Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:41])[C@@H:4]([NH:9][C:10]([C:12]1[N:13]=[C:14]([CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]1)[CH:16]=2)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.CO>[C:30]([CH:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:22]([C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]([NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([OH:41])=[O:2])=[O:11])[N:13]=[C:14]3[CH2:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:19][CH:18]=2)=[O:34])[CH2:25][CH2:26]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H](NC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(NC(=O)c2ccc3cc(C(=O)N[C@H](C(=O)O)C(C)(C)C)nc(CC4CCCC4)c3c2)CC1
Yield: 85.3 %

Procedure:
A solution of (2S)-{[7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}3,3-dimethylbutyric acid methyl ester (18 mg, 0.032 mmol) in THF:MeOH(4:1, 2.0 mL) was treated with a solution of LiOH (2.0 M, 0.240 mL) by the general procedure I to give 15 mg of 2(S)-{[7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]amino}3,3-dimethylbutyric acid as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:11]([N:17]([CH3:19])[CH3:18])=[C:12]([C:15]#[N:16])[C:13]#[N:14])[N:3]=CC1C=CC=CC=1.Cl>>[NH2:14][C:13]1[C:12]([C:15]#[N:16])=[C:11]([N:17]([CH3:19])[CH3:18])[N:2]([CH3:1])[N:3]=1
Reactant: CN(C)C(=C(C#N)C#N)N(C)N=Cc1ccccc1
Agent: Cl
Product: CN(C)c1c(C#N)c(N)nn1C

Procedure:
The product of stage (b) (19 g) was heated for 20 minutes with 1 M hydrochloric acid. The mixture was cooled and benzaldehyde was removed by extraction with dichloromethane. The aqueous phase was neutralised with sodium hydroxide to precipitate 3-amino-4-cyano-1-methyl-5-dimethylaminopyrazole (7.2 g), m.p. 100°-102° C.
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH3:3].N(C(OC[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=O)[C@H](C(NCC(N)=O)=O)C>CO>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH2:3][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Solvent: CO
Product: NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Z-D-Ala-Gly-NH2 (21) (Richman et al., Int. Peptide Protein Res., 25:648-662 (1985), which is hereby incorporated by reference): 1H and 13C NMR data are identical to (8). HRMS (FAB+) MH+ calcd 280.1297 found 280.1298; [α]27D+10.5 (c 0.72, MeOH); lit. [α]D=+10.5.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:31][CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C1CCN(CCCC2CCNCC2)CC1
Product: O=C1Nc2cccnc2N(C(=O)N2CCC(CCCN3CCCCC3)CC2)c2ccccc21
Yield: 81 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[3-(1-piperidinyl)propyl]piperidine in a yield of 81% of theory. Colourless crystals, m.p. 200° C.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:9]([F:33])[CH:8]=1)=[O:6])[CH3:3].[CH:34]([C:36]1[N:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)=O>>[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][C:10]([CH:11]=[CH:34][C:36]2[N:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[C:9]([F:33])[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Agent: [Br-]
Product: CCOC(=O)c1ccc(C=Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c(F)c1
Yield: 98.8 %

Procedure:
By a method similar to Production Example 108, step 4, [4-(ethoxycarbonyl)-2-fluorobenzyl](triphenyl)phosphonium bromide (2.513 g, 4.802 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (1.166 g, 4.002 mmol) were condensed to give tert-butyl 4-(6-{2-[4-(ethoxycarbonyl)-2-fluorophenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (1.802 g, yield 98.9%, E/Z mixture) as a pale-brown solid.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28](N(OC)C)=[O:29]>O1CCCC1>[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28]([C:22]1[S:21][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH2:14][CH2:15]2)=[N:24][CH:23]=1)=[O:29]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nccs2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3F)s2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A 2.5M n-butyl lithium in tetrahydrofuran solution (0.9 ml, 2.25 mmol) was added dropwise to a solution of tert-butyl-4-(thiazol-2-yl)-1,4-diazepane-1-carboxylate (570 mg, 2 mmol) in tetrahydrofuran (7 ml), cooled to −78° C. Thirty minutes later, a solution of 2-fluoro-N-methoxy-N-methylnicotinamide (370 mg, 2 mmol) in tetrahydrofuran (2 ml) added dropwise. The reaction mixture was stirred at −78° C. for one hour, then at 0° C. for an extra hour. It was quenched with a saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with ethyl acetate, then washed with brine. The organic was dried over magnesium sulfate, then concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel, pentane/ethyl acetate) to afford the title compound (300 mg, 38%). 1H NMR (CD3OD): 1.42 (9H, s), 1.90-2.00 (2H, M0, 3.45-3.50 (2H, m), 3.65-6.75 (2H, m), 3.80-3.90 (2H, m), 7.46-7.49 (1H, t), 7.67-7.69 (1H, d), 8.10-8.15 (1H, t), 8.39-8.40 (1H, d). MS (ES+): 407.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].IC.[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Yield: 92.8 %

