Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]#[N:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]3[NH:24][N:25]=[N:26][N:22]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1cc(C#N)sc1-c1ccc(Cl)cc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1cc(Cl)ccc1-c1cc(-c2nnn[nH]2)sc1-c1ccc(Cl)cc1C
Temperature: 110 °C
Yield: 90 %

Procedure:
A round-bottomed flask was charged with 4,5-bis(4-chloro-2-methylphenyl)thiophene-2-carbonitrile (600 mg, 1.67 mmol), zinc bromide (945 mg, 4.20 mmol) and sodium azide (273 mg, 4.20 mmol). After degassed, DMF (5 mL) was added. The reaction mixture was heated to 110° C. and stirred at this temperature until complete. The reaction was cooled to rt, and 30 mL of 0.1 N aqueous HCl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 603 mg (90%) of product was obtained as a white solid, 1H NMR (DMSO, 500 MHz) δ 7.82 (s, 1H), 7.36 (d, J=2.04 Hz, 1H), 7.34 (d, J=1.94 Hz, 1H), 7.31 (d, J=8.25 Hz, 1H), 7.28 (dd, J1=8.26 Hz, J2=1.99 Hz, 1H), 7.17 (dd, J1=8.20 Hz, J2=2.05 Hz, 1H), 7.02 (d, J=8.28 Hz, 1H), 2.17 (s, 3H), 2.03 (s, 3H); 13C NMR (DMSO, 125 MHz) δ 140.58, 139.14, 139.12, 138.19, 133.59, 133.39, 132.94, 132.47, 131.71, 131.17, 130.57, 130.17, 130.11, 126.00, 125.80, 19.69, 19.57.
Reaction SMILES: O=[C:2]1[NH:9][CH2:8][CH:7]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH2:5][CH2:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[S:27]=[C:2]1[NH:9][CH2:8][CH:7]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: CC(C)(C)OC(=O)N1C2CCCC1C(=O)NC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCCC1C(=S)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.4 %

Procedure:
To a solution of tert-butyl 2-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (733 mg, 3.05 mmol) in THF (10 mL) was added Lawesson's reagent (700 mg, 1.68 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in EtOAc and washed 3× with saturated aqueous NaHCO3 solution. The combined aqueous layers were extracted several times with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on SiO2 eluting with EtOAc/Hex to afford the title compound as a colorless foam (622 mg, 79%). MS (ESI): mass calcd. C12H20N2O2S, 256.12; m/z found, 257.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.54-8.20 (m, 1H), 5.23-4.97 (m, 1H), 4.66-4.33 (m, 1H), 3.81-3.63 (m, 1H), 3.28-3.17 (m, 1H), 2.22-2.11 (m, 1H), 1.90-1.58 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17](N)[S:18][C:14]=2[CH:13]=1.[ClH:24]>C(#N)C.[Cu](Cl)Cl>[Cl:24][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:10]([F:23])([F:22])[F:9])[CH:21]=[CH:20][C:15]=2[N:16]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing dry copper (II) chloride (3.44 g, 25.62 mmol) and tri(ethylene glycol)dimethyl ether (10 g) in acetonitrile (150 mL) was added isoamyl nitrite (4.5 mL, 32.02 mmol). The reaction mixture was stirred at rt under argon for 30 minutes. To this suspension was added dropwise, a solution containing 6-trifluoromethoxy-1,3-benzothiazol-2-ylamine (5 g, 21.35 mmol) and tri(ethylene glycol)dimethyl ether (10 g). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 3 h. The mixture was cooled to rt, poured cautiously into aqueous 6 N HCl, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous HCl and brine, and concentrated under reduced pressure to give the desired compound in near-quantitative yield, which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:12]=[C:13](Cl)[N:14]=[N:15][C:16]=2[O:17][CH3:18])[OH:10])=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C(C2[CH:35]=[C:34]([O:36]C)N=NC=2Cl)O)=CC=1)C>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:12]=[CH:13][N:14]=[N:15][C:16]=2[O:17][CH3:18])=[CH:5][CH:4]=1)[CH3:2].[C:34]([OH:36])(=[O:10])[CH3:35].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:12]=[CH:13][N:14]=[N:15][C:16]=2[O:17][CH3:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2cc(OC)nnc2Cl)cc1
Reactant: CCc1ccc(C(O)c2cc(Cl)nnc2OC)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc(Cc2ccnnc2OC)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The 6:1 mixture of (4-ethylphenyl)-(3-chloro-6-methoxypyridazin-5-yl)-methanol and (4-ethylphenyl)-(3-chloro-6-methoxypyridazin-4-yl)-methanol (10.7 g), 5% palladium/carbon (5.4 g) and acetic acid (80 ml) were suspended and stirred under a hydrogen atmosphere at room temperature for 22 hours. After filtration to remove the insoluble materials, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to chloroform:methanol=10:1) to give 4-(4-ethylbenzyl)-3-methoxy-pyridazine (2.88 g) and 4-(4-ethylbenzyl)-3-methoxy-pyridazine acetate salt (3.32 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1>ClCCl>[C:1]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1)(=[O:3])[CH3:2]
Reactant: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](N)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(-n3cc(C)c4c(-c5cnc6ccccc6c5)ccnc43)ccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.012 mL) and triethylamine (0.021 mL) were added to a solution of compound (61) (0.050 g) prepared in Example 61 in dichloromethane (10 mL), followed by stirring at room temperature for 1 hr. The solvent was distilled away under reduced pressure, and water was added to the residue. The precipitate was collected by filtration, washed by sprinkling water and ether, and dried under reduced pressure to obtain (62) (0.043 g, 78%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]#[N:13].C(OC(=O)C)(=O)C.[N+:21]([O-])([OH:23])=[O:22]>>[CH3:11][N:10]1[C:6]([C:2]2[O:1][C:5]([N+:21]([O-:23])=[O:22])=[CH:4][CH:3]=2)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]1
Reactant: Cn1ncc(C#N)c1-c1ccco1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cn1ncc(C#N)c1-c1ccc([N+](=O)[O-])o1

