 (d, 1H, J=6.5 Hz), 7.96 (d, 1H, J=8 Hz), 7.87 (s, 1H), 7.76 (d, 1H, 10.5 Hz), 7.51 (t, 1H, J=5 Hz), 3.38 (s, 3H), 2.78 (q, 2H, J=7.5 Hz), 1.23 (t, 3H, 3.75 Hz), 1.13 (s, 9H).
Reaction SMILES: O[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:13])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:13][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cccnc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(O)c1cccnc1Cl
Reaction time: 12 h

Procedure:
Heat a mixture consisting of 24.4 g of 2-hydroxy nicotinic acid and 42 ml. of phosphorous oxychloride to 100°-108° C and hold for 1 hour. Add 36.4 g of phosphorous pentachloride and heat the resulting mixture at reflux for another hour. Remove the excess phosphorous oxychloride in vacuo and pour the viscous residue on ice with stirring. Age the resulting slurry at room temperature for about 12 hours. The slurry is filtered, washed and dried to yield 2-chloro-nicotinic acid, m.p. 190° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[C:7]([CH3:20])=[N:6][C:5]=1[CH:21]1[CH2:23][CH2:22]1.[OH-].[Na+].Cl>CO>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][O:10][C:8]1[C:7]([CH3:20])=[N:6][C:5]([CH:21]2[CH2:23][CH2:22]2)=[C:4]([CH:9]=1)[C:3]([OH:24])=[O:2])#[N:19]
Reactant: COC(=O)c1cc(OCc2cccc(C#N)c2)c(C)nc1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(C2CC2)c(C(=O)O)cc1OCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
To a solution of 5-(3-cyano-benzyloxy)-2-cyclopropyl-6-methyl-nicotinic acid methyl ester (184) (500 mg, 1.55 mmol) in methanol (10 mL), added aqueous sodium hydroxide (10 mL, 1N) and stirred at room temperature for 3 days. Hydrochloric acid (5 mL, 12N) was added to the reaction mixture and methyl alcohol was evaporated. The precipitate was collected by filtration to give 5-(3-cyano-benzyloxy)-2-cyclopropyl-6-methyl-nicotinic acid (185) (300 mg, 63% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(C(=O)N3CCOCC3)ccc21
Product: CC1c2ccc(C(=O)N3CCOCC3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with (1-Methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-morpholin-4-yl-methanone to provide the title compound in moderate yield.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])C[CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)C2.C1(CCCO)CCCCC1>>[Cl:17][C:18]1[C:19]([O:46][CH2:45][CH2:35][CH2:36][CH:37]2[CH2:43][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCCCC1CCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 3-cyclohexylpropan-1-ol, the title compound was obtained as a colorless solid (0.03 g, 7%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 4.12 (t, J=6.2 Hz, 2H), 2.87 (s, 6H), 1.80-1.58 (m, 7H), 1.35-1.11 (m, 6H), 0.94-0.88 (m, 2H); MS (ES−) m/z 419.2, 421.2 (M−1).
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:9]([O:12][C@H:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[C@@H:15]([NH:24][CH2:25][C@@H:26]([OH:38])[C@@H:27]([NH2:37])[CH2:28][C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[CH2:14]1)[CH:10]=[CH2:11]>>[CH2:9]([O:12][C@H:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[C@@H:15]([NH:24][CH2:25][C@@H:26]([OH:38])[C@@H:27]([NH:37][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[CH2:28][C:29]2[CH:30]=[C:31]([Cl:36])[CH:32]=[C:33]([Cl:35])[CH:34]=2)[CH2:14]1)[CH:10]=[CH2:11]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(Cl)cc(Cl)c2)c2cc(OC)ccc21
Reactant: C=CCCCC(=O)O
Product: C=CCCCC(=O)N[C@@H](Cc1cc(Cl)cc(Cl)c1)[C@H](O)CN[C@H]1C[C@@H](OCC=C)c2ccc(OC)cc21
Yield: 91.3 %

