Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[SH2:15].[Na]>CO>[NH2:12][C:11]1[C:2]([SH:15])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: S
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cnc(S)c(N)c1
Yield: 484 %

Procedure:
To a solution of 6 g of methyl 6-chloro-5-nitronicotinate in methanol (100 ml) was added 6.7 g of sodium hydrogensulfide and the resulting mixture was heated under reflux for 2 hours. After distilling off the solvent under reduced pressure, dilute hydrochloric acid was added to the residue followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 24.7 g of the title compound as yellow crystals.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH:29][C:30]#[N:31])[CH:23]=1>>[C:16]1([C:14]2[N:15]=[C:11]3[CH:10]=[C:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2)n1)c1ccccc1
Reactant: N#CC=Cc1cccnc1
Product: Nc1cc(-c2cccnc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, mp. 201-203° C., MS m/e (%): 288 (M+H+, 100), was prepared in accordance with the general method of example 22 from 3-benzenesulfonylmethyl-5-phenyl-1H-[1,2,4]triazole and 3-pyridin-3-yl-acrylonitrile.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:11][CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([NH:8][C:9]([C:10]1[NH:11][C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]2[C:14]=1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18]2)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccc1)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 36.1 g. of 1-benzyl-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 300 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.11 mol. of sodium hydride (4.8 g. of a 55% dispersion in mineral oil). The mixture is first heated to 60° C. over a period of about 30 minutes, and then stirred for 1 hour at this temperature for an additional 1 hour at 70° C. After cooling, 10 ml. of water are added dropwise and the mixture is poured into 3 liters of ice-water. After the addition of 100 g. of sodium chloride, the separated product is extracted with methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oily residue is chromatographed on 1000 g. of silica gel with methylene chloride/ethyl acetate (4:1) as the eluant. The homogeneous fractions are combined, evaporated and triturated with a small amount of ether, and there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid benzylamide in the form of fibrous, greenish crystals; melting point 202°-204° C. (decomposition). Recrystallization from chloroform does not increase the melting point.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1.[C:23]([N:31]=[C:32]=[O:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1)=[O:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)OCC(C(O)CN1CCC(N)CC1)O2
Reactant: O=C=NC(=O)c1ccccc1
Product: COc1ccc2c(c1)OCC(C(O)CN1CCC(NC(=O)NC(=O)c3ccccc3)CC1)O2

Procedure:
Using the procedure of Example 4 erythro 4-amino-1-[2-(6-methoxy-1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine may be reacted with benzoyl isocyanate to give the title compound.
Reaction SMILES: FC1C2C(C(=O)NC)=C(C3C=CC(F)=CC=3)OC=2C=CC=1C1C=C(C=CC=1C)C(O)=O.[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:39]2([NH2:42])CC2)=[N:37][CH:38]=1>>[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:39]#[N:42])=[N:37][CH:38]=1
Reactant: Cc1cnc(C2(N)CC2)cn1
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Product: Cc1cnc(C#N)cn1

Procedure:
This example was prepared from the coupling of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid with 1-(5-methylpyrazin-2-yl)cyclopropanamine (obtained from 5-methylpyrazine-2-carbonitrile by the reaction using Ti(OiPr)4/EtMgBr/BF3OEt2), and was isolated as a TFA salt after purification by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Sunfire Prep C18 19×100 5 um, Fraction Collection: 7.15-7.72 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 8.44 (s, 1H), 8.43 (s, 1H), 7.95 (m, 2H), 7.90 (dd, J=7.93, 1.83, 1H), 7.83 (s, 1H), 7.55 (d, J=8.55, 1H), 7.49 (d, J=7.93, 1H), 7.33 (d, J=8.24, 1H), 7.29 (t, J=8.85, 2H), 2.96 (s, 3H), 2.51 (s, 3H), 2.30 (s, 3H), 1.67 (m, 2H), 1.41 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=553.22, HPLC Rt=1.647 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.01 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.04 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=10.24 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:4])=[O:3].[Br:17]Br.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:17][C:11]1[C:10]([O:15][CH3:16])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]2
