Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1>N.CO.[Ni]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc(C#N)ccc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cn1ccc2cc(CN)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a solution of 294 (800 mg, 5.12 mmol) in 7M ammonia in MeOH (50 mL) was added Raney Ni (2.0 g) and the reaction mixture was stirred vigorously under H2 (1 atm.) atmosphere at RT for 18 h. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo to afford 800 mg of (1-methyl-1H-indol-5-yl)methanamine (296) as yellow oil: MS (ESI) m/z=144.3 [M-NH2]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:29])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:19]([NH:21][CH:22]3[CH2:24][CH2:23]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.BrCCOC1C=C2C(C(C)=[CH:39][N:40]([C:45]3[CH:46]=C(C=C[C:56]=3C)C(NC3CC3)=O)C2=O)=CC=1.[I-].[K+].CNC(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([N:11]3[CH:10]=[C:9]([CH3:29])[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:40]([CH:45]([CH3:46])[CH3:56])[CH3:39])=[CH:6][CH:7]=4)[C:12]3=[O:15])[CH:17]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C)c2ccc(OCCBr)cc2c1=O
Agent: CNC(C)C
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C)c2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 150 °C

Procedure:
A mixture of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide and 3-[7-(2-bromoethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide (4:1, 225 mg), potassium iodide (182 mg), and N-methylisopropylamine (0.34 ml) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave N-cyclopropyl-3-[7-{2-[isopropyl(methyl)amino]ethoxy}-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (105 mg) as a pale yellow foam; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 0.97 (d, 6H), 2.10 (s, 3H), 2.24 (s, 3H), 2.27 (s, 3H), 2.76 (t, 2H), 2.80-2.89 (m, 2H), 4.14 (m, 2H), 7.09 (s, 1H), 7.45-7.51 (m, 2H), 7.70-7.75 (m, 3H), 7.86 (d, 1H), 8.45 (d, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]([CH3:21])[N:13]=1.C[Li].[CH3:26]COCC.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([C:18](=[O:20])[CH3:26])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: CCN(c1nc(C)cc(C(=O)O)n1)c1ccc(C(C)C)cc1Br
Reactant: CCOCC
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(C)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 78 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamine (3.7 g, 9.8 mmol) in anhydrous THF (25 mL) was cooled with stirring to 31 78° C. under a nitrogen atmosphere. A solution of methyl lithium in ether (1.4M, 7 mL, 9.8 mmol) was added dropwise and the reaction mixture was stirred at -78° C. for 1 h. The CeCl3 suspension was transferred via cannula into the reaction mixture and stirring at -78° C. was continued for 5 h. A solution of methyl lithium in ether (1.4M, 7 mL, 9.8 mmol) was added dropwise and the reaction mixture was then warmed gradually to room temperature over 16 h. After cooling the reaction mixture to -78° C., the reaction was quenched with a 1N HCl solution and warmed to room temperature. The resulting mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an orange yellow oil. Column chromatography (ethyl acetate:hexanes::1:4) afforded the title product as an oil (2.5 g, 68% yield, Rf 0.5): NMR (CDCl3, 300 MHz): 7.55 (d, 1H, J=1), 7.25-7.15 (m, 2H), 6.95 (s, 1H), 4.30-4.10 (m, 1H), 3.90-3.70 (m, 1H), 3.00-2.85 (m, 1H), 2.80-2.05 (m, 6H), 1.35-1.20 (m, 9H); CI-HRMS: Calcd (C18H22BrN3O): 376.1024 (M+H), Found: 376.1042.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]OC1C=CC(Cl)=CC=1Br)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([I:26])=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[I:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(Cl)c1I
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: CC(C)(C)OC(=O)COc1cccc(Cl)c1I
Yield: 86 %

