Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)C(C)C)(C)C.[Cl:45][C:46]1[C:54]([S:55]([NH:58][CH3:59])(=[O:57])=[O:56])=[CH:53][CH:52]=[C:51]([Cl:60])[C:47]=1[C:48](O)=[O:49].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:45][C:46]1[C:47]([C:48]([N:13]2[CH2:12][CH2:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14]2)=[O:49])=[C:51]([Cl:60])[CH:52]=[CH:53][C:54]=1[S:55]([NH:58][CH3:59])(=[O:57])=[O:56]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1-(8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (100 mg, 0.16 mmol, 1 equiv) and N,N-diisopropylethyl amine (117 μL, 0.66 mmol, 4 equiv) in dimethylformamide (2 mL) was added the mixture of 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 880-1 b. After stirring at RT for several min, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (62 mg, 0.16 mmol, 1 equiv) was added and the reaction was stirred for 18 h. The mixture was partitioned between dichloromethane and satd. aq. NaHCO3. The organic layer was dried and concentrated and the residue was purified by SiO2 flash column chromatography (100% EtOAc→10% 2M NH3 in MeOH in EtOAC) to provide 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide (example 880) as a white solid (25 mg, 22% yield).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13]>>[CH3:9][O:10][C:11](=[O:14])[C@H:12]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])[NH2:13]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CN
Product: COC(=O)[C@@H](N)C(O)c1ccccc1

Procedure:
European Patent Application No. 0 220 923, published May 6, 1987, corresponding to commonly assigned copending U.S. Patent application Ser. No. 789,595, filed Oct. 21, 1985, describes the use of SHMT obtained from a genetically engineered Escherichia coli strain transformed with the pGS29 plasmid for condensing benzaldehyde and glycine methyl ester to produce betaphenylserine methyl ester. The reaction conditions employed during the condensation reaction include a pH of from 6.5 to 9, a temperature of from 10 to 65° C., a benzaldehyde concentration of from 10 to 100 mM and a glycine ester from 10 to 150 mM. While at a betaphenylserine methyl ester yield of 1.48 g/l, this process produced a beta-phenylserine methyl ester product containing as much as 83% erythro isomer, it has been found that as the yield is increased the amount of threo isomer present in the product increases until at commercial rates of production substantial amounts of threo isomer are present.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18](OC)=[O:19])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].O>CO>[O:22]=[C:11]1[NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18](=[O:19])[N:10]1[CH2:9][C:8]1[CH:23]=[CH:24][C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)Nc2ccsc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cn2c(=O)[nH]c3ccsc3c2=O)cc1
Temperature: 60 °C
Yield: 95.1 %

Procedure:
To a suspension of 253 (422 mg, 1.21 mmol) in MeOH (15 ml) was added NaOH (145 mg, 3.63 mmol). The reaction mixture was heated at 60° C. during 16 h. Water (1 ml) was then added and the reaction mixture was stirred for 1 more hour. The solvent was evaporated and the residue was dissolved in water and acidified to pH 5 with HCl 1M. The precipitate was filtered to afford the desired compound 254 (348 mg, 95%) as a white solid. LRMS: 302.0 (Calc.); 303.0 (found).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22]C(C)(C)C)=O)[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[F:27][CH:28]([F:32])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:15][N:16]([C:20](=[O:22])[CH:28]([F:32])[F:27])[CH2:17][CH2:18][O:19]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C(F)F)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
The (R)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (3.00 g, 8.0 mmol) was dissolved in the solution of HCl in ethyl acetate (20 mL), and the mixture was stirred at room temperature for 2 hours until TLC indicated Boc group was removed. The volatile materials were removed in vacuo and the residues were dissolved in dichloromethane. To the solution, difluoroacetic acid (1.15 g, 12 mmol), HATU (7.60 g, 20.0 mmol) and DIPEA (6.20 g, 48.0 mmol) were added subsequently and stirred at room temperature overnight. The mixture was purified by C18 column chromatography to give the desired amide as yellow solid (2.1 g). MS (m/z): 358 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH4-].[Na+].O>C(O)C>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[CH:16]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1cncc(CNCCCN2CCN(CCCNCc3cccnc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 3-pyridinecarboxaldehyde (561 mg, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 249.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[CH2:12][S:13]([CH2:15][C:16]1[O:20][CH:19]=[CH:18][CH:17]=1)=[O:14])=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+].Cl>C(O)C>[N:25]1([CH2:1][C:3]2[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=2)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[CH2:12][S:13]([CH2:15][C:16]2[O:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(OCCCNC(=O)CS(=O)Cc2ccco2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CS(=O)Cc1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53 %