Procedure:
Following the procedure of Example 21, react 1.3 g of 5-(2-furyl)-1-methylpyrazole-4-carbonitrile [German Offenlegungsschrift (DOS) 1,809,386] with 11.5 ml of acetic anhydride and 3 ml of 65% nitric acid to obtain 1-methyl-5-(5-nitro-2-furyl)pyrazole-4-carbonitrile [m.p. 149.5° to 151.5° C].
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)N>>[CH3:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCO)c34)cc2C)cn1
Yield: 81.9 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (1.50 g, 6.72 mmol) and 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (1.44 g, 6.72 mmol) to give the title compound as a white solid (2.16 g, 82%); NMR Spectrum: 2.20 (s, 3H), 2.44 (s, 3H), 3.81 (br t, 2H), 4.32 (t, 2H), 5.14 (br s, 1H), 6.96 (d, 1H), 7.19 (dd, 1H), 7.24 (d, 1H), 7.58 (dd, 1H), 7.62 (s, 1H), 8.17 (d, 1H) 8.28 (s, 1H), 8.44 (br s, 1H); Mass Spectrum: 393 (MH+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH:22]=[C:21]([CH3:33])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ncc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.23 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) to yielded the title compound as a light brown solid (0.028 g, 6%). MS (ISP) 467.1 [(M+H)+]; mp 230° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([O:1][CH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=1)(=[O:16])[CH3:15]
Reactant: OCc1cnc(-c2ccccc2)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cnc(-c2ccccc2)[nH]1
Temperature: 52.5 °C

Procedure:
Mix 5-hydroxymethyl-2-phenyl-1H-imidazole (1.3 Kg) and toluene (10.4 L) at 20-25° C., and then heat the mixture with stirring to 50-55° C. Add acetic anhydride (780 ml, 1.1 equivalents) slowly and continue heating at 50-55° C. until the reaction is complete (typically 3-4 hours). Cool the reaction mixture to -5-0° C., filter off the product, wash it with toluene (3×700 ml) and then dry it under vacuum at 50-55° C. to constant weight.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:26].C(OCC)(=O)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:10]2[C:8]3[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=3[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11]2=[O:22])=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2c(=O)c(-c3c(Cl)cccc3Cl)cc3cnc(N)nc32)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 7 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (195 mg, 0.64 mmol). The mixture was heated at 40° C. to 50° C. for 20 minutes, resulting in a clear solution. Methyl 4-(bromomethyl) benzoate (206 mg, 0.90 mmol) was added, and the reaction mixture was heated at 40° C. to 50° C. for 15 minutes, then poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to 1:2 hexane: ethyl acetate, then dried in vacuo to provide 204 mg of 4-[2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-ylmethyl]-benzoic acid methyl ester containing 0.16 equivalents of ethyl acetate; mp 235°-237° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][CH3:22])[C:16]3=[O:23])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1F.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1[N:21]([CH3:22])[C@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:6]3[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)[C:16]1=[O:23]
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](NC)C3=O)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](N(C)c4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 130 °C
Yield: 26.9 %

