Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C@@H:14]([NH:24][C:25](=[O:41])[CH2:26][N:27]2[C:31]3[C:32]([F:37])([F:36])[C@@H:33]4[CH2:35][C@@H:34]4[C:30]=3[C:29]([CH:38]([F:40])[F:39])=[N:28]2)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[N:4][C:5]([N:8]2[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]2)=[CH:6][CH:7]=1.[CH3:42][N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2B2OC(C)(C)C(C)(C)O2)[C:45]([NH:61][S:62]([CH3:65])(=[O:64])=[O:63])=[N:44]1.C(=O)(O)[O-].[Na+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.O1CCOCC1>[F:40][CH:38]([F:39])[C:29]1[C:30]2[C@H:34]3[CH2:35][C@H:33]3[C:32]([F:37])([F:36])[C:31]=2[N:27]([CH2:26][C:25]([NH:24][C@H:14]([C:3]2[C:2]([C:50]3[CH:49]=[CH:48][CH:47]=[C:46]4[C:51]=3[N:43]([CH3:42])[N:44]=[C:45]4[NH:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:7][CH:6]=[C:5]([N:8]3[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]3)[N:4]=2)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[O:41])[N:28]=1
Reactant: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)n2)C1
Reactant: Cn1nc(NS(C)(=O)=O)c2cccc(B3OC(C)(C)C(C)(C)O3)c21
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1nc(NS(C)(=O)=O)c2cccc(-c3ccc(N4CC(C)(O)C4)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 150 °C

Procedure:
In a microwave tube were charged with of N—((S)-1-(3-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (45 mg, 0.07 mmol), N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide (36 mg, 0.1 mmol) and PdCl2[P(Cy)3]2 (5 mg, 0.007 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated up in a microwave synthesizer at 150° C. for 20 min. After cooled down to room temperature, it was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, methanol-d4) δ 7.79 (dd, 1H), 7.51 (dd, 1H), 7.29-6.45 (m, 5H), 6.48-6.24 (m, 2H), 4.85 (m, 3H), 4.19-3.91 (m, 4H), 3.58-2.75 (m, 8H), 2.49 (m, 2H), 1.61 (d, J=2.2 Hz, 3H), 1.41 (q, J=7.0 Hz, 1H), 1.20-0.83 (m, 1H). MS (m/z) 789.11 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:42][CH:39]4[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]4)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)N1CCC(N)CC1
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(C)C1N(CC(=O)NC2CCN(S(C)(=O)=O)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 34.3 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 1-methylsulfonyl-piperidin-4-yl-amine (0.15 g, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methylsulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 92 mg, 38.3%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[ClH:20]>C(OCC)C>[ClH:20].[CH2:1]([NH:5][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of isobutylamine (0.90 mL, 0.0091 mol), bromoacetic acid, ethyl ester (1.0 mL, 0.0090 mol), and triethylamine (1.28 mL, 0.00918 mol) in diethylether (15 mL) was stirred at room temperature for 24 hours. The resulting suspension was filtered off and washed with diethylether. The filtrate and washings were combined and rotary evaporated to an oil. The oil was chromatographed on silica gel (150 g, 230-400 mesh) eluting with dichloromethane-diethylether (19:1, 8×125 mL; 15:1, 7×125 mL; 10:1, 15×125 mL). Fractions containing product were combined and rotary evaporated to give an oil. The oil was dissolved in diethylether, concentrated hydrochloric acid (0.52 mL, 0.0063 mol HCl) was added, and the volatiles were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 1.0 g (59%). 1H-NMR (DMSO-d6): δ9.23 (br s, 2H), 4.22 (q, 2H), 3.96 (m, 2H), 3.41 (br s, H2O), 2.78 (m, 2H), 2.00 (m, 1H), 1.25 (t, 3H), 0.94 (d, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].O1CCOCC1.[CH3:39][NH2:40]>C(Cl)Cl.CN(C=O)C>[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH3:39])=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Yield: 32 %

Procedure:
Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringe wise to (+)-4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoic acid (300 mg, 0.79 mmol, prepared in example 1a) in CH2Cl2 (20 mL) while stirring under nitrogen at room temperature. Immediately, 1 drop of DMF was added by pipette initiating a foaming of the mixture. The reaction was stirred one hour at this temperature and then concentrated under reduced vacuum to yield a white semi-solid. This material was placed into dioxane (20 mL) and added dropwise to a stirring solution of 40% methylamine (5 mL) at room temperature and the mixture was stirred overnight. In the morning, the solution was concentrated under reduced vacuum and the resulting oil was taken into methylene chloride and the organic layer was washed once with H2O, dried over K2CO3, filtered, and concentrated under reduced vacuum to yield 271 mg as a semi-solid. This material was purified via silica gel chromatography employing the Chromatotron and using a 2000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 1:1 to yield the title compound (100 mg, 32%) as a white solid. Ion spray M.S. 391.2 (M*−1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[Cl:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])(=O)C.[Na+]>ClC(Cl)C.O.C(Cl)Cl>[Cl:11][C:12]1[CH:16]=[C:15]([CH:9]=[O:10])[NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CN(C)C=O
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
A solution of phosphorous oxychloride (3.21 ml, 34.5 mmol) was added dropwise over a period of 15 min to a 0° C. solution of DMF (2.67 ml, 34.5 mmol) under nitrogen. The mixture was allowed to warm to RT and stirred for 30 min. Dichloroethane (20 mL) was added and the reaction mixture cooled to 0° C. A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (5 g, 31.3 mmol) in dichloroethane (20 mL) was added dropwise over 30 min. The reaction mixture was warmed to RT and allowed to stir for 1 h. The flask was placed in an oil bath at 90° C. and stirred for 30 min. The reaction mixture was cooled to RT, a solution of sodium acetate (25 g, 305 mmol) in water (25 mL) was added and stirred for 15 min. Methylene chloride (100 mL) was added and the layers separated. The aqueous layer was extracted with methylene chloride (2×25 mL), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude material was purified by column chromatography (hexanes: EtOAc; 10-100%) to afford three isolated materials. The first compound to elute was a mixture of starting materials and product. The second fraction to elute was evaporated and recrystallized from a minimal amount of EtOAc to afford methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (1.2 g, 6.40 mmol, 20% yield) as yellowish crystals. The third fraction to elute was evaporated and recrystallized from hexanes: EtOAc to afford methyl 3-chloro-4-formyl-1H-pyrrole-2-carboxylate (1.05 g, 18% yield) as a tan solid. Methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate: 1H NMR (400 MHz, DMSO-d6): 6 ppm 14.0 (br. s., 1H), 9.64 (d, 1H) 7.01 (s, 1H) 3.82 (s, 3H). MS: m/z 188.0 (M+1). Methyl 3-chloro-4-formyl-1H-pyrrole-2-carboxylate: 1H NMR (400 MHz, DMSO-d6): 6 ppm 14.0 (br. s., 1H) 9.77 (s, 1H) 7.77 (s, 1H) 3.80 (s, 3H). MS: m/z 188.0 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].Cl>CO.O1CCOCC1>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][Br:1]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCBr)c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The product of step (vi) (35.8 g) was dissolved in methanol (400 ml) and treated with 4M hydrogen chloride in dioxane (100 ml). The mixture was stirred at ambient temperature for 6 hours and concentrated in vacuo. Dichloromethane (500 ml) was added and concentrated in vacuo, which afforded a foam that was taken onto the next step without further purification. Yield 38 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([NH2:19])[CH2:17][CH3:18].C(N(CC)CC)C>>[CH2:16]([NH:19][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[CH2:17][CH3:18]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 712.8 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.3 g, 4.48 mmol), propylamine (264 mg, 4.48 mmol) and triethylamine(0.94mL, 6.72 mmol) were reacted to form the desired product (10 g, 71%). 1H NMR (MeOD-d4): δ7.92 (d, 1H), 7.78 (d, 1H), 3.00 (t, 2H), 1.50 (m, 2H), 0.88 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5]2.N12CCCN=C1CCCCC2.O=C1CCC(=O)N1[O:38][C:39](=O)[C@H:40]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH3:41]>CN(C)C=O.O>[C:45]([O:44][C:43]([NH:42][C@H:40]([CH3:41])[C:39]([O:19][CH2:18][CH2:17][CH2:16][NH:15][C:6]1[C:7]2[N:8]([CH:12]=[CH:13][N:14]=2)[C:9]2[C:4]([N:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:38])=[O:49])([CH3:48])([CH3:47])[CH3:46]