Procedure:
N-[3-(3-formylphenoxy)propyl]-2-(furfurylsulfinyl)acetamide (13.85 g) was dissolved in 150 ml of ethanol, and while 5.06 g of piperidine was added dropwise, the mixture was stirred at room temperature for 15 hours. The reaction solution was cooled with ice, and 1.5 g of sodium borohydride was added. The mixture was stirred for 5 hours. 1N-HCl was added to the reaction solution to make it acidic, and the solvent was evaporated. The residue was poured into water and extracted with ethyl acetate. The aqueous layer was made basic by adding anhydrous sodium carbonate, and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to give 8.80 g (yield 53%) of N-{3-[3-(piperidinomethyl)phenoxy] propyl]-2-(furfurylsulfinyl) acetamide.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[NH:13]1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.[C:54](O)(=[O:58])[C:55]([CH3:57])=[O:56]>C(Cl)(Cl)Cl>[C:54]([N:13]1[C@H:14]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1)(=[O:58])[C:55]([CH3:57])=[O:56]
Reactant: O=C(OCc1ccccc1)[C@@H]1Cc2ccccc2CN1
Reactant: CC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC(=O)C(=O)N1Cc2ccccc2C[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
13.17 g of benzyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate tosylate (N. Yoneda, et al., Chem.Pharm.Bull., 31, 312 (1983)) was suspended in 30 mL CHCl3. N-methylmorpholine was added until the pH was 7, 6.8 g of dicyclohexylcarbodiimide and 3.17 g of pyruvic acid was added at -5° C. The reaction mixture was stirred at -50° C. for one hour and 0° C. for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give a semi-solid, which was purified by passing through a silica gel column and eluting with ethyl acetate:hexane (1:1) to give benzyl N-pyruvoyl-(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate as a yellow oil, [α]D25 -10.3°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].I[CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14]1)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: CCCI
Reactant: CCOC(=O)c1cn(C[C@H]2CCNC2)c2cnc(Br)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCN1CC[C@H](Cn2cc(C(=O)OCC)c(=O)c3cc(Br)ncc32)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
To a solution of (5)-ethyl 6-bromo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate Intermediate 94 (511.5 mg, 1.2 mmol, 1 equiv.) in acetonitrile (3 mL) and DMF (1 mL) was added iodopropane (0.234 mL, 2.4 mmol, 2 equiv.) followed by potassium carbonate (663 mg, 4.8 mmol, 4 equiv.). The reaction was stirred at 60° C. for 2 days. The reaction was cooled to 23° C. and concentrated. The residue was re-suspended and partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organics were dried and concentrated to afford (S)-ethyl 6-bromo-4-oxo-1-((1-propylpyrrolidin-3-yl)methyl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate (211 mg, 38%). Calcd for C19H24BrN3O3 [M+H]+: 424.0.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[NH4+].[Cl-].CCOCC>C1COCC1>[CH3:1][C@H:2]1[C@@:7]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc([C@]2(O)OCC(C)(C)N[C@H]2C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A solution of morpholin-2-one 15 (270 mg, 1.88 mmol) in anhydrous THF (1.9 mL) was cooled to −78° C. and treated with p-tolylmagnesium bromide (1.2 equiv., 2.26 mmol, 2.26 mL, 1 M solution in THF) under an N2 atmosphere. After stirring the reaction mixture at −78° C. for 1.5 h, saturated aqueous solution of NH4Cl (30 mL) was added to the reaction vessel, and the mixture was allowed to warm to room temperature. Ether (30 mL) was added to the reaction flask, the organic layer was separated. The aqueous phase was extracted with ether (twice). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to give 271 mg (41%) of 4j as a yellow foam: [α]22D +21.2° (c 0.9, CHCl3); 1H NMR (CDCl3) δ 7.47 (d, 2H, J=8.2 Hz), 7.16 (d, 2H, J=8.0 Hz), 3.85 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.2 Hz), 3.20-3.07 (m, 1H), 2.35 (s, 3H), 1.39 (s, 3H), 1.08 (s, 3H), 0.81 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 129.6, 128.60, 128.49, 125.9, 103.2, 96.2, 69.4, 53.9, 53.4, 49.6, 27.3, 22.8, 16.5; LCMS (ESI) m/z 236.3 [(M+H)+, M=C14H21NO2].
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH2:14][CH3:15])=[C:10](Cl)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH2:14][CH3:15])=[C:10]([O:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: OCc1ccc(Cl)cc1
Reactant: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OCc2ccc(Cl)cc2)cnn(C(C)(C)C)c1=O
Yield: 76.2 %

