Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]([CH3:53])([CH:50]([CH3:52])[CH3:51])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45](Br)[CH:44]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28].CC1(C)C(C)(C)OB([C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[NH2:1][C@:2]([CH3:53])([CH:50]([CH3:52])[CH3:51])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:62]3[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=3)[CH:44]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)C)[C@H](n4ncnc4-c4ccnc(Br)c4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)C)[C@H](n4ncnc4-c4ccnc(-c6ccncc6)c4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 135 °C
Reaction time: 0.28 h
Yield: 82.5 %

Procedure:
(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-14-[5-(2-bromo-4-pyridinyl)-1H-1,2,4-triazol-1-yl]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 175, 10.1 mg, 0.011 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (29.2 mg, 0.142 mmol), palladium(II) acetate (1.8 mg, 8.02 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′biphenyl (4.3 mg, 9.02 μmol), cesium carbonate (46.1 mg, 0.141 mmol), and 1,4-dioxane (0.5 ml) were combined in a 0.5-2 ml microwave vial. The reaction mixture was purged with nitrogen before the vial was sealed. The reaction mixture was heated at 135° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered (0.45 μm syringe filter), diluted with methanol, and evaporated under reduced pressure to give a light brown residue. The residue was dissolved in methanol and purified using a single HPLC run on a 30×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 20 ml/min and the HPLC method employed a 17 minute 20%-100% acetonitrile/water gradient followed by a 2 minute acetonitrile flush. The product fractions were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give the title compound (7.2 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6](N)=[CH:5][CH:4]=1.N([O-])=O.[Na+].[I-:18].[K+]>OS(O)(=O)=O.O>[I:18][C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(N)c(C(F)(F)F)n1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1ccc(I)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 220 %

Procedure:
6-methoxy-2-(trifluoromethyl)pyridin-3-amine (1 g) was dissolved in H2SO4 (3 ml) and a dropwise addition of sodium nitrite (718 mg) in H2O (3 ml) was made to reaction mixture at 0° C. After 2 hour of stirring at 0° C., it was raised to room temperature. Potassium iodide (1.73 g) in H2O (3 ml) was added to the reaction mixture in a drop-wise fashion. It was heated to 60° C. for 3 hour. It was extracted with ethyl acetate, washed with sodium thiosulfate solution (Sat.), dried (MgSO4), filtered and concentrated. The flash column chromatography (SiO2, 1˜5% EtOAc in heptane) gave the title compounds (3.47 g, 67%). 1H NMR (CDCl3) δ 3.97, 6.68; 8.08; 19F NMR (CDCl3) δ 66.16; IR (liq.) 2478 (w), 2364 (w), 2230 (w), 2173 (w), 2026 (w), 1585 (s), 1471 (s), 1422 (s), 1396 (s), 1338 (s), 1280 (s), 1238 (s), 1200 (s), 1180, 1140 (s) cm−1 Anal. Calcd for C7H5F3INO: C, 27.75; H, 1.66; N, 4.62; F, 18.81. Found: C, 27.93; H, 1.80; N, 4.62.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH:19]([O:27][CH3:28])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[OH:26]>CC#N>[CH3:28][O:27][CH:19]([O:18][CH3:17])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[O:26][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: COC(OC)c1ccncc1O
Reactant: N#Cc1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(OC)c1ccncc1OCc1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 6-(bromomethyl)pyridine-3-carbonitrile (3 g, 15.23 mmol, 1.00 equiv) in CH3CN (100 mL). Potassium carbonate (4.24 g, 30.68 mmol, 2.00 equiv) and 4-(dimethoxymethyl)pyridin-3-ol (2.83 g, 16.73 mmol, 1.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 50° C., and then it was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.4 g (32%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[N:17]1)[N:9]=[CH:8][N:7]=[CH:6]2.CN(C=O)C.S(Cl)([Cl:28])=O>>[Cl:28][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH:20]=[CH:19][N:18]=[N:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2cncnc2cc1OCCn1ccnn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCn1ccnn1