Procedure:
Step DQ (1): 5-Hexenoic acid (Alfa Aesar, 0.096 mmole) and (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (0.04 mmol, from Preparation BG) were coupled by a procedure analogous to Step DL (1) to afford 20 mg of N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-dichlorophenyl)-3-hydroxy-butan-2-yl)hex-5-enamide as a clear oil. LC-MS Rt 2.1 min (method A), (M+H)+=547.1.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2C(C(N(C(C)C)C(C)C)=O)=[C:13]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[N:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:38][CH2:39][OH:40]>Cl>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][C:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[C:38]=3[C:39]2=[O:40])=[CH:5][CH:6]=1
Reactant: CC(C)N(C(=O)c1c(CNc2ccc(-c3ccccc3)cc2)ccnc1NCc1ccncc1)C(C)C
Reactant: CCO
Agent: Cl
Product: O=C1c2c(ccnc2NCc2ccncc2)CN1c1ccc(-c2ccccc2)cc1

Procedure:
A solution of 4-(biphenyl-4-ylaminomethyl)-N,N-diisopropyl-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide (13 mg, 0.026 mmol, Step C) in absolute EtOH (3 mL) and HCl (12 N, 1 mL) was heated to reflux for 2 days, then concentrated in vacuo. The crude material was dissolved in 1:1 DMSO to MeOH (2 mL) and purified by reverse phase HPLC (10-95% CH3CN in H2O). MS (ES+): 393.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1C=CC(N(C2CCNCC2)C(=O)[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47]C)[CH:42]=2)=CC=1.C12OC1CCCC2>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C@@H:42]3[CH2:41][CH2:46][CH2:45][CH2:44][C@H:43]3[OH:47])[CH2:13][CH2:12]2)[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:26][CH:27]=1
Reactant: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCNCC2)c1
Reactant: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: C1CCC2OC2C1
Product: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCN([C@@H]3CCCC[C@H]3O)CC2)c1

Procedure:
The title compound, MS (ISP): m/e=519.4 (M+H+), white foam, was prepared as for example 98, steps (A) to (F). Step (A) was performed using 4-chloro-aniline, and yielded 4-(4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester which was acylated to 4-[(4-chloro-phenyl)-(3-methoxy-benzoyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester in step (B). This was then deprotected to N-(4-chloro-phenyl)-3-methoxy-N-piperidin-4-yl-benzamide (C), and reacted with cyclohexene oxide to give (+/−)—N-(4-chloro-phenyl)-N-[trans-1-(2-hydroxy-cyclohexyl)-piperidin-4-yl]-3-methoxy-benzamide [step (D)]. Oxidation to (+/−)-N-(4-chloro-phenyl)-3-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzamide in step (E) and reaction with phenyl lithium [step (F)] led to the title compound of the example.
Reaction SMILES: CS[C:3](=[NH:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][C:12]3[N:14]=[CH:15][CH:16]=[N:17][C:11]=3[N:10]([CH2:18][O:19][CH3:20])[C:9]=2[CH:21]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.CO>[C:24]1([NH:23][C:3](=[NH:22])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[S:13][C:12]4[N:14]=[CH:15][CH:16]=[N:17][C:11]=4[N:10]([CH2:18][O:19][CH3:20])[C:9]=3[CH:21]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COCN1c2cc(CC(=N)SC)ccc2Sc2nccnc21
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COCN1c2cc(CC(=N)Nc3ccccc3)ccc2Sc2nccnc21

Procedure:
350 mg of methyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate was dissolved in a solvent mixture of tetrahydrofuran (7 ml) with methanol (15 ml). After adding 0.5 ml of aniline, the resulting mixture was heated under reflux for 5 hours. Then the reaction mixture was brought back to room temperature. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 250 mg of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[C:7]1=[O:30])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]=3[N:21]=2)[C:7]1=[O:30])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3cccnc3n2)C[C@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3c(n2)NCCC3)C[C@H]1Cc1ccccc1

