Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10]12[O:15][CH:11]1[CH2:12][CH2:13][CH2:14]2>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[OH:15]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C1CC2OC2C1
Product: O[C@@H]1CCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Yield: 44 %

Procedure:
A solution of 50.0 g. (0.31 mole) of 3,4-dichloroaniline in 100 ml. of cyclopentene oxide is refluxed for 7 days. The solution is evaporated and the residue triturated with 250 ml. of petroleum ether (b.p. 30°-60° C.) five times to remove unreacted 3,4-dichloroaniline. The residue is treated with excess ethereal hydrogen chloride and the resulting crude hydrochloride salt is recrystallized twice from a methanol/ethyl ether mixture to give trans-2-(3,4-dichloroanilino)cyclopentanol, 38.7 g. (44% yield), m.p. 167°-168° C. The ultraviolet, infrared and nuclear magnetic resonance spectra are consistent with the structure of this product.
Reaction SMILES: [C:1]1([N:7]2[C:11]([B:12]([OH:14])[OH:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1.ClCCl>[C:1]1([N:7]2[C:11]([B:12]3[O:13][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:14]3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccnn1-c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Temperature: 40 °C
Reaction time: 48 h
Yield: 55.1 %

Procedure:
(1-Phenyl-1H-pyrazol-5-yl)boronic acid (25.0 g) was dissolved in toluene (700 mL), pinacol (18.0 g) was added thereto at room temperature, and the mixture was stirred at 40° C. for 2 days. The reaction mixture was diluted with dichloromethane, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was collected by filtration, and washed with hexane to give the title compound (19.8 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C@H:19]([CH2:22][OH:23])[O:18][C:17]=2[CH:24]=1.O>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:19]2[O:18][C:17]3[CH:24]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[O:21][CH2:20]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COc2ccc(Cl)cc2O1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(Cl)cc3O2)cc1
Reaction time: 4 h

Procedure:
4-Toluenesulphonyl chloride (5.9 g) was added to a solution of (S)-7-chloro-1,4-benzodioxan-2-ylmethanol (6.0 g; prepared by the method described above) in pyridine (40 ml) and the mixture stirred for 4 hours. More 4-toluenesulphonyl chloride (250 mg) was added, stirring continued for 2 hours, then further 4-toluenesulphonyl chloride (250 mg) was added and stirring continued for 1 hour. The mixture was poured into water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined extracts were washed with hydrochloric acid (2M; 2×200 ml), saturated aqueous sodium bicarbonate solution (2×200 ml) and brine (200 ml), then dried over magnesium sulphate. The solvent was removed in vacuo and the residue recrystallised from ether to give (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (7.00 g) m.p. 90-91° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[C:15]([CH2:29][NH2:30])=[CH:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1COCC1>[CH2:5]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[C:15]([CH2:29][NH:30][C:1](=[O:3])[CH3:2])=[CH:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCn1cc(CN)c2cc(-c3cccc(C)c3)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCn1cc(CNC(C)=O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Acetyl chloride (44 μl, 0.434 mmol) was added to a solution of (1-octyl-5-m-tolyl-1H-indol-3-yl)methanamine (220 mg, 0.628 mmol) and triethylamine (131 μl, 0.651 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to stir at room temp for 60 min, the precipitate formed was filtered off, the filtrate was concentrated, and the residue was subjected to column chromatography (silica gel, CH2Cl2) to give sulphonamide 23 in 65% yield.
Reaction SMILES: [N:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][N:12]=3)[C:7](=O)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)C>[CH:4]1[C:5]2[C:6]3[C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[N:12][C:13]=4[C:14]=2[N:1]=[CH:2][CH:3]=1)=[N:24][C:17]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:23]=3
Reactant: O=C1C(=O)c2cccnc2-c2ncccc21
Reactant: Nc1ccccc1N
Solvent: CCO
Product: c1ccc2nc3c4cccnc4c4ncccc4c3nc2c1
Reaction time: 0.08 h