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid (20.16 g, 100 mmol), iodomethane (15.6 g, 110 mmol), and potassium carbonate (15.0 g, 108.5 mmol) in DMF (100 mL) was stirred at room temperature for 48 h. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 20.0 g (93%) of the title compound 2-chloro-3-nitrobenzoic acid, methyl ester as a white solid (MW 215.59).
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([NH:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([C:35]([O:37][CH2:38][C:39]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:40])=[O:36])[CH2:31][CH2:30]3)=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.[ClH:47]>CN(C)C=O.[Pd]>[ClH:47].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([NH:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([C:35]([O:37][CH2:38][C:39]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:40])=[O:36])[CH2:33][CH2:34]3)=[O:27])[CH2:24][CH2:25]2)=[CH:16][CH:15]=1)(=[NH:11])[NH2:13]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(N2CCN(C(=O)N[C@H]3CC[C@H](C(=O)OCC(=O)N4CCOCC4)CC3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)c1ccc(N2CCN(C(=O)N[C@H]3CC[C@H](C(=O)OCC(=O)N4CCOCC4)CC3)CC2)cc1

Procedure:
A solution of 300 mg of 1-[4-(N-benzyloxycarbonyl-amidino)-phenyl]-4-[N-[trans-4-[(morpholinocarbonyl)-methoxycarbonyl]-cyclohexyl]-aminocarbonyl]-piperazine in 20 ml dimethylformamide is hydrogenated for 2 hours in the presence of 0.3 g of a catalyst consisting of 10% palladium on activated charcoal under an excess hydrogen pressure of 5 bar. Ethereal hydrochloric acid is added and the mixture is filtered. The filtrate is evaporated down under reduced pressure and the residue remaining is triturated with ether/acetone, acetone and acetone/methylene chloride and suction filtered. Yield: 210 mg (83% of theory), Rf value: 0.27 (silica gel; methylene chloride/methanol/conc. ammonia=4:1:0.25)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[Cl-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of 100 g of 3,4-dichlorophenylacetonitrile in 500 ml of THF is added dropwise at 20° C. over 30 minutes to a suspension of 16.5 g of sodium hydride in 200 ml of dry THF, and the reaction mixture is then stirred at RT for 2 hours. It is cooled to -20° C., a solution of 118 g of 1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 100 ml of THF is added and the mixture is left stirring for 2 hours while allowing the temperature to rise to RT. A solution of 50 g of ammonium chloride in 3 litres of water is then added, the product is extracted with 1.5 litres of ether, and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed on silica, eluting with DCM and then with a DCM/AcOEt (95:5; v/v) mixture. 118 g of the expected product are obtained in the form of an oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]1[CH:22]2[CH2:23][CH:24](Br)[CH:20]([CH2:21]2)[CH2:19]1>O>[CH:20]12[CH2:21][CH:22]([CH2:23][CH2:24]1)[CH2:18][CH:19]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 80 °C
Yield: 87.2 %

Procedure:
Isovanillin (50 g, 0.328 mol) is placed in a 1 liter round bottom flask which is equipped with a stir bar and reflux condensor and is charged with 500 ml of dimethylformamimde. Potassium carbonate (45.3 g, 0.328 mol) is added to the reaction mixture which is heated to 80° C. At this temperature exo-2-bromonorbornane (12.57 g, 0.072 mol, 0.219 equivalents) is added and the reaction mixture is heated to 120° C. for 48 hours. The reaction is then cooled to room temperature and poured into 300 ml of water. The aqueous layer is extracted with ethyl ether (3×100 ml). The ethereal layer is washed with 1N sodium hydroxide solution (4×100 ml), water (3×100 ml) and saturated sodium chloride solution (3×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 15.47 g of a green/brown oil. The crude product is purified by flash chromatography using a gradient eluent system of ethyl acetate/hexane [10% ethyl acetate/hexane→20% ethyl acetate/hexane] to yield 7.76 g (14.4%) of the aldehyde as a white solid. MP: 75.5° C.-79.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[S:37]([N:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[C:21]([Cl:43])=[CH:20][N:19]=1>>[Cl:43][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[S:37]([N:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CN(C)S(=O)(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4S(=O)(=O)N(C)C)n3)cc2CC1

