Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:21]2[CH:20]=[N:19][N:18]=[CH:22]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6])=[CH:12][CH:13]=1
Reactant: c1nc[nH]n1
Reactant: C=CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Solvent: CC#N
Product: C=CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cnnc1
Yield: 20 %

Procedure:
89 g (0.28 mol) of 5-bromo-5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one, dissolved in 120 ml of acetonitrile, were added dropwise, in the course of 30 minutes, to a solution of 115.9 g (1.68 mols) of 1,2,4-triazole in 1,000 ml of acetonitrile at 50° C. After the solution had been heated at the boil for three hours, the solvent was distilled off and the residue was taken up in 300 ml of ethyl acetate. The solution was washed three times with 50 ml of water, and the organic phase, after having been dried over anhydrous sodium sulphate, was concentrated by evaporation under reduced pressure. The residual oil was dissolved in 400 ml of acetone, and a solution of 80.6 g of naphthalene-1,5-disulphonic acid in 400 ml of acetone was added. The salt which had crystallized out was filtered off under suction and washed with acetone, 250 ml each of water and dichloromethane were stirred with the salt, and the mixture was then rendered alkaline with a 10% strength sodium carbonate solution. The oil which remained after the organic phase had been evaporated off was dissolved in a small amount of ether, and petroleum ether was then slowly added to the solution. The product which crystallized out in the process was filtered off and washed with a small amount of ether/petroleum ether. 17.1 g (20% of theory) of 5-(4-chlorophenoxy)-3,3-dimethyl-5-(1,2,4-triazol-4-yl)-pent-1-en-4-one (Compound 3) of melting point 124° to 126° C. were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:47][NH:48][CH3:49]>C(Cl)Cl.CCN(CC)CC>[CH3:47][N:48]([CH3:49])[C:26]([C:24]1[CH:23]=[CH:22][C:20]2[S:21][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:18][C:19]=2[CH:25]=1)=[O:27]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2s1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)N(C)C)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-5-carboxylic acid (210 mg, 0.464 mmol) in CH2Cl2 (5.0 mL) is treated with Et3N (1.0 mL), HOBT (94 mg, 0.70 mmol), and EDC (134 mg, 0.70 mmol). The mixture is stirred for 10 min at RT, and dimethylamine (1.0 mL, 2.0 M in THF) is added. The reaction mixture is stirred for 18 h, loaded onto a silica gel column, and eluted with 65% EtOAc/Hex to afford the title compound (90 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])[CH:14]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37])(=[NH:32])=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:32]=[S:30]([C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])([CH3:29])=[O:31])=[O:7])=[CH:9][C:10]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])[CH:14]=1
Reactant: COC(=O)c1cccc(S(C)(=N)=O)c1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Temperature: 60 °C
Reaction time: 16.5 h

Procedure:
To a solution of 6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinic acid (68 mg, 0.18 mmol), methyl 3-(S-methylsulfonimidoyl)benzoate (42 mg, 0.198 mmol), and N,N-diisopropylethylamine (0.063 ml, 0.36 mmol) in 1.5 ml DMF at room temperature was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (88 mg, 0.198 mmol). The reaction was heated at 60° C. for 3.5 hours, then at 48° C. for 16.5 hours. The mixture was partitioned between EtOAc and dilute brine. The EtOAc layer was washed with NaHCO3 solution, dilute HCl, NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The dark foam was chromatographed eluting with hexane/acetone yielding light pink solid (38 mg, 37%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Cl:45])[CH:43]=2)[C:17]2([CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[CH2:21][C:20](=[O:30])[N:19]([CH3:31])[CH:18]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[C:16]1=[O:46])=O)(C)(C)C>ClCCl>[Cl:45][C:42]1[CH:43]=[C:44]2[NH:15][C:16](=[O:46])[C:17]3([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[CH2:21][C:20](=[O:30])[N:19]([CH3:31])[CH:18]3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:39]2=[CH:40][CH:41]=1
Reactant: Cc1ccccc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-methyl-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.20 g, 0.35 mmol) prepared in example 24c in dichloromethane (10 mL). The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo. To this residue was added saturated NaHCO3 solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over MgSO4. The solvent was removed and the residue was purified by chromatography (EtOAc:CH2Cl2=1:4) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.075 g, 46%).
Reaction SMILES: [Cl:1][C:2]([Cl:16])([F:15])[S:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13]O)[CH:5]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:13][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([S:3][C:2]([Cl:16])([Cl:1])[F:15])=[CH:5]1
Reactant: OCn1cc(SC(F)(Cl)Cl)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(Cl)(Cl)Sc1cn(CCl)c2ccccc12

