Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:12][C:8]=2[CH:7]=1)(=O)C>[OH-].[K+].CO>[OH:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]([S:13](=[O:15])(=[O:16])[NH2:14])=[CH:12][C:8]=2[CH:7]=1
Reactant: CC(=O)OCc1ccc2sc(S(N)(=O)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NS(=O)(=O)c1cc2cc(CO)ccc2s1
Yield: 38.8 %

Procedure:
A solution of 5-acetoxymethyl-2-sulfamoylbenzo[b]thiophene (5.6 g, 19.6 mmol) in 25 ml of 1M aqueous KOH and 25 ml of methanol was stirred at room temperature for 2 hours and at reflux for 21/2 hours. The mixture was filtered and the methanol was removed in vacuo. The remaining aqueous suspension was acidified with excess 6N HCl and the solid was filtered, washed with ice water and dried. The crude material (3.1 g) was chromatographed on silica gel using 5% (V/V) methanol in chloroform. Product was obtained as a yellow solid (1.85 g), m.p. 174°-176° C. Yield 41%.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([S:16][CH2:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])(=[O:15])[CH3:14]>>[C:13]([S:16][CH2:17][CH:18]([CH3:22])[C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:20])(=[O:15])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)SCC(C)C(=O)Cl
Product: CC(=O)SCC(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Following the procedure of Example 16, L-phenylalanine is reacted with 3-acetylthio-2-methylpropanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-phenylalanine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CCNCC
Product: CCN(CC)CCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Diethylamine were converted to yield {5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-diethyl-amine, MS: 383 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:20])[CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:21]([O-])=O)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:20])[CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:21])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: CN(C)c1cc(-c2cccc(Cl)c2)nc2ccc([N+](=O)[O-])cc12
Product: CN(C)c1cccc(-c2cc(N(C)C)c3cc(N)ccc3n2)c1

Procedure:
The title compound was prepared from N-[2-(3-chlorophenyl)-6-nitro-4-quinolinyl]-N,N-dimethylamine by the procedure of step D2 of Method D using dimethylamine.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH3:25].[H-].[Na+]>C1C=CC=CC=1>[CH2:25]([O:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=[CH:13][CH2:12][CH:11]=[CH:10][CH2:9][CH3:8]
Reactant: CCC=CCC=CCC=CCCCCCCCCBr
Reactant: O=C1C=CCS1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC=CCC=CCC=CCCCCCCCCOc1cccs1
Reaction time: 24 h

Procedure:
A mixture of 20.0 g (0.2 mole) of 3-thiolen-2-one [R. T. Hawkins, J. Heterocyclic Chem., 11 291-4 (1974)] 65.5 g (0.2 mole) of 1-bromo-9,12,15-octadecatriene, and 4.8 g (0.2 mole) of sodium hydride in benzene is refluxed with stirring for 24 hours after which the solvent is removed, and the product distilled to give 2-(9,12,15-octadecatrienyloxy)thiophene.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(C)=[O:17].S([O-])([O-])(=O)=O.[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>C(Cl)(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)NC1CCCc2ccccc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc2c1C(=O)CCC2
Reaction time: 0.33 h

