Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ncc2ccn(-c3ccccn3)c2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
A suspension of 2-chloro-7H-pyrrolo-[2,3-d]pyrimidine 3 (0.53 g, 3.5 mmol), 2-bromopyridine (0.66 mL, 1.1 g, 6.9 mmol), copper(I) iodide (0.20 g, 1.0 mmol), trans-1,2-diaminocyclohexane (0.12 mL, 0.1 Ig, 1.0 mmol), and potassium phosphate (2.2 g, 10 mmol) in 10 mL 1,4-dioxane is heated to 100° C. and stirred for four hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic extract was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, Hexane : Ethyl acetate/5:1) provided 4 (0.69 g, 87%) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]([C:16](OCC)=[O:17])[CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C)C)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:7]([CH:6]([CH2:4][OH:3])[CH2:16][OH:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCC(C)C(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCC(CO)CO

Procedure:
Quantities: compound from Example 3 (72.2 g, 0.3 mol) and lithium aluminum hydride (20 g, 0.53 mol). The experimental procedure was as described in Example 6. The pure product was recrystallised from light petrol/ethyl acetate; (49:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([OH:44])=O)[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[S:52][S:53][CH2:54][CH2:55][NH2:56].CCN(C(C)C)C(C)C.C(Cl)CCl>CC(N(C)C)=O>[CH3:14][N:12]1[C:11]([C:15](=[O:16])[NH:17][C:18]2[N:19]=[C:20]([C:24](=[O:25])[NH:26][C:27]3[CH:28]=[C:29]([C:33](=[O:34])[NH:35][C:36]4[CH:37]=[C:38]([C:42](=[O:44])[NH:56][CH2:55][CH2:54][S:53][S:52][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][N:46]=5)[N:39]([CH3:41])[CH:40]=4)[N:30]([CH3:32])[CH:31]=3)[N:21]([CH3:23])[CH:22]=2)=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13]1
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cc1C(=O)O
Reactant: NCCSSc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cc1C(=O)NCCSSc1ccccn1
Yield: 68.2 %

Procedure:
4-(4-(4-(4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylic acid (102 mg, 0.17 mmol), 2-(pyridin-2-yldisulfanyl)ethanamine hydrogen chloride salt (40 mg, 0.18 mmol), DIPEA (30 ul, 0.17 mmol) and EDC (200 mg, 1.04 mmol) in 2 ml of DMA were stirred under Ar for 24 h, evaporated and purified on SiO2 chromatography eluted with THF/DCM (1:5 to 1:4) to afford 90 mg (68%) of the title compound. 1H NMR (DMSO) 10.93 (s, 1H), 10.19 (s, 1H), 10.06 (s, 1H), 9.03 (s, 1H), 8.81 (m 1H), 8.29 (m, 1H), 8.03 (m, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.18 (m, 1H), 6.87 (s, 1H), 3.96 (s, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.73 (s, 3H), 3.58 (m, 2H), 2.48 (m, 2H), 1.45 (s, 9H); MS m/z+ 798.0 (M+Na), 776.0 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C[O-].[Na+].Cl.[C:20]([O-])(O)=[O:21].[Na+]>CO>[CH3:20][O:21][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)c(OC)cn1

Procedure:
300 mg of dimethyl 5-bromopyridine-2,4-dicarboxylate (from Example 3) are dissolved in 5 ml of absolute methanol, and 120 mg of sodium methylate are added. After 60 hours under reflux, the mixture is poured onto ice and 2 ml of 2N HCl, rendered alkaline with NaHCO3 and extracted with 2 portions of CH2Cl2. After the extract has been dried over MgSO4, the solvent is evaporated. 175 mg of a white solid remain.
Reaction SMILES: [CH2:1]([C:3]1[S:40][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][C:37](=[O:39])[O:36][N:35]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]([CH2:12][C:13](=[O:19])[C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:41](OC(=O)C)(=[O:43])[CH3:42].C(OCC)(=O)C.O>N1C=CC=CC=1>[C:41]([O:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13](=[O:19])[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:40][C:6]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[CH:24][CH:23]=2)[C:8]1=[O:20])(=[O:43])[CH3:42]
Reactant: CCc1cc2c(=O)n(CC(=O)C(C)(C)CO)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc2c(=O)n(CC(=O)C(C)(C)COC(C)=O)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 6-ethyl-3-(4-hydroxy-3,3-dimethyl-2-oxobutyl)-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.1 g) in pyridine (0.5 mL) was added acetic anhydride (0.034 mL), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.S(Cl)(Cl)=O.[CH3:18]O>>[Br:1][CH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH3:18])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(O)CC1(CCBr)CCCCC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1(CCBr)CCCCC1
Reaction time: 18 h