Procedure:
To 10 ml of dry N,N-dimethylformamide was added 0.75 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and was added dropwise with a solution of 2.2 g of 2-t-butyl-5-chloro-4-ethyl-3(2H)-pyridazinone dissolved in 15 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 1.4 g of p-chlorobenzyl alcohol dissolved in 15 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was reacted at 80° C. for one hour. The resulting solution was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sulfate and freed of solvent by distillation under reduced pressure to give a crude product. The crude product was recrystallized from hexane to obtain 2.4 g of 2-t-butyl-5-(p-chlorobenzyloxy)-4-ethyl-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3OC=C[O:19]3)=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(=Cc2ccc(C3OC=CO3)cc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCN1C(=O)NC(=Cc2ccc(C=O)cc2)C1=O

Procedure:
3-n-Butyl-5-[4-(1,3-dioxol-2-yl)benzylidene] hydantoin (2.7g; 0.0085 mole) was dissolved in acetone (100 ml.) and stirred overnight at room temperature with p-toluene sulphonic acid (0.5 g.). The hazy solution was evaporated in vacuo and the resultant solid suspended in water (100 ml) and neutralised to pH 7 using dilute sodium bicarbonate solution. The residual solid was filtered off, washed with water and dried to give the title compound m.p. 180° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(CBr)cc1
Yield: 33.2 %

Procedure:
Methyl p-tolylacetate (11 g) was dissolved in 250 ml of carbon tetrachloride, followed by addition of 11.7 g of N-bromosuccinimide and 0.15 g of benzoyl peroxide, and refluxed under heating for 2.5 hours. The reaction mixture obtained was cooled, followed by filtration and distillation of the solvent, which was then fractionated at 4 mmHg and 142 to 150 ° C. to produce methyl 4-bromomethylphenylacetate (5.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=O)=[CH:4][CH:3]=1.[NH2:25][NH2:26].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C#Cc2ccc(Cl)cc2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(Cl)cc3)n[nH]2)CC1
Temperature: 75 °C

