Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:22]#[N:23]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:22]#[N:23])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CCNCC2)cc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Temperature: 140 °C
Yield: 16 %

Procedure:
A mixture of 4-(4-chloro-phenyl)-4-(4-iodo-phenyl)-piperidine and copper (I) cyanide in DMF was heated at 140° C. under nitrogen for 6 hours then allowed to cool. The mixture was diluted with ethyl acetate, washed with a mixture of conc. ammonia and brine (×5), dried (MgSO4), filtered and concentrated to give a residue which was partially purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 10%) and dichloromethane to afford the title compound (46 mg, <16%). This was taken on to the next reaction without further purification. LCMS (PS-A2) Rt 2.39 min [M+H]+297.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Yield: 20.5 %

Procedure:
To a mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol) and tert-butyl (1R,2S)-2-aminocyclohexylcarbamate (173 mg, 0.808 mmol) in ACN (5 mL) was added N,N-diisopropylethylamine (0.141 mL, 0.808 mmol). The reaction mixture was heated in a sealed vial at 100° C. for several hours after which additional amine (0.5 eq) was added. The mixture was heated overnight and the solvent was subsequently removed in vacuo. The residue was dispersed in DMSO and MeOH (1/1) and the resulting mixture was filtered. The filtrate was purified via preparative HPLC. The fractions were collected and dried in vacuo to give the title compound as a tan solid (60.7 mg, 21%). [M+H] calc'd for C27H34ClFN4O5, 550; found, 550
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[CH:24]([C:27]1[NH:28][C:29](=[O:51])[C:30]2[C:31]3[N:40]([CH3:41])[C:39]([NH:42][C:43]4[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=4[Cl:50])=[N:38][C:32]=3[CH:33]=[CH:34][C:35]=2[C:36]=1[CH3:37])[CH:25]=[CH2:26])(=O)C.C(N(CC)CC)C.[CH3:59][NH:60][CH2:61][CH2:62][CH2:63][NH:64][CH3:65]>O1CCCC1.[Pd]>[Cl:49][C:48]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:50])[C:43]=1[NH:42][C:39]1[N:40]([CH3:41])[C:31]2[C:30]3[C:29](=[O:51])[NH:28][C:27](/[CH:24]=[CH:25]/[CH2:26][N:60]([CH3:59])[CH2:61][CH2:62][CH2:63][NH:64][CH3:65])=[C:36]([CH3:37])[C:35]=3[CH:34]=[CH:33][C:32]=2[N:38]=1
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reactant: CNCCCNC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNCCCN(C)C/C=C/c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reaction time: 0.33 h

Procedure:
A solution of tris(dibenzylidineacetone)dipalladium (0) (0.016 g, 0.01697 mmol) in tetrahydrofuran under nitrogen atmosphere was treated with triphenylphosphine (0.007 g, 0.0255 mmol). The reaction mixture was stirred for about 20 minutes under a nitrogen atmosphere. A solution of 1-[2-(2,6-dichloroanilino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allyl acetate (Snow et al., 2001) (0.080 g, 0.1697 mmol) in tetrahydrofuran was added to the palladium solution. Triethylamine (0.052 g, 0.509 mmol) and N,N′-dimethyl-1,3-propanediamine (0.087 g, 0.8485 mmol) were added to the reaction solution. The reaction mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Tetrahydrofuran was removed from the reaction mixture under reduced pressure. Acetic acid (0.5 mL) and dimethylformamide (5 mL) were added. The reaction mixture was filtered through a Gelman filter disk and was then purified by preparative HPLC chromatography. The preparative column afforded 0.012 g (14%) of pure 13, 2-(2,6-dichloroanilino)-1,6-dimethyl-7-((E)-3-{methyl[3-(methylamino)propyl]amino}-1-propenyl)-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-9-one. 1H NMR (CDCl3, 400 MHz) δ 7.8572-7.8355 (d, 1H J=8.68 Hz), 7.5408-7.5189 (d, 1H, J=8.76 Hz), 7.399-7.366 (m, 2H), 7.118-7.078 (t, 1H) 6.786-6.746 (m, 1H), 6.312-6.256 (m, 1H), 4.288 (s, 3H), 3.213-3.199 (m, 2H), 2.696-2,663 (t, 2H), 2.518-2.483 (t, 2H), 2.443 (s, 3H), 2.377 (s, 3H), 2.24 (s, 3H), 1.740-1.689 (m, 2H)); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% CH3CN over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), M+ 513.5 and 515.5.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC(C)=O.O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])=[N:5][N:4]=[N:3]1
Reactant: CCNCCCSc1nnnn1C
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CCCSc1nnnn1C)C(=O)C1CCCCC1
Reaction time: 2 h
Yield: 58.2 %

