Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:3]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1cccnc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccnc1NC(=O)C1CCNCC1

Procedure:
Benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate from Step 1 above (5.45 g, 15.42 mmol) was suspended in absolute ethanol (250 mL) and was treated with 10% palladium on carbon (1.50 g) and stirred vigorously for 18 h under 1 atm of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure giving the piperidine-4-carboxylic acid (3-methyl-pyridin-2-yl)-amide as yellow oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(#N)C>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[CH:15]=[C:16]([Br:23])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C1CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C1CC1)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of N-trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.025 g, 0.08 mmol) in acetonitrile (1 mL) was treated with N-bromosuccinimide (0.032 g, 0.18 mmol) and stirred for 2 hrs. at 50 C. The product mixture was concentrated and then purified by flash chromatography (10% EtOAc in hexanes, silica) resulting in 0.014 g of a white solid. MS calculated for C15H15BrF3NO2+H: 378, observed: 378.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:26]=2[CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:26]=2[CH:25]=[C:24]1[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1ccc2c(C(=O)OCc3ccccc3)cccc21
Reactant: CCOC(=O)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C(=O)OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (322 mg) in tetrahydrofuran (5.0 ml) was added dropwise a solution of n-butyllithium (1.6 M n-hexane solution 1.3 ml) at −70˜−60° C. and the solution was stirred at 0° C. for 30 minutes. A solution of benzyl 1-tert-butoxycarbonylindole-4-carboxylate (500 mg) in tetrahydrofuran (2.5 ml) was added dropwise to the above solution at −70˜−60° C. and the mixture was stirred at −70° C. for 30 minutes. To the mixture was added a solution of ethyl chloroformate (185 mg) in tetrahydrofuran (2.5 ml) at such a rate as to maintain the temperature below −60° C. The solution was stirred at −70° C. for 2 hours and the reaction was quenched with aqueous saturated ammonium chloride solution at −20° C. The aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; n-hexane:ethyl acetate=15:1) to give benzyl 1-tert-butoxycarbonyl-2-ethoxycarbonylindole-4-carboxylate (100 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl[S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:10])[S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1cccc(Br)c1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CN(Cc1cccc(Br)c1)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
1-(3-Bromophenyl)-N-methylmethanamine (0.100 g, 0.5 mmol) in DCM (5 mL) was added TEA (0.139 mL, 1.000 mmol) and 3-(chlorosulfonyl)benzoic acid (0.110 g, 0.500 mmol). The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched with HCl (1 N), concentrated and redissolved in EtOAc (10 mL) which was washed with H2O (2×3 mL), brine (3 mL), then dried with Na2SO4. It was then filtered and concentrated to afford the title compound (0.1505 g, 78%). LC-MS m/z 384 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]1[CH2:45][O:44][CH2:43][CH2:42][NH:41]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:41]2[CH2:42][CH2:43][O:44][CH2:45][C@H:40]2[CH3:39])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[CH:26]=3)[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccccc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: C[C@@H]1COCCN1
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccccc3F)cc21

Procedure:
Prepared from (2R,5R)-5-chloromethyl-4-{2-[6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and (R)-3-methyl-morpholine in a similar manner to General Procedure 6. MS: [M+H]+=610.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:21]#[N:22])=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:25][CH:24]=2)[C:3]=1[C:34]#[N:35].[OH-].[Li+].Cl>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:21]#[N:22])=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:25][CH:24]=2)[C:3]=1[C:34]#[N:35]
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(SC(C)c3cccc(C(=O)OC)c3)c2C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SC(C)c3cccc(C(=O)O)c3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.307 mmol) of methyl 3-[1-({6-amino-3,5-dicyano-4-[4-(2-methoxyethoxy)phenyl]-pyridin-2-yl}sulfanyl)ethyl]benzenecarboxylate (Example 65A) were dissolved in 7 ml of tetrahydrofuran. After addition of 14.7 mg (0.61 mmol) of lithium hydroxide, the mixture was stirred at RT overnight. The mixture was then stirred at 40° C. for 4 h. Using 1N hydrochloric acid, the pH of the reaction solution was adjusted to pH 4, and the clear solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C(=O)(O)O.[K]>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[N:25]=[CH:24][N:23]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)O
Agent: [K]
Solvent: CCO
Product: COc1cc([N+](=O)[O-])ccc1-c1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
2-(2-methoxy-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2 g, 7.17 mmol) was dissolved in 20 ml of EtOH and the resulting solution was concentrated to ˜15 ml and diluted with EtOH (30 ml). To this solution was added 4,6-dichloropyrimidine (1.495 g, 10.03 mmol), Bis(triphenylphosphine)palladium(II) chloride (0.075 g, 0.107 mmol) and aqueous potassium hydrogenbicarbonate (2.152 g, 21.50 mmol) (in 10 ml of water) at rt. The resulting mixture was stirred at 80° C. for 2 h. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc/aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 ml) and brine (20 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage Horizon system (25 g column of Thomson Single Step, EtOAc/Hexane, Griadient: 0%˜30%) to get 0.66 g (35%) of product as white solid. LC-MS (M+H)+=266.1. 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3H) 7.90 (d, J=2.26 Hz, 1H) 7.98 (dd, J=8.53, 2.26 Hz, 1H) 8.09 (d, J=1.00 Hz, 1H) 8.26 (d, J=8.53 Hz, 1H) 9.10 (d, J=1.25 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22](C)=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[Cl:26]C1C2C=CC(Cl)=CC=2SC=1C(O)=O>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([Cl:26])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(O)c1sc2cc(Cl)ccc2c1Cl
Reactant: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(Cl)ccc2c1Cl

