Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([NH:19][C@@:20]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]4[C@H:21]3[C@H:22]4[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: C=C1C[C@@](N)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@@](NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add solid 9-fluorenylmethyl chloroformate (3.15 g, 12.2 mmol) portion wise over 5 minutes to a stirred solution of diethyl (1S,2S,5R,6S)-2-amino-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.8 g, 11.1 mmol) and sodium bicarbonate (2.04 g, 24.3 mmol) in tetrahydrofuran (28 mL) and water (8.4 mL) cooled to 0-5° C. After 1 hour, add water (10 mL) and extract with ethyl acetate (50 mL). Wash the extract with brine solution (20 mL), dry, filter and evaporate to a pale yellow oil (6.5 g). Purify by flash chromatography eluting with ethyl acetate:iso-hexane (10:90 to 20:80) to give a viscous colorless oil (4.58 g). Repurify by flash chromatography eluting with ethyl acetate:iso-hexane (20:80) to give a white semi-solid foam of title compound (4.22 g, 80%). MS (m/z): 476 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[K+].[CH:14]([B-](F)(F)F)=[CH2:15]>>[Cl:12][C:4]1[CH:3]=[C:2]([CH:14]=[CH2:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: [K+]
Product: C=Cc1ccc(C(=O)OC)c(Cl)c1

Procedure:
The title compound was prepared from methyl 4-bromo-2-chlorobenzoate and vinyltrifluoroborate potassium salt according to the procedure for the preparation of Example 135, part A. 1H NMR (400 MHz, CDCl3): δ 3.92 (3H, s), 5.41 (1H, d, J=11.2 Hz), 5.85 (1H, d, J=9.2 Hz), 6.66 (1H, dd, J=11.2 Hz, 17.6 Hz), 7.32 (1H, d, J=8.0 Hz), 7.47 (1H, s), 7.81 (1H, d, J=8.0 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([NH:17][C:18]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: CC(C)(C)N=C=S
Solvent: CCOCC
Product: CC(C)(C)NC(=S)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added a solution of 3.45 g. of tert-butyl isothiocyanate in 50 ml. of anhydrous ether. The mixture is stirred for 30minutes and the resulting solid is collected and recrystallized from 50 ml.of ethanol, giving 5.85 g. of the desired product as white crystals, m.p. 153°-156° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4]([O:9][C:10]2C=CC=CC=2)=[CH:5][CH:6]=[CH:7][CH:8]=1.N.C[OH:19]>>[NH2:1][C:2]1[C:8](=[O:19])[CH:7]=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Nc1ccccc(Oc2ccccc2)c1=O
Reactant: CO
Agent: N
Product: COc1cccc(=O)c(N)c1
Temperature: 80 °C

Procedure:
A solution of 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one [described above in (b), 2.4 g] in methanol (70) is cooled to -25° C and saturated with ammonia gas. The solution is heated in a pressure bottle at 80° C for 4 hours and cooled to -70° C. The pressure bottle is opened and the solvent is evaporated to give 2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[H-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]([C:2]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(O)c1cc(Cl)ccc1Oc1cccc(C(F)(F)F)c1
Yield: 32.6 %

Procedure:
2,5-Dichlorobenzoic acid (5 g) and 3-trifluoromethylphenol (4.24 g) were dissolved in xylene and the solution placed under dry oxygen-free nitrogen. Sodium hydride (1.25 g) was slowly added and when effervescence had ceased, cuprous bromide was added and the solution or suspension refluxed for 6 hours. The xylene was removed by low pressure distillation. The solid residue was treated with water and acidified with dilute hydrochloric acid. The resulting oil was extracted into diethyl ether and the ether removed by low pressure distillation to give a light yellow solid which was recrystallised from diethyl ether/petroleum ether to give the title compound (2.7 g), mp, 124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][CH:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:31][CH2:30][CH:29]([CH3:33])[CH3:28])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)NCCC(C)C)nc2n1
Yield: 80.6 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3 g) in anhydrous dimethylformamide (65 cc), N,'-carbonyldiimidazole (1.3 g) and 3-methylbutylamine (0.61 g). After recrystallization in ethanol, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-(3-methylbutyl)acetamide (2.45 g), m.p. 136° C., is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[O:1]=[C:2]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)([CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CCCCCBr
Reactant: O=C1C(Cc2ccncn2)c2ccccc2N1c1ccccc1
Product: N#CCCCCC1(Cc2ccncn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 68 %

