Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32]12[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:34]5[CH2:33][CH:32]6[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:36]([CH2:37][CH2:38]6)[CH2:35]5)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCCC1
Yield: 73 %

Procedure:
Following amide formation method 1, 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (75 mg, 0.178 mmol, 1.0 eq) was combined with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.7 mg, 0.18 mmol, 1.0 eq) to give tert-butyl 3-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (80 mg, 0.130 mmol, 73% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (s, 1H) 8.68 (d, J=8.59 Hz, 1H) 8.42-8.57 (m, 1H) 8.40 (d, J=2.02 Hz, 1H) 7.83 (dd, J=8.59, 2.02 Hz, 1H) 6.49 (s, 1H) 4.46-4.62 (m, 2H) 4.29 (br s, 2H) 3.19 (s, 6H) 2.56-2.73 (m, 2H) 1.84-2.12 (m, 8H) 1.65-1.84 (m, 6H) 1.54-1.65 (m, 3H) 1.52 (s, 9H);
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]([F:24])([F:23])[F:22])[NH2:16]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([O:20][C:21]([F:22])([F:23])[F:24])=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)F)c(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and 3-fluoro-4-trifluoromethoxy-aniline to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.43 min, UPLC-MS (Condition 3) tR=1.29 min, m/z=413 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=4)[CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[S:49])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=3)[CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:15][C:8]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 125.6 %

Procedure:
To a solution of 74 (235 mg, 0.5 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (159 mg, 0.9 mmol) was added and the reaction was allowed to stir for 30 min. The solvent was removed under reduced pressure and the resulting product was purified by chromatography on silica gel using EtOAc/hexane (1:1) as eluting system to give the desired product (440 mg, 90%) as a white solid. 1H NMR (DMSO) δ (ppm): 8.52 (d, J=5.3 Hz, 1H), 8.01 (t, J=6.5 Hz, 2H), 7.79 (d, J=7.4 Hz, 1H), 7.70 (s, 1H), 7.53-7.52 (m, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.34 (d, J=4.5 Hz, 4H), 7.30-7.24 (m, 2H), 6.67 (d, J=5.3 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H), 3.42 (s, 2H), 3.22 (s, 3H), 2.50 (q, J=2.2 Hz, 4H), 1.45-1.33 (m, 9H).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[C:14]([O:13][C:11]([NH:10][C@@H:9]1[CH2:8][CH2:7][C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5][C@@H:4]1[NH2:1])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](N=[N+]=[N-])C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](N)C1
Yield: 104.8 %

