Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>O1CCCC1>[F:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][C:20](=[O:22])[CH3:21])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A stirred solution of 7-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 4 in 30 ml of tetrahydrofuran was added with triethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. The resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide (1.2 g, 96%) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@:11]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[N:32]=[CH:31][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:29][C:28]=3[CH2:27]2)=[O:25])[CH2:15][C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][CH2:9][CH2:10][C@@:11]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[N:32]=[CH:31][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:29][C:28]=3[CH2:27]2)=[O:25])[CH2:15][C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO[Si](C)(C)C(C)(C)C)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 1 h

Procedure:
To a solution of the product of Step C (3.52 g, 6.18 mmol, 1 eq) in THF (50 mL) at rt was added TBAF in THF (12.36 mL of a 1 M solution, 12.36 mmol, 2 eq). After 1 hr, water was added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (80 g column) eluting with 2 to 6% methanol/DCM with ammonia afforded the title compound of Step D. 1H NMR (CHLOROFORM-d) δ: 8.71 (s, 1H), 7.70 (s, 1H), 6.28 (dd, J=5.9, 2.0 Hz, 1H), 5.78 (dd, J=5.9, 2.0 Hz, 1H), 4.70-4.95 (m, 4H), 3.99-4.10 (m, 1H), 3.85-3.96 (m, 1H), 3.68 (br. s., 2H), 3.09-3.18 (m, 2H), 2.65 (dd, J=12.9, 7.4 Hz, 1H), 1.99-2.21 (m, 3H), 1.82-1.93 (m, 1H), 1.38-1.49 (m, 9H). Calculated for C22H28F3N3O4: 456.2 (M+1). found: 456.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([NH:14][CH:15]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:13])[CH:8]=2)=[CH:5][CH:4]=[N:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:17][CH2:16][CH:15]([NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:13])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2cccc3ccccc23)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1cc(C(=O)NC(CN)c2cccc3ccccc23)cs1
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A solution of 1,1-dimethylethyl [2-({[5-(1-methyl-1H-pyrazol-5-yl)-3-thienyl]carbonyl}amino)-2-(1-naphthalenyl)ethyl]carbamate (76 mg, 0.16 mmol) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound (14 mg, 23%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](OCC)=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>CC(N(C)C)=O>[NH2:17][C:18]1[CH:19]=[C:20]([C:25]2[C:26](=[O:27])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([Cl:1])[CH:9]=3)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=Cc1cnc(Cl)cc1Nc1ccccc1
Reactant: CCOC(=O)Cc1ccc(F)c(N)c1
Solvent: CC(=O)N(C)C
Product: Nc1cc(-c2cc3cnc(Cl)cc3n(-c3ccccc3)c2=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A mixture of 6-Chloro-4-(phenylamino)nicotinaldehyde (3 g, 13 mmol), ethyl 2-(3-amino-4-fluorophenyl)acetate (2.6 g, 13 mmol), and KF/Al2O3 (40 wt %, 10 g, 69 mmol) in DMAc (30 mL) was stirred at RT for 2 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. Recrystallization (EtOAc) provided 3-(3-amino-4-fluorophenyl)-7-chloro-1-phenyl-1,6-naphthyridin-2(1H)-one (2.6 g, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1 H), 8.20 (s, 1 H), 7.62-7.56 (m, 3 H), 7.40 (d, J=7.2 Hz, 2 H), 7.13 (d, J=7.6 Hz, 1 H), 7.02 (t, J=10.0 Hz, 1 H), 6.82 (m, 1 H), 6.26 (s, 1 H), 5.19 (s, 2 H); MS (ESI) m/z: 366.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[CH2:7][C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(C)=O)=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[ClH:37]>>[ClH:37].[CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[CH2:7][C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1)CC2
Agent: Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(N)c([N+](=O)[O-])c1)CC2

Procedure:
1.0 gm (1.75 mmols) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{4-acetamino-3-nitro-phenyl}-ethyl)-amino]-propane was heated in 50 ml of methanolic hydrochloric acid for two hours at 45°-50° C. The reaction solution was then evaporated; the residue was dissolved in methylene chloride; the solution was washed with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate, and the solvent was distilled off in vacuo. After purification of the residue on silica gel with methylene chloride and 5% ethanol as the eluant, the hydrochloride was precipitated from acetone by addition of ethereal hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=[CH2:15].[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc2ccccc2c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Product: Fc1ccc(N2CCN(CCc3ccc4ccccc4c3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.34 g) of 2-vinylnaphthalene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (1:1) gives the product 1-(4-fluorophenyl)-4-[2-(2-naphthyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>C(O)CCC>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:14](=[O:15])[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[C:11]([O:15][CH2:14][CH2:13][CH2:12][CH3:11])=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1c1nc2ccccc2[nH]1
Solvent: CCCCO
Product: CCCCOC(=O)c1ccccc1C(=O)Nc1nc2ccccc2[nH]1

