Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].O>O1CCCC1>[CH2:21]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Sodium hydride (60%, 5.78 g, 144.59 mmol) was added to anhydrous tetrahydrofuran (250 ml) and cooled to 0° C. To this mixture, diethyl malonate (25.09 g, 156.64 mmol) was slowly added dropwise, followed by stirring for 1 hour at room temperature. 7-Iodo-1-heptene (27 g, 120.49 mmol) dissolved in anhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to the mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give diethyl 2-(6-heptenyl)malonate (25.8 g, Yield 84%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C@H:3]([NH:10][CH3:11])[CH2:4][N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1.CCN(C(C)C)C(C)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:10]([C@@H:3]([CH:2]([CH3:12])[CH3:1])[CH2:4][N:5]2[CH2:6][CH:7]([OH:9])[CH2:8]2)[CH3:11])=[O:29])=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CN[C@H](CN1CC(O)C1)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
(S)-1-(3-Methyl-2-(methylamino)butyl)azetidin-3-ol (Compound K2) (1.0 g, 3.48 mmol) was dissolved in DCM (13.3 mL), DIPEA (1.82 mL, 10.4 mmol), 4-chlorobenzoic acid (0.654 g, 4.18 mmol), and TBTU (1.45 g, 4.53 mmol) were added. The reaction was stirred for 2 h at rt whereupon saturated NaHCO3 (aq.) was added. The organic layer was separated and evaporated in vacuo. The residue was redissolved in THF/water and 3.8 M NaOH was added (1.2 mL) the reaction mixture was stirred for 15 min whereupon water was added and some of the organics was evaporated. The water phase was extracted with DCM, separated using a phase-separator and evaporated. The residue was evaporated and redissolved in DMSO and purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/ACN/NH3 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. The compounds were detected by UV at 220 nm to give the target compound pooling of pure fractions and evaporation of solvents in vacuo gave (S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbenzamide (0.67 g, 62%). Mixture of rotamers: 1H NMR (600 MHz, CD3OD) δ 0.81-0.88, 0.99, 1.09, 1.72-2.00, 1.95, 2.63-2.76, 2.80, 2.85-2.97, 3.12-3.19, 3.26-3.35, 3.46-3.67, 4.10-4.19, 4.28-4.56, 7.44-7.54. Ratio major:minor:1:0.2. Total no of protons: 27.3 (5.3 from CH3CO2H). HRMS (M+H)+: calculated 311.1526. found 311.1528.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27]>CN(C=O)C>[C:26]([O:29][CH2:30][C:31]([N:14]1[CH2:13][CH2:12][CH:11]([C:3]2[CH:4]=[C:5]([I:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15]1)=[O:32])(=[O:28])[CH3:27]
Reactant: COc1cc(F)c(C2CCNCC2)cc1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1I