Procedure:
1-Methyl-5-[3-(N-ethylamino)propylthio]-1,2,3,4-tetrazole (1 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). To the mixture is added potassium carbonate (0.7 g) and thereto is added dropwise with stirring cyclohexanecarboxylic acid chloride (0.9 g) under ice-cooling. Stirring is continued for 2 hours under ice-cooling. After acetone is distilled off, water is added to the resulting residue and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and then the residue is purified by column chromatography (Wakogel C-200), followed by eluting with chloroform to give 1-methyl-5-[3-(N-ethyl-N-cyclohexylcarbonylamino)propylthio]-1,2,3,4-tetrazole (0.9 g), colorless liquid, nD23.5 =1.5267.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([CH2:50][NH2:51])[CH:43]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][NH2:32])[CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:6]([N:13]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([CH2:50][NH:51][S:2]([CH3:1])(=[O:4])=[O:3])[CH:43]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(CCN(CCCCCCN(CCc2ccc(OC)c(CN)c2)Cc2ccccc2)Cc2ccccc2)cc1CN
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CCN(CCCCCCN(CCc2ccc(OC)c(CNS(C)(=O)=O)c2)Cc2ccccc2)Cc2ccccc2)cc1CNS(C)(=O)=O
Reaction time: 8 h

Procedure:
Following the procedure of Example 6, 2.5 g. of methanesulfonyl chloride is added to a solution of 6.78 g. (0.01 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-aminomethyl-4-methoxyphenyl)-ethyl]-hexamethylenediamine in 30 ml. of pyridine and the mixture is allowed to stand at room temperature overnight to yield N,N'-dibenzyl-N,N'-bis[2-(3-methanesulfonamidomethyl-4-methoxyphenyl)-ethyl]-hexamethylenediamine. The latter as the dihydrochloride is demethylated and then debenzylated as described in Example 9 to furnish the product N,N'-[2-(4-hydroxy-3-methanesulfonamidomethylphenyl)-ethyl]-hexamethylenediamine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15]([OH:16])=[N:14][N:13]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.C(OCC)C>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15]([OH:16])=[N:14][N:13]([C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(O)cc3)nc(O)c12
Temperature: 160 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
7-Chloro-1-hydroxy-3-(4-methoxyphenyl)-3,4,5,10-tetrahydropyridazino[4,5-b]quinoline-4,10-dione (0.800 g, 2.16 mM) was stirred in methanesulfonic acid (16 mL) to give an amber solution. This solution was heated to 160° C. for 6 hours and cooled to room temperature. Addition of ethyl ether (250 mL) gave a tan precipitate which was stirred for 1 hour. The solid was collected and washed with methanol/ether to give the title compound (0.661 g, 77%) as a tan powder, mp 393-395° C.; MS(CI): 356 (M+H).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([C:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=1[CH3:24])[C@@H:11]([OH:13])[CH3:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[Si:5]([O:13][C@@H:11]([CH3:12])[C@H:10]([C:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=1[CH3:24])[OH:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1noc([C@H](O)[C@H](C)O)c1C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc([C@H](O)[C@H](C)O[Si](C)(C)C(C)(C)C)c1C
Temperature: 25 °C