Procedure:
10 gm of 1-acetylamino-tetraline was dissolved into a mixed solvent of 400 ml acetone and 40 ml of 15% aqueous solution of magnesium sulfate. The solution was kept at 0° C. to add 42 gm of potassium permanganate, followed by stirring for 20 minutes at the same temperature. 800 ml of water was added to the residue obtained by concentrating the solvent. Precipitates thus obtained was extracted with chloroform and the extract was washed with brine and dried over magnesium sulfate. The residue obtained by the concentration of the solvent was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 5.46 gm of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:21]=[C:20]([CH3:35])[CH:19]=2)=[CH:16][N:17]=1)[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].C1COCC1.Cl>CO.C(Cl)(Cl)Cl>[OH:1][CH:2]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:21]=[C:20]([CH3:35])[CH:19]=2)=[CH:16][N:17]=1)[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCC(C(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)C3CCC(C(=O)O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-{hydroxyl[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2 yl]methyl}cyclohexanecarboxylate in methanol (1.96 mL) was added 1N NaOH (0.79 mL, 0.79 mmol) and the mixture was stirred at room temperature for 16 h. THF (1.96 mL) was added and the mixture was stirred at 60° C. for 6 h, then cooled to room temperature and added HCl (1M in H2O) until the pH=3. The mixture was diluted with 3:1 CHCl3:isopropanol and the organic layers were separated, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford 4-{hydroxy[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylic acid as a white solid. The cis and trans isomers were separated by supercritical fluid chromatography (chiral OJ column, 1:3 methanol/CO2 with an 11 minute run time). Characterization data for the cis isomer (Rt=5.15 min): MS ESI calc'd. for C23H24F3N4O3S [M+H]+ 493. found 493. 1H NMR (500 MHz, CD3OD) δ 8.69 (d, J=4.8, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.11 (s, 1H), 7.10 (s, 1H), 4.68 (d, J=5.1, 1H), 3.34 (s, 1H), 2.36 (s, 3H), 2.20 (m, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.70 (m, 1H), 1.50-1.18 (m, 3H). Second eluting enantiomer Rt=8.26 min.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22].[C:23]12([CH2:33][C:34](Cl)=[O:35])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2>>[C:23]12([CH2:33][C:34]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:22])=[O:35])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: Nn1nc(-c2ccc(C(F)(F)F)cc2)c2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccc(C(F)(F)F)cc2)c2ccccc2c1=O

Procedure:
The product of Example 147A and 2-(adamantan-1-yl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.42-8.45 (m, 1H), 7.96-8.01 (m, 2H), 7.93-7.97 (m, 2H), 7.83-7.86 (m, 2H), 7.72-7.76 (m, 1H), 2.06 (s, 2H), 1.93-1.96 (m, 3H), 1.58-1.73 (m, 12H); MS (APCI+) M/Z 482 (M+H)+.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C@H:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[Br:31])[NH:16]2)[OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(Cl)=[O:44]>C(Cl)Cl>[Br:31][C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:21]=1[C@H:17]1[N:16]2[C:43](=[O:44])[O:14][C@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([CH3:2])[CH:4]=3)[C@@H:15]2[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)Cl
Reactant: O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCC[C@@H](c2cc(C(F)(F)F)ccc2Br)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@H]2OC(=O)N3[C@H](c4cc(C(F)(F)F)ccc4Br)CCC[C@@H]23)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To (R)-[3,5-bis(trifluoromethyl)phenyl]{(2S,6S)-6-[2-bromo-5-(trifluoromethyl)phenyl]piperidin-2-yl}methanol (280 mg, 0.509 mmol) in DCM (5 mL) was added DIPEA (0.9 mL, 0.509 mmol) and phosgene (252 mg, 0.509 mmol). The reaction mixture was stirred at room temperature for 30 minutes before the solvent was removed and the reaction was diluted with ethyl acetate (15 mL) and aqueous KOH (15 mL). The organic was dried over sodium sulfate, filtered, and concentrated before purification by preparative TLC to yield (1R,5S,8aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-methyl-5-(trifluoromethyl)phenyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (200 mg, 0.347 mmol). MS ESI calc'd. for C22H16BrF9NO2 [M+H]+ 576.0 and 578.0. found 576.1 and 578.1.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C.[OH:13][CH2:14][CH2:15][NH2:16]>C(Cl)Cl.CO>[CH3:12][N:9]1[CH2:8][CH2:7][CH:6]([C:4]([NH:16][CH2:15][CH2:14][OH:13])=[O:5])[CH2:11][CH2:10]1
Reactant: NCCO
Reactant: CCOC(=O)C1CCN(C)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(C(=O)NCCO)CC1
Temperature: 60 °C
Yield: 52 %