Procedure:
To a solution of 1-(2-bromoethyl)cyclohexylacetic acid (4.98 g) in methanol (50 mL) was added thionyl chloride (1.76 mL) dropwise under ice cooling. After completion of the dropwise addition, the reaction solution was stirred for 18 hours, while its temperature was allowed to rise to room temperature. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. The solution was washed in turn with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure to give the title compound (5.41 g). This product was subjected to the subsequent step without further purification.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].N[C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:10]=2[CH:9]=1.Cl.O.O.O.C([O-])(=O)C.[Na+].[CH3:29][S-:30].[Na+].[OH-].[Na+]>O>[CH3:29][S:30][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:10]=2[CH:9]=1
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Reactant: C[S-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: O
Product: CSc1ccc2c(c1)C(=O)CCCC2
Yield: 46 %

Procedure:
A solution of sodium sulfite (3.31 g, 47.94 mmol) in water (5 ml) was added dropwise to a mixture of 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (8.00 g, 45.65 mmol) and 35% hydrochloric acid (20 ml) under ice-cooling and stirred under ice-cooling for 20 minutes. Sodium acetate trihydrate (33 g) was added to the reaction mixture and the resulting mixture was added dropwise to a 15% aqueous sodium thiomethoxide solution (42.67 g, 91.31 mmol). The reaction mixture was stirred at 80° C. for 1.5 hours, adjusted to pH 9 with an aqueous sodium hydroxide solution and then extracted with ethyl acetate. The extract solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to obtain 4.33 g of 3-methylthio-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:18]4[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]4)[CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.I.CS[C:24]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[NH:25]>C(O)C.[Pd]>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16]1)[CH:13]([C:8]1[C:7]3[C:11](=[CH:12][C:4]([NH:1][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])=[CH:5][CH:6]=3)[NH:10][CH:9]=1)[CH2:14]2
Reactant: O=[N+]([O-])c1ccc2c(C3=CN4CCC3CC4)c[nH]c2c1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(C3CN4CCC3CC4)c[nH]c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 36 h
Yield: 76.9 %

Procedure:
Compound 109 (0.4 g, 1.485 mmol) in dry ethanol (10 mL) was treated with Pd—C (˜0.05 g), purged with hydrogen gas and stirred for 36 h at room temperature under hydrogen atm (balloon pressure). The reaction was filtered through celite bed and washed with ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.84 g, 2.970 mmol) at room temperature and stirred for over night (14 h). The solvent was evaporated, crude was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 112 (0.4 g, 77%) as a solid. mp 144-146° C.; 1H NMR (DMSO-d6) δ 1.20-1.28 (m, 1H), 1.56-1.74 (m, 3H), 2.62-2.72 (m, 1H), 2.79-2.92 (m, 3H), 3.09-3.34 (m, 4H), 6.30 (s, 2H), 6.53 (d, 1H, J=8.4 Hz), 6.79 (s, 1H), 7.07-7.10 (m, 2H), 7.38 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=4.5 Hz), 7.72 (d, 1H, J=3.0 Hz), 10.61 (s, 1H); ESI-MS (m/z, %): 351 (MH+, 38), 176 (100); ESI-HRMS calculated for C20H23N4S (MH+), calculated: 351.1637; observed: 351.1637.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH2:19])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (0.0194 mol) of 4-benzyloxy-3-aminophenyl acetate, 3.3 ml (0.0236 mol) of triethylamine and 3.0 ml (0.0236 mol) of benzenesulphonyl chloride in 150 ml of methylene chloride is stirred at room temperature overnight. The mixture is then washed with water and the organic phase is dried, followed by purification by chromatography on a silica gel column, eluting with a 7/3 cyclohexane/ethyl acetate mixture. The compound of the title is obtained.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:33])[NH2:32])[C:20]([CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]>ClCCl.[Br-].[Zn+2].[Br-]>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([NH2:32])=[O:33])[C:20]([CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C=CCON([C@@H]1C=C(C)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 83, 2.785 g, 5.61 mmol) and zinc(II) bromide (2.53 g, 11.22 mmol) was added DCM (10 mL) and stirred at rt overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford the desired product (2.015 g, 91%) as a beige foam.
Reaction SMILES: C([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([N:25]([CH3:45])[C:26](=[O:44])[C:27]([C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=3)([CH3:29])[CH3:28])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]2[CH:10]=[N:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[F:43][C:40]([F:41])([F:42])[C:32]1[CH:31]=[C:30]([C:27]([CH3:29])([CH3:28])[C:26]([N:25]([C:15]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[CH3:45])=[O:44])[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=1
Reactant: Cc1cc(F)ccc1-c1c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc2c1cnn2Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(F)ccc1-c1c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc2[nH]ncc12
Temperature: 60 °C
Reaction time: 20 h
Yield: 41.2 %

Procedure:
To a solution of N-[1-benzyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide (0.40 g, 0.636 mmol) in MeOH (12 mL) was added Pd/C (120 mg) and aqueous HCl (0.078 mL, 37% in H2O) and was put under hydrogen pressure at 10 bars. The reaction mixture was stirred at 60° C. for 20 hours before volatiles were removed, pH adjusted to 8 with aqueous NaOH, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, and purification by column chromatography (SiO2, EtOAc/Heptane 1/1) yielded 141 mg (41%) of the title compound as a white powder. ES-MS m/e: 539.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