Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(C(F)(F)F)C[O:4][C:5](=[O:26])[C@H:6]([OH:25])[CH2:7][C@H:8]([NH2:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1.[OH:32][N:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[N:35]=[N:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([F:23])=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C@@H:8]([NH:24][C:38]([C:36]3[N:35]=[N:34][N:33]([OH:32])[CH:37]=3)=[O:39])[CH2:7][C@@H:6]([OH:25])[C:5]([OH:4])=[O:26])=[CH:15][CH:14]=2)[CH:21]=1
Reactant: O=C(O)c1cn(O)nn1
Reactant: N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
(2R,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 2,2,3,3,3-pentafluoropropyl ester (32.1 mg, 68.3 μmol), 1-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid (10.6 mg, 82 μmol) and HATU (39.0 mg, 102 μmol) were stirred in DMF (1.0 mL, 12.9 mmol) for 10 minutes. DIPEA (35.7 μL, 205 μmol) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated and to yield a clear yellow liquid, which was purified using preparative scale C18 column chromatography (small column; 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (4.9 mg). MS m/z [M+H]+ calc'd for C23H19ClF6N4O5, 581.09. found 581.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:17])[N:10]([CH2:11][CH:12]3[CH2:14][C:13]3([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CO.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[F:15][C:13]1([F:16])[CH2:14][CH:12]1[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:18]#[N:19])=[CH:3][CH:4]=2)[S:8][C:9]1=[O:17]
Reactant: O=c1sc2nc(Cl)ccc2n1CC1CC1(F)F
Reactant: N#Cc1ccccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1ccc2c(n1)sc(=O)n2CC1CC1(F)F
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-chloro-1-[(2,2-difluorocyclopropyl)methyl][1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-5) (0.025 g, 0.090 mmol), (2-cyanophenyl)boronic acid (0.020 g, 0.14 mmol), cesium carbonate (0.059 g, 0.18 mmol), bis(tri-tert-butylphosphine) palladium (0.009 g, 0.02 mmol), 1,4-dioxane (1 mL), and water (0.2 mL). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 2-(1-{[2,2-difluorocyclopropyl]methyl}-2-oxo-1,2-dihydro[1,3]thiazolo[5,4-b]pyridin-5-yl)benzonitrile (1-6) as a brown solid. 1H NMR (400 MHz, CD3OD): δ 7.87-7.72 (m, 5H); 7.60-7.54 (m, 1H); 4.25-4.10 (m, 2H); 2.23-2.15 (m, 1H); 1.61-1.54 (m, 1H); 1.38 (m, 1H). HRMS (M+H)+: observed=344.0669, calculated=344.0664.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH2:24][CH3:25])=[C:6]([CH:12]([NH:15][C:16](=[O:22])[O:17][C:18](C)(C)C)CO)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].C(Cl)(Cl)=O>ClCCCl.C1(C)C=CC=CC=1>[C:1]([C:4]1[C:5]([O:23][CH2:24][CH3:25])=[C:6]([CH:12]2[CH2:18][O:17][C:16](=[O:22])[NH:15]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)Cl
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1COC(=O)N1
Temperature: 80 °C

Procedure:
tert-Butyl [1-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-hydroxyethyl]carbamate (234 mg, 0.62 mmol) (from Step 8) was dissolved in 1,2-dichloroethane (12 mL) and a solution of 2.0 M phosgene in toluene (0.93 mL) was added. The mixture was heated to 80° C. for 1.5 hours. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-85%) gave the desired compound, 175 mg, 93%. LCMS calculated for C13H14ClFNO4 (M+H)+: m/z=302.1; found: 302.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[CH:34][CH:35]=3)[CH:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: Cl
Product: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2ccccn2)cc1