Procedure:
1.0 g of 1,10-phenanthroline-5,6-dione in the Fourteen Preferred Embodiment was dissolved into 200 g of ethanol to prepare a solution. 1.0 g of o-phenylene diamine was dissolved into 100 ml of ethanol to prepare a solution. The latter solution was added into the former solution, and the mixed solution was current-circulated for 5 minutes. Then, the mixed solution was vacuum-concentrated to precipitate a crystal. The precipitated crystal was recrystallized by water-ethanol to obtain dipyrido (3,2-a:2',3'-c) phenazine. The melting point of dipyrido (3,2-a:2',3'-c) phenazine as the condensed polycyclic compound was 257° C. according to the DSC measurement.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
Acetic anhydride (30 mL) was added at room temperature dropwise to 3-chloro-4-fluoroaniline (13.0 g, 0.1 mol) and stirred for 3 h. The reaction mixture was poured on ice (300 g) and the solid was filtered and dried to afford N-(3-chloro-4-fluorophenyl)acetamide (18.4 g, 98%) as a white solid. mp 96-97° C.; IR (KBr) 3303, 1671 cm-1 ; 1H NMR (CDCl3) δ 2.20 (s, 3H, CH3), 7.05 (t, J=8.9 Hz, 1H), 7.28 (m,1H), 7.66 (d, J=4.6 Hz, 1H), 8.05 (s, 1H, NH); Mass (m/z) 187 (M+).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=2)(=[O:14])=[O:13])[CH2:8]1)(C)(C)C.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]2[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=2[C:47]=1[O:48][CH3:49]>>[Cl:28][C:27]1[C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([N:9]2[CH2:10][CH2:11][C@@H:7]([OH:6])[CH2:8]2)(=[O:13])=[O:14])=[N:23][C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=3[C:47]=2[O:48][CH3:49])=[N:25][CH:26]=1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine (150 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford an off-white foam. Mp: 90-2° C. LCMS (m/e) 603 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.37 (s, 1H), 8.49 (d, J=8 Hz, 1H), 8.16 (s, 1H), 7.98 (m, 2H), 7.61 (t, J=8 Hz, 1H), 7.52 (br s, 1H), 7.28 (m, 1H), 6.81 (m, 1H), 4.37 (m, 1H), 3.74 (s, 3H), 3.61 (m, 2H), 3.42 (m, 3H), 3.29 (m, 1H) 2.98-2.68 (m, 7H), 2.09-1.73 (m, 8H), 1.60 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:20][C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][N:17]=1.Cl>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[S:20][C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][N:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (275 mg, 1.18 mmol) in pyridine (5 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (200 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 156-157° C., in 76% yield (312 mg, 0.81 mmol); 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, 3H, J=7.0 Hz), 2.07 (s, 3H), 4.06 (s, 2H), 4.15 (q, 2H, J=7.0 Hz), 7.72 (m, 4H), 10.29 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 24.1, 35.7, 61.3, 118.6, 127.0, 135.5, 142.9, 151.6, 167.8, 168.1, 169.0; MS (LCQ, ESI+) Calcd for C14H17N4O5S2 385.1, found 385.1 (M+H)'; HRMS (ESI+, m/z) Calcd for C14H17N4O5S2 385.0640, found 385.0638 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7])#[N:2].[CH3:12][Mg]Br>C1COCC1>[F:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:12])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: C[Mg]Br
Reactant: N#Cc1cc(C=O)ccc1F
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)c(C#N)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
3-Cyano-4-fluorobenzaldehyde (2.17 g, 14.7 mmol) was dissolved in THF (50 mL) then cooled to −70° C. To this mixture was added methyl magnesiumbromide (5.34 mL, 16.0 mmol). The mixture was stirred for 1 h, then was quenched with brine and extracted with ether. The ethereal layer was separated, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by MPLC chromatography through a 120 g Redi-sep column using 0-50% EtOAc/hexane eluent to yield 2-fluoro-5-(1-hydroxyethyl)benzonitrile: LC-MS: M+1=166.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH:17]=[CH:18][C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C(OCC)(=O)C.CN(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][C@H:12]1[CH:17]=[CH:18][C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ccnc1C=C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CN(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccnc1C=C[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-[2-(1-methylimidazol-2-yl)vinyl]pyrrolidine (5.45 g) in a mixture of ethyl acetate (60 ml) and trimethylamine (3.01 ml) was added dropwise methanesulfonyl chloride (1.42 ml) under ice-cooling with stirring and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added ethyl acetate (100 ml) and water (50 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[2-(1-methylimidazol-2-yl)vinyl]pyrrolidine (5.70 g).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][C:5](=[O:8])[O:6][CH3:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]#[N:33]>C1COCC1>[C:16]([O:15][C:13]([NH:1][C@@H:2]([CH2:3][CH:4]([CH2:31][C:32]#[N:33])[C:5]([O:6][CH3:7])=[O:8])[C:9]([O:11][CH3:12])=[O:10])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
To a solution of Boc-Glu(OMe)-OMe (20.0 g., 72.6 mmol) in THF (50 mL) was added dropwise a solution of LiHMDS (26.3 g, 157 mmol) in THF (250 mL) at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1.5 h and bromoacetonitrile (13.0 g, 108 mmol) was added dropwise over 1 h while maintaining the temperature below −70° C. The reaction mixture was stirred at −78° C. for 2 h and quenched with pre-cooled methanol (10 mL) in one portion. The mixture was stirred for 10 min and then treated with a pre-cooled solution of acetic acid (9 mL) in THF (60 mL). The mixture was stirred for 10 min and poured into brine (200 mL). The resulting mixture was extracted with EtOAc (300 mL×2) and the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=1:1) to afford (2S)-dimethyl 2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate (16.0 g, 70% yield) as a light brown oil.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1.C(O)[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][C:25]4[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=4)=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1
Agent: Cl
Product: COc1ccc2[nH]c3c(c2c1)CCNC3C1(C(=O)OCc2ccccc2)CCC1