Procedure:
0.54 g of 3-{[dichlorofluoromethyl]thio}-1H-indole-1-ylmethanol was dissolved to 10 ml of chloroform. 0.3 ml of thionyl chloride was added to the solution, and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.61 g of 1-(chloromethyl)-3-{[dichlorofluoromethyl]thio}-1H-indole.
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.[CH3:10][N:11]([CH3:16])[S:12](Cl)(=[O:14])=[O:13].[Cl:17][C:18]1[CH:43]=[CH:42][C:21]2[N:22]3[C:26]([CH2:27][NH:28][CH2:29][C:20]=2[CH:19]=1)=[N:25][N:24]=[C:23]3[CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[N:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:32][CH2:31]1>ClCCl>[NH3:4].[CH3:10][N:11]([CH3:16])[S:12]([N:28]1[CH2:27][C:26]2[N:22]([C:23]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:37]=[CH:38][CH:39]=[CH:40][N:41]=4)[CH2:34][CH2:35]3)=[N:24][N:25]=2)[C:21]2[CH:42]=[CH:43][C:18]([Cl:17])=[CH:19][C:20]=2[CH2:29]1)(=[O:14])=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Product: N
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
N,N-Diisopropylethylamine (77 μl, 0.44 mmol), followed by dimethylsulphamoyl chloride (50 μl, 0.44 mmol) were added to an ice-cold solution of the amine from example 12 (150 mg, 0.4 mmol) in dichloromethane (10 ml), and the reaction mixture was stirred at room temperature for 4 hours. TLC analysis showed that starting material remained, so additional dimethylsulphamoyl chloride (91 μl, 0.8 mmol) and N,N-diisopropylethylamine (140 μl, 0.8 mmol) were added, and the mixture was stirred at room temperature for a further 18 hours. The mixture was evaporated under reduced pressure, the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution, the layers were separated, and the organic phase was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to afford the title compound as an off-white solid (135 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[OH:43])=[O:31]
Reactant: O=C(Br)CBr
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)N[C@H]2c3ccccc3C[C@H]2O)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([OH:11])[CH2:10][CH2:9][CH2:8]1.Cl.F[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[N:15]=1.ClCCl>CS(C)=O.O>[CH:7]1([O:11][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[N:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: Fc1cccc(C2CCNC2)n1
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: c1cc(OC2CCC2)nc(C2CCNC2)c1
Reaction time: 48 h

Procedure:
Potassium tert-butoxide (337 mg, 3 mmol, 3 eq) is added portionwise at room temperature to a solution of cyclobutanol (144 mg, 2 mmol, 2 eq) in DMSO (2 ml) and the mixture is stirred for 2 days. 2-Fluoro-6-(pyrrolidin-3-yl)pyridine hydrochloride (202 mg, 1 mmol, 1 eq) in DMSO (2 ml) is added and the mixture is stirred for 48 hours. Dichloromethane and water are then added to the reaction mixture, and the two phases are separated after vigorous shaking. The aqueous layer is reextracted with dichloromethane. The combined organic layers are dried on MgSO4, filtered and the filtrate condensed under reduced pressure to afford crude 2-(cyclobutyloxy)-6-(pyrrolidin-3-yl)pyridine a1-72, which is used in the next step without any further purification.
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].CCN(C(C)C)C(C)C.[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C1COCC1.O>[CH3:17][C:12]1[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:18])[C:2]3([N:37]2[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)(N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
676 mg (2.0 mmol) of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one and 774 mg (6.0 mmol) of DIPEA were dissolved in 20 ml of THF, after the addition of 774 mg (4.0 mmol) of tert-butyl piperazine-1-carboxylate, the reaction solution was stirred for 0.5 h at room temperature. Subsequently, the solution was diluted with water. The aqueous phase was extracted with CH2Cl2 (2×30 mL). The combined organic phases were washed with aqueous NaHCO3 and with water, dried and concentrated in vacuum. The resulting residue was purified by chromatography (eluent: CH2Cl2/MeOH=20/1) to give product (940 mg, 96%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δH 10.75 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.25-7.38 (m, 6H), 6.98 (d, J=8.0 Hz, 1H), 3.27-3.29 (m, 4H), 2.47-2.38 (m, 4H), 2.36 (s, 3H), 2.18 (s, 3H), 1.35 (s, 9H). MS (ESI) m/e [M+1]+ 489.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:20])(=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:27][CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 40 h
Yield: 75.5 %