Procedure:
In the same manner as in Example A-68, a reaction was conducted using 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-methoxycarbonylmethylpiperazine (723 mg) and 4-(2-pyridyl)benzoic acid hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[N:21]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>ClCCCl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[N:21]=2)[C:32]([NH:31][CH2:29][CH3:30])=[O:33])[CH2:16][CH2:17]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(C#N)n2)CC1
Reactant: CCN=C=O
Solvent: ClCCCl
Product: CCNC(=O)N(Cc1cccc(C#N)n1)C1CCN(C(C)CCNC(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.067 g, 0.17 mmol) and ethyl isocyanate (20 μL, 0.25 mmol) were combined in 1,2-dichloroethane (5 ml) and the resulting mixture was stirred at 55° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 93:6:1, v/v/v) to give (3-{4-[1-(6-cyano-pyridin-2-ylmethyl)-3-ethyl-ureido]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.075 g, 95%) as a white foam. 1H NMR (CDCl3) δ 0.93 (d, 3H, J=6.0 Hz), 1.12 (t, 3H, J=7.5 Hz), 1.40 (s+m, 13H), 1.65 (m, 1H), 1.92 (m, 2H), 2.18 (br t, 1H, J=9.0 Hz), 2.52 (m, 2H), 2.69-2.85 (m, 3H), 3.09 (m, 1H), 3.21-3.33 (m, 3H), 4.12 (m, 1H), 4.44 (s, 2H), 5.33 (br s, 1H), 5.95 (br s, 1H), 7.57 (d, 1H, J=9.0 Hz), 7.61 (d, 1H, J=9.0 Hz), 7.83 (t, 1H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[N:21]=[C:20]([C:30]([OH:32])=[O:31])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCNCC2)n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCNCC4)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesized by an analogous method to Example 310 starting from methyl 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-piperazin-1-ylpyrimidine-4-carboxylate (Example 317) and 2 N lithium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 18 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 3′,4′-dichloro[1,1′-biphenyl]-4-sulfonyl chloride (17.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 18% yield (4.1 mg). MS (ESI+) calcd mass for C19H13Cl2N5O2S 445.016701, found 445.016581.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17]2[C:22]([C:23]3[N:24]=[C:25]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]4=[N:27][CH:28]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12]1)=O)C1C=CC=CC=1>CCO>[NH:11]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17]2[C:22]([C:23]3[N:24]=[C:25]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]4=[N:27][CH:28]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCN(C(=O)OCc4ccccc4)C3)cnc21
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reaction time: 2 h
Yield: 82 %

