Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:11]1([C:17]2[O:18][CH2:19][CH:20]([OH:29])[CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([O:29][CH:20]2[CH2:19][O:18][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:22][CH:21]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCCl
Product: O=C(Nc1cccc(Cl)c1)OC1COC(c2ccccc2)=NC1c1ccccc1
Yield: 72.6 %

Procedure:
3- Chlorophenyl isocyanate (0.8 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.2 g) in 1,2-dichloroethane (20 cc). The solution obtained is heated to reflux for 7 hours 30 minutes and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 40 g) contained in a column 2 cm in diameter, collecting 15-cc fractions. Fractions 1 to 3, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume) are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, (4RS, 5RS)-5-(3-chlorophenylcarbamoyloxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.4 g), m.p. 160° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:1][C:2]1[S:3][C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:6]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)Cc1sc(N)nc1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1sc(NC(C)=O)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 13.4 grams of ethyl (2amino-4-p-chlorophenyl-thiazol-5-yl)acetate and 10.2 grams of acetic anhydride in 50 c.c. of anhydrous pyridine is refluxed for 1/2 an hour. The solution is poured on ice. The precipitated solid is filtered off, washed several times with H2O, and recrystallised from 80% alcohol, m.p. 187°-88°C.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([CH:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=1)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=O.O>C1COCC1>[CH3:51][O:50][C:48]([C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH:32]([CH:30]=[CH:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[O:3][CH3:2])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:43][CH:44]=1)=[O:49]
Reactant: COc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCC(C=O)Cc1ccc(C(=O)OC)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(C=Cc1ccccc1OC)Cc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 77.4 mg (0.17 mmol) of 2-methoxybenzyltriphenylphosphonium bromide from Ex. IVj are suspended under argon in 20 ml of THF, and 0.115 ml of buthyl-lithium (0.18 mmol, 1.6 M solution in hexane) are added. The deep-orange solution is stirred at 0° C. for 30 min. At this temperature, a solution of 51.2 mg (0.17 mmol) of methyl 6-formyl-7-(4-methoxycarbonylphenyl)heptanoate (synthesis analogously to EP-A-0 341 551, p. 32, Ex. 44) in 15 ml of THF is added dropwise. The mixture is stirred at 0° C. for 30 min. At 0° C., water is added and the mixture is warmed to room temperature and extracted with ethyl acetate. The organic phase is washed with sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. For purification, the substance is chromatographed on silica gel 60 (particle size 0.040-0.063 mm) using cyclohexane/ethyl acetate 9:1 to 1:1 as mobile phase.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28](OCC)(OCC)OCC>>[O:1]1[CH:28]=[N:27][C:3]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[C:13]4[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=4[C:11]3=[O:26])[CH:7]=[CH:8][CH:9]=2)=[N:2]1
Reactant: CCOC(OCC)OCC
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncon3)c1)C2=O
Temperature: 80 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (180 mg, 0.47 mmol) obtained in Step 1 of Example 75 was suspended in triethyl orthoformate (6.0 mL), and the mixture was stirred at 80° C. for 2 days. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(1,2,4-oxadiazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (144 mg, 78%).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[O:11]=[C:3]1[NH:4][C:5]2[CH:10]=[C:9]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:8]=[CH:7][C:6]=2[S:1][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1CSc2ccccc2N1
Product: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered 4H-benzo[1,4]thiazin-3-one (7.0 g) was added cautiously, portionwise (over 20 minutes), to chlorosulfonic acid (15 mL), cooled in ice. After 1 hour, the blue solution was allowed to warm to room temperature and it was heated at 45° C. for 2 hours, cooled and poured into ice. The solid was collected, washed with water, and hexane, and dried in vacuo, to give a white solid (7.0 g): LC-MS (ES) m/e 263 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([F:36])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([F:36])=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]3[N:22]=[N:23][NH:24][CH:25]=3)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=2)[CH:28]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Temperature: 90 °C
Yield: 4.7 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 5-chloro-2-fluorophenylboronic acid (32.2 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (2 mg). MS m/z [M+H]+ calc'd for C22H22ClFN4O4, 461.13. found 461.2.
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3F)[O:8][C:4]=2[CH:3]=1.[C:22](=O)([O-])[O-:23].[K+].[K+].CO>O>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[O:23][CH3:22])[O:8][C:4]=2[CH:3]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Temperature: 60 °C
Yield: 44.7 %