Procedure:
Into a solution of methyl 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.31 g) in THF-methanol (5-2.5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 65° C. for 40 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (226 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][SiH:2](Cl)Cl.[CH3:5][C:6]([CH3:8])=[O:7]>>[CH3:1][SiH:2]([O:7][C:6]([CH3:8])=[CH2:5])[O:7][C:6]([CH3:8])=[CH2:5]
Reactant: CC(C)=O
Reactant: C[SiH](Cl)Cl
Product: C=C(C)O[SiH](C)OC(=C)C

Procedure:
Methyl di(isopropenyloxy)silane of the structural formula HSiMe(OCMe=CH2)2 was synthesized according to a known procedure by the reaction of acetone and methyl dichlorosilane followed by purification by distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][N:28]3[C:32](=[O:33])[CH2:31][CH2:30][C:29]3=[O:34])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:35]#[N:36])[CH:18]=1>O1CCOCC1.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>[O:33]=[C:32]1[CH2:31][CH2:30][C:29](=[O:34])[N:28]1[CH2:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:18][C:19]([C:35]#[N:36])=[N:20]2)=[CH:25][CH:24]=1
Reactant: N#Cc1cc(Cl)c2ccc(CN3C(=O)CCC3=O)cc2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)cc2n1
Temperature: 100 °C

Procedure:
To a room temperature solution of 4-fluorophenylboronic acid (5.96 g, 42.6 mmol, 1.2 equiv.) in dioxane:water (10:1, 177 mL, 0.2 M) was added sodium bicarbonate (5.96 g, 71.0 mmol, 2.0 equiv.), 4-chloro-7-[(2,5-dioxopyrrolidin-1-yl)methyl]quinoline-2-carbonitrile (2-5, 10.6 g, 35.5 mmol), and Pd(PPh3)4 (4.1 g, 3.55 mmol, 0.1 equiv.). The resulting mixture was warmed to 100° C. for 4 hr. The reaction was then cooled to 0° C. and a precipitate formed. The solids were then collected by vacuum filtration and washed with water and cold acetonitrile to afford 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-6) which was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.115 (d, J=1.10 Hz, 1H); 7.897 (d, J=8.79 Hz, 1H); 7.655 (dd, J1=8.79 Hz, J2=1.83 Hz, 1H); 7.603 (s, 1H); 7.439-7.475 (m, 2H); 7.243-7.286 (m, 2H); 4.909 (s, 2H); 2.796 (s, 4H). LRMS m/z (M+H)+ 360.3 found, 360.1 required.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:13]=2[O:14][CH3:15])=[C:5]([CH3:25])[C:4]=1[F:26])#[N:2].C1C=C2N=NN(O)C2=CC=1.O.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.[CH2:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH3:60]>CN(C=O)C>[CH2:59]([N:61]1[CH2:66][CH2:65][N:64]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:12]3[C:13]([O:14][CH3:15])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:26])[C:5]=4[CH3:25])[CH:10]=[N:11]3)=[N:17][CH:18]=2)=[O:22])[CH2:63][CH2:62]1)[CH3:60]
Reactant: CCN1CCNCC1
Reactant: COc1c(-c2ccc(C#N)c(F)c2C)cnn1-c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3OC)nc2)CC1
Yield: 52 %