Procedure:
(R)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid benzyl ester (0.535 g, 0.98 mmol) was dissolved in 20 ml of EtOH and the flask was flushed with argon. 20% Pd(OH)2/C (0.105 g) was added and the system was flushed with argon again and at last was flushed with hydrogen. A hydrogen balloon was placed on the flask, with a needle, so that the gas bubbled directly into the solution at atmospheric pressure and the reaction was left for 2 h. The catalyst was removed by filtration and the solution was concentrated to dryness, giving 0.330 g (81%) of (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine which was used as is in the following steps.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[C:20]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]=4[N:22]=[CH:23][C:18]=3[C:17](=[O:35])[NH:16][C:15]2=[O:36])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:37].CO>CO.[C].[Pd]>[ClH:37].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[C:20]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:21]=4[N:22]=[CH:23][C:18]=3[C:17](=[O:35])[NH:16][C:15]2=[O:36])[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n(C3CCN(Cc4ccccc4)CC3)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n(C3CCNCC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione (360 mg, 0.712 mmol) and 5% palladium-carbon (100 mg) in a mixture of methanol and 10 wt % hydrogen chloride-methanol solution (0.5 mL) were stirred with at room temperature for 2 hours under a hydrogen atmosphere, then at 40° C. for 5 hours and at room temperature for one day. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (324 mg, quantitative yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][C:37](=[O:39])[CH3:38])=[CH:16][C:15]=2[N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(OCCNC(C)=O)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.480 g, 1.03 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.430 mL, 3.09 mmol) were combined and stirred for 10 minutes. Acetic anhydride (0.097 mL, 1.03 mmol) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform). Fractions containing product were combined and concentrated. Trituration of the product in acetonitrile provided 0.319 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)acetamide as fine white crystals, mp 165-167° C.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A solution of 5-cyclohexyl-1,3-dihydro-3(R,S)-[ (benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one(7.0 g, 18 mmol)in dimethylformamide (84 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.77 g of a 55-60% dispersion in mineral oil, 18 mmol) in one portion, at -10° C. After 30 min at -10° C., 1-iodo-2-methylpropane (2.3 ml, 19.8 mmol) was added in one portion and the solution allowed to reach 0° C. over 2 h, then stirred at ambient temperature overnight. After this time the solvent was removed under reduced pressure, and the crude residue partitioned between water (500 ml) and dichloromethane (500 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×500 ml). The combined organic layers were washed with brine (500 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using 2:1 petrol:ethyl acetate as the eluant, to afford the title compound (4.5 g, 56%) as a white solid. mp 148°-150° C. 1H NMR (360 MHz, CDCl3) δ 0.73 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 1.14-2.09 (11H, m), 2.80 (1H, m), 3.42 (1H, dd, J=14 and 5 Hz), 4.27 (1H, dd, J=14 and 9 Hz), 5.10 (3H, m), 6.55 (1H, d, J=8 Hz), 7.23-7.34 (8H, m), 7.45 (1H, t, J=8 Hz), 7.56 (1H, d, J=8 Hz).
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.C(O[C:11](=[O:31])[CH2:12][CH:13]([C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>C1C=CC=CC=1>[CH3:30][O:29][C:28]1[C:20]([CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([NH:2][CH3:1])=[O:31])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2
Reactant: CCOC(=O)CC(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Temperature: 25 °C

Procedure:
To a 0° C. suspension of MeNH2—HCl (15.6 mg, 0.231 mmol) in benzene (2 ml) was added Me3Al (2M in toluene, 115 μl, 2.31 mmol). The mixture was stirred at 0° C. for 5 min and at RT for 2 hours after which a solution of 3-(5-methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester XLIX in benzene (4 ml) was added. The reaction mixture was stirred at reflux for 5 hours and at room temperature for 16 hours, and quenched by addition of HCl (0.5 M). The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to yield crude 3-(5-Methoxy-1H-Indol-4-yl)-N-methyl-3-phenyl-propionamide L (37 mg, yellow oil), which was used without purification in the next step.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[C:14]([NH:16][C:17]3[N:22]=[CH:21][C:20]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[C:14]([NH:16][C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Oc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)C(Oc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of tert-butyl 6-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)acetyl]amino]pyridine-3-carboxylate (Example A7; 1.6 g, 2.94 mmole) in DCM (5 mL) was added TFA (7 mL) dropwise at 0° C. Reaction mixture was stirred at rt for 3 hr. TFA was removed invaccuo, residue was neutralised using sat.NaHCO3 solution, extracted with ethyl acetate (3×25 mL) washed with brine, dried over anhydrous sodium sulfate and concentrated. Crude solid was triturated in diisopropyl ether and filtered washed with diisopropyl ether to afford pure product (1.2 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[OH-].[Na+:11]>O>[NH2:1][CH:2]([CH:3]([CH3:4])[CH2:5][CH3:6])[C:7]([O-:9])=[O:8].[Na+:11]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)C(N)C(=O)[O-]