Procedure:
The title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-5-morpholin-4-yl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a light brown foam (0.043 g, 30%). MP: 74-85° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.96 (s, 1H), 8.29 (d, J=9.1 Hz, 1H), 8.07 (s, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.22 (dd, J=8.0 Hz and J=2.1 Hz, 1H), 7.10 (dd, J=9.2 Hz and J=2.9 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.88 (s, 1H), 3.92-3.88 (m, 4H), 3.54 (t, J=5.6 Hz, 2H), 3.36 (s, 3H), 3.22-3.18 (m, 4H), 2.93-2.83 (m, 4H), 2.78-2.68 (m, 12H). MS: 616.18 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH3:16])[CH:10]4[CH2:14][C:13]([CH3:15])([C:7]3([CH3:17])[C:6]=2[CH:18]=1)[CH2:12][CH2:11]4.[Mg].II.[O:22]1CCC[CH2:23]1>>[CH3:15][C:13]12[CH2:14][CH:10]([C:8]3([CH3:16])[C:7]1([CH3:17])[C:6]1[CH:18]=[C:2]([CH:23]=[O:22])[CH:3]=[CH:4][C:5]=1[O:9]3)[CH2:11][CH2:12]2
Reactant: CC12CCC(C1)C1(C)Oc3ccc(Br)cc3C21C
Reactant: C1CCOC1
Agent: II
Agent: [Mg]
Product: CC12CCC(C1)C1(C)Oc3ccc(C=O)cc3C21C
Yield: 74 %

Procedure:
13.76 g (44.8 mmol) of 8-bromo-THTMDBF obtained in Example 2 were added dropwise into a three-necked flask under nitrogen containing 1.31 g of magnesium and an iodine crystal in 5 ml of tetrahydrofuran, and the mixture was maintained under reflux for 2 h, 30 min. After the magnesium was filtered off, the reaction medium was poured into ice-cold water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ether. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to yield 8.47 g (74%) of the expected compound, melting at 144.7° C.; αD =-7° (c=1, chloroform).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].C([Li])(C)(C)C.C(NC(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:33][C:34]([CH2:36][C:37]2[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=2)=[O:35])[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].C(Br)C=C>CCCCC.O1CCCC1.O>[CH2:3]([CH:33]([C:25]1[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:34]([CH2:36][C:37]1[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=1)=[O:35])[CH:1]=[CH2:2]
Reactant: COc1cc(CC(=O)Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C=CCBr
Solvent: CC(C)NC(C)C
Product: C=CCC(C(=O)Cc1cc(OC)c(OC)c(OC)c1)c1cc(OC)c(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (prepared from the addition of 38.2 ml of a 1.7M solution of tert.-butyl lithium in pentane to 9.53 ml of diisopropylamine in 100 ml of tetrahydrofuran at -10° C.) which was cooled to -78° C. was slowly added 24.1 g of the compound prepared in (c) above in 450 ml of tetrahydrofuran. The resultant mixture was then stirred for 45 minutes, while maintaining the temperature of -78° C., after which time it was cannulated into a solution of 159 ml of allyl bromide in 244 ml of tetrahydrofuran at -78° C. over a period of 90 minutes. The reaction mixture was then stirred for an additional 30 minutes at -78° C., after which time it was allowed to warm to room temperature. 150 ml of water was then added and the tetrahydrofuran was removed by evaporation at 40° C. The crude residue was then extracted with a mixture of ethyl acetate and water and dried, after which time the organic fraction was evaporated to yield a solid.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
2.16 g (0.01 mole) of 4-hydroxy-4'-chlorobenzophenone and 1.2 g (0.015 mole) of pivaloyl chloride in solution were warmed to 50° C. for 3 hrs in 60 mls of dry pyridine with a drying tube attached. The solvent was removed via rotary evaporator and H2O added. The product was filtered and recrystallized from ethanol; 2.3 g (73%) yield; M.P.~113°-114° C.
Reaction SMILES: [CH3:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Cl:11])[CH:5]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:11][C:6]1[CH:5]=[C:4]([S:3]([CH2:2][CH3:1])=[O:20])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: CCSc1ccc(F)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-ethanesulphanyl-1-fluorobenzene (2.40 g) in DCM (100 mL) was added 75% m-chloroperbenzoic acid (4.35 g) and the mixture stirred at ambient temperature for 16 h. The mixture was washed successively with saturated potassium carbonate (30 mL) and brine (30 mL) then dried (MgSO4), filtered and reduced in vacuo. The resultant residue was chromatographed on silica (eluting with 0-50% ethyl acetate in iso-hexane) and the slower running product isolated (1.26 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:6].[Br-].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Zn+]>C(OCC)(=O)C>[Cl:21][C:20]1[CH:19]=[CH:18][C:4]([C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1
Reactant: COc1cc(NC(=O)c2ccc(Cl)c(Br)c2)cc(OC)c1
Reactant: [Zn+]c1ccccn1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2ccc(Cl)c(-c3ccccn3)c2)cc(OC)c1
Temperature: 155 °C

