Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]CC(O)=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:31][CH:30]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccc(C(F)(F)F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.086 g, 0.27 mmol) and 3-(4-(trifluoromethyl)phenyl)propanoic acid (60 mg, 0.27 mmol) taken in dry DCM (20 mL), DIPEA (72 mg, 1.37 mmol) followed by HATU (208 mg, 0.55 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.118 g, 90.07%) as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1cccnc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4cccnc4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl) oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 3-chloromethylpyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 70 mg (yield 71%) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[N+:11]=[N-:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of 4-fluorobenzonitrile (10.0 g, 82.57 mmol, 1.00 equiv) and NaN3 (6.0 g, 92.29 mmol, 1.12 equiv) in DMSO (100 mL) was stirred at 100° C. for 2 h. The reaction was cooled to room temperature and then diluted with 700 mL of water. The precipitate was collected by filtration and air-dried to give 5.8 g (49%) of 4-azidobenzonitrile as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.88 (d, J=13.5 Hz, 2H), 7.31 (d, J=13.5 Hz, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:27][CH:24]([CH3:26])[CH3:25])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 5 h

Procedure:
A solution of (3S,4S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7.7 g, 22.41 mmol) and isopropylamine (5.78 mL, 67.24 mmol) in 1,2-dichloroethane (200 mL) is stirred 25 min before the addition of NaBH(OAc)3 (11.88 g, 56.03 mmol). The solution is stirred for 5 h, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The aqueous layer is back extracted twice with CH2Cl2 and the combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is used in the next step without further purification. TLC, Rf (CH2Cl2/MeOH 9:1)=0.39. MS (LC-MS): 387.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:25].[CH3:26][O:27][CH2:28]Cl>C1COCC1.O>[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]2)=[CH:8][CH:7]=[CH:6][C:5]=1[O:25][CH2:26][O:27][CH3:28]
Reactant: COCCl
Reactant: CCCC1CCC(c2ccccc2-c2cccc(O)c2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(c2ccccc2-c2cccc(OCOC)c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.6 %

Procedure:
Under a nitrogen atmosphere, 1.52 g of sodium hydride was added to 9.45 g of 2-fluoro-3-((4-propylcyclohexyl)phenyl)phenol (5) dissolved in 60 mL of THF cooling with iced water, and the mixture was stirred at ambient temperature for 30 minutes. 3.07 g of chloromethyl methyl ether was added to the solution under cooling with iced water, followed by stirring at ambient temperature for 4 hours. After terminating the reaction by pouring water into the reaction solution, the aqueous layer was extracted with toluene, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 11.6 g of 2-fluoro-3-((4-propylcyclohexyl)phenyl)-1-methoxymethoxybenzene (6).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br-:26].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:26])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [Br-]
Reactant: CC(=O)N1CCc2ccc(N3CCN(C)CC3)cc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2cc(Br)c(N3CCN(C)CC3)cc21
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A stirred mixture of 1-acetyl-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1H-indole (D11, 2.0 g, 0.0077 mole) and anhydrous potassium carbonate (2.12 g, 0.015 mole) in a mixture of dichloromethane (100 ml) and methanol (50 ml) at -5° C. under argon was treated portionwise over 20 minutes with benzyltrimethylammonium tribromide (3.14 g, 0.0081 mole). The mixture was allowed to warm to room temperature over 1 h, then concentrated in vacuo and the residue dissolved in dichloromethane (150 ml), washed with water (2×100 ml), dried (Na2SO4) and concentrated in vacuo to afford the title compound as a beige solid (2.52 g, 97%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[C:10](Br)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1>C1COCC1.O>[Br:5][C:6]1[CH:11]=[C:10]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Reactant: CC(C)N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Nc1cc(Br)ncc1[N+](=O)[O-]
Reaction time: 5.5 h

Procedure:
A solution of isopropylamine (17 ml, 34.0 mmol) in THF (14 ml) was added dropwise over 1 h to a mixture of 2,4-dibromo-5-nitropyridine (4.94 g, 17.0 mmol) in THF (85 ml) at room temperature. After 5.5 h, the reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and evaporated to give the crude title compound as a yellow solid. (UPLC-MS 6) tR 1.03; ESI-MS 260.0/262.0 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]([NH:10][C@@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:12]([OH:16])[C:13]([OH:15])=[O:14])=[O:9])[CH3:6].S(=O)(O)O.Cl.[CH3:29]O>C1(C)C=CC=CC=1>[CH3:29][O:14][C:13](=[O:15])[C@@H:12]([OH:16])[C@@H:11]([NH:10][C:8]([O:7][CH2:5][CH3:6])=[O:9])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CO
Agent: Cl
Agent: O=S(O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)OC
Temperature: 25 °C