Procedure:
tertbutyldimethylsilyl chloride (6.3 g, 41.5 mmol) was added portionwise to ethyl 5-((1R,2S)-1,2-dihydroxypropyl)-4-methylisoxazole-3-carboxylate (Intermediate B)(8.65 g, 37.7 mmol), 4-dimethylaminopyridine (1.38 g, 11.32 mmol) and triethylamine (5.80 mL,) in DMF (100 mL) at 0° C. and the reaction was allowed to warm to room temperature. After 18 h the reaction was partitioned between EtOAc and brine, washed with saturated aqueous ammonium chloride, brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 15% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[F:20].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c(N)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cc(F)c(N)c(F)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 106 %

Procedure:
Diethyl (4-amino-3,5-difluorophenyl)propanedioate (0.770 g, 2.68 mmol) was dissolved in ethanol (50 ml) and treated with sodium hydroxide (0.107 g, 2.68 mmol) in water (1.5 ml). This was heated to 90° C. for 55 minutes. Further sodium hydroxide (0.016 g, 0.40 mmol) was added to the reaction and heating continued for 15 minutes. The mixture was cooled to room temperature and evaporated. This was acidified with 2N HCl (20 ml) and extracted ×2 with ethyl acetate (25 ml). The combined organics were washed with brine (50 ml), dried over magnesium sulphate, filtered and evaporated to give the title compound as a pale brown oil (0.610 mg, 2.84 mmol, >100%). LC/MS: Rt=2.52, [MH]+ 216.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH2:19]>C(O)C>[NH2:19][C@@H:18]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:6]([OH:7])[CH2:8][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1
Reactant: CN
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(A)(ii) A suspension of 26.55 g of N-tert.butyl-2-[2(R) -hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 1) in 100 ml of ethanol was treated with 25 ml of a 30% solution of methylamine in ethanol at room temperature for 1 hour. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 250 ml of ethanol, treated with 250 ml of a saturated solution of hydrogen chloride in ethyl acetate and stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, made basic with solid sodium carbonate and then extracted with dichloromethane. The dichloromethane extract was washed with sodium chloride solution and evaporated to dryness. The residue was triturated with diethyl etcher and, after filtration, there were obtained 17.48 g of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N -tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 402 [M+H]+.
Reaction SMILES: ClC1C=CC=CC=1NN[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(NNc1ccccc1Cl)c1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5.2 g of 2-fluorobenzoic acid, 2-(2-chlorophenyl)hydrazide, 64.3 g of triphenylphosphine, 500 ml of anhydrous acetonitrile and 19.3 ml of carbon tetrachloride was stirred at ambient temperature for 16 hours, concentrated in vacuo, and extracted with diethyl ether (4×200 ml). The extract was filtered and concentrated to an oil which, was flash chromatographed on silica utilizing hexane/ethyl acetate (25%) as the eluent. Concentration of the appropriate fractions yielded 47.5 g of α-chloro-2-fluorobenzaldehyde, (2-chlorophenyl)hydrazone.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([CH3:17])[CH3:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.CCOC(C)=O.CO.N>>[CH:15]([C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([CH3:17])[CH3:16]
Reactant: CC(C)C1(O)CCN(Cc2ccccc2)CC1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C1(O)CCNCC1

Procedure:
The product was obtained analogously to Example IP 5d from 9.85 g (42.2 mmol) of 1-benzyl-4-isopropylpiperidin-4-ol. Yield: 1.13 g (19% of theoretical); C8H17NO (M=143.227); calc.: molpeak (M+H)+: 144; found: molpeak (M+H)+: 144; Rf value: 0.07 (silica gel, EtOAc/MeOH/NH3 5:5:0.5).
Reaction SMILES: [CH2:1]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:13]1[S:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCc1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1ccc(Br)s1
Temperature: 100 °C
Yield: 94 %