Procedure:
A mixture of 12-6 (220 mg, 0.5270 mmol) and 10% Pd/carbon (100 mg) in EtOH (4 mL) was stirred under a balloon of hydrogen for 2 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH to give 12-7 as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1(Br)[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[CH3:1][C:2]1([N:24]=[N+:25]=[N-:26])[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(Br)O[C@@H]1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(N=[N+]=[N-])O[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Methyl 2,3,4,-tri-O-acetylglucopyranuronosyl bromide (7.94 g, 20 mmol) was dissolved in 250 ml of dimethylformamide and 2.6 g, that is 40 mmol of sodium azide was added. The mixture was stirred at room temperature for 24 hours and then poured into 500 ml of H2O. The organic soluble material was extracted three times with 150 ml ethyl acetate. The combined ethyl acetate extracts were washed twice with 100 ml H2O, brine, dried over MgSO4, and concentrated to dryness. The residue was recrystallized from ethanol to yield 5.46 g (76%) of methyl 2,3,4,-tri-O-acetylglucopyranuronosyl azide. Methyl 2,3,4,-tri-O-acetylglucopyranuronosyl azide had the melting point of 152°-154°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (560 mg, 1.80 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine (620 mg, 2.70 mmol) to afford the desired product (335 mg, 43%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.9, 2.1 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 4.12-3.84 (m, 1H), 2.91-2.72 (m, 1H), 2.42-2.26 (m, J=6.6 Hz, 8H), 2.21 (d, J=11.6 Hz, 2H), 1.94 (d, J=12.1 Hz, 2H), 1.75-1.59 (m, 1H), 1.59-1.35 (m, 2H), 1.25-0.98 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([NH:30][CH3:31])[CH3:29]>>[CH2:28]([N:30]([CH3:31])[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26])[CH3:29]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: CCNC
Product: CCN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with ethylmethylamine at 22° C. to give the title compound as a white solid. MS: 417.3 ([M−H]−).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:12](Cl)[O:13][CH3:14]>CN(C=O)C>[CH3:12][O:13][CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To the suspension of NaH (3.25 g, 0.135 mol) in DMF (150 mL) was added 4-hydroxy-benzaldehyde (15.0 g, 0.123 mol) in DMF (10 mL) at 0° C., 5 min. later the reaction mixture became a cake. The heterogeneous mixture was stirred at 0° C. for 30 min. MOMCl (9.96 g, 0.123 mol) was added slowly and the reaction mixture was allowed to warm up to r.t. After stirring at r.t. for 16 h, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water and the water layer was further extracted with ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:4) to afford 4-methoxymethoxy-benzaldehyde (19.0 g, 93%): 1H NMR (300 MHz, CDCl3): δ 9.94 (s, 1 H), 7.88 (m, 2H), 7.18 (m, 2H), 5.29 (s, 2H), 3.53 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:4); Rf=0.86.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O1CCOCC1>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1B(O)O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccccc1B(O)O
Temperature: 100 °C
Yield: 83.4 %

Procedure:
To a solution of o-aminophenylboronic acid (6.73 g, 49.1 mmoles) in dioxane (100 ml) is added acetic anhydride (25.1 g, 246 mmoles). The reaction is heated at 100° C. for 17 hours. After cooling, the reaction volatiles are removed under reduced pressure to leave a thick yellow gel, which after chromatography affords o-N-acetylaminophenylboronic acid (7.33 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1C(Cl)=O.Cl>C(#N)C.C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1sccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1sccc1Cl
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Potassium 3-(ethyoxy)-3-oxopropanoate (1.97 g, 11.6 mmol, 2.1 equiv) was suspended in acetonitrile (15 mL), cooled to 0° C. and treated with successively with triethylamine (2.46 mL, 17.7 mmol, 3.2 equiv) and magnesium(II) chloride (1.31 g, 13.8 mmol, 2.5 equiv). The ice bath was removed and the mixture was warmed to ambient temperature and stirred for an additional for 2.5 hours. An acetonitrile solution (5 mL) of 3-chlorothiophene-2-carbonyl chloride (1.00 g, 5.52 mmol) was added and the mixture was stirred for 72 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was concentrated from toluene (1×75 mL), providing a white solid. The solid was suspended in toluene (˜50 mL), cooled to 0° C. and treated with hydrochloric acid (˜20 mL, 12 N aqueous) with vigorous stirring. After 15 minutes, the ice bath was removed and the mixture was warmed to ambient temperature and stirred for 45 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 75:25; hexanes:ethyl acetate), providing the titled compound.