Procedure:
N-(Benzimidazol-2-yl)phthalimide (4 g.) in 200 ml. of n-butyl alcohol is heated at 115° C. for 35 minutes. On cooling, colorless needles form. These are removed by suction filtration, washed with butyl alcohol and finally with diethyl ether. After drying for three hours at 125° C. under vacuum, a yield of 2.5 g. of N-(benzimidazol-2-yl)-2-(n-butoxycarbonyl)-benzamide, m.p. 187° C., is obtained. Additional heating to higher temperatures causes a reclosure to the phthalimide and remelting which corresponds to the phthalimide, m.p. 267°-268° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH3:11])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]1[CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH3:11])=[C:6]([O:8][CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH:7]=1
Reactant: CCOc1ccc(Br)cc1O
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1OC1CCC1
Temperature: 65 °C
Yield: 97.3 %

Procedure:
The intermediate 5-bromo-2-ethoxy-phenol (15 g, 73.9 mmol) was dissolved in DMF (100 mL) then treated with anhydrous K2CO3 (20.4 g, 148 mmol) followed by the addition of bromocyclobutane (19.1 g, 128 mmol). The reaction was heated at 65° C. for 12 h, then cooled to room temperature, diluted with diethyl ether, and the solution washed with a 1 N aqeuous NaOH solution followed by water. The organic layer was then dried over MgSO4, filtered, and concentrated to afford titled compound as an oil (19.5 g, 90%). 1H NMR (CDCl3) 6.98 (dd, J=8.4, 2.1, 1H), 6.83 (d, J=2.4, 1H), 6.73 (d, J=8.7, 1H), 4.65-4.57 (m, 1H), 4.05 (q, J=7.1, 2H), 2.50-2.42 (m, 2H), 2.30-2.18 (m, 2H), 1.90-1.81 (m, 1H), 1.73-1.63 (m, 1H), 1.44 (t, J=7.1, 3H). 13C NMR 148.2, 147.8, 123.4 (CH), 117.0 (CH), 114.7 (CH), 112.7, 72.5 (CH), 64.8 (CH2), 30.6 (CH2), 14.7 (CH3), 13.1 (CH2). LC/MS (Method B) 4.18 min, [M+1]+ 271/273.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[F:16])=[N:7][C:6]2[NH:17][N:18]=[C:19]([CH3:20])[C:5]=2[C:4]=1[C:21](O)=[O:22])#[N:2].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[F:16])=[N:7][C:6]2[NH:17][N:18]=[C:19]([CH3:20])[C:5]=2[C:4]=1[C:21]([N:27]1[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]1)=[O:22])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
To 200 mg (0.57 mmol) of 5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid diluted in 4 ml of anhydrous dimethylformamide are added at 0° C. 121 mg (0.57 mmol) of tert-butyl piperazine-1-carboxylate, 76 mg (0.62 mmol) of N,N-dimethylpyridine-4-amine (DMAP), 110 mg (0.62 mmol) of N,N-dimethyl-N-[(methylimino)methylene]propane-1,3-diamine hydrochloride (EDCI) and 84 mg (0.62 mmol) of 1H-benzo[d][1,2,3]triazole-1-ol (HOBT). The reaction mixture is stirred 20 h at room temperature. The solvent is concentrated, water is added and the product extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 5:5 to 3:7) to yield 158 mg of tert-butyl 4-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl)piperazine-1-carboxylate in the form of a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].FC1C=CC(F)=CC=1[N+]([O-])=O>C1(O)CCCCC1.CCOC(C)=O.CCOC(C)=O.CCCCCC>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cc(F)ccc1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OC1CCCCC1
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(Nc2ccc(F)cc2[N+](=O)[O-])CC1