Procedure:
2-Decylthiophene (52.8 g, 0.235 mol) prepared above and DMF (200 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. A solution of N-bromosuccinimide (hereinafter referred to as “NBS”) (44.0 g, 0.247 mol) in DMF (100 ml) was added dropwise to the solution at room temperature in an argon gas stream over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred with heating at 100° C. for about 2 hr. After the completion of the reaction, water (300 ml) was added to the reaction solution, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 2-bromo-5-decylthiophene as a yellow liquid (67.0 g, yield 94.0%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 14H), 1.61 (m, 2H), 2.73 (t, 2H, J=7.32 Hz), 6.52 (d, 1H, J=3.90 Hz). 6.83 (d, 1H, J=3.90 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[C:4]([C:21](=[O:24])[CH2:22][CH3:23])[CH:3]=1>C(O)C.C(O)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[C:4]([C:21](=[O:24])[CH2:22][CH3:23])[CH:3]=1
Reactant: CCOC(=O)N1C2C=C(c3ccc(Cl)cc3C(=O)CC)CC1CC2
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)N1C2CCC1CC(c1ccc(Cl)cc1C(=O)CC)C2

Procedure:
A solution of ethyl 3-(4-chloro-2-propionylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2-6) (1.50 g, 4.31 mmol,) in 10 mL of ethanol and 10 mL acetic acid was shaken under hydrogen at 1 atmospheric pressure with platinum oxide (980 mg, 0.431 mmol, added in portions) for 60 h at room temperature. Solid was filtered through a pad of Celite and rinsed with ethanol. The ethanol solution was concentrated to give (2-7) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=3)[N:28]=2)=[CH:19]1
Reactant: Cc1cccc(N)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Cc1cccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c1
Yield: 45.5 %

Procedure:
Using the procedure of example 1, m-toluidine (87 mg) was reacted with compound 1f (100 mg) to provide compound 9 (37 mg, 46%). 1H NMR (400 MHz, CD3OD) δ 8.90 (d, J=8;0 Hz, 1H), 8.30 (m, 2H), 8.18 (s, 1H), 7.63 (s, 1H), 7.43(d, J=8.0 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.22 (m, 1H), 7.17 (d, J=5.2 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 2.42 (s, 3H). MS (ESI) m/z: 302 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][NH:11][C:10]3=O)=[N:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: Cc1nnc(-c2ccc3nc[nH]c(=O)c3c2)o1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1

Procedure:
6-(5-Methyl-1,3,4-oxadiazol-2-yl)quinazolin-4-one (0.3 g) was treated with phosphorus oxychloride at reflux under N2 for 5 hours. The mixture was concentrated in vacuo and the residue azeotroped with toluene. This was then taken up in ethyl acetate and washed with 5% sodium bicarbonate and saturated brine, dried over magnesium sulphate and concentrated in vacuo to give the title compound (0.22 g) as a yellow solid; δH [2H6]DMSO 12.65 (1H,bs), 8.71(1H,d), 8.45 (1H,dd), 8.33 (1H,s), 7.95 (1H,s) 2.73 (3H,s).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a stirring solution of 110 mg (0.17 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 15 mL of a 10% solution of formic acid in absolute ethanol is added 100 mg of 10% palladium on carbon. The resulting black suspension is heated at reflux for 24 h, then cooled to RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the residue by gradient silica gel flash column chromatography using hexane/EtOAc 3/2 up to 2/3 as eluent followed by further purification via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O as eluent and lyophilization afforded 62 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.81 (d, 1H, J=8.0), 7.41-6.90 (m, 17H), 5.00 (m, 1H), 4.23 (m, 3H), 3.84 (s, 3H), 3.79 (d, 1H, J=7.9), 3.61 (dd, 1H, J=5.8, 16.1), 1.06 (m, 6H); low resolution MS (FAB)m/e 588 (MH+), 423, 223; Anal. (C35H33N5O4.H2O) Calcd. C, 70.45; H, 5.91; N, 11.74 Found C, 70.62; H, 5.76; N, 11.78.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:11]([C:7]2[N:8]=[CH:9][CH:10]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:6]=23)[C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cn1ccc2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc2ccnc(N(C(=O)c3ccc(Br)cc3)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a solution of Preparation 4 (R)-tert-butyl 3-((1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)amino)piperidine-1-carboxylate (45.0 g, 136 mmol) and 4-bromobenzoyl chloride (31.3 g, 143 mmol) in dry THF (250 mL) was added 1 M lithium bis(trimethylsilyl)amide (163 mL, 163 mmol) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 15 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by recrystallization (petroleum ether:EtOAc=2:1) to afford the title compound as an off-white solid (50 g, 72%).