Procedure:
17.1 g. (0.1 mole) 1-Methylpiperidine-4-carboxylic acid ethyl ester (literature: J.A.C.S., 74, 3831/1952). are heated to 60° C. for 48 hours with 9 ml. (0.15 mole) 2-hydroxyethylamine and purified over a silica gel column with methylene chloride/methanol (9:1 v/v). There are obtained 9.5 g. of base in the form of a viscous oil. Yield 52% of theory.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[CH3:28][NH:29][CH2:30][CH:31]=[C:32]([F:43])[C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:29]([CH3:28])[CH2:30][CH:31]=[C:32]([F:43])[C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CNCC=C(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 1 h
Yield: 151.6 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one and 2.21 g of methyl-(3,4,4,5,5,6,6,6-octafluoro-hex-2-enyl)-amine are dissolved in 20 ml of N-methylpyrrolidone and stirred for 1 hour at a bath temperature of 80° C. After the reaction solution is cooled to room temperature, the batch is added to saturated common salt solution, extracted with diethyl ether, dried and concentrated by evaporation in a vacuum. 1.69 g of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(3,4,4,5,5,6,6,6-octafluoro-hex-2-enyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without purification in the next stage.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[CH2:26][CH2:27][NH2:28])([CH3:24])[CH3:23]>CN1C(=O)CCC1.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:28][CH2:27][CH2:26][N:25]([CH:29]([CH3:31])[CH3:30])[CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)N(CCN)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Yield: 99.1 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (100 mg, 0.225 mmol) and N,N-diisopropylethylenediamine (395 μl, 2.25 mmol) in 5 ml of NMP is heated at 150° C. by microwave using an “Emrys™ Optimizer” machine for 20 minutes. The crude reaction product is taken up in 50 ml of ethyl acetate and the resulting solution is washed with 5 times 50 ml of water. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure to give 100 mg of 4-(2-diisopropylaminoethylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:27]=[C:26]([C:28](OC)=[O:29])[CH:25]=[CH:24][C:19]=2[C:20](OC)=[O:21])[CH:15]=[CH:16][CH:17]=1>C1COCC1>[OH:21][CH2:20][C:19]1[CH:24]=[CH:25][C:26]([CH2:28][OH:29])=[CH:27][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][CH:8]([CH3:7])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:13]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(-c2cccc(OCCC(C)CCCC(C)C)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCOc1cccc(-c2cc(CO)ccc2CO)c1
Reaction time: 4 h
Yield: 82.3 %

Procedure:
LiAlH4 (9.4 g, 248 mmol) was added to 300 ml of THF under N2. At RT, dimethyl 2-(3′-(3,7-dimethyloctyloxy)phenyl)terephthalate (75.5 g, 177 mmol), dissolved in 120 ml of THF, was then slowly added dropwise. The mixture was subsequently stirred for 4 hours under reflux. After cooling, excess LiAlH4 was carefully destroyed by addition of H2O. Half-concentration H2SO4 was then carefully added dropwise (about 50 ml). The mixture became very viscous during this addition. After stirring further for 1 hour, a clear solution was obtained and a slimy gray precipitate could be seen at the bottom of the flask. The clear solution was decanted off and the solvent was taken off. The precipitate which remained was stirred with a large amount of water and ethyl acetate and, after filtration, the organic phase was separated off, the solvent was taken off and combined with the first organic phase. The combined organic phases were taken up in ethyl acetate and extracted five times with water. After drying over MgSO4, the solvent was taken off. The resulting oil was stirred a number of times with hexane and dried in an oil pump vacuum. The product was thus obtained as a pure pale yellow, highly viscous oil (54 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]2[C:15]=1[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[NH:12][C:11](=O)[CH2:10]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)(O)[O-].[Na+].O>COCCOCCOC>[Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]2[C:15]=1[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[NH:12][C:11](=[S:22])[CH2:10]2
Reactant: O=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: S=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Temperature: 110 °C
Yield: 15.7 %