Procedure:
A solution of ethyl 4-amino-1-piperidine carboxylate (9.0 g, 52 mmol.) and 2-chloro-5-fluoronitrobenzene (10.3 g, 58 mmol.) in cyclohexanol (30 mL) containing powdered sodium carbonate (6.1 g, 57 mmol.) was refluxed (>160° C.) for 30 hours or until no further reaction was indicated by tlc (30% EtOAc/hexane). (Alternatively, 2,5-difluoro-nitrobenzene can be used in place of the 2-chloro-5-fluoronitro-benzene). The deep reddish reaction mixture was cooled and diluted with EtOAc. This solution was washed with dil. aq. HCl (3×), water, and then the organic layer dried (anhydrous Na2SO4) and the solvent evaporated to give a red oil. This oil was flash chromatographed on a column of silica gel and the product eluted with a 10-25% EtOAc/hexane gradient. The appropriate fractions were combined, the solvents evaporated, and the residue triturated with 10% Et2O/hexane to give 1-ethoxycarbonyl-4-(4-fluoro-2-nitroanilino)-piperidine as a bright reddish-orange solid, mp: 115-116° C., which was used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:45])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:30]3[NH:34][C:33]4[CH:35]=[CH:36][C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:38][C:32]=4[N:31]=3)=[N:20][N:21]2C2CCCCO2)=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl>[F:45][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:30]3[NH:31][C:32]4[CH:38]=[C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH:36]=[CH:35][C:33]=4[N:34]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1)=[O:13]
Reactant: O=C(Nc1ccc2c(-c3nc4cc(N5CCOCC5)ccc4[nH]3)nn(C3CCCCO3)c2c1)C1CC1(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2c(-c3nc4ccc(N5CCOCC5)cc4[nH]3)n[nH]c2c1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
TFA (546 mg, 4.78 mmol) was added to solution of 2,2-difluoro-N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)cyclopropan-ecarboxamide (25 mg, 0.048 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (11 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.28 (d, 1H, J=1.2 Hz), 8.19 (d, 1H, J=8.8 Hz), 7.61 (d, 1H, J=9.2 Hz), 7.33 (dd, 1H, J=1.6 and 8.8 Hz), 7.25 (dd, 1H, J=2.0 and 8.8 Hz), 7.13 (s, 1H), 3.86 (m, 4H), 3.21 (m, 4H), 2.78-2.70 (m, 1H), 2.14 (m, 1H), 1.90-1.84 (m, 1H); ESI-MS [M+H]+: 439.1.
Reaction SMILES: [BrH:1].Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29](=[O:32])[CH2:30][CH3:31])[CH2:23][CH2:22]2)=[CH:6][CH:5]=1.Br.BrBr>C(O)(=O)C>[BrH:1].[BrH:1].[Br:1][CH:30]([CH3:31])[C:29](=[O:32])[CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12]2[N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=2)[CH2:22][CH2:23]1
Reactant: CCC(=O)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred mixture of 37.5 parts of 1-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-pentanone dihydrobromide and 500 parts of acetic acid was added a hydrobromic acid solution in glacial acetic acid. Then there were added slowly dropwise 10.5 parts of bromine. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was suspended in 2-propanone. The product was filtered off and dried, yielding 37.5 parts (89%) of 4-bromo-1-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-pentanone dihydrobromide (183).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31](B(O)O)[CH:30]=[N:29]2)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O.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>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH:32]=[C:31]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:4][CH:3]=3)[CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cnn(-c4ccc(F)cc4)c3)cc2)C1
Temperature: 150 °C
Yield: 36.6 %

Procedure:
A mixture of (S)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (100 mg, 0.29 mmol), 1-(4-fluorophenyl)-1H-pyrazole-4-ylboronic acid (60 mg, 0.29 mmol), tribasic potassium phosphate (124 mg, 0.585 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.5 mg, 0.0117 mmol) in dimethylacetamide (2 ml) was placed in a microwave tube, closed and heated at 150° C. for 10 min using a microwave synthesizer (Personal Chemistry Emrys Optimizer). After cooling water (10 ml) was added, and the reaction mixture was extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (12 g silica gel, 10 to 50% ethyl acetate in heptane) to yield a light brown solid (45 mg, 36%). MS (ISP): 424.1 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[CH:11](O)=O>>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[N:10]=[CH:11][NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=CO
Product: Clc1cc2nc[nH]c2cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 mg of 1,2-diamino-4,5-dichlorobenzene dissolved in 5 mL of 97% formic acid was heated to 100° C. in a sealed tube for 15 hours. After cooling to room temperature, the reaction was quenched by the addition of 3.3 mL of concentrated aqueous NH4OH and stirred for 30 minutes. Following dilution with 20 mL of H2O, and extraction with 2×20 mL EtOAc, the organic phases were dried over MgSO4 and concentrated under reduced pressure to yield 210 mg of the title compound as a brown oil. No further purification was performed. RF: 0.38 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, CD3OD): δ 8.22 (s, 1H), 7.74 (s, 2H). Mass Spectrum (ESI) 188 (M+1).
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:26])([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SCCCC(N1CC(O)(C2C=CC(C)=CC=2)C[C@H]1C(O)=O)=O)(=O)C>>[OH:26][C:17]1([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: Cc1ccc(C2(O)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C2)cc1
Agent: CC(=O)SCCCC(=O)N1CC(O)(c2ccc(C)cc2)C[C@H]1C(=O)O
Product: Cc1ccc(C2(O)CN[C@H](C(=O)O)C2)cc1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-[(4-methyl)phenyl]-L-proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-[(4-methyl)phenyl]-L-proline. This amino acid is then reacted with 4-acetylthiobutyroyl chloride according to the procedure of Example 1 (c) to yield 1-[4-(acetylthio)-1-oxobutyl]-4-hydroxy-4-[(4-methyl)phenyl]-L-proline.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]([O:19]CC)=[O:18])=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[OH-].[Na+].CCO>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]([OH:19])=[O:18])=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2[nH]c3c(C(N)=O)cc(-c4ccc(Cl)c(Cl)c4)cc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)cc2c1[nH]c1ccc(C(=O)O)cc12
Yield: 89.5 %