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 6.56 g (50 mmol) of Isoleucine is dissolved in 200 ml of water. To this is added 55 ml of 1M sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-amino-3-methylpentanoate, shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:13]([CH:15]([CH2:26][CH3:27])[CH2:16][C:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:14]>N1C=CC=CC=1>[CH2:13]([CH:15]([CH2:26][CH3:27])[CH2:16][C:17]1([C:23]([NH:1][C:2]2[C:3]([S:12][C:23]([C:17]3([CH2:16][CH:15]([CH2:26][CH3:27])[CH2:13][CH3:14])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:24])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:14]
Reactant: Nc1cc2ccccc2cc1S
Reactant: CCC(CC)CC1(C(=O)Cl)CCCCC1
Solvent: c1ccncc1
Product: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2SC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Temperature: 60 °C

Procedure:
To a solution of 3-amino-naphthalene-2-thiol in pyridine are added two mol equivalents of 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride at room temperature. After completion of the addition, the reaction mixture is heated to 60° C. for 2 hours. The pyridine is then removed under reduced pressure, water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with sat. NaHCO3-solution, diluted hydrochloric acid and brine, dried (Na2SO4) and concentrated to obtain crude 1-(2-ethyl-butyl)-cyclohexanecarbothioic acid S-(3-{[1-(2-ethyl-butyl)-cyclohexanecarbonyl]-amino}-naphthalen-2-yl)ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10](=S)=S)=[CH:5][CH:4]=1.[CH:13]1([Mg]Br)[CH2:15][CH2:14]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH:13]1([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: CSc1ccc(C[SH](=S)=S)cc1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(CSC2CC2)cc1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of (4-methylsulfanyl-phenyl)-methanethiol disulfide from Step 1 in THF (50 mL) at 21° C. was added cyclopropylmagnesium bromide (excess) dropwise. The reaction mixture was stirred 18 h at 21° C., then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 98:2) provided the 1-cyclopropylsulfanylmethyl-4-methylsulfanyl-benzene compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C@H:18]([CH3:29])[C:19]([O:21]CC2C=CC=CC=2)=[O:20])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C@H:18]([CH3:29])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](CS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](CS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A 300 mL Fisher Porter vessel equipped with magnetic stirring bar was charged with 7.2 g benzyl 3-(4-tert-butoxycarbonylpiperizin-1-ylsulfonyl)-2(R)-methylpropionate, 600 mg 10% Pd—C, and 100 mL MeOH. The reaction vessel was charged with 50 psi H2 and stirred for 2 hours at room temperature. The reaction mixture was filtered thru Celite and concentrated in vacuo to yield 5.25 g (93%) white solid. The free acid was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([N:15]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[N:18]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]#[C:37][CH3:38])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:17][CH2:16]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:40][OH:41].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O.O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[C:7]([N:15]1[CH2:21][CH2:20][CH:19]([C:22]([NH:40][OH:41])=[O:24])[N:18]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]#[C:37][CH3:38])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:17][CH2:16]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CCC2C(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CCC2C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.4 %

Procedure:
To oxalyl chloride (0.72 mL of a 2 M solution in dichloromethane) in dichloromethane (1 mL) at 0° C. was added dimethylformamide (0.11 mL). After 15 min a solution of 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic acid (0.328 g, 0.718 mmol) in dimethylformamide was added and the resulting reaction mixture was stirred at room temperature for 1h In a separate flask, 1.5 mL of triethylamine was added to a 0° C. mixture of 0.50 g of hydroxylamine hydrochloride in 15.4 mL of tetrahydrofuran and 3.8 mL of water. After this mixture stirred for 15 min at 0° C., the acid chloride solution was added to it in one portion and the resulting solution was allowed to warn to room temperature and stirred for another 18h. Ethyl acetate and aqueous sodium bicarbonate were then added to the reaction flask The organic phase was washed with aqueous sodium bicarbonate (3×) and dried over anhydrous potassium carbonate. Concentration in vacuo gave a thick gum (0.35 g) which was chromatographed on silica gel eluting with dichloromethane/methanol to give an off-white foam (0.22 g) which was triturated with diethyl ether to give 1-benzoyl-{[4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide as an off white powder (0.173 g). Electrospray Mass Spec 472.3(M+H)+.