Temperature: 80 °C
Yield: 71 %

Procedure:
A solution of 6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (920 mg, 3.2 mmol) in thionyl chloride (10 ml) containing DMF (0.9 ml) was heated at 80° C. for 1 hour. After evaporation of the volatiles, the residue was azeotroped with toluene. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with solid sodium hydrogen carbonate. The organic layer was washed with water, brine, dried (MgSO4), and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4) to give 4-chloro-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (693 mg, 71%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]2[N:21]=[N:22][NH:23][N:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:43]=[CH:44][CH:45]=1)[O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[N:21]=[N:22][N:23]([CH2:32][CH2:33][C:34]3[CH:35]=[C:36]([CH:43]=[CH:44][CH:45]=3)[O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[N:24]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(C(c2ccccc2)c2nn[nH]n2)cc1
Reactant: COC(=O)COc1cccc(CCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(CCn2nnc(C(c3ccccc3)c3ccccc3)n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Diethyl azodicarboxylate (0.96 g, 5.5 mmol) was added to a stirred solution of 5-(diphenylmethyl)-2H-tetrazole (1.00 g, 4.2 mmol), methyl [3-(2-hydroxyethyl)phenoxy]acetate (0.98 g, 4.6 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) in dry THF (17 mL) cooled to 0° C. in an ice bath. The ice bath was removed and the mixture stirred at room temperature for 1 hour before the solvent was evaporated. The residue was chromatographed on a column of silica gel using a mixture of hexanes and ethyl acetate (3:1) to give methyl [3-[2-[5-(diphenylmethyl)-2H-tetrazol-2-yl]ethyl]phenoxy]acetate (1.06 g, 58%) as a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[C:9]([CH3:26])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[ClH:27]>O1CCOCC1.CCOCC>[ClH:27].[ClH:27].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[C:9]([CH3:26])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To tert-butyl 4-(4-(cyclopropylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (1.490 g, 4.15 mmol) was added Hydrochloric acid solution (8.72 mL, 34.9 mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30 min. The resulting suspension was diluted with Et2O (10 mL), filtered, rinsed with Et2O (3×5 mL), and the resulting solid was dried in vacuo to provide N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (1.37 g, 4.15 mmol, 100% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.61 (m, 2H) 0.61-0.70 (m, 2H) 2.28 (s, 3H) 2.82 (tq, J=7.41, 3.99 Hz, 1H) 3.02-3.13 (m, 4H) 3.14-3.29 (m, 4H) 7.05 (d, J=8.34 Hz, 1H) 7.62-7.69 (m, 2H) 8.32 (d, J=4.29 Hz, 1H) 9.38 (br. s., 2H). ESI-MS: m/z 260.2 (M+H)+. mp=171.5-172.8° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: ClCC1CO1
Reactant: Cc1ccc(C2=NNC(=O)CC2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(C2=NNC(=O)CC2)cc1OCC1CO1
Yield: 77 %

Procedure:
A mixture of powdered 6-(3-hydroxy-4-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone (5.0 g, 0.024 mole), epichlorohydrin (19.3 ml, 0.24 mole), and piperidine (0.2 ml) was heated on a steam bath for 1 hour. Evaporation of the solution under reduced pressure gave an oil which was dissolved in a small volume of dichloromethane and stirred with dilute sodium hydroxide solution (15 ml). The organic phase was washed with water, dried, and evaporated to an oil which under reduced pressure gave a solid, 6.2 g, 98%. Trituration with ethanol-ether gave crude 6-[3-(2,3-epoxypropoxy)-4-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone 4.81 g, 76%, m.p. 128°-132°C. Purification, by recrystallisation from ethanol, or by column chromatography (silica, chloroform) gave the pure epoxide, m.p. 140°-142.5°C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:6]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:20]3[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(C(F)(F)F)c3)cs2)CC1
Yield: 47.9 %

Procedure:
A solution of 2-bromo-4-[3-(trifluoromethyl)phenyl]-1,3-thiazole (2.88 g, 9.35 mmol), tert-butyl piperazine-1-carboxylate (3.48 g, 18.7 mmol) and potassium carbonate (1.29 g, 9.35 mmol) in dimethylformamide (30 ml) was stirred at 120° C. for 12 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.85 g (47.9%) of the desired product as an oil.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[N:11][CH:10]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)=[N:11][CH:10]=1
Reactant: OCc1ccncn1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccncn2)n1
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
Into 4 g of N,N-dimethylformamide were dissolved 304 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 200 mg of 4-pyrimidylmethyl alcohol, 87 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 15 minutes. After stirring for 2 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 210 mg of 5-(4-pyrimidylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (39)).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: Brc1ccccn1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccccn4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromopyridine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[C:15]2/[C:16](=[O:37])[N:17]([CH2:24][C:25]3[CH:30]=[C:29]([O:31]C)[C:28]([O:33]C)=[C:27]([O:35]C)[CH:26]=3)[C:18]3[C:23]/2=[CH:22][CH:21]=[CH:20][CH:19]=3)/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=CC(/C(=C2\C(=O)N(CC3C=C(OC)C(OC)=C(OC)C=3)C3C\2=CC=CC=3)/C2C=CC=CC=2)=CC=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[C:15]2/[C:16](=[O:37])[N:17]([CH2:24][C:25]3[CH:26]=[C:27]([OH:35])[C:28]([OH:33])=[C:29]([OH:31])[CH:30]=3)[C:18]3[C:23]/2=[CH:22][CH:21]=[CH:20][CH:19]=3)/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc(OC)c1OC
Agent: BrB(Br)Br
Agent: COc1cc(CN2C(=O)/C(=C(/c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc(OC)c1OC
Solvent: ClCCl
Product: O=C1/C(=C(\c2ccccc2)c2ccc(Cl)cc2)c2ccccc2N1Cc1cc(O)c(O)c(O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-one and 3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-one (317 mg, 0.62 mmol) in dichloromethane (5 ml) was added a solution of boron tribromide (1M in CH2Cl2, 3 ml) at room temperature. The mixture was stirred at room temperature for 5 h. After being quenched by pouring into ice water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with (hexane/ethyl acetate=1/1) to give 3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one (60 mg). 1H NMR (300 Hz, CDCl3): δppm 4.66 (s, 2H), 5.60 (b, 1H), 6.31 (s, 2H), 6.56 (d, 1H), 6.67-6.82 (m, 2H), 7.00-7.23 (m, 8H), 7.38 (d, 2H); and 3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one (40 mg). 1H NMR (300 Hz, CDCl3): δppm 4.72 (s, 2H), 5.33 (b, 1H), 6.05 (b, 1H), 6.40 (s, 2H), 6.44 (d, 1H), 6.67 (t, 1H), 6.82 (d, 1H), 7.00 (d, 2H), 7.10-7.15 (m, 3H), 7.23-7.26 (m, 2H), 7.37-7.46 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[C:18]#[N:19])[CH2:5][CH2:4]1)[CH3:2].N#N>CCO.CCOC(C)=O.[Pd]>[NH2:15][C:11]1[C:10]([C:18]#[N:19])=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCN1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1CCN(c2cccc(N)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-Ethylpiperazinyl)-6-nitrobenzenecarbonitrile (1.0 eq) was dissolved in EtOH and EtOAc. The flask was purged with N2, and 10% Pd/C (0.1 eq) was added. The flask was evacuated and purged with H2 three times. The resulting mixture was stirred overnight at room temperature. The mixture was filtered through Celite, and the filter pad was washed with EtOAc. The solvent was removed in vacuo to provide the desired product as a yellow solid. LC/MS m/z 231.2 (MH+), Rt 1.42 minutes.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11](Br)[C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:17])=[C:11]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)c(Cl)c(SCc2ccccc2)c1
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1c1cc(F)cc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 35 (4 g, 12.06 mmol) was coupled with piperidin-2-one (1.434 g, 14.47 mmol) in close analogy to the procedure described in step 1.6). After workup the crude oil is purified by chromatography on silica gel (n-heptane-ethyl acetate 4:1).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1(C)[CH2:16][CH2:15][CH2:14]1)[N:8]([CH:18]1[CH2:20][CH2:19]1)[C:7]2=[O:21].[CH3:23][C@@H:24]1[C:28]2[NH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][C:27]=2[C:26](=[O:41])[NH:25]1>>[CH:18]1([N:8]2[C:7](=[O:21])[C:6]3[C:11](=[C:2]([C:30]4[NH:29][C:28]5[C@@H:24]([CH3:23])[NH:25][C:26](=[O:41])[C:27]=5[CH:31]=4)[C:3]([F:22])=[CH:4][CH:5]=3)[N:10]=[C:9]2[NH:12][C:13]2([CH3:16])[CH2:14][CH2:15]2)[CH2:19][CH2:20]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CCC1
Product: C[C@H]1NC(=O)c2cc(-c3c(F)ccc4c(=O)n(C5CC5)c(NC5(C)CC5)nc34)[nH]c21
Yield: 51.7 %

Procedure:
(R)-3-Cyclopropyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (78 mg, 50% yield) as a light yellow solid was prepared according to the procedure described for Example 495, using 8-bromo-3-cyclopropyl-7-fluoro-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (498a; 137 mg, 0.37 mmol) and boronic ester 705 (147 mg, 0.45 mmol) as starting material. MS (ESI, pos. ion) m/z: 422 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (1H, s), 7.86 (1H, dd, J=8.8, 6.3 Hz), 7.66 (1H, s), 6.98-7.14 (2H, m), 6.51 (1H, d, J=1.8 Hz), 4.57 (1H, q, J=6.6 Hz), 2.72-2.84 (1H, m), 2.35-2.44 (2H, m), 2.06 (2H, dt, J=12.3, 6.1 Hz), 1.78-1.91 (2H, m), 1.59 (3H, s), 1.39 (3H, d, J=6.7 Hz), 1.16-1.31 (2H, m), 0.75-0.83 (2H, m).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([O:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:48][CH2:47][C:46]4[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=4[NH:44][C:43]3=[O:53])[CH2:38][CH2:37]2)=[O:35])[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9]>CO>[O:53]=[C:43]1[N:42]([CH:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C@H:11]([CH2:10][C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([Cl:2])[CH:4]=3)[C:12](=[O:13])[N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:35])[CH2:37][CH2:38]2)[CH2:48][CH2:47][C:46]2[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=2[NH:44]1
Reactant: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1Cl
Agent: Cl
Solvent: CO
Product: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 mL 1 M HCl were added to a solution of 130 mg (0.14 mmol) tert-butyl 4-(1-{(R)-3-(3-chloro-4-methyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate (Example 99) in 1 mL MeOH and the reaction mixture was stirred for 24 h at RT.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)C>[NH:19]1[CH2:18][CH2:17][CH:16]([CH:15]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]3[CH:22]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution 66.27 g (0.21 mole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta(1,2-b]pyridin-11-ylidene)-piperidine (product from Preparative Example 1 Example, step G), in THF (1 L) was added lithium aluminum hydride (24.32 g, 0.64 mole) and the reaction mixture was heated to reflux overnight. The reaction mixture was then cooled to room temperature and ˜3 L of diethyl ether is added followed by dropwise addition of saturated sodium sulfate until a white gray precipitate forms. MgSO4 was then added to the separated organic layer and stirred for 30 minutes. All the volatiles were then removed and the resulting crude mixture was chromatographed on a silica gel column eluting with 10% MeOH saturated with ammonia in CH2Cl2. The material obtained contained both the desired compound and the des-chloro compound. Separation on HPLC using reverse phase column and eluting with 40% MeOH-water afforded the desired compounds as white solids (Product A's mp=95.2-96.1° C., Product B's mp=145.1-145.7° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:16][CH:17]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Br)nc4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
To a solution of 6-bromonicotinic acid (0.16 g, 0.78 mmol) in dry THF (5 ml) was added under an atmosphere of argon 1,1′-carbonyldiimidazole (0.13 g, 0.78 mmol) and the reaction mixture stirred at room temperature for 5 h. To the reaction mixture was added 2-(4-aminophenyl)-6-methoxybenzothiazole (0.2 g, 0.78 mmol) over 2 mins, stirring continued at room temperature for 1 h, then heated under reflux for 18 h. After cooling to room temperature, the reaction mixture was diluted with Et2O (30 ml) and the precipitate was collected by filtration, washed with Et2O (50 ml) and dried under high vacuum to give the title compound (0.101 g, 29%) as an orange solid.