Procedure:
Thionyl chloride (596 mg) was added to methanol (1.39 g) over 10 minutes under ice-cooling, and the mixture was reacted at the same temperature for 1 hour. The resultant solution was added to a solution of (2S,3S)-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid (HPLC area ratio of erythro-isomer/threo-isomer=99/1) (1.04 g) and toluene (10 ml) over 10 minutes under ice-cooling. The mixture was reacted at the same temperature for 2 hours and then warmed to room temperature. From the resultant reaction solution, methanol and thionyl chloride as well as components secondarily produced from these reagents and having a low boiling point such as sulfurous acid, hydrogen chloride or the like were distilled off under reduced pressure. Tetrahydrofuran was added to the resultant residue to obtain a tetrahydrofuran solution (10.12 g) of (2S,3S)-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid methyl ester. The HPLC area ratio of erythro-isomer/threo-isomer was 99/1, and the diastereomer excess was 99% d.e.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O-])(=O)C.[K+].[N:23](Cl)=[O:24]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N:23]([N:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:7][CH:8]=1)[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[O:24]
Reactant: CCCCCc1ccc(NC(=O)C(C)C)cn1
Reactant: O=NCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCCc1ccc(N(N=O)C(=O)C(C)C)cn1

Procedure:
24.8 g of N-(2-pentyl-5-pyridyl)-isobutyramide (boiling point 167°-171°/0.27 bar; obtainable by reacting 2-chloro-5-nitropyridine with Na-2-butylmalonic acid diethyl ester to give 2-(5-nitro-2-pyridyl)-2-butylmalonic acid diethyl ester, hydrolysis and decarboxylation to give 2-pentyl-5-nitropyridine, hydrogenation on 10% strength Pd-C in methanol at 40°-50° under 1 bar to give 2-pentyl-5-aminopyridine and acylation with isobutyric anhydride) are dissolved in a mixture of 110 ml of acetic acid and 50 ml of acetic anhydride, 49 g of anhydrous potassium acetate are added, and a solution of 6.9 g of nitrosyl chloride in 27 ml of acetic anhydride is then added at 0°. N-nitroso-N-(2-pentyl-5-pyridyl)-isobutyramide is formed as the intermediate and is not isolated. After the mixture has been stirred at 0° for 15 minutes, it is poured onto ice and extracted five times with 140 ml of thiophene each time. The phases are separated, the organic phase is kept at 0° and made into a slurry with 22 g of K2CO3 and 35 g of Na2SO4, and the slurry is decanted. The organic phase is warmed at 50° and, when the evolution of gas has ended, boiled for 2 hours, and evaporated and the residue is separated on silica gel using toluene. 2-(2-Pentyl-5-pyridyl)-thiophene, boiling point 180°-185°/0.013 bar, c.p. -45° is obtained; a little 3-(2-pentyl-5-pyridyl)-thiophene, boiling point 170°-180°/0.015 bar, c.p. -80°, is also formed.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([Cl:17])=[CH:10][C:11]([Cl:16])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:16][C:11]1[CH:10]=[C:9]([Cl:17])[C:8]2[C:13](=[C:14]([CH3:15])[N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=2)[CH:12]=1
Reactant: Cc1c2cc(Cl)cc(Cl)c2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1c2cc(Cl)cc(Cl)c2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5,7-dichloro-3-methyl-2H-indazol-2-yl)propionitrile (40 mg, described in Example 103) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (64 mg, 92%). MS (ES): M/Z [M+H]=487. 1H NMR: (400 MHz, DMSO-d6): 1.83 (s, 3H), 2.73 (s, 3H), 5.00 (d, 1H), 5.06 (d, 1H), 7.45 (dd, J=1.6 Hz, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.91 (dd, J=1.6 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H) and 9.16 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:35]3[CH:36]=[CH:37][C:38]4[C:33]([CH:34]=3)=[N:32][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:39]=4)[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(Cc2cc(Br)c3c(N)ncnn23)C1
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 94.3 %

Procedure:
To a stirred, degassed mixture tert-butyl 3-[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]azetidine-1-carboxylate (397 mg, 1.04 mmol), Intermediate C (521 mg, 1.56 mmol), Na2CO3 (330 mg, 3.12 mmol) and H2O (1.6 mL) in DMF (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol). The reaction was heated (110° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and H2O (50 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 500 mg (80%) of the desired product, which contained trace impurities.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:16])[N:14]=1)([O-])=O.O1CCCC1>[Pd].CN(C=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:16])[N:14]=1
Reactant: O=C(Nc1nnn[nH]1)c1csc(-c2ccccc2[N+](=O)[O-])n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccccc1-c1nc(C(=O)Nc2nnn[nH]2)cs1
Reaction time: 22 h
Yield: 89.5 %