Reactant: OCCCNc1nc2cc(F)ccc2n2ccnc12
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCCCNc1nc2cc(F)ccc2n2ccnc12
Temperature: 60 °C
Reaction time: 65 h
Yield: 11.6 %

Procedure:
To a solution of commercially available (Peakdale) 3-[(7-fluoroimidazo[1,2-a]quinoxalin-4-yl)amino]propan-1-ol (20 mg, 0.08 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (12 μL, 0.08 mmol) in anhydrous dimethylformamide (600 μL) under argon was added dropwise a solution of tert-butyl {(1R)-2-[(2,5-dioxopyrrolidin-1-yl)oxy]-1-methyl-2-oxoethyl}carbamate (22 mg, 0.08 mmol) in anhydrous dimethylformamide (200 μL). The mixture was stirred at 60° C. for 65 h, then diluted with cold water and extracted four times with chloroform and once with chloroform/isopropanol (5:1). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica, dichloromethane/methanol 20/1) to afford the title compound as a colorless oil (4 mg, 12%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][C:16]=1[Cl:28]>COCCOC.CN(C)C=O.[Cl-].[NH4+]>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:22])=[CH:17][C:16]=1[Cl:28])[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: O=C(c1ccc(CBr)c(Cl)c1)N1CCCC1
Reactant: CCOC(=O)CC(=O)CC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1Cl)C(=O)CC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-oxopentanoic acid ethyl ester (14 mL) in 1,2-dimethoxyethane (25 mL) was added to a stirred suspension of sodium hydride (60% in oil, 3.7 g) in 1,2-dimethoxyethane (250 mL) and N,N-dimethylformamide (30 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 10 minutes. A solution of (4-bromomethyl-3-chlorophenyl)pyrrolidin-1-ylmethanone (9.7 g) in 1,2-dimethoxyethane (25 mL) was added and the resulting mixture warmed to room temperature and then stirred at this temperature for 20 hours. The mixture was diluted with saturated aqueous ammonium chloride solution, extracted with diethyl ether and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9:1 by volume) to afford title compound, 1.8 g.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH2:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:8]([O:10]C)=[O:9])[CH2:6][C:5]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[OH-].[K+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+]>C(O)C.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]2[CH:13]=[C:4]([C:3]([OH:30])=[O:2])[C:5]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:6][C:7]=2[C:8]([OH:10])=[O:9])=[CH:16][CH:17]=1
Reactant: COC(=O)C1=C(Nc2ccc(Cl)cc2)CC(C(=O)OC)=C(Nc2ccc(Cl)cc2)C1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
8.9 Parts of 2,5-di(p-chloroanilino)-3,6-dihydroterephthalic acid dimethyl ester, 50 parts of ethanol, 5.37 parts of KOH, 24.35 parts of water and 6 parts of sodium m-nitrobenzenesulfonate were charged into a 200-ml flask of stainless steel, and refluxed with stirring for 10 hours. When the suspension changed to a black solution, ethanol was steam-distilled, and the reaction mixture was filtered to remove a solid. The remaining solution was heated up to 80° C. with stirring, and after 35 parts of a 10% hydrochloric acid aqueous solution was dropwise added, the mixture was maintained for 1 hour. Then, the mixture was filtered, washed with hot water and dried to give 8.21 parts (98.4% of the theoretical yield) of 2,5-di(p-chloroanilino)terephthalic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([CH:18]=[O:19])=[C:6]1[CH2:20][CH2:21][CH3:22].CC(=CC)C.[Na].Cl([O-])=[O:34].[Na+].Cl>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([C:18]([OH:34])=[O:19])=[C:6]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(C=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCc1c(C(=O)O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a mixture of methyl 1-(2-chlorobenzyl)-3-formyl-2-propylindole-6-carboxylate (263 mg), 2-methyl-2-butene (220 mg) and sodium dihydrogenohosphate (128 mg) in a mixture of tert-butanol (7 ml) and water (1.3 ml) was added sodium chlorite (219 mg) at 20° C. The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid at 0° C. and extracted with chloroform three times. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:2) to give 1-(2-chlorobenzyl)-6-methoxycarbonyl-2-propylindole-3-carboxylic acid (94 mg) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[N:24]=[C:25]=[O:26].C(=O)=O.CC(C)=O.Cl>CN(C)C=O>[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[N:24]1[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:25]1=[O:26]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COc1ccc(N=C=O)c(F)c1