Procedure:
A mixture of 0.28 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.24 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 6-chloro-2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 91”).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14]([O:18][C:19]([CH:21]([O:23][NH2:24])[CH3:22])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([CH:21]([O:23][N:24]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])[CH3:22])=[O:20])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(ON)C(=O)OC(C)(C)C
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Product: CC(ON=C(C(=O)O)c1ccc(O)c(Cl)c1)C(=O)OC(C)(C)C
Yield: 96.3 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.) and O-(1-t-butoxycarbonylethyl)hydroxylamine (3.2 g.) were reacted according to a similar manner to that of Preparation 5-(7) to give 2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (3.3 g.), mp 148° to 151° C.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:15]=[C:9]2[N:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Cl:14][C:12]1[CH:11]=[N:10][C:9]2=[CH:15][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=[C:8]2[CH:13]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Cl)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, 2-amino-3-(6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (35 mg, described in Example 155) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (13 mg, 20%). MS (ES): M/Z [M+H]=440. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.86 (d, J=14.0 Hz, 1H), 5.01 (d, J=14.0 Hz, 1H), 7.71-7.83 (m, 2H), 7.83-7.92 (m, 2H), 8.02 (dd, J=2.1, 0.9 Hz, 1H), 8.12 (s, 1H), 8.43 (d, J=0.7 Hz, 1H) and 8.56 (d, J=2.1 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 3-acetoxyphenol (3.04 g, 20 ml) in dimethylformamide were added calcium carbonate (2.76 g, 20 mmol) and ethyl bromoacetate (2.2 ml, 20 mmol), and the mixture was stirred for 2 hours at room temperature. The reaction was quenched by water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=10:1) to give ethyl [3-(acetyloxy)phenoxy]acetate (3.30 g, 69%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([CH2:15][CH2:16][OH:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:6][N:8]1[CH2:11][C:10]2([CH2:14][N:13]([CH2:15][CH2:16][OH:17])[CH2:12]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC2(CN(CCO)C2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC2(C1)CN(CCO)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
tert-Butyl-6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.620 g, 2.56 mmol) was dissolved in dry THF (13 mL) and chilled to 0° C. Lithium aluminum hydride (7.68 mL, 7.68 mmol, 1M in THF) was added by syringe. Once addition was complete, the mixture was brought to reflux for 16 hours. The reaction was cooled to 0° C., quenched with 291 μL of water, 291 μL of 15% aq. NaOH, and 873 μL of water, stirred vigorously for two hours, and then filtered. The filtrate was concentrated under reduced pressure to give 268 mgs (67%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li].C(NC(C)C)(C)C.C([Li])CCC.[C:21]1([CH3:39])[CH:26]=[CH:25][C:24]([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[CH:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl.[O:41]1CCC[CH2:42]1>CN(C)C=O>[C:21]1([CH3:39])[CH:22]=[CH:23][C:24]([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[C:31]2[CH:42]=[O:41])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc(S(=O)(=O)n2c(C=O)cc3cccnc32)cc1
Temperature: -75 °C
Reaction time: 3 h

Procedure:
A solution of lithium diisopropylamine {prepared by treating a solution of diisopropylamine (33.6 mL) in tetrahydrofuran (250 mL) with butyl lithium in hexanes (70.4 mL, 2.5M) at −35° C., at −75° C., was treated dropwise with a solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [40 g, Reference Example 9(a)] in dry tetrahydrofuran (250 mL) at −75° C. whilst maintaining the reaction temperature below −60° C. After stirring at −75° C. for 3 hours the reaction mixture was allowed to warm to 5° C. over 2 hours then recooled to −75° C. and then treated with dimethylformamide(62 mL). The reaction mixture was left to warm to room temperature over 1 hour then poured into hydrochloric acid (800 mL, 1%) and then evaporated to remove the tetrahydrofuran. The resulting suspension was filtered and the solid was washed with water, then dried and then was subjected to flash column chromatography on silica eluting with dichloromethane to give the title compound (24.37 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][N:21]=2)[CH2:11][CH2:10]1.CCOC(C)=O>C1COCC1.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][N:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2cnc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCc2cnc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Yield: 93.3 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,6]naphthyridin-2-one (0.417 g, 0.937 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 2 hours. The reaction was filtered and concentrated to give a white solid. EtOAc was added and the product crashed out. The precipitate was filtered and dried to give the title compound as a white solid (0.391 g, 93%). MS: APCI: M+1: 447.2 (Exact Mass: 446.16).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:7]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(NCCOCCCSc2cccc3nccn23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(CCOCCCSc1cccc2nccn12)c1ccccc1
Yield: 1.2 %