Procedure:
A stirred solution of 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine (50 mg; 0.149 mmol) in DMF (1.2 mL) under N2 was treated with N,N-diisopropylethylamine (26 μL; 0.149 mmol), followed by acetoxyacetyl chloride (16 μL, 0.149 mmol). The resultant solution was stirred at room temperature for 5 h. The reaction was partitioned between EtOAc (25 mL) and saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic fractions were washed with water and brine (25 mL each), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with EtOAC/hexanes, to afford 2-[4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]-2-oxoethyl acetate as a colorless oil. LCMS=435.8 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.52 (d, J=8.2 Hz, 1 H), 6.56 (d, J=12.2 Hz, 1 H), 4.76 (s, 2 H), 4.76-4.70 (m, 1H), 3.85 (s, 3 H), 3.76 (br d, J=13 Hz, 1 H), 3.17 (t, J=12.6 Hz, 1 H), 2.98 (tt, J=12.1, 3.4 Hz, 1 H), 2.68 (t, J=12.4 Hz, 1 H), 2.20 (s, 3 H), 1.90-1.82 (m, 2 H), 1.70-1.62 (m, 2H).
Reaction SMILES: [C-]#[N:2].[K+].[C:4]([C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[NH:14][C:15](=O)C(Cl)Cl)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(O)C.C>[NH2:2][C:15]1[C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([OH:11])[C:12]2[C:13](=[CH:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[N:14]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Potassium cyanide (18 g) in water (150 ml) was added to a suspension of 2'-benzoyl-2,2,4'-trichloro-acetanilide (30 g) in ethanol (400 ml). The reaction was stirred overnight and after treatment with charcoal diluted with water, 2-Amino-5-chloro-3-phenyl-3H-indol-3-ol (19.57 g) was obtained as off white crystals m.p. 205°-208°C after recrystallization from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.O1CCCC1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[C:15]3[NH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[S:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2c1Nc1ccccc1S2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2S3)cc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
107 mg (0.5 mmol) of 1-amino-10H-phenothiazine was dissolved in 4 ml of pyridine. Then 2 ml of a solution of 115 mg (0.55 mmol) of 4-methoxybenzenesulfonyl chloride in tetrahydrofuran was added thereto under stirring at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated. Then ethyl acetate and water were added to the residue and the organic layer was separated, washed with water and dried over magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography and recrystallized from ethanol. Thus 115 mg of the title compound was obtained.
Reaction SMILES: C(O)(=O)C.[CH3:5][S:6]([C:9]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[NH2:21])(=[O:8])=[O:7].[C:22]([O:26][C:27](=O)[O:28]C(C)(C)C)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:22]([O:26][C:27]([N:18]1[CH2:17][CH2:16][CH:15]([C:13]2[CH:12]=[CH:11][C:10]([NH2:21])=[C:9]([S:6]([CH3:5])(=[O:8])=[O:7])[CH:14]=2)[CH2:20][CH2:19]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cc(C2CCNCC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(S(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 2-methanesulfonyl-4-piperidin-4-yl-phenylamine; compound with acetic acid (1.5 g) in dichloromethane (30 ml) was added di-tert-butylcarbonate (1.15 g) and saturated aqueous sodium carbonate solution (10 ml). The reaction mixture was stirred at rt for 3 h and extracted with dichloromethane. The organic phases were dried and concentrated, and the residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (0.64 g) as an off-white solid. MS (ISP): 355.1 (M+H)+
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1CO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)N(NC(=O)c1ccccc1CO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
0.7 g of N'-t-butyl-N-(2-hydroxymethylbenzoyl)-hydrazine and 1.1 g benzoyl chloride are combined in 10 ml of 5% NaOH and stirred at room temperature for 1.5 hours. The solids are filtered off, washed with water, then ether, to afford 0.6 g of white solid N'-t-butyl-N-(2-(benzoyloxymethyl)benzoyl)-N'-benzoylhydrazine. m.p. 190°-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH3:31]OC(OC)N(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:31])[N:10]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Temperature: 105 °C
Yield: 52 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (92) (570 mg, 1.29 mmol) and N,N-dimethylformamide dimethyl acetal (12 mL) was heated to 105° C. for 4.5 h. At this time, the reaction was cooled to 25° C. and diluted with methylene chloride. This solution was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 methylene chloride/methanol) afforded 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (93) (310 mg, 52%) as an off-white solid; ES-HRMS m/e calcd for C23H19Cl2N3O3 (M+H)+ 456.0876, found 456.0876. Exact Mass=455.0803; Molecular Weight=456.3322.
Reaction SMILES: CC1C=CC(S(O[C@H:12]([CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:13][CH3:14])(=O)=O)=CC=1.[CH2:22]([O:24][C:25](=[O:41])[CH2:26][N:27]=[C:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1>[C:29]1([C:28](=[N:27][CH:26]([C@H:12]([CH2:13][CH3:14])[CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[C:25]([O:24][CH2:22][CH3:23])=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=CCCC(C)C[C@H](CC)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCCC(C)C[C@@H](CC)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 110 °C
Yield: 36 %

Procedure:
To a solution of (S)-5-methylnon-8-en-3-yl 4-methylbenzenesulfonate (15 g, 48 mmole) and N-(diphenylmethylene)glycinate ethyl ester (15.5 g, 58.0 mmole) in toluene (150 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (“LiHMDS”, 72.5 mL, 72.5 mmole, 1 M solution in THF). The reaction mass was allowed to come to room temperature, and then was heated at 110° C. for 2 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4; filtered; then concentrated under reduced pressure to get crude compound (7.0 g, 35.7%). The crude compound was taken to the next step without further purification. MS: MS m/z 406.4 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5].CCN(C(C)C)C(C)C.C([O:42][CH2:43][C:44](Cl)=[O:45])(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:43](=[O:42])[CH2:44][OH:45])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)C(=O)CO)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
To a solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (177 mg, 0.39 mmol) in 1,2-dichloroethane (5 ml) was added DIPEA (0.35 ml, 2.01 mmol) followed by acetoxyacetyl chloride (0.1 ml, 0.93 mmol) and the reaction stirred at 65° C. for 3 h. The solution was cooled, treated with saturated aqueous NaHCO3 (25 ml) and extracted with CH2Cl2 (3×15 ml). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 96:4:0 then 88:10:2) provided the desired amide (88 mg, 41%) as a brown oil. To a solution of the acetate from above (80 mg, 0.14 mmol) in MeOH (5 ml) was added K2CO3 (67 mg, 0.49 mmol) and the reaction stirred overnight. The mixture was concentrated then diluted with CH2Cl2 (25 ml) and saturated aqueous NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 96:4 then 9:1) afforded COMPOUND 65 (48 mg, 59%) as a pale yellow foam and a mixture of two rotational isomers. 1H NMR (CDCl3) δ 0.94-0.99 (m, 3H), 1.19-1.43 (m, 2H), 1.50-1.73 (m, 5H), 2.09-2.14 (m, 1H), 2.35 and 2.38 (s, total 3H), 2.51-2.57 (m, 1H), 2.70-2.85 (m, 3H), 3.19-3.40 (m, 1H), 3.75-3.82 (m, 1H), 3.98-4.28 (m, 5H), 6.93-6.95 (m, 1H), 7.02-7.05 (m, 1H), 7.12-7.15 (m, 1H), 7.23-7.35 (m, 1H), 7.86-7.88 and 8.57-8.60 (m, total 1H); ES-MS m/z 513 (M+H). Anal. Calcd. for C23H30N4O3SCl2.0.3H2O: C, 53.24; H, 5.94; N, 10.80. Found: C, 53.27; H, 5.88; N, 10.54.
Reaction SMILES: S[CH2:2][C@H:3]([NH:7][C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:4](O)=[O:5].[OH-].[Na+].ClCC1C=CC=C[N:28]=1.Cl>>[F:11][C:10]([F:13])([F:12])[C:9]([F:15])([F:14])[C@@H:8]([NH:7][C@H:3]([CH3:2])[C:4]([NH2:28])=[O:5])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1
Reactant: O=C(O)[C@H](CS)N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 0.2 M stock solution of 3-mercapto-2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-propionic acid in NaOH (10 mL, 2 mmol), 2-chloromethylpyridine (0.328 g, 2 mmol) and 1 N solution of NaOH (1 mL) were added. After stirring the reaction mixture for 5 h at room temperature, 1 M HCl solution was added until pH 5-6. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate and concentrated to give N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl)-2(R)-[3,3,3,2,2-pentafluoro-1(S)-(4-fluorophenyl)propylamino]-propionamide as a foam (0.692 g) which was converted to the title compound as described in Example 6 above.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15]>>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:15])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Product: NC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Yield: 94 %