Procedure:
By substituting 2,3-Dihydro-2-oxo-1-phenyl-3-(4-pyrimidinylmethyl)1H-indole and 5-bromopentanenitrile in Example 1, the desired product was obtained in 68% yield as an oil; NMR(CDCl3TMS): δ1.21 (m, 1H); 1.35 (m, 1H); 1.60 (m, 1H); 1.65 (m, 1H); 2.00 (m, 1H); 2.20 (m, 1H); 2.26 (m, 2H); 3.25 (d, 1H, J=14 Hz); 3.55 (d, 1H, J=14 Hz); 6.65 (d, 1H, J=8 Hz); 6.98 (m, 1H); 7.09 (m, 2H); 7.21 (m, 1H); 7.27 (m, 2H); 7.42 (m, 1H); 7.51 (t, 2H, J=7 Hz); 8.44 (d, 1H, J=5 Hz); 8.90 (s, 1H); IR(KBr): 1718, 1612, 1583, 1549, 1500, 1481, 1465, 1454, 1376, 1326, 1221, 758, 733, 700 cm-1 ; mass spec m/e 383 (M+1). HRMS: m/e calcd 383.187187, m/e found 383.185396 (M+H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C1CCN2C(=NCCC2)CC1>C(O)(C)C>[N:17]1([CH2:16][CH2:15][CH2:14][S:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: O=C1CCc2cc(S)ccc2N1
Reactant: BrCCCn1cncn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: O=C1CCc2cc(SCCCn3cncn3)ccc2N1

Procedure:
2.4 Grams (13.4 mM) of 6-mercapto-3,4-dihydrocarbostyril, 3,3 g (17.4 mM) of 1-(3-bromopropyl)-1,2,4-triazol, and 2.6 ml (17.4 mM) of DBU were added to 60 ml of isopropanol, and the whole mixture was refluxed by heating for 2 hours. After the reaction was completed, the reaction mixture was concentrated, the resulting residue was extracted with chloroform. The chloroform extract was washed with water, an aqueous solution saturated with sodium hydrogen carbonate, and water in this order, then dried with anhydrous sodium sulfate. The dried extract was concentrated by removing the solvent by evaporation, the residue was purified by means of a silica gel column chromatography (eluent: dichloromethane: methanol=20:1), and recrystallized from ethanol-n-hexane to yield 2.5 g of 6-[3-(1H-1,2,4-triazol-1-yl)propylthio]-3,4-dihydrocarbostyril. Colorless needle-like crystals.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=O>C(O)C>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: O=C(NN=Cc1ccc2ccccc2n1)c1ccccc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 4.08 gm (0.03 mole) of benzhydrazide, 4.72 gm (0.03 mole) of 2-quinolinecarboxaldehyde and 100 ml of absolute ethanol is refluxed 4 hr. The hot solution is filtered and cooled slowly to room temperature. The mixture is chilled. The crystals which separate are collected, washed with ether and dried to give 4.06 gm (50%) of the title compound having a melting point of 170.7° C.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].[SH:15][CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:21]([O:20][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[CH2:18][CH2:17][CH2:16][S:15][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5])[CH3:22]
Reactant: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Reactant: CCO[Si](CCCS)(OCC)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCO[Si](CCCSC(C)CC(=O)C1C(C)=CCCC1(C)C)(OCC)OCC
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
A solution of α-damascone (9.60 g; 50.0 mmol) and 3-mercaptopropyltriethoxysilane (95% pure, 12.52 g, 50.0 mmol) in THF (40 ml) was treated with DBU (1.52 g, 10.0 mmol) and stirred at 40° C. for 90 min. The reaction solution was treated with 5% HCl, extracted twice with ether, washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl, dried over Na2SO4 and concentrated at 70° C./0.01 mbar. The reaction yielded 21.2 g (99%). of crude product:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]([CH3:22])[C:12](=[O:19])[CH:11]=1
Reactant: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-5-nitropyridin-2(1H)-one (1.28 g, 3.41 mmol) was dissolved in dry DMF (20 mL) and cooled to 0° C. under an ice-bath. To the solution was added NaH (60% in oil) (168 mg, 4.2 mmol) portion-wise. The resulted mixture was stirred at 0° C. for 1 hour, followed by the addition of methyl iodide (260 uL, 4.17 mmol) drop-wise through a syringe. The solution was allowed to warm to room temperature and stirred for 16 hours. Water (20 mL) was added slowly and stirring was continued for 30 minutes. The resulted yellow precipitate was filtered, dried under vacuum at 40° C. for 5 hours, and used for the next reaction without further purification. (1.017 g, 77% yield)
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:19]([O-])=O)=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:6].[H][H]>CO.[C].[Pd]>[NH2:19][C:3]1[C:2]([OH:1])=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[O:6]
Reactant: COc1ccc(NC(=O)c2cccc(O)c2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NC(=O)c2cccc(O)c2N)cc1
Yield: 93.8 %