Procedure:
Combined 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)nicotinic acid (106 mg, 0.300 mmol), HOBT hydrate (68.9 mg, 0.450 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (86 mg, 0.450 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.157 mL) in DMF (1 mL) and stirred for 5 min. The mixture was then added to 1-ethylpiperazine (68.5, 0.600 mmol). After 18 hours the reaction mixture was purified via preparative HPLC (20-40% acetonitrile in water, with TFA) to give 4-(1-(5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)-5-methoxy-1H-pyrazol-4-yl)-2-fluoro-3-methylbenzonitrile (70 mg, 0.156 mmol, 52%). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.CN(CCN(C)C)C.[CH2:20]([O:22]CC)C.[Li]CCCC.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH:20]=[O:22])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: CCOCC
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(OC)c1C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
A solution of 1-chloro-3,5-dimethoxybenzene (5 g, 29.0 mmol) and TMEDA (4.37 mL, 29.0 mmol) in diethyl ether (100 mL, 962 mmol) at −78° C. under N2 atmosphere was charged with BuLi (19.91 mL, 31.9 mmol) dropwise over a period of 30 minutes using a syringe pump. After stirring for 4 hours at −78° C., DMF was added and the reaction mixture continued to stir for 1.5 hours after which 1N HCl (˜30 mL) was added (all at −78° C.). The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by ISCO using hexanes/EtOAc as eluent. Fractions containing the desired product were concentrated to dryness to give the title material (1.97 g, 9.82 mmol, 33.9% yield) as a light yellow solid. LC (Method B): 1.924 min. LCMS (APCI) calcd for C9H10ClO3 [M+H]+ m/z 201.03. found 201.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 10.28 (s, 1H), 6.87 (s, 2H), 3.86 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]C=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:7][CH2:6][CH:5]3[CH2:3][CH2:2][NH:1][CH2:9][CH2:4]3)=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: Clc1ccc2[nH]c3c(OCCC4CCNCC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-(+)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1H), 8.11 (d, J=2.0 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.29 (dd, J=8.4, 2.4 Hz, 2H), 4.36 (t, J=7.2 Hz, 2H), 3.09-3.01 (m, 2H), 2.62 (td, J=12.4, 2.4 Hz, 2H), 1.96-1.87 (m, 2H), 1.83-1.70 (m, 3H), 1.33-1.18 (m, 2H); MS (ESI) m/z 450.2 (M−H)−; MS (ESI) m/z 452.1 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1.[OH-].[K+]>O>[NH3:8].[CH3:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:2][CH2:3][CH2:4][OH:5]
Reactant: C[C@@H]1CCCN1
Reactant: OCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CCCN1CCCO
Product: N
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
3-Bromopropan-1-ol (5.28 mL, 58.4 mmol) was added to a solution of (R)-2-methylpyrrolidine (7.1 g, 58.4 mmol) in water (200 mL). KOH (7.53 g, 134 mmol) was then added and the mixture stirred at ambient temperature for 48 hours. The reaction mixture was then extracted with dichloromethane (5×80 mL) and ethyl acetate (5×80 mL). The combined organic extracts were dried using MgSO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, (90:10:1) to give the title compound as a pale brown oil (5.44, 65%). LCMS (APCI+) 144 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[N+](C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([O:32][N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
17-{3-[tert-Butoxycarbonyl (2-carboxyethyl)amino]propionylamino}heptadecanoic acid tert-butyl ester (0.122 g, 0.2 mmol) was dissolved in THF (5 mL). DIEA (39 ul) was added and the mixture was cooled to 0° C. TSTU (66 mg, 0.22 mmol) was added. The mixture was stirred at 0° C. for 30 min, then for 16 h at RT. The mixture was concentrated under vacuum. AcOEt (15 mL) and the solution was washed with 0.2 N HCl (5 ml) and sat. NaCl (5 ml), dried over MgSO4, and dried under vacuum. The residue was purified by flash chromatography (silica) eluting with AcOEt/heptane (9:1) and AcOEt. The appropriate fractiones were pooled and concentrated under vacuum to yield 58 mg.