Procedure:
Following the 2a synthetic method, using 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (123.55 mg, 0.5 mmol) instead of 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid gave 3a as a white powder; (182.94 mg, 92.8%). [α]D25: −23.2 (c=0.24, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.59 (d, J=6.9 Hz, 1H), 7.42 (dd, J=1.8, 8.7 Hz, 1H), 7.37-7.25 (m, 5H), 5.16-5.14 (m, 1H), 3.41-3.28 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.51, 160.41, 138.97, 135.33, 135.18, 134.21, 132.38, 129.47, 128.82, 127.52, 126.51, 124.16, 122.38, 119.64, 54.12, 37.28; HRMS (ESI): calcd for: C18H13Cl2NO3S [M−H]−=391.9920, obsd [M−H]−=391.9921.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClCCl>[C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][OH:32])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCOC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: C=CCOC1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
5 g of (d) was dissolved in 125 ml of a methanol/dichloromethane mixture (30:70) containing 4% (m/v) of para-toluene sulphonic acid (PTSA). This was stirred at ambient temperature for 3 h. The reaction mixture was then neutralised, washed with water and dried. After evaporating off the solvents, the crude product obtained was purified over silica to produce a white solid: 2 g (yield: 62%).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2Cl)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[OH2:21]>>[CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2[OH:21])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Yield: 68.3 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-cyclopropyl-2,6-dichloro-3-nitrobenzenesulfonamide (1.15 g, 3.70 mmol), 60% NaH (444 mg, 11.1 mmol) and water (67 μL, 3.70 mmol) were reacted to form the desired product (740 mg, 68%). 1H NMR (MeOD-d4): δ 8.06 (d, 1H), 7.24 (d, 1H), 2.29 (m, 1H), 0.60 (m, 4H).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1)(=[O:14])=[O:13])(C)(C)C.CO>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[NH2:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Reaction time: 4 h
Yield: 100 %

Procedure:
A 4N HCl solution in 1,4-dioxane (22 mL) is added to a stirred solution of [2-(7-phenyl-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (2.50 g, 5.85 mmol) in CH2Cl2 (40 mL)/CH3OH (6 mL) at ambient temperature under nitrogen. The resultant white suspension is stirred for 4 hours. At filtration and vacuum drying at 50° C., 2.34 g (5.85 mmol, 100% yield) of the title compound is obtained as a white solid. ESIMS: m/z 328 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:21][C@@H:22]([CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]>C(Cl)Cl>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:21][C@@H:22]([CH2:31][N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)[C@H:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:24])=[O:20])([OH:19])=[O:18]
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reactant: O=C1CCCCCCCCC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCCCCCCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 5 h
Yield: 30.4 %