Procedure:
A mixture of 18.0 gms. pentachlorobenzonitrile and 200 ml concentrated sulfuric acid (97 weight % H2SO4) was heated to 145° C. over a period of approximately 40 min. Complete dissolution of the pentachlorobenzonitrile was observed to occur at 130° C. thereby giving a pale straw solution. When cool, the reaction mixture was poured onto ice and the white solid thereby formed was isolated by filtration. In this manner there was formed 18.0 gms. (94% yield) pentachlorobenzamide. Identity of the product was established with the aid of both analytical and spectral data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([OH:30])=O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([NH:17][C:14]3[CH:15]=[CH:16][C:11]([N:7]4[C:8]5[C:4](=[CH:3][C:2]([NH:1][C:28]([C:24]6[CH:23]=[C:22]7[C:27](=[CH:26][CH:25]=6)[N:19]([CH3:18])[CH:20]=[CH:21]7)=[O:30])=[CH:10][CH:9]=5)[CH:5]=[N:6]4)=[CH:12][CH:13]=3)=[O:30])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: Cn1ccc2cc(C(=O)O)ccc21
Product: Cn1ccc2cc(C(=O)Nc3ccc(-n4ncc5cc(NC(=O)c6ccc7c(ccn7C)c6)ccc54)cc3)ccc21

Procedure:
Compound 1004 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 1-methylindole-5-carboxylic acid. [M+H]+ calcd for C33H26N6O2: 539.21; found: 539.11.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[C:11]([O:15][C:16](=[O:26])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:16](=[O:26])[O:15][C:11]([CH3:13])([CH3:14])[CH3:12])=[CH:20][CH:21]=1)=[O:10]
Reactant: Cc1ccccc1N=C=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
2-Methylphenylisocyanate (7.57 g, 59.83 mmol) was added dropwise at 0° C. to a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (13.30 g, 59.83 mmol, prepared analoguous to: Moloney, Gerard P.; Martin, Graeme R.; Mathews, Neil; Milne, Aynsley; Hobbs, Heather; et al. J Med. Chem. 1999, 42, 2504–2526) in 120 mL DCM. The reaction was heated under reflux for 16 h, cooled to r.t. and the precipitated product was collected by filtration and dried in vacuum (19.20 g, 54.00 mmol). M.p. 200–202° C.; TLC (PE/EtOAc 1/1) Rf 0.65; 1H NMR (400 MHz, D6-DMSO) δ 1.39 (s, 9H); 2.24 (s, 3H); 4.06 (d, J=6 Hz, 2H); 6.93 (mc, 1H); 7.12–7.17 (m, 4); 7.32 (mc, 1H); 7.40 (mc, 2H); 7.85 (mc, 1H); 7.90 (s, 1H); 8.98 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:12][N:13]=1)=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)=[CH:12][N:13]=1)=[O:7]
Reactant: O=C(Nc1ncc(-c2cccc(C(F)(F)F)c2)s1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncc(-c2cccc(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide (2.2 g, 4.62 mmol, 1.00 equiv) in methanol (30 mL). The solution was treated with Pd/C (2 g, 10%), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (7:1). This resulted in 1.2 g (58%) of product as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:37][CH2:38][CH2:39]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:39][CH2:38][Br:37])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCCBr
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OCCBr)cc12
Temperature: 85 °C
Yield: 75.3 %

Procedure:
To a stirred solution of 6-hydroxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester (73 mg, 0.18 mmol) in N,N dimethylformamide (2 mL) was added potassium carbonate (197 mg, 1.42 mmol) and 1,2-dibromoethane (0.046 mL, 0.89 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the crude product was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 30% ethyl acetate/hexane) afforded 6-(2-bromo-ethoxy)-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester as a white solid (70 mg, 75% yield).