Procedure:
Following the general method as outlined in Intermediate 1, starting from 3-chloro-2-iodophenol (prepared as described in J. Org. Chem., 2005, 70, 6548-6551), the title compound was obtained as a white solid in 86% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)([CH3:22])[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
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: CC#N
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3ccccc3C(C)C)nc1-2
Yield: 29.4 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-isopropylphenylboronic acid (65 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 298 (23 mg). ESI-MS: 363.1 (M)+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([N:10]1[CH:4]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1CCCCC(=O)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCCCC(=O)N1Cc1ccccc1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Sodium hydride (95%, 1.74 g, 68.7 mmol, 1.15 equiv) was added to a solution of 7-methylazepan-2-one (2-2, 7.60 g, 59.8 mmol, 1 equiv) in THF (150 mL) at 0° C. and the resulting mixture was warmed to 23° C. and stirred for 20 h. Benzyl bromide (7.82 mL, 65.7 mmol, 1.10 equiv) was added followed by 2 drops of water, and the resulting mixture was stirred at 23° C. for 20 h. Excess sodium hydride was quenched carefully with water and the mixture was concentrated. The residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 100% EtOAc) to give 1-benzyl-7-methylazepan-2-one (2-3) as a colorless oil. LRMS m/z (M+H) 218.2 found, 218.2 required.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[N:17].N1CCCCC1>CO>[C:16]([C:18](=[CH:10][C:9]1[CH:8]=[C:7]([O:12][CH3:13])[C:6]([O:14][CH3:15])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]([O:21][CH3:22])=[O:20])#[N:17]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 78.1 %

Procedure:
To a mixture of 7.00 g (33.15 mmol) of 6-nitroveratraldehyde (80%) and 3.4 mL (38.42 mmol) of methyl cyanoacetate in 70 mL of methanol is added 0.7 mL of piperidine. An additional 100 mL of methanol is added and the thick suspension is warmed slightly until the mixture stirred freely. After stirring at room temperature for 1 hour, the solids are collected by filtration washing with methanol followed by diethyl ether to give 7.57 g (78%) of methyl 2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)-2-propenoate as a pale yellow solid, mp 162–164° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][CH2:17][CH:12]([O:11][CH3:10])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(I)cc1
Reactant: COC1CCNCC1
Solvent: ClCCl
Solvent: CCO
Product: COC1CCN(Cc2ccc(I)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 4-methoxypiperidine. Yield: 0.93 g (66.7% of theory); C13H18INO (M=331.19); calc.: molecular ion peak (M+H)+: 332; found: molecular ion peak (M+H)+: 332; Rf value: 0.55 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)Cl.Cl>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccccc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 1-(2-bromophenyl)methanamine hydrochloride salt (1 eq.) in CH2Cl2 (0.3M) at room temperature was added triethylamine (2.1 eq) then acetic anhydride (1.1 eq.). The mixture was stirred at room temperature for 6 h, poured in aqueous HCl (0.5N) and extracted with CH2Cl2. The organic extract was dried over MgSO4 filtered and concentrated to afford the desired compound as a white solid.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]([C:32]2[N:36]=[C:35]([O:37][CH2:38][O:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])[N:34]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[N:33]=2)[C:16]2[C:17]([F:31])=[C:18]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].CN(C=O)C.[N+](C1C=CC([O:66][C:67](=O)[O:68][CH2:69][CH:70]([CH3:72])[CH3:71])=CC=1)([O-])=O.C(N(CC)CC)C>O.C(OCC)(=O)C>[NH2:7][C:5](=[N:6][C:67]([O:68][CH2:69][CH:70]([CH3:72])[CH3:71])=[O:66])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C@@H:15]([C:32]2[N:36]=[C:35]([O:37][CH2:38][O:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])[N:34]([C:46]3[N:47]=[CH:48][CH:49]=[CH:50][N:51]=3)[N:33]=2)[C:16]2[C:17]([F:31])=[C:18]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:12][CH:13]=1
Reactant: COc1cc(OCCOC(C)=O)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)OC(C)C)n(-c3ncccn3)n2)c1
Reactant: CC(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OCCOC(C)=O)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)C)cc2)c2nc(OCOC(=O)OC(C)C)n(-c3ncccn3)n2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a mixture of Acetic acid 2-{3-[(R)-(4-carbamimidoylphenylamino)-(5-isopropoxycarbonyloxymethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester acetic acid salt (23 mg) obtained in Example 67a and DMF (1 ml), carbonic acid isobutyl ester 4-nitrophenyl ester [CAS No. 112240-73-0] (10 mg) and triethylamine (50 μL) were added, and the resulting mixture was stirred at room temperature for 64 h. Ethyl acetate and water were added to the mixture, and the organic layer was collected. The organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (14.99 mg).
Reaction SMILES: [CH2:1]([N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:18]([NH2:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:11]1[C:12](=[O:17])[CH2:13][CH:14]([NH:28][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: CCCCCCCCCCN1C(=O)C=CC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC1CC(=O)N(CCCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-decyl maleimide (0.01 M) prepared as described in Example 11 above, decylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4)cc23)cc1