Agent: Cl
Agent: O=C=O
Agent: [H-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
A stirred mixture of 2.5 grams (0.062 mole) of sodium hydride (60% in mineral oil) in 50 mL of N,N-dimethylformamide was cooled to 0° C., and a solution of 11.2 grams (0.062 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 mL of N,N-dimethylformamide was added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. during a 30 minute period. After this time the reaction mixture was cooled in a dry ice-acetone bath, and a solution of 10.4 grams of 2-fluoro-4-methoxyphenyl isocyanate in 50 mL of N,N-dimethylformamide was added dropwise. Upon completion of addition, the reaction mixture was maintained at the dry ice-acetone bath temperature for one hour. After this time the reaction mixture was allowed to warm to ambient temperature, where it was stirred for about 18 hours. The reaction mixture was then poured into an aqueous 0.25N hydrochloric acid solution. The mixture was extracted with diethyl ether, and the extract was washed with water. The diethyl ether extract was in turn extracted with aqueous 1M sodium bicarbonate, and this extract was washed with diethyl ether. The sodium bicarbonate extract was then made acidic with concentrated hydrochloric acid, and it was in turn extracted with diethyl ether. The diethyl ether extract was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 5.5 grams of 3-(2-fluoro-4-methoxyphenyl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution (0.1 M) of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate in DMF was treated at 0° C. with NaH (1.3 eq.) and then stirred at 25° C. for 1 h. The solution was treated with tert-butylbromoacetate (1.2 eq.) and stirred 25° C. for 12 h. The mixture was diluted with EtOAc and washed sequentially with HCl (1 N) and brine. The dried organic phase was concentrated and the residue purified by flash chromatography on silica gel (5:95 EtOAc/PE) to afford the title compound (83%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.31-1.53 (m, 3H), 1.42 (s, 9H), 1.64-2.02 (m, 7H), 2.77-2.96 (m, 1H), 3.88 (s, 3H), 5.12 (s, 2H), 7.68 (dd, J 8.4, 1.2, 1H), 7.84 (d, J 8.4, 1H), 8.16 (d, J 1.2, 1H); MS (ES+) m/z 452 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([O:30][CH3:31])=[O:29])=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:21][C:20]1[N:22]=[C:23]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COC(=O)c1cccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)c1
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2nc(C)c3cnc(Nc4cc(OC)c(OC)c(OC)c4)nn23)c1
Yield: 63.6 %

Procedure:
In a similar manner as described for Example 9, methyl 3-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (Intermediate 21) (0.26 g, 0.56 mmol) and 1,2,4-triazole (240 mg, 3.4 mmol) in pyridine (4 mL) and phosphorus oxychloride (0.16 mL, 1.7 mmol) gave methyl 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzoate (0.16 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.66 (s, 1H), 9.28 (s, 1H), 8.94 (dd, J=1.7, 1.3 Hz, 1H), 8.74 (ddd, J=8.5, 1.9, 1.2 Hz, 1H), 8.01 (ddd, J=7.7, 1.8, 1.2 Hz, 1H), 7.65 (dd, J=8.3, 7.9 Hz, 1H), 7.08 (s, 2H), 3.84 (s, 3H), 3.68 (s, 6H), 3.65 (s, 3H), 2.55 (s, 3H). MS m/z 450 (M+1).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[N:18][C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]2[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1>C(#N)C>[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[N:18][C:17]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[C:16]2[C:27]1[CH:28]=[C:29]([NH:33][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reaction time: 3 h
Yield: 73 %

Procedure:
Phenyl isocyanate (0.075 g, 0.63 mmol) was added to a stirred solution of 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine (0.025 g, 0.076 mmol) in 5 mL of ACN at room temperature. The reaction mixture was stirred for 3 hours and concentrated. The residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide 0.025 g of the title compound as a gray solid. HRMS (ESI, [M+H]+) 451.1310.