Procedure:
Methyl (1R*,3R*,4S*)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (230 mg) was dissolved in ethyl acetate (8 ml), and a catalytic amount of 10% palladium on carbon was added to stir the mixture at room temperature for 20 hours in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (220 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[O:4][N:3]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Br:7][C:6]1[C:2]([NH:1][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[N:3][O:4][C:5]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)c1onc(N)c1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1onc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3-Amino-4-bromo-5-tert-butylisoxazole (21 9 mg, 1.0 mmol) was dissolved in dry pyridine (1 ml). Benzenesulfonyl chloride (0.14 ml, 1.1 mmol) and 4-dimethylamino-pyridine (5 mg) were added and the solution was stirred at 50° C. for 6 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (50 ml) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography (9:1 hexanes/ethyl acetate). A crystalline solid was obtained after recrystallization from ethyl acetate/hexanes, m.p. 139°-141° C.
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]([C:8](=[CH2:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.C[Si](Cl)(C)C>ClCCl>[CH2:12]([O:11][C:9]([CH:8]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:19][PH:1](=[O:2])[OH:3])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[PH2]O
Reactant: C=C(CC(C)C)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(C[PH](=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
A vigorously stirred mixture of 17.6 g (0.27 mol) of crystalline phosphinic acid and 43.6 g (0.2 mol) of benzyl 2-isobutylacrylate in 400 ml of dichloromethane was cooled to 0° C. and treated dropwise with 53.4 g (0.53 mol) of triethylamine while maintaining the temperature at below 5° C. After completion of the addition, a solution of 56.0 g (0.52 mol) of trimethylsilyl chloride in 100 ml of dichloromethane was added while stirring vigorously and maintaining the temperature at 10-12° C. After 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 24 hours. The mixture was then treated with 200 ml of water and 30 ml of 10% sulfuric acid. The organic phase was separated and washed with 200 ml of saturated sodium chloride solution. The combined aqueous extracts were re-extracted with 100 ml of dichloromethane and the organic phase was washed with 100 ml of sodium chloride solution and added to the previously obtained dichloromethane extracts. After drying over anhydrous sodium sulfate, the dichloromethane was removed by evaporation to give 59.2 g of [(RS)-2-[(benzyloxy)carbonyl]-4-methylpentyl]phosphinic acid in the form of a colorless oil. (b) The compound prepared in the preceding paragraph was dissolved in 600 ml of ethyl acetate. Thereafter, 25.0 g of S(-)-α-methylbenzylamine were added and the solution was left to crystallize for 24 hours. The crystalline salt was collected by filtration and dried to give 34.0 g of a white solid which was recrystallized overnight from a mixture of 120 ml of ethanol and 48 ml of ethyl acetate. The solid was collected and dried to give 21.3 g of a crystalline salt which was recrystallized overnight from a mixture of 120 ml of ethanol and ethyl acetate. There were obtained 16.8 g of [(R or S)-2-[(benzyloxy)carbonyl]-4-methylpentyl]phosphinic acid S(-)-α-methylbenzylamine salt in the form of white crystals of melting point 137-138° C. and [α]58920 =-8.9° (c=5% in ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[CH3:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH2:21][CH2:20][N:19]([CH3:31])[CH3:18])[CH3:30])=[CH:28][CH:27]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 54.1 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.28 g, 1.0 mmol) and N-[2-(dimethylamino)ethyl]-N-methylbenzene-1,4-diamine hydrochloride (0.30 g, 1.0 mmol) were stirred in N,N-dimethylformamide (5 mL) with triethylamine (0.6 mL). The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[[2-(dimethylamino)ethyl](methyl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.24 g, 55%) as a golden powder.
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][S:55][CH2:54][CH2:53]2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[OH:23][C:24]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:53][CH2:54][S:55][CH2:56][CH2:57]2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:39]=[CH:38][C:30]=1[C:31]([OH:33])=[O:32])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCSCC2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(N2CCSCC2)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
Thioanisole (1.0 mL) was added to a trifluoroacetic acid (2.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(thiomorpholin-4-yl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and a 4 mol/L hydrogen chloride-dioxane solution (0.5 mL) and ethyl acetate (1.0 mL) were added to the residue, followed by stirring at room temperature for 3 hours. The solid substance was collected by filtration, and water and ethyl acetate were added to the obtained solid substance. After adjusting the pH to 6.5 with a saturated aqueous solution of sodium bicarbonate, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: chloroform] to obtain 0.047 g of 2-(2-hydroxy-5-(thiomorpholin-4-yl)benzamido)-4-phenylbenzoic acid as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([OH:22])=O)[N:19]=2)[C:7]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:3])[CH3:2].[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.ClCCl>O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([NH:47][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:22])[N:19]=2)[C:7]=1[C:24]([O:26][CH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Reactant: NCc1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)NCc4ccccc4)cs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 176 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(4-carboxy-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 33.3 mg of benzylamine, 79 mg of 2-ethoxy-1(2H)-quinolinecarboxylic acid, ethyl ester and 3 ml of dichloromethane was stirred at room temperature for 1 hour, then added to water and extracted with dichloromethane. The dichloromethane extract was evaporated, giving the desired compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][CH:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: Cc1ccc(C(=O)Nc2ccc([C@H]3CCC(N4CCC[C@@H]4C)C3)cc2)cc1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)cyclopentyl]-phenylamine (Intermediate 14) and 4-methylbenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.CI.[CH3:21]C(C)=O.C(=O)=O.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: CC(C)=O
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,8,9-tetrahydro-6H-pyrimido [4,5-b][1,4] diazepin-6-one (318 mg, 0.0012 mol) and MeI (88 μl, 0.0014 mol, 1.18 eq) were added to DMF (5 ml) and the solution cooled to −10° C. using acetone/dry ice before the addition of NaH (30 mg, 0.0013 mol, 1.07 eq). The RM was then stirred at 0° C. for 30 min and rt for 30 min. The RM was concentrated and the product extracted using EtOAc/H2O. The organic extracts were combined, washed with sat NaCl, dried using MgSO4, filtered and the filtrate evaporated under reduced pressure and further dried in vacuo to give the product as a purple oily residue (252 mg, 75%); Rt=13 min (Vydac 1); MS+ve: 281.2.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[C:6]([C:14]#[N:15])=[C:5]2[C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O>CN(C=O)C>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:33]4[N:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH:11]=3)[C:6]([C:14]#[N:15])=[C:5]2[C:16]2[CH:17]=[CH:18][C:19]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: CC(C)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of (1-cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-1H-indole-3-carbonitrile (0.099 g, 0.3 mmol), Cs2CO3 (0.244 g, 0.75 mmol), 2-chloropyrimidine (0.069 g, 0.6 mmol) in DMF (2.0 mL) was stirred at 70° C. overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide 1-cyclopropyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile as a solid (0.104 g, 85%).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:27])=[C:16]([O:23][C:24](=[O:26])[CH3:25])[C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:28][O:29][CH2:30]Cl>C1COCC1>[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:27][CH2:28][O:29][CH3:30])=[C:16]([O:23][C:24](=[O:26])[CH3:25])[C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: COCCl
Reactant: CC(=O)Oc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1c(OC(C)=O)c(=O)n(C)c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
After addition of 1.87 g of triethylamine (18.5 mmol) to a mixture of 3.2 g of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone (11.5 mmol) in 64 ml of THF, 1.89 g of chloromethyl methyl ether (23.0 mmol) was dropped to the mixture, and stirred at room temperature for 1 hour. Filtration of the reaction mixture, the filtrate was concentrated under reduced pressure to give 3.6 g of 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone. In accordance with EXAMPLE 4, the obtained 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was used instead of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-nitro-3-hydroxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was provided. Then in accordance with EXAMPLE 2, 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was given by methylation reaction. Finally, to a mixture of the obtained 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone in 40 ml of methanol was added 0.22 g of p-toluenesulfonic acid monohydrate and stirred at room temperature for 1 hour. To the reaction mixture was added water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was crystallized from THF and hexane to yield 1.45 g of the title compound (18). (yield=54%)
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH2:19])=[NH:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=O)[C:29](=[CH:32]N(C)C)[CH2:28][C:27](=[O:36])[N:26]([CH2:37][CH2:38][CH2:39][N:40]3[C:48](=[O:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:50])[C:25]=2[CH:51]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]3[N:18]=[C:17]([NH:16][C:10]4[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=4)[N:19]=[CH:32][C:29]=3[CH2:28][C:27](=[O:36])[N:26]([CH2:37][CH2:38][CH2:39][N:40]3[C:41](=[O:50])[C:42]4[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:48]3=[O:49])[C:25]=2[CH:51]=1
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)C=C1CC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(CCCN2C(=O)c4ccccc4C2=O)C(=O)C3)cc1OC