Procedure:
The title compound, light yellow solid (41 mg, 31%), MS (ISP) m/z=374.1 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(Cl)=CC=C(Cl)C=1.C(OCC1OC1)(=O)C(C)=C>>[CH3:11][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH2:10].[CH3:11][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH2:10]
Reactant: CC(C)c1ccccc1
Agent: C=C(C)C(=O)OCC1CO1
Agent: [O-]O
Solvent: Clc1ccc(Cl)cc1
Product: C=C(C)c1ccccc1
Temperature: 900 °C

Procedure:
A high temperature initiator, cumene hydroperoxide, was included in this run to drive the polymerization further towards completion and to reduce residual monomer. The flask was charged with brominated styrene monomer (10002.6), dichlorobenzene (497 g), glycidyl methacrylate (5.13 g, 0.0360 mol), 2,4-diphenyl-4-methyl-l-pentane (20.26 g, 0.08571 mol), VAZO-52™ azo type initiator (1.05 g, 4.22 mmol) and cumene hydroperoxide (1.06 g, 6.96 mmol). In one embodiment, the monomer/polymerization initiator blend may be reacted under conditions effective to polymerize at least about 80% of the monomers in a time of between about 1 minute and about 20 minutes. The solution was then heated to about 900° C. until exotherm. Peak temperature reached was 163° C. after which the mixture was heated the mixture was heated to 190° C. over 5-10 mm and held at 190° C. for 40-45 mm. Heating was halted; the solution (1513.7 g) was transferred to a 2-liter bottle, and cooled to room temperature. The material was split into four parts. Each part was precipitated into a 5-liter flask of 3400 mL acetone and 400 mL methanol. The precipitate was filtered over frit, dried at ambient temperature for about 14 h and oven dried at 110° C. for 8 h. A white powder (883 g) was isolated.
Reaction SMILES: I[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[OH:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1>C(=O)([O-])[O-].[Ag+].[Ag+].C1C=CC=CC=1>[CH3:29][O:28][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:30][CH3:31])[N:4]=[C:3]([CH2:2][O:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: Cn1ccnc1O
Reactant: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(COc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
A mixture of ethyl 2-iodomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (9.0 g), 2-hydroxy-1-methylimidazole (1.8 g), silver (I) carbonate (Ag2CO3)(5.1 g) and benzene (100 ml) was stirred at 50° C. for 18 hours. The insoluble solid was filtered off. The filtrate was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (5/1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methyl-2-imidazolyl)oxymethyl]quinoline-3-carboxylate (0.8 g, 9%) which was then recrystallized from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:49][CH:50]([NH2:52])[CH3:51]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[C:27]([C:28]([NH:52][CH:50]([CH3:51])[CH3:49])=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=4)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added (1-methylethyl)amine (0.765 mL, 8.91 mmol). The resulting mixture was let stir at rt for 40 min at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (101 mg, 0.138 mmol) as a yellow solid (only 85% pure by LCMS) (ESIMS (M+H)+=733)
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:17]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:4]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CC1CCCCC1
Reactant: NC(=O)c1ccccc1N
Product: O=C1NC(C2CCCCC2)Nc2ccccc21

Procedure:
Anthranilamide was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 172-174° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[O:26]=[S:25]1(=[O:27])[CH2:24][CH2:23][CH2:22][N:2]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-aminomethylbenzoate hydrochloride (1.61 g) and triethylamine (2.45 mL) were dissolved in dichloromethane (40 mL), 3-chloropropane-1-sulfonyl chloride (1.17 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (8 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.46 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:ethyl acetate) to give the title compound (1.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[S:15][C:14]([CH:17]=[C:18]([CH3:20])[CH3:19])=[N:13][C:12]=3[CH:11]=[C:10]([CH3:21])[C:9]=2[O:22]C)=[CH:4][CH:3]=1>I(O)(=O)(=O)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[S:15][C:14]([CH:17]=[C:18]([CH3:19])[CH3:20])=[N:13][C:12]=3[CH:11]=[C:10]([CH3:21])[C:9]=2[OH:22])=[CH:6][CH:7]=1
Reactant: COc1c(C)cc2nc(C=C(C)C)sc2c1-c1ccc(Cl)cc1
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Product: CC(C)=Cc1nc2cc(C)c(O)c(-c3ccc(Cl)cc3)c2s1

Procedure:
Compound 8E was synthesized from compound 8D according to the procedure used to prepare compound 5C of Example 1.