Procedure:
3-Hydroxy-4′-methoxy-2-nitrobenzanilide (1.15 g) was suspended in 50 ml of methanol, 300 mg of 10% palladium-carbon powder were added and the mixture was stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through Celite and washed with methanol and the filtrate was concentrated in vacuo to give 966 mg of 2-amino-3-hydroxy-4′-methoxybenzanilide.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]([O:16]CC)=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.Cl.[O:23]1C=CN=C1.CO>O1CCCC1>[C:14]([C:11]1[C:12]([F:13])=[C:6]([OH:5])[C:7]([NH:8][C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:23])=[C:9]([C:20]#[N:21])[C:10]=1[CH3:19])(=[O:16])[CH3:15]
Reactant: c1cocn1
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1c(C)c(C#N)c(NC(=O)C2CC2)c(O)c1F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-78) (1.0 g, 3.49 mmol) was dissolved in tetrahydrofuran (10 ml), aqueous 1 N hydrochloric acid solution (2.0 ml) was added, followed by stirring at room temperature for 19 hours. At this point in time, it was known that a mixture with an oxazole-opened compound is given, and for complete ring opening, methanol (5 ml) was added followed by stirring overnight at room temperature. The solvent was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, followed by fractionation with water.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]([C:55]#[N:56])[CH:51]=[C:52]([F:54])[CH:53]=1.C1(C)C=CC=CC=1.[CH2:64]([O:66]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:65]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:64]([C:48]1[CH:49]=[C:50]([C:55]#[N:56])[CH:51]=[C:52]([F:54])[CH:53]=1)(=[O:66])[CH3:65]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(F)cc(C#N)c1

Procedure:
Under an argon atmosphere, 824 mg (0.900 mmol) of tris(dibenzylideneacetone)dipalladium and 1.23 g (1.98 mmol) of rac-1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) are added to 9.00 g (45.0 mmol) of 3-bromo-5-fluorobenzenecarbonitrile in toluene (300 mol). After the addition of 19.5 g (54.0 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 300 ml of THF. After the addition of 100 ml of an aqueous 2N hydrogen chloride solution, the mixture is stirred at room temperature for 2 h. The reaction mixture is subsequently neutralized using a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9:1). 7.11 g (97% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].C(N(CC)CC)C.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[O:3][CH2:1][CH3:2])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 100.5 %

Procedure:
To a stirred solution of 0.362 g of 2-ethoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0,500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.890 g of solid which is crystallized from ethyl acetate to give 0.540 g of the desired product as a white solid, m.p. 160°-176° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[CH3:32][C:33](OC(C)=O)=[O:34]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH:14][C:33](=[O:34])[CH3:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCN)C2CCCc3cccnc32)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCN(Cc1ncc(C)cc1C)C1CCCc2cccnc21
Yield: 71.2 %

Procedure:
To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (78 mg, 0.23 mmol) in CH2Cl2 (2.5 mL) was added Et3N (100 μL, 0.72 mmol) followed by Ac2O (40 μL, 0.43 mmol). The resultant solution was stirred at room temperature for 45 minutes. The mixture was diluted with CH2Cl2 (20 mL), washed with brine (3×5 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 60 mg (71%) of the free base of the title compound as a white foam. Conversion of the foam to the HBr salt gave COMPOUND 362 as a white solid. 1H NMR (D2O) δ 1.42-1.47 (m, 2H), 1.71-1.80 (m, 4H), 1.99-2.17 (m, 2H), 2.32-2.39 (m, 2H), 2.41 (s, 3H), 2.45 (s, 3H), 2.62-2.72 (m, 1H), 2.92-2.97 (m, 4H), 4.11 (d, 1H, J=17.1 Hz), 4.33 (d, 1H, J=17.1 Hz), 4.45 (dd, 1H, J=10.5, 5.7 Hz), 7.84 (dd, 1H, J=8.1, 5.4 Hz), 8.19 (s, 1H), 8.32 (d, 1H, J=8.1 Hz), 8.42 (s, 1H), 8.57 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 17.13, 17.56, 20.45, 20.65, 22.17, 27.85, 28.05, 37.58, 49.78, 52.00, 61.10, 125.88, 136.64, 137.42, 137.79, 139.39, 140.75, 148.15, 148.73, 149.28, 151.16, 174.37; ES-MS m/z 367 (M+H). Anal. Calcd. For C22H30N4O.2.9HBr.3.7H2O: C, 39.57; H, 6.08; N, 8.39; Br, 34.70. Found: C, 39.62; H, 5.85; N, 8.04; Br, 34.70.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 5 h