Reactant: BrBr
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1Br
Reaction time: 24 h

Procedure:
A solution of 2-methanesulfonyl-6-methoxy-quinoline (237 mg, 1 mmole ) in CH2Cl2 was treated with 2 mmoles Br2 and stirred for 1 day. The mixture was poured into a solution of NaHCO3 and sodium thiosulfate. The product was extracted with CH2Cl2. The organic layer was dried and evaporated to afford 5-bromo-2-methanesulfonyl-6-methoxy-quinoline, 287 mg (91%), as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=3)=[C:4]2[CH:3]=1.C(=O)(O)[O-:34].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[N:5]2[N:14]=[C:15]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23]([CH3:24])=[O:34])[N:18]=3)=[C:4]2[CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(S(C)=O)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a solution of N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (133 mg, 0.28 mmol) in chloroform (10 mL) was added sodium bicarbonate (24 mg, 0.28 mmol). The reaction mixture was cooled to 0° C. m-Chloroperoxybenzoic acid (57˜86%, 86 mg, 0.50 mmol) was added. After stirring at 0° C. for 1.5 hours, the reaction mixture was quenched by addition of aqueous sodium bicarbonate and the resulting mixture extracted with dichloromethane. The organics were combined and washed with water, then dried over magnesium sulfate. Filtration and concentration followed by chromatography (19:1 dichloromethane/methanol) gave N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (121 mg, 88%) as a yellow solid. 1H NMR (CDCl3) δ 8.43 (d, 1H), 7.93 (d, 1H), 7.51 (d, 2H), 7.00 (d, 2H), 6.98 (d, 1H), 6.11 (d, 1H), 6.08 (d, 1H), 3.96 (m, 1H), 3.88 (s, 3H), 2.99 (s, 3H), 2.13 (m, 2H), 1.82-1.66 (m, 6H). MS m/z 482 (M+1).
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]#[CH:23]>C(O)C.O>[CH2:23]([O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[C:4]2[CH2:3][C@H:2]([OH:1])[CH3:14])[C:22]#[CH:21]
Reactant: C[C@@H](O)Cc1n[nH]c2ccc(O)cc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2[nH]nc(C[C@@H](C)O)c2c1
Temperature: 75 °C
Yield: 69.5 %

Procedure:
To a stirred mixture of the product from Step A (1.50 g, 7.81 mmol) in a mixture of ethanol in water (50 mL/10 mL) was added potassium carbonate (1.62 g, 11.7 mmol) and propargyl bromide (80% in toluene, 1.74 g, 1.30 mL, 11.7 mmol). The mixture was heated at 75° C. for 2 hours under nitrogen, evaporated to dryness, mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. Chromatography on silica (gradient, 25% to 95% ethyl acetate in hexane) gave an oil (1.25 g, 69%): LC/MS (+APCI) m/z 231 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([S:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][CH:6]=1
Reactant: N#Cc1nc(Cl)cnc1Cl
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc(Cl)cnc1Sc1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In 50 mL of N,N-dimethylformamide was dissolved 10.0 g of 3,6-dichloro-2-pyrazinecarbonitrile. After adding 6.49 mL of thiophenol and 11.91 g of potassium carbonate successively, the mixture thus obtained was stirred at 40° C. for 3 hours. The reaction mixture was poured into a mixture of 100 mL of ethyl acetate and 100 mL of water, and pH was adjusted to 2 with 6 mol/L hydrochloric acid. The organic layer was separated, washed successively with water and saturated aqueous solution of sodium chloride, and dried on anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:n-hexane=1:3] to obtain 3.80 g of 6-chloro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile as a light yellow-colored oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[S:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:31]=[C:29]([CH2:28][CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:30][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)CCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ccc(-c2sc(CCCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, step 3) (0.100 g, 0.295 mmol) in ethanol (3 mL) in a 10 mL round bottom flask was added 4-phenylthiobutyramide from step 1 (0.055 g, 0.310 mmol) and the mixture heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with Na2CO3 (10% solution), brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude thiazole was flash chromatographed (9:1, hexane:ethyl acetate) yielding 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-(3-phenylpropyl)thiazole (0.118 g, 95%) as crystalline solid: mp 62°-63° C.; 1HNMR (CDCl3) 300 mHz 7.49 (d of d, J=5.52 and 8.85, 2H), 7.33-7.14 (m, 9H), 6.98 (t, J=8.85, 2H), 3.05 (t, J=7.74, 2 H), 2.82 (t, J=7.74 Hz, 2H), 2.49 (s, 3H), 2.18 (m, 2 H); MS (FAB) m/z 420 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][C:15]=2[O:19][CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Cl)cc2)c(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chlorobenzoyl chloride (1.0 g, 5.8 mmol) and 1,3-dimethoxybenzene (788.5 mg, 5.8 mmol) in CH2Cl2 (150 mL) at 0° C. was added AlCl3 (841.5 mg, 6.4 mmol). The reaction mixture was warmed to room temperature. After 12h the reaction mixture was poured into aq. NaHCO3 and extracted with CH2Cl2 (twice). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide a 1:1 mixture of(4-chlorophenyl)(2-hydroxy-4-methoxyphenyl)methanone and (4-chlorophenyl)(2,4-dimethoxyphenyl)methanone. Purification by silica gel chromatography provided methoxyphenyl)methanone (650 mg, 2.5 mmol) and (4-chlorophenyl)(2,4-dimethoxyphenyl)methanone(700 mg, 2.5 mmol). The combined molecules (2.7 g) were dissolved in AcOH (50 mL) and 49% HBr (50 mL) was added. After 12h at 90° C. all volatiles were evaporated in vaccuo to afford (4-chlorophenyl)(2,4-dihydroxyphenyl)methanone in quantitative yield. Without purification this was subjected to alkylation with 1,8-dibromooctane (4.0 g, 14.7 mmol) and K2CO3 (2.0 g, 14.7 mmol) in DMF (50 mL). After 12 h the reaction mixture was diluted with water (150 mL) and the water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone(1.9 g, 4.4 mmol). To a stirred solution of (4-(8-bromooctyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone (1.9 g, 4.4 mmol) in THF (25 mL) was added N-methylprop-2-en-1-amine (938.1 mg, 13.2 mmol) and NaHCO3 (13.2 mmol). After 36h at room temperature the reaction mixture was filtered through a glass-filter. The filtrate was evaporated in vaccuo. Purification by silica gel chromatography provided (4-(8-(allyl(methyl)amino)octyloxy)-2-hydroxyphenyl)(4-chlorophenyl)methanone (1.8 g, 1.9 mmol); 1H-NMR (300 MHz, CDCl3) 12.6 ppm (s, 1H) , 7.64 (d, J=9.6 Hz, 2H), 7.60-7.48 (m, 3H), 6.59 ( s, 1H), 6.45 (d, J=9.6 Hz, 1H), 6.05-5.84 (m, 1H), 5.39-5.12 (m, 2H), 4.05 (t, J=7.7 Hz, 2H), 3.21-2.99 (m, 2H), 2.51-2.11 (m, 7H), 1.92-1.80 (m, 2H), 1.79-1.21(m, 8H); 13C-NMR (75 MHz, CDCl3) 196.3 ppm, 162.5, 138.1, 137.8, 134.2, 132.3, 131.7, 128.5, 110.9, 101.8, 68,8, 60.4, 57.0. 43.8, 29.6, 29.3, 27.3, 28.1; ESI-MS calcd for C25H33ClNO3 [M+H+]: 430.2. found 430.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-chloro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.3 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.81 g, 4.3 mmol). The product was isolated as a white foam. Yield 1.15 g (64%). mp 90-95° C. FDMS m/e=423 (M+ of free base). α[D]589=+8.81 (c=0.98, methanol/dimethylsulfoxide).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([Cl:11])[C:5]=1[O:12][CH:13]([F:15])[F:14])=[N+]=[N-].[BH4-].[Na+]>CO>[Br:10][C:8]1[N:7]=[C:6]([Cl:11])[C:5]([O:12][CH:13]([F:15])[F:14])=[C:4]([NH2:1])[CH:9]=1
Reactant: [N-]=[N+]=Nc1cc(Br)nc(Cl)c1OC(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1cc(Br)nc(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
4-Azido-6-bromo-2-chloro-3-(difluoromethoxy)pyridine (0.563 g, 1.880 mmol) was then dissolved in CH3OH (15 mL), and NaBH4 (0.107 g, 2.82 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 min at which point thin-layer chromatographic (TLC) analysis indicated complete consumption of starting material. The reaction mixture was concentrated and partitioned between EtOAc and H2O. The organic phase was dried and concentrated. The product was purified by flash chromatography (SiO2, EtOAc/hexane gradient) to yield the title compound as a white solid (0.398 g, 77%): mp 138-140° C.; 1H NMR (600 MHz, DMSO-d6) δ 6.98 (t, J=73.1 Hz, 1H), 6.84 (d, J=14.6 Hz, 2H); EIMS m/z 274.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][CH:10]=2)[CH:7]=1.[NH2:11][C:12]1[C:21]2[C:16](=[C:17](Br)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]>>[NH2:11][C:12]1[C:21]2[C:16](=[C:17]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[N:9][CH:10]=4)[CH:7]=3)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: Brc1ccc2cncn2c1