Procedure:
(S)-1′-(5-ethylpyrimidin-2-yl)-3-(methylamino)-1,4′-bipiperidin-2-one (0.040 g, 0.13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 0.053 g, 0.25 mmol) and Na2CO3 (0.040 g, 0.38 mmol) were dissolved in DMF (1 mL) and heated at 130° C. overnight. The reaction was concentrated and the residue was purified using preparative TLC (100% EtOAc) to afford (S)-3-((2,5-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (0.018 g, 0.035 mmol, 28% yield) as yellow solid. Mass spectrum (apci) m/z=508.3 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][NH2:11])=O.C([O-])([O-])=O.[K+].[K+]>CO.CCO>[S:6]1[C:5]2[C:3](=[O:2])[NH:11][CH2:10][C:9]=2[CH:8]=[CH:7]1
Reactant: COC(=O)c1sccc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: O=C1NCc2ccsc21
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 3-aminomethyl-thiophene-2-carboxylic acid methyl ester (0.82 g, 4.79 mmol) in 1:1 MeOH-EtOH (125 mL), is added K2CO3 (0.66 g, 4.79 mmol) and the mixture is stirred at 90° C. for 5 hours. The solvent is removed in vacuo and the residue purified by silica gel column chromatography eluting with 97:3 DCM:MeOH. The title compound is isolated (0.365 g, 55%).
Reaction SMILES: CS([C:4]1([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:8])=O.[NH3:20]>O1CCCC1>[NH2:20][C:4]1([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:8]
Reactant: CS(=O)C1(NC(=O)COc2ccccc2)CNC1=O
Reactant: N
Solvent: C1CCOC1
Product: NC1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The sulphoxide (26) (186 mg) in dry tetrahydrofuran (6 ml) was treated with dry ammonia gas (14.8 ml) and the mixture stirred at room temperature for 3 days. The solvent was evaporated and the residue chromatographed on silica gel to give the product, (27) (113 mg).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7].[ClH:11]>>[ClH:11].[Cl:11][CH2:2][CH2:3][NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]
Reactant: O=C(O)[C@H](CS)NCCO
Agent: Cl
Product: O=C(O)[C@H](CS)NCCCl
Reaction time: 8 h
Yield: 70 %

Procedure:
44 g of 2-hydroxyethyl cysteine was added into a 1000 ml round-bottom flask, dissolved in 600 ml of concentrated hydrochloric acid, heated till the external temperature was 90-95° C., stirred and reacted for 7 h. After the reaction, the system was refrigerated and left to stand overnight, and a large number of needle-like solid was precipitated from the system. The solvent was removed by sucking filtration, the obtained solid was naturally dried to give a gray white solid wherein the mp is 185-186° C., the weight is about 40 g, and the yield is more than 70%. 1H-NMR (400 MHz, D2O) δ: 4.30477-4.26952 (m, 1H), 3.81913-3.78409 (m, 2H), 3.25903 (dd, 1H, J1=4.444 Hz, J2=14.984 Hz), 3.18877 (dd, 1H, J1=7.352 Hz, J2=15.072 Hz), 3.04410-3.00625 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[C:7](=[O:9])[CH:8]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[O:9]=[C:7]1[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:5][O:4][C:3]([CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:8]1
Reactant: O=c1cc(CO)occ1OCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCSc2ccnc3cc(C(F)(F)F)ccc23)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-hydroxymethyl-5-[5-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-pentyloxy]-4H-pyran-4-one EHT 5909 (0.10 g, 0.23 mmol) in 4 mL of dichloromethane at 5° C. were added triethylamine (35 μl, 0.25 mmol) and methanesulfonyl chloride (19.4 μl, 0.25 mmol). The reaction mixture was stirred 18 h at room temperature. Dichloromethane (20 mL) was added and the solution was washed with aqueous NaHCO3 10% (2×30 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography on silica using as eluent CH2Cl2:MeOH=98:2. After evaporation methanesulfonic acid 4-oxo-5-[6-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-hexyloxy]-4H-pyran-2-ylmethyl ester 9 (83 mg, 69%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[O:9]1CC[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C>O>[C:10]([NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3][O:2][CH3:1])(=[O:9])[CH3:11]
Reactant: COCC(N)C(=O)O
Reactant: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCC(NC(C)=O)C(=O)O
Yield: 90 %