Procedure:
In a manner similar to that described for method I (NaHCO3 used instead of K2CO3), 1-(3,4-dimethoxyphenyl)guanidine and 8-chloro-4-((dimethylamino)-methylene)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (I-40-b) were converted to I-40-c and carried on crude: MS m/z=584 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=N1.N1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([N:37]5[CH2:38][CH2:43][CH2:42][CH2:41]5)=[O:28])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Product: O=C([C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)N1CCCC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and pyrrolidine. Melting point: 206°-209° C.; Rf : 0.52 (silica gel; petroleum ether/ethyl acetate/methanol=10:8:3)
Reaction SMILES: [Cl-].[C:2]1([N+:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.[NH2:17][C:18]1[N:19]=[C:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:21][C:22](=[O:24])[CH:23]=1.[OH-].[Na+]>O>[NH2:17][C:18]1[N:19]=[C:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:21][C:22](=[O:24])[C:23]=1[N:9]=[N:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#[N+]c1ccccc1
Reactant: Nc1cc(=O)[nH]c(Cc2ccccc2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Nc1ccccc1
Product: Nc1nc(Cc2ccccc2)[nH]c(=O)c1N=Nc1ccccc1
Reaction time: 1 h

Procedure:
A cold solution of benzenediazonium chloride (prepared by the method well known in the art, from 2 g. aniline) was added dropwise with stirring to a solution of 4-amino-2-benzylpyrimid-6-one (4 g.) and sodium hydroxide (1.6 g.) in water (50 ml.) at 5° C. After stirring for a further 1 hour, the solid was filtered off and recrystallised from a mixture of dimethylformamide and water (4:1 v/v) to give 4-amino-2-benzyl-5-phenylazopyrimid-6-one (3.8 g.) in the form of orange needles, which decomposed at 256°-257° C.
Reaction SMILES: [Li]CCCC.[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])#[CH:7].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:6]#[C:7][Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
n-BuLi (1.6 M, 24.4 mL, 39 mmol) was added dropwise to a solution of ethynyltrimethylsilane (4.0 g, 41 mmol) in THF (40 mL) at −78° C. and gradually warmed to 0° C. over 30 min. The reaction mixture was cooled to −78° C. again and tributyltin chloride (11.4 mL, 39 mmol) in THF (30 mL) was added dropwise to the resultant mixture. The reaction mixture was stirred for 18 h at room temperature and quenched with water (20 mL). The mixture was extracted with diethyl ether (2×100 mL) and the combined organic extracts were washed with brine (50 mL). The organic phase was dried and concentrated to give yellow oil (15.0 g, 95%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.67-1.45 (m, 6H), 1.45-1.20 (m, 6H), 0.98 (t, 6H, J=8.4 Hz), 0.90 (t, 9H, J=7.2 Hz), 0.16 (s, 9H).