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2cncn2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromoimidazo[1,5-a]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.45 (s, 3 H), 6.77 (dd, J=9.22, 1.39 Hz, 1 H), 7.47 (s, 1 H), 7.72 (d, J=9.09 Hz, 1 H), 7.67 (d, J=9.35 Hz, 1 H), 8.10-8.32 (m, 2 H), 8.37 (s, 1 H); ESI-MS m/z [M+H]+ 319.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[S:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[S:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)Sc1ccncc1-c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccncc1-c1ccc(C#N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To ethyl 2-(3-(4-cyanophenyl)pyridin-4-ylthio)-2-methylpropanoate (step C, 49 mg, 0.15 mmol) was added methanol (0.8 mL), and sodium hydroxide (2 M aqueous, 0.8 mL). The resulting mixture was stirred at ambient temperature for 2 hours. The volume was reduced (˜0.8 mL) by rotary evaporation. To the residue was added HCl (6 N aqueous) with stirring until pH reached 6, resulting in the formation of a white precipitate, which was isolated by filtration. The solid was washed with water (6×1 mL), air dried for 1 hour and dried under vacuum (P2O5) overnight to yield a white powder (28 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24](Cl)=[O:25])[C@H:20]([CH2:27][CH3:28])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][O:5][C:24]([N:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:17])[CH2:19][C@H:20]1[CH2:27][CH3:28])=[O:25]
Reactant: OCc1cc(I)ccc1F
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
A mixture of 2-fluoro-5-iodo-benzylalcohol (5.0 g, 19.8 mM) and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester (5.5 g, 19.8 mM) in dimethylformamide (70 mL) was added slowly to a suspension of sodium hydride (1.3 g, 55%, 1.89 mM) in dimethylformamide (30 mL). The mixture was stirred at room temperature for 5 h and partitioned between water and diethylether. Organic phases were pooled, washed with brine and dried with Na2SO4 to yield after evaporation a yellow oil (11.2 g). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 3:1) to yield 9.4 g (97%) of the product as a yellowish oil. MS (ISP): 510.3 (M+NH4)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([F:19])[CH:18]=1)[NH2:15].Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>C1COCC1.CCOCC>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:21](=[O:22])[O:23][CH:24]([CH3:26])[CH3:25])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)OC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
Lithium bis(trimethylsilyl) amide (1.0 M solution in tetrahydrofuran, 542 mL, 0.542 mol) was added to a solution of 3,5-difluoroaniline (35 g, 0.271 mol) in THF (60 mL) at 0° C. Isopropyl chloroformate (1M solution in toluene, 406 mL, 0.406 mol) was then added dropwise at 0° C. and the mixture allowed to warm to room temperature over 2 h. The reaction mixture was diluted with ether and washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, brine and dried (MgSO4). Solvent was removed under vacuum and the residue was triturated in hexanes to obtain the title compound.
Reaction SMILES: [Mg].[CH:2](Cl)([CH3:4])[CH3:3].II.[CH3:8][CH:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH:11]=[O:12]>CCOCC>[CH3:3][CH:2]([CH:11]([OH:12])[CH2:10][CH:9]([CH3:8])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:4]
Reactant: CC(C)CC(C)CC=O
Reactant: CC(C)Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CC(C)CC(O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
26.4 g (1.1 gram atom) of magnesium shavings and 100 ml of dry ether are added to a round flask which is provided with a stirrer, condenser, thermometer and dropping funnel. There is now slowly added thereto a solution of 86.4 g (1.1 mol) of isopropyl chloride in 150 ml of anhydrous ether and the mixture is held at reflux temperature. The reaction is initiated by the addition of a small amount of iodine to the magnesium. After completion of the addition of the isopropyl chloride, the mixture is held for a further 1 hour at reflux temperature. There are now slowly added thereto at 5° C. 128.2 g (1 mol) of 3,5-dimethylhexanal dissolved in 250 ml of anhydrous ether. The mixture is again held for 3 hours at reflux temperature. The mixture is then cooled down to 0° C. and the product is decomposed by the addition of 340 ml of ice-cold 10% hydrochloric acid. The ethereal solution is washed neutral with water and dried, and the solvent is evaporated. There are thus obtained 176 g (70%) of crude product, fractional distillation of which yields 121.4 g of 2,5,7-trimethyl-octan-3-ol of boiling point 79° C./5 mmHg; nD20 =1.4362.