Procedure:
The procedure is as in Example 23, using as substrate the product of Example 7 and as reagent benzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[C:26]1NN=[N:28][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=2[Cl:18])=[N:27][N:28]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Clc1cccc(-c2nnn[nH]2)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2cccc(Cl)c2Cl)o1
Yield: 36.6 %

Procedure:
The title compound (0.70 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.13 g), 5-(2,3-dichlorophenyl)tetrazole (1.0 g) and dicyclohexylcarbodiimide (0.98 g) according to the method of description 1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[C:23]=4[F:26])[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(F)c(F)c2F)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (13 mg, 15%), MS (ISP) m/z=342.4 [(M+H)+], mp 294° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 2,3,4-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1
Reactant: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(/C=C/c2ccccc2)nc2c1CCC(=O)N2
Yield: 90.9 %

Procedure:
To a suspension of 4-chloro-2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.45 g, 1.58 mmol) in MeOH (10 mL) was added NaOMe (0.094 g, 1.74 mmol). The reaction mixture was heated at reflux for 3 h, at which time an additional 0.10 g NaOMe was added and refluxing was continued. This was repeated two more times over 9 h. After the disappearance of all starting material (LCMS), the reaction was concentrated onto silica gel and purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as an off-white solid (0.404 g, 91%).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4](OCC)=[O:5].O.[NH2:20][NH2:21]>C(O)C>[CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4]([NH:20][NH2:21])=[O:5]
Reactant: NN
Reactant: CCOC(=O)C(OC)c1cccc2ncccc12
Solvent: O
Solvent: CCO
Product: COC(C(=O)NN)c1cccc2ncccc12
Temperature: 85 °C
Yield: 76.7 %