Procedure:
A mixture of 12.5 g 13-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 22.6 g phosphorus pentasulfide and 8.6 g sodium bicarbonate in 240 ml diglyme was heated at 110° C. for two hours. The resulting mixture was cooled and poured into 2.5 L water to precipitate a solid. The solid was collected, washed with water and dried (P2O5) to give 11.9 g crude product. Recrystallization of 3.3 g from toluene (300 ml) gave 2.08 g fluffy solid, m.p. 280°-282° C. (dec.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[N:19][C:18]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31][CH3:32])[CH:26]=2)[CH2:11][CH2:10]1)=[O:7]>CN(C)C=O>[F:23][C:21]1[CH:20]=[N:19][C:18]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31][CH3:32])[CH:26]=2)=[C:17]([CH:22]=1)[C:16]([NH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([N:8]2[CH2:2][CH2:3][CH2:4][CH2:5][C:6]2=[O:7])[CH2:10][CH2:11]1)=[O:33]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)CCCCCl)CC2)c1
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N3CCCCC3=O)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
trans-N-{4-[(5-Chloropentanoyl)amino]cyclohexyl}-5-fluoro-2-[3-(methylsulfanyl)phenoxy]nicotinamide (220 mg, 0.405 mmol) was dissolved in dimethylformamide (5 ml) sodium hydride 60% dispersion in oil (41 mg, 1.01 mmol) was added. The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium hydrogen carbonate solution (10 ml) and dichloromethane (15 ml) and the aqueous phase was extracted with dichloromethane (3×15 ml). The combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give the title compound (78 mg) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[N:6][C:5]1=[O:22])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].S(=O)(=O)(O)O>>[C:23]([O:21][C:17]1[CH:16]=[C:15]([C:7]2[C:8]3[C:13](=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:22])[N:6]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(-c3cccc(O)c3)nc(=O)n(C(C)C)c2c1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cccc(-c2nc(=O)n(C(C)C)c3cc(C)ccc23)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To 5.0 g of refined 1-isopropyl-4-(3-hydroxyphenyl)-7-methyl-2(1H)-quinazolinone in a vessel, is added 100 ml. of acetic anhydride and 0.5 ml of concentrated sulfuric acid. The resulting mixture is allowed to stand for 16 hours. The reaction mixture is then poured over salted ice in a vessel. After the ice has melted, the resulting liquid is extracted twice with 300 ml portions of benzene: n-butanol (4:1) and the combined extracts washed with distilled water until free of acid, and then evaporated to obtain a residue. The residue is crystallized from methanol to obtain the title product, m.p. 148°-150°.
Reaction SMILES: [C:1]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O:3][CH2:4][CH3:5])=[O:2].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[N:8]=[C:14]=[O:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1N=C=O

Procedure:
2-Carboethoxy-phenylisocyanate (0.20 g, 1.0 mmol) was prepared by the reaction of 2-carboethoxyaniline and triphosgene in toluene at reflux, followed by removing the solvent in vacuo. The isocyanate and the compound resulting from Example 1B (0.24 g, 1.0 mmol) were combined in 40 mL of toluene and heated at reflux for 3 hours. The product was then partitioned between 5% NaHCO3 and hot ethyl acetate, and the organic phase was dried (K2CO3) and evaporated. The resulting product was converted to its hydrochloride salt and recrystallized from ethanol-ether to yield 0.12 g of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, 1H), 7.65 (t, 1H), 7.12-7.27 (m, 2H), 7.08 (t, 1H), 6.72 (dd, 2H), 4.02 (t, 2H), 3.73 (s, 3H), 3.12-3.3 (m, 3H), 2.52-2.65 (m, 3H), 2.38-2.48 (m, 2H), 2.1-2.3 (m, 2H), 1.57-1.68 (m, 1H), 1.37-1.5 (m, 1H). Anal calcd for C23H25N3O3 ·HCl·H2O: C, 61.95; H, 6.33; N, 9.42. Found: C, 61.94; H, 6.10; N, 9.18.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:30]([CH2:29][C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)cnc1OCC(F)(F)F
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Agent: Cl
Product: Cc1cc(CN2C(=O)c3ccnc(Cl)c3C2C)cnc1OCC(F)(F)F
Yield: 20 %

Procedure:
The title compound is prepared in 20% yield (41 mg, pale brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol, Step-1, racemate) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (146 mg, 0.53 mmol, Amine-3) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH2:44]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: COCCOCCOCCN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCCOCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 71.5 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylamine [CAS-no. 74654-07-2] (0.334 mg, 2.04 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.180 g, 71%) as a light yellow oil. MS (ISP) 616.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:23])=[N:6][C:7]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1)[CH3:2]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]2[C:7](=[N:6][C:5]=1[CH3:23])[N:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]2[OH:20])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(OCC)c(C)n1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1O

Procedure:
16.1 g of the Compound VI obtained as above was added to 160 ml of boiling Dowtherm (produced by Dow Chemical Co.) and refluxed for 1 hour. After cooling, the precipitated crystals were collected by filtration to obtain 11.8 g of crude crystals which were then recrystallized from dimethylformamide to yield ethyl 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (Compound VII where R2 =R3 =C2H5), m.p. 279°-282° C. (with decomposition).