Procedure:
3-bromo-4-chloro-N-(3,5-dimethoxyphenyl)benzamide was dissolved in 0.5 M 2-pyridylzincbromide (2.5 mL) and treated with Pd(PPh)3)4 (20 mg, 0.02 mmol). The reaction mixture was heated to 155° C. in a sealed tube for 20 min. in a microwave reactor. The resultant solution was diluted with Ethyl acetate and washed with 0.1 N sodium hydroxide and then brine. The organic layer was dried (MgSO4) and concentrated, and the crude residue was partially purified by silica gel chromatography. Pure 4-chloro-N-(3,5-dimethoxyphenyl)-3-(pyridin-2-yl)benzamide was obtained by a second purification on reverse phase HPLC. MS (Q1) 369.1 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCCN2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(NC(=O)OC(C)(C)C)ccc43)CC2C)cc1OC
Yield: 12.9 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (712 mg, 2.18 mmol) prepared in Reference Example 1 and tert-butyl N-(1,2,3,4-tetrahydro-6-quinolinyl)carbamate (1.35 g, 5.44 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (157 mg, yield: 13%) as a white crystal. (cis:trans=4.8:1)
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].[CH3:14][C:15]1[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=1>>[CH3:14][C:15]1[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[S:3])[CH:19]=1
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3ccccc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanatobenzoate (0.093 g. 0.48 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.067 g, 0.48 mmol) as described above.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH2:5]1[CH2:15][C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[NH:1]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:15][C:13]1=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2ccccc2N1
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a stirred suspension of 13.4 g (207 mmol) of sodium azide and 25.0 ml (188 mmol) of α-tetralone in 150 mL of chloroform, was added 50.0 mL of concentrated sulfuric acid, dropwise over 1 h. After 30 min., the chloroform phase was decanted and the acidic phase poured into 1 L of water. The precipitated solid was collected on a filter, washed with water, and recrystallized from 1 L of boiling water. The product was collected and dried under vacuum to yield 14.3 g (47%) of tan needles. 1H NMR (300 MHz, CDCl3) d 8.63 (1H, bs), 7.24 (2H, m), 7.13 (1H, m), 7.03 (1H, d, J=8 Hz), 2.82 (2H, t, J=6 Hz), 2.38 (2H, t, J=6 Hz), 2.24 (2H, m).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([N:11]([CH2:17][C:18]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>N.[Ni].CO>[N:1]1[C:10]2[CH:9]([N:11]([CH2:17][C:18]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(CN(CCCC#N)C2CCCc3cccnc32)nc2ccccc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(CN(CCCCN)C2CCCc3cccnc32)nc2ccccc21
Reaction time: 16 h
Yield: 66.7 %

Procedure:
4-{(5,6,7,8-Tetrahydro-quinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-ylmethyl]-amino}-butyronitrile (840 mg, 1.75 mmol) was dissolved in NH3 saturated MeOH (15 mL), treated with Raney nickel (excess), and placed under 45 psi H2 on a Parr shaker for 16 hours. The mixture was diluted with MeOH and filtered through Celite. The cake was washed with MeOH and the combined filtrate was concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 50:2:1) afforded the desired amine (560 mg, 66%) as an orange syrup. 1H NMR (CDCl3) δ −0.10 (s, 9H), 0.81 (t, 2H, J=9.0 Hz), 1.43-1.50 (m, 4H), 1.59-1.76 (m, 1H), 1.86-2.09 (m, 2H), 2.08-2.23 (m, 1H), 2.56-2.71 (m, 4H), 2.76-2.85 (m, 2H), 2.41 (t, 2H, J=8.1 Hz 4.07-4.12 (m, 3H), 5.71 (d, 1H, J=11.1 Hz), 7.37 (d, 1H, J=11.1 Hz), 7.05 (dd, 1H, J=7.5, 4.5 Hz 7.21-7.29 (m, 2H), 7.34 (d, 1H, J=6.6 Hz), 7.40-7.45 (m, 1H), 7.71-7.76 (m, 1H), 8.58 (d, 1H, J=3.6 Hz).