Procedure:
Into a vessel, equipped with a mechanical stirrer, was added O-methyl-D,L-serine (1.0 eq.) at 20° C. Tetrahydrofuran (6 volumes) and water (0.65 volume) were added. Acetic anhydride (1.2 eq.) was added dropwise over 5 minutes. The white suspension was stirred mechanically until complete conversion was observed by HPLC monitoring (approximately 16 h), by which time the reaction mixture had become homogeneous. The tetrahydrofuran and water were removed azeotropically. Toluene was added in order to effect complete removal of water and acetic acid (KF and GC control). The wet solid was dried at 40° C. under vacuum overnight. The title compound (90% yield) was obtained as a white solid with a chemical purity of >98% as measured by HPLC.
Reaction SMILES: [Li+].[BH4-].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH2:29][CH2:30][C:31](OC)=[O:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH2:29][CH2:30][CH2:31][OH:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)CCn1nc(-c2ccc(C(F)(F)F)cc2)c2c1CCN(C(=O)OC(C)(C)C)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCO)C1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of LiBH4 (26 mg, 1.2 mmol) in THF (0.5 mL) was added to a 0° C. solution of 1-(2-methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (317 mg, 0.70 mmol) in THF (4.0 mL). The mixture was stirred for 5 min then additional LiBH4 (15 mg) was added and stirring continued for 17 h. The mixture was partitioned between EtOAc (80 mL) and saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 0-8% MeOH/CH2Cl2) afforded 268 mg (95%) of the title compound. HPLC (reverse phase conditions), tR=6.82 min. MS (electrospray): m/z calculated for C21H26F3N3O3 [M++Na] 448.18, found 448.10. 1H NMR (CDCl3, 400 MHz): 7.73 (br d, J=8.2 Hz, 2H), 7.65 (br s, 2H), 4.64 (br s, 2H), 4.21 (t, J =6.4 Hz, 2H), 3.76 (br s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.73 (br t, J=5.4 Hz, 2H), 2.04 (q, J=6.1, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][C:3]=1[NH:11]C(=O)CCCC.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][C:3]=1[NH2:11]
Reactant: CCCCC(=O)Nc1cc2nc[nH]c2nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2[nH]cnc2cc1N
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a solution of 2-butyl-3-[2'-(1,1-dimethylethyl)aminosulfonyl][1,1'-biphenyl]-4-yl]methyl]-5-methyl-6-[(1-oxopentyl)amino]-3H-imidazo[4,5-b]pyridine (347 mg, 0.589 mmol) in MeOH (3 mL) was added conc. HCl (2 mL). After the solution was stirred at rt for 42 h, the solution was diluted with EtOAc, neutralized by saturated aq. NaHCO3, washed with brine, and dried over anhydrous MgSO4. Concentration followed by flash chromatography (100% EtOAc, 10% MeOH/EtOAc) afforded 2-butyl-3-[2'-(1,1-dimethylethyl)aminosulfonyl][1,1'-biphenyl]4-yl]methyl]-5-methyl-6-amino-3H-imidazo[4,5-b] pyridine as a solid. To this solid (100 mg, 0.198 mmol) and DMAP (10 mg, 0.08 mmol) in pyridine (2 mL) was added iso-propylisocyanate (24 mL, 0.24 mmol). After the solution was stirred at rt for 18 h, the solution was quenched with MeOH, and stirred at rt for additional 2 h. Concentration gave a brown glass, which was dissolved in TFA (2 mL) and stirred at rt for 18 h. After TFA was removed in vacuo, the residue was dissolved in EtOAc and washed with saturated aq. NaHCO3. The aqueous layer was extracted with EtOAc (2X). The combined organic layer was washed with brine, and dried over anhydrous MgSO4. Concentration followed by flash chromatography (hexanes: EtOAc=1:1, 100% EtOAc, 10% MeOH/EtOAc) afforded the title compound as a foamy powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH:13]=O)=[CH:5][NH:6]2.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[C:11]([C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]2[C:7]=1[NH:6][CH:5]=[C:4]2/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:12]
Reactant: N#Cc1ccc(F)c2c(C=O)c[nH]c12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2c(C#N)ccc(F)c12
Yield: 74.5 %

Procedure:
To a mixture of 4-fluoro-3-formyl-1H-indole-7-carbonitrile (D42) (9.0 g) in CH3CN (120 mL) was added ethyl (triphenylphosphoranyliden)acetate (25.0 g). The reaction was heated at reflux overnight. After the mixture was filtered, the filtrate was concentrated and purified by preparative TLC to afford ethyl (2E)-3-(7-cyano-4-fluoro-1H-indol-3-yl)-2-propenoate (D43) (9.2 g) as a yellow solid.