Procedure:
To a solution of ethyl 2-methoxy-2-(quinolin-5-yl)acetate (0.9 g, 3.67 mmol) in absolute ethanol (25 mL) was added hydrazine hydrate (1.0 mL, 20.5 mmol) and the mixture was heated at 85° C. for 18.5 hours. After cooling to room temperature, the mixture was poured into ice-water (˜150 mL) then concentrated in vacuo. The residue was taken up in EtOAc, washed with diluted brine once, water twice then brine. The organics were dried over Na2SO4 and concentrated in vacuo to give 2-methoxy-2-(quinolin-5-yl)acetohydrazide as an off-white foam (0.651 g, 77% yield) that was used without further purification.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[OH:63])[CH3:56]>C(Cl)(Cl)Cl>[Br:1][C:61]1[CH:60]=[CH:59][C:58]([OH:63])=[C:57]([CH2:55][CH3:56])[CH:62]=1
Reactant: CCc1ccccc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1O
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A solution of tetrabutyl ammonium tribromide (19.7 g, 41 mmol) in CHCl3 (100 mL) was added to a stirred solution of 2-ethylphenol (5 g, 41 mmol) dissolved in CHCl3 (150 mL). The reaction mixture was stirred for 2 hrs and then quenched with 5% solution of sodium thiosulfate (150 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (0–10% EtOAc in hexanes) to give the desired product (8.1 g, 98%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2 H), 6.64 (d, J=8.5 Hz, 1 H), 7.17 (dd, J=8.5, 2.5 Hz, 1 H), 7.24 (d, J=2.5 Hz, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)[CH:26]=[CH:25][N:24]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[CH:30]=3)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of acryloyl chloride (37 μL, 0.45 mmol) in CH2Cl2 (2.32 mL) was added dropwise over 5 minutes to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 143, 189 mg, 0.43 mmol) in CH2Cl2 (5.8 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (67 mg, 32%) as an pale yellow solid after trituration with diethyl ether; 1H NMR: 2.29 (3H, s), 2.36-2.41 (2H, m), 2.53-2.58 (2H, m), 2.98-3.02 (2H, m), 3.90 (3H, s), 3.91 (3H, s), 5.69-5.73 (2H, m), 6.22 (1H, dd), 6.52 (1H, dd), 6.86 (1H, s), 7.20-7.28 (3H, m), 7.52-7.55 (1H, m), 7.88 (1H, s), 8.33-8.37 (2H, m), 8.43 (1H, s), 8.45 (1H, s), 9.34 (1H, s); m/z: ES+ MH+ 495.70.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(OC)C(CC)=CC=2)=[O:8])C=CC=CC=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([O:51][CH3:52])=[C:32]([C:40]([CH2:43][S:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:41][CH:42]=2)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:26]1>>[C:45]1([S:44]([CH2:43][C:40]2[C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:31]([O:51][CH3:52])[C:30]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)=[CH:42][CH:41]=2)=[O:8])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Product: COc1c(-c2ccoc2)ccc(CS(=O)c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 2, starting from t-butyl 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoate (Intermediate 222).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19].[K+].[Br-]>C(O)C>[CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Clc1ncnc2c1ncn2OCc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Nc1ncnc2c1ncn2OCc1ccccc1

Procedure:
A solution of 9-benzyloxy-6-chloropurine (38.4 g; 0.147 mmol) in ethanol (300 ml) saturated with ammonia was heated at 100° C. in an autoclave for 16 hours. After cooling the suspension was evaporated to dryness and the residue partitioned between chloroform (750 ml) and water (500 ml). The separated aqueous phase was washed with chloroform (200 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated, affording an orange solid homogeneous on t.l.c. (31.1 g, 87%). IR: νmax (KBr) 3372, 3300, 3187, 3038, 1660, 1637, 1600, 1581 cm-1 ; 1H NMR: δH [(CD3)2SO] 5.3(2H, s, CH2Ar), 6.8(2H, br.s, D2O exchangeable, NH2), 7.3(6H, s, H-8, Ar), 7.7(1H, s, H-2). Found: C, 59.39; H, 4.60; N, 29.07%; m/e 241 0949. C12H11N5O requires: C, 59.73; H, 4.60; N, 29.03%; m/z 241.0964.
Reaction SMILES: [N:1](=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]1=[O:15])O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Pd]>[C:16]([NH:1][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]1=[O:15])(=[O:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(=O)C(=NO)CC2
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Product: COc1ccc2c(c1)C(=O)C(NC(C)=O)CC2
Reaction time: 3 h

Procedure:
A mixture of 2-oximino-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (8.7 gm, 0.04 m), palladium on carbon (10%, 1 gm) tetrahydrofuran (150 ml) and acetic anhydride (25 ml) was hydrogenated on a Parr apparatus for 3 hours. The catalyst was filtered, and the solvents were removed under reduced pressure to yield the product as an oil, which was used in the next step without further purification.