Procedure:
To a solution of 5-[3-[2-(phenylamino)ethyloxy]propylthio]imidazo[1,2-a]pyridine (1.034 g, 3.158 mmoles) and triethylamine (0.88 ml, 6.3 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.37 ml, 4.7 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 16 mg of the desired product (brown oily product)
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[SH:12])[CH:5]=[CH:4][CH:3]=1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>CO>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[S:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[N:2]=[CH:3][CH:4]=[CH:5]2
Reactant: Sc1cccc2cccnc12
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: c1cnc(Sc2cccc3cccnc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 210 mg. (1.06 m mole) of quinoline-8-thiol hydrochloride in 5 ml. of dry methanol was added 128 mg. (1.05 mmol) of 2-chloropyrimidine in 2 ml. of the same solvent followed by 0.148 ml (1 mmol) of dry triethylamine. The reaction mixture was allowed to stir at room temperature overnight followed by the removal of the methanol in vacuo. The residue was partitioned between a saturated sodium bicarbonate solution and ethyl acetate. The organic phase was separated, dried and concentrated. The residue was redissolved in chloroform and concentrated without heat. The residue was triturated with ethyl acetate, filtered and dried, 170 mg., m.p. 165°-168° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[NH:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:22][C:20]2[NH:21][C:17]3[CH:16]=[C:15]([C:14]([F:26])([F:25])[F:13])[CH:24]=[CH:23][C:18]=3[N:19]=2)[C:8]=1[CH3:9])[CH3:12]
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: CCOc1ccnc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5 g of 2-(chloromethyl) 4-ethoxy-3-methylpyridine and 5 g of 5-(trifluoromethyl) 2 benzimidazolethiol in 130 ml of abs. acetone was treated with 5 g of finely ground potassium carbonate and stirred at room temperature under argon for 2 hours. 100 ml of acetone were distilled off in a vacuum, whereupon the remaining portion of the reaction mixture was poured onto ice The crystallized-out product was filtered off and dissolved in methylene chloride. The solution obtained was washed with water, dried and concentrated. The residue was chromatographed on silica gel while eluting using methylene chloride and methylene chloride/ethyl acetate (1:1), with the medium pressure flash chromatography method. 2-[[(4 ethoxy-3-methyl-2-pyridyl) methyl]thio]-5-(trifluoromethyl)benzimidazole which melts at 173°-177° was obtained after recrystallization from ethyl acetate/ether.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C@H:11]([CH:14]([O:19][C:20]2[C:21]([CH3:27])=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:10]1)=O)(C)(C)C>ClCCl>[Cl:26][C:23]1[N:22]=[C:21]([CH3:27])[C:20]([O:19][CH:14]([C@H:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)[CH2:15][CH:16]2[CH2:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: Cc1nc(Cl)ccc1OC(CC1CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(Cl)ccc1OC(CC1CC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Add HCl (4M in 1,4-dioxane, 52.7 mL, 627 mmol) to a solution of (3S)-3-[1-(6-chloro-2-methyl-3-pyridyloxy)-2-cyclopropyl-ethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (S-1) (13.4 g, 35.2 mmol) in dichloromethane (40.2 mL). Stir under nitrogen at room temperature for 1 h. Evaporate the solvent and dissolve the residue in a mixture of t-butylmethylether (40 mL) and water (40 mL). Separate the phases, wash the aqueous phase with t-butylmethylether (2×). Adjust the pH of the aqueous phase to 9 by the addition of 10% aqueous K2CO3, extract with t-butylmethylether (3×). Wash the combined organic phases with water and brine. Evaporate the volatiles to obtain (3S)-3-[1-(6-chloro-2-methyl-3-pyridyloxy)-2-cyclopropyl-ethyl]-pyrrolidine (S-1) (9.6 g, 97%). MS (m/z)=281.2 [M+1]
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:27])=O>ClCl>[Cl:27][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Agent: ClCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CCl)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (203 mg, 0.64 mmol) in CH2 Cl2 (20 mL) was added thionyl chloride (761 mg, 6.40 mmol) and the resulting mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2 Cl2 (30 mL). The aqueous layer was extracted further with CH2 Cl2 (2×30 mL). The combined organic extracts were dried over Na2 SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=336 (M+1).
Reaction SMILES: [N:1]1C=CC=C(C(N)C)C=1.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](=O)[CH3:21])=[CH:12][CH:11]=1.N.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]([NH2:1])[CH3:21])=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccnc2ccccc12
Reactant: CC(N)c1cccnc1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1ccnc2ccccc12

Procedure:
The title compound was prepared by the same procedure for preparing 1-pyridin-3-yl-ethylamine from 1-quinolin-4-yl-ethanone, (1.71 g, 10 mmol, Aldrich), 2 M ammonia solution in methyl alcohol, (40 mL, 80 mmol, Aldrich), acetic acid (10 mL, J. T. Baker) and sodium cyanoborohydride (5.0 g, 80 mmol, Aldrich). The title compound obtained in form as light yellow solid in 100% yield (1.72 g, 10 mmol).