Procedure:
Methylene chloride (10 ml), triethylamine (190 μl, 1.37 mmol) and sebacic anhydride (292.4 mg, 1.59 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (316.2 mg, 1.34 mmol), followed by stirring for 5 hours. Then, the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=20:1 and chloroform:methanol=9:1) to obtain the title compound (171.1 mg, yield 30.4%) as colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]#[CH:9])[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([CH2:10][O:11]CC=C)[C:4](=[O:22])[N:3]1[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:5]2([CH2:10][OH:11])[C:4](=[O:22])[N:3]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:24]=3)[C:2](=[O:1])[N:6]2[CH2:7][C:8]#[CH:9])=[CH:16][CH:17]=1
Reactant: C#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COCC=C)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.45 g of 4-[2,5-dioxo-4-(4-fluorophenyl)-4-[(2-propenyloxy)methyl]-3-(2-propynyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in step 1 is dissolved in 5 mL of DCM under argon atmosphere. 0.2 mL of trifluoroborane-dimethylsulfide complex is added. The mixture is stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution is slowly added. The product is extracted with DCM and the organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 6/1 DCM/ethyl acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]Br)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=4)[C:9]3=[O:21])[CH2:2]2)=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)C2
Reactant: Cc1ccc(CCBr)cc1
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(C)cc3)C1)C2

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-isoindole and 2-(4-methyl-phenyl)-ethyl bromide analogously to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:31])=[O:23])=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1.O>CN(C=O)C>[Cl:18][C:16]1[CH:17]=[C:12]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:31])=[O:23])=[CH:20][N:21]=2)[N:15]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccc(F)cn3)cc(Cl)nn12
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of 5-fluoropyridin-2-amine (20.63 mg, 0.184 mmol) in DMF (1 mL) was added 60% NaH (7.36 mg, 0.184 mmol). The mixture was stirred for 10 min until cessation of H2 evolution. 8A (24 mg, 0.074 mmol) was added. The mixture was stirred at room temperature overnight. Water was added, and the yellow solid was collected by filtration and dried to give 16A (25.2 mg, 57%). [M+H]=4 01. HPLC Peak Rt=3.345 minutes (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 3-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.83 g (82%) of the product 4-(3-methoxy-phenyl)-1H-indole as colorless syrup.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)(=O)C.Cl>CO>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:7]2[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH2:5][O:4][CH3:1])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(COC(C)=O)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1c(-c2ccccc2)oc(COC)c1-c1ccc(F)cc1

Procedure:
A mixture of ethyl 5-[(acetoxy)methyl]-4-(4-fluorophenyl)-2-phenylfuran-3-carboxylate (4.020 g, 10.51 mmol) and a solution (50 ml) of 10% hydrogen chloride in methanol was stirred at room temperature for 2.5 days. The solvent of the reaction solution was evaporated under reduced pressure and the obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give the objective substance.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20](O)=[O:21])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:21])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][C:38]([F:37])=[CH:39][CH:40]=3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: NCc1ccc(F)cc1
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NCc1ccc(F)cc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 46 %

Procedure:
The title compound (27 mg, 46%) was obtained from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and 4-fluorobenzyl amine as in Example 1, Part C. HPLC: RT=10.66 min. MS (ESI−): mass calcd. for C29H21Cl3FN5O4S2, 693.00; m/z found, 690/692 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.55 (s, 1H), 8.38 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.6, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.68 (d, J=1.9, 1H), 7.35-7.32 (m, 1H), 7.30-7.25 (m, 2H), 7.12-7.07 (m, 2H), 7.05-6.99 (m, 5H), 6.94 (dd, J=8.4, 1.9, 1H), 6.88-6.81 (m, 1H), 5.79-5.72 (m, 1H), 4.67-4.59 (m, 1H), 4.47-4.40 (m,1H), 4.29-4.25 (m, 1H), 3.15-3.11 (m, 1H), 3.00-2.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[N:14]([O-])=O.[Na+]>O.Cl>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([NH:6][NH2:14])=[C:4]([F:13])[CH:3]=1
Reactant: O=N[O-]
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(NN)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A stirred solution of 11.0 g (0.054 mole) of 4-chloro-2-fluoro-5-(1-methylethoxy)aniline and 50 mL of concentrated hydrochloric acid was cooled to 0° C. and a solution of 3.7 g (0.054 mole) of sodium nitrite in 15 mL of water was added dropwise. The reaction mixture temperature was not allowed to rise above 6° C. during the addition. Upon completion of addition the reaction mixture stirred at 0° C. for 30 minutes and a solution of 26.8 g (0.12 mole) of stannous chloride in 30 mL of concentrated hydrochloric acid was added dropwise. Upon completion of addition the reaction mixture was stirred at 0° C. for one hour then was filtered to collect a solid precipitate. The solid was slurried in 100 mL of aqueous 25% sodium hydroxide and collected by filtration to give 11.0 g of 4-chloro-2-fluoro-5-(1-methylethoxy)phenylhydrazine.