Procedure:
To a solution of 2-(2-nitrophenyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (200 mg) in a mixed solvent of dry tetrahydrofuran (THF, 30 ml) and dry DMF (13.7 ml) was added (10%) palladium on charcoal (200 mg) and the mixture was hydrogeneted for 22 hours. The catalyst was sucked off and the filtrate was concentrated under reduced pressure. The residue was treated with water (200 mg) to form crystals, which were filtered and dried to give colorless solids of 2-(2-aminophenyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (162 mg, 89%).
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[N:10]1([C:19]2[CH:50]=[CH:49][C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][S:30][CH2:31][C@H:32]([NH:36][C:37](=[O:48])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([N+:45]([O-:47])=[O:46])[CH:40]=4)[C:33]([OH:35])=[O:34])=[CH:25][CH:24]=3)=[CH:21][CH:20]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(O)(=O)C.C(OCC)(=O)C>[N:10]1([C:19]2[CH:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][S:30]([CH2:31][C@H:32]([NH:36][C:37](=[O:48])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([N+:45]([O-:47])=[O:46])[CH:40]=4)[C:33]([OH:35])=[O:34])=[O:5])=[CH:25][CH:24]=3)=[CH:49][CH:50]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N[C@@H](CS(=O)Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
Sodium perborate tetrahydrate (97 mg, 0.63 mmol) was added as a solid to a stirred solution of (2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-[2-(3-nitrophenyl)-acetylamino]-propionic acid (330 mg, 0.58 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a light brown solid (206 mg, 61%): mp. 197-198° C. Rf 0.15 (15% methanol in dichloromethane): 1H NMR (DMSO-d6, 300 MHz) δ 8.46 (1H, d, J=8 Hz, NH), 8.18 (1H, t, J=2 Hz, Ar—H), 8.08 (1H, ddd, J=8, 2, 1 Hz, Ar—H), 7.87 (2H, d, J=8 Hz, Ar—H), 7.72 (2H, d, J=8 Hz, Ar—H), 7.54-7.69 (7H, m, Ar—H), 7.35 (2H, d, J=8 Hz, Ar—H), 7.21 (1H, td, J=7, 2 Hz, Ar—H), 7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.71 (1H, d, J=3 Hz, Ar—H), 4.36 (1H, m, CHN), 4.20 (1H, d, J=13 Hz, PhCHHS), 3.84 (1H, d, J=13 Hz, PhCHHS), 3.66 (2H, m, PhCH2CO), 3.11 (1H, dd, J=13, 5 Hz, CHHCHN), 2.99 (1H, dd, J=13, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C32H27N3O6S 581.646, found 582 (M+H)+, 604 (M+Na)+.
Reaction SMILES: B(F)(F)F.CCOCC.Br[CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=O.[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH2:30]>C1COCC1>[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[O:31][CH:11]=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:30]=1
Reactant: COC(=O)CCCCC(N)=O
Reactant: COc1cccnc1C(=O)CBr
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ncccc2OC)co1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
Add boron trifluoride etherate (0.30 mL, 1.00 mmol) to a sealed tube containing 2-bromo-1-(3-methoxy-pyridin-2-yl)-ethanone (231 mg, 1.00 mmol), 5-carbamoyl-pentanoic acid methyl ester (222 mg, 1.39 mmol), and THF (anhydrous, 3 mL). Flush with N2, seal, heat at 80° C. overnight. Partition between saturated aqueous NaHCO3 solution and 20% i-PrOH/CHCl3, separate layers. Extract from aqueous layer with 20% i-PrOH/CHCl3 (×3), dry combined organic layers with MgSO4 and concentrate. Adsorb on SiO2 and purify by flash chromatography on silica gel eluting with 1-3% methanol/CHCl3 to afford the title compound (97 mg, 33%). MS (IS) 291 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][CH:20]([C:22](O)=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C@H:20]([C:22]([NH:10][C:8](=[O:9])[C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[NH2:2])=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-leucinamide hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared. This compound was then purified by column chromatography, eluted first with 1:1 EtOAc/hexane, then with 5% MeOH) in methylene chloride.
Reaction SMILES: [Cl-].C([P+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Cl:31][SiH:32]([Cl:34])[Cl:33]>>[CH2:23]([Si:32]([Cl:34])([Cl:33])[Cl:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Product: CCCCCCCC[Si](Cl)(Cl)Cl
Temperature: 170 °C
Yield: 87 %

Procedure:
In a 25 ml oven dried stainless steel tube, 0.22 g (0.67 mmol) of benzyltributylphosphonium chloride, 1.00 g (6.73 mmol) of 1-chlorooctane, and 2.71 g (20.0 mmol) of trichlorosilane were added under a dry nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 170° C. for 2 hrs. The resulting mixture was distilled to yield 1.45 g of n-octyltrichlorosilane (yield; 87%).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[C:9]([O:32][CH3:33])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:34][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:32][CH3:33])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 140, 130 mg, 0.28 mmol), iron (94 mg, 1.68 mmol) and NH4Cl (10.48 mg, 0.20 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2.5 h. The mixture was allowed to cool to r.t., filtered and concentrated in vacuo. Part-purification by ion exchange chromatography, using an SCX column, eluting with 0.7M methanolic ammonia provided crude material as a brown gum. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (111 mg, 91%) as a brown gum; 1H NMR (CDCl3): 1.90-1.98 (2H, m), 2.04-2.12 (2H, m), 2.20 (6H, s), 3.08-3.16 (1H, m), 3.23 (2H, t), 3.35 (1H, s), 3.56 (2H, t), 3.84 (3H, s), 3.93 (2H, dd), 4.20 (2H, t), 6.37 (1H, s), 6.76 (1H, d), 7.35 (1H, s), 7.87 (1H, s), 7.95 (1H, s), 8.28 (1H, d); m/z: ES+ MH+ 435.58.