Procedure:
To a solution of tert-butyl 4-[3-(4-chlorophenyl)prop-2-ynoyl]piperidine-1-carboxylate (5.28 g, 15.18 mmol) in ethanol (160 mL) was added hydrazine (0.953 mL, 30.4 mmol) and triethylamine (4.23 mL, 30 4 mmol). The mixture was heated at 75° C. for 3 h. The solvent was evaporated under reduced pressure, and dried under vacuum to give INTERMEDIATE 1. LC-MS m/z 362.19 [M+H]+, 306.14 [M−56+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-thiophene-2-carboxylic acid (2.00 g, 10.47 mmol) was dissolved in DCM (10 mL) to which was added oxalyl chloride (1.99 g, 15.71 mmol) and a catalytic amount of DMF (100 μL). This reaction mixture was stirred at room temperature for 1 hr at which time the solvent was removed under vacuum and taken forward immediately.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[C:19]([CH:23]([C:25](Br)([F:27])[F:26])[Br:24])([F:22])([F:21])[F:20]>>[C:19]([C:23](=[C:25]([F:27])[F:26])[Br:24])([F:22])([F:21])[F:20]
Reactant: FC(F)(F)C(Br)C(F)(F)Br
Agent: C1COCCOCCOCCOCCOCCO1
Product: FC(F)=C(Br)C(F)(F)F

Procedure:
To a 250 mL 3-necked round bottom flask operating under nitrogen purge, equipped with a water condenser (at about 15-20° C.), stirrer, and fitted with a dry ice trap (at about −78° C.), was added 100 mL aqueous potassium hydroxide (23 wt. %) solution and the crown ether, 18-crown-6, (0.1 g, 0.37 mmol) To this solution at about 20° C., was added CF3CHBrCF2Br (24.6 g, 84 mmol) drop-wise via an addition funnel over a period of about 35 minutes. The dehydrobrominated product, CF3CBr═CF2 (gas chromatograph retention time, 2.0 min), as formed, was continuously collected in the dry ice trap. After complete addition of CF3CHBrCF2Br, the reaction mixture was stirred for an additional 60 minutes. A total of 17.1 g (81 mmol) of CF3CBr═CF2 (96% yield), was collected in the dry ice trap. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1.Cl.[OH-].[NH4+:32]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:25])[NH2:32])[CH:6]=[CH:7][CH:8]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C(F)(F)F)c1
Yield: 50 %

Procedure:
A solution of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (250 mg, 0.625 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 30 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 120 mg (50%) of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.5 (m, 5H), 7.3 (t, 1H, J=8 Hz), 7.15 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3429, 3206, and 1630. MS (ES) m/e 383, 385.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH2:27])[CH:22]=[CH:21]2.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:9])[CH:22]=[CH:21]2
Reactant: Nn1ccc2cc(F)ccc21
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1.20 mmol) and K2CO3 (2 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt, and the reaction mixture is stirred at rt overnight. The reaction mixture is extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give a solid. The solid is triturated with EtOAc/heptane to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (122 mg, 35%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.77 (s, 3H), 6.55 (m, H) 7.06 (m, H), 7.32-7.66 (m, 4H), 8.02 (m, H), 8.45 (d, H), 8.79 (s, H), 9.26 (s, H), 12.00 (s, N—H). IC50=17 nM.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.Br[C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:24])[CH:21]=3)[NH:16][C:15]=2[C:14]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:13]2[NH:31][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=3[C:12]=12>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:13]1[C:14]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:24])=[CH:21][C:22]=4[C:23]3=[C:11]([N:1]3[CH2:9][CH2:4][CH2:3][CH2:2]3)[C:12]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)CCOc1c2[nH]c3ccc(Cl)cc3c2c(Br)c2c1[nH]c1ccc(Cl)cc12
Product: CN(C)CCOc1c2[nH]c3ccc(Cl)cc3c2c(N2CCCC2)c2c1[nH]c1ccc(Cl)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 126 except the starting indole is 2-(12-bromo-2,10-dichloro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine. 1H-NMR (400 MHz, CDCl3) δ ppm 10.14 (br s, 2 H), 8.11 (s, 2 H), 7.37-7.28 (m, 4H), 4.34 (t, J=4.4 Hz, 2 H), 3.67-3.55 (m, 4 H), 2.72 (t, J=4.4 Hz, 2 H), 2.53 (s, 6 H), 2.45-2.33 (m, 4H); MS (ESI) m/z 479.1 (M−H)−; MS (ESI) m/z 481.1 (M+H)+