Procedure:
Ethyl 8-carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazole-3-carboxylate (980 mg, 2.294 mmol), 1 M aqueous sodium hydroxide (5.73 mL, 5.73 mmol) in THF (13 mL)/EtOH (13 mL) was heated in an oil bath at 85° C. for 24 h. The solvent was removed under reduced pressure. The solid was suspended in water (200 mL). To this suspension was added aqueous 1N HCl solution until pH ˜2-3. The solid was collected by filtration and dried. The crude was purified using silica gel column chromatography (CH2Cl2-MeOH-3 to 50%) to afford 820 mg of 8-carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazole-3-carboxylic acid which was used as such in the next reaction. MS (ESI) m/z 397.2 (M−H). 1H NMR (DMSO-d6) δ ppm 12.64 (1H, br. s.), 11.80 (1H, s), 8.83-9.08 (2H, m), 8.42 (1H, br. s.), 8.39 (1H, s), 8.29 (1H, d, J=2.14 Hz), 8.03-8.07 (1H, m), 8.00 (1H, dd, J=8.55, 2.14 Hz), 7.74-7.81 (2H, m), 7.63 (1H, br. s.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:9][C:10]1[S:14][C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:12][CH:11]=1)[C:6](O)=O)[CH3:2].C=O.C(Cl)Cl.C(NCC)C>O>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH2:9][C:10]1[S:14][C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:12][CH:11]=1)=[CH2:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)s1)C(=O)O
Agent: C=O
Solvent: O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(Cc1cnc(NC(=O)OC(C)(C)C)s1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a mixture of 2-(2-tert- butoxycarbonylamino-thiazol-5-ylmethyl)-malonic acid monoethyl ester (94 mg; 0.27 mmol), a 36% aqueous solution of formaldehyde (36 μl; 1.2 mmol), CH2Cl2 (0.2 mL) and water (0.2 mL) was added at 0° C. diethyl amine (30 μl; 0.40 mmol). The reaction mixture was stirred at room temperature overnight, poured onto ice-water and extracted with CH2Cl2. The combined organic phases were washed with 5% NaHCO3, dried and concentrated to yield 2-(2-tert-butoxycarbonylamino-thiazol-5-ylmethyl)-acrylic acid ethyl ester (69 mg, 80.9%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:33]1[S:37][CH:36]=[N:35][CH:34]=1)CCC.O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:7]1[C:2]([C:33]2[S:37][CH:36]=[N:35][CH:34]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:9]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[C:4]2=[N:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cncs4)c(Cl)cnc32)cc1
Temperature: 100 °C

Procedure:
A solution of Example 113C (0.148 g, 0.351 mmol) and 5-(tributylstannyl)thiazole (0.184 g, 0.492 mmol), in N,N-dimethylformamide (1.3 mL) was degassed via nitrogen sparge for 5 minutes. The reaction was treated with bis(triphenylphosphine)palladium (II) chloride (0.025 g, 0.35 mmol) and heated at 100° C. for 6 hours. The reaction was cooled to ambient temperature, treated with water (20 mL) and extracted with ethyl acetate (80 mL). The aqueous layer was extracted with additional ethyl acetate (40 mL). The combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of from 0% to 50% ethyl acetae in hexanes, to provide the title compound as an off-white solid. MS ESI(+) m/z 470.2 [M+H]+.