Procedure:
To a solution of 1-benzylpiperidin-4-amine (10 g) in dichloromethane (80 ml), cooled to 5° C., was added pyridine (5.1 ml) followed by acetyl chloride (4.5 ml) and the resulting mixture was stirred for 5 hours. The reaction mixture was washed with 1N NaOH (×2) and then the organic layers were dried and evaporated to dryness to give a solid which was recrystallised from ethyl acetate to give N-(1-benzylpiperidin-4-yl)acetamide. Yield 8.8 g. NMR (d6 DMSO): 1.4 (m, 2H), 1.7 (m, 2H), 1.8 (s, 3H), 2.0 (m, 2H), 2.75 (m, 2H), 3.45 (s, 2H), 3.55 (m, 1H), 7.3 (m, 5H), 7.75 (d, 1H).
Reaction SMILES: [OH:1]O.[NH:3]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]3[C:13]=2[CH2:12][CH2:11][CH2:10]3)[C:5](=[O:15])C1=O.[OH-].[Na+].Cl>O>[NH2:3][C:14]1[C:6]([C:5]([OH:15])=[O:1])=[CH:7][CH:8]=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: OO
Reactant: O=C1Nc2c(ccc3c2CCC3)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Add 30% aqueous hydrogen peroxide solution (5 mL) in water (44 mL) to a solution of 1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione (3.80 mg, 20.3 mmol) and sodium hydroxide (5.03 g, 126 mmol) in water (97 μL) over a period of 30 minutes, stir the mixture at room temperature for 1 h. Acidulate with 1N hydrochloric acid, filter the solid, wash with water and dry to afford 4-Amino-indan-5-carboxylic acid (3.13 g, 87%). Dissolve 4-Amino-indan-5-carboxylic acid (3.07 g, 17.3 mmol) in ethyl acetate (87 mL) and ethanol (87 mL) and add (trimethylsilyl) diazomethane (17.3 mL, 34.6 mmol, 2M in hexanes) at room temperature and stir the solution for 1 hour. Remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (2.50 g, 76%). 1H NMR (MeOD, 300 MHz) δ 2.12 (quintuplet, J=7.6 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 3.83 (s, 3H), 6.53 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H). MS (ES+): 192 (M+H).
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46](=[O:48])[NH2:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:36]=[CH:35][C:34]([C:31]3[CH:32]=[CH:33][N:29]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:16]([CH3:18])([CH3:19])[CH3:17])=[O:13])[CH2:10][C:9]([OH:49])=[O:8])[CH:30]=3)=[CH:39][CH:38]=2)=[CH:45][CH:44]=1)(=[O:48])[NH2:47]
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(=O)Nc1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 81 %

Procedure:
According to the procedure described in Example 5(a), 3(R)-[3-(4'-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(N-(pyridin-4-yl)carbamoyl)propyl]succinamic acid benzyl ester was hydrogenolyzed in MeOH/EtOAc to provide 35 mg (81%) of 3(R)-[3-(4'-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(N-(pyridin-4-yl)carbamoyl)propyl]succinamic acid as a yellow solid, mp 194-6° C. 1H NMR (CD3OD): δ 8.35 (d, 2H, J=6.5 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.75 (d, 3H, J=8.4 Hz), 7.70-7.52 (m, 6H), 7.28 (t, 1H, J=2.0 Hz), 6.90 (t, 1H, J=2.8 Hz), 6.52 (dd, 1H, J=6.9, 16.8 Hz), 1.20 (s, 9H). IR (KBr): 3400, 2962, 1665, 1606, 1511, 1402 cm-1. HRFABMS: Calculated for C32H34N5O5 (M+H+): 568.2560. Found: 568.2575. Anal. Calculated for C32H33N5O5.0.7 HOAc.0.5 CHCl3 : C, 60.83; H, 5.47; N, 10.46. Found: C, 60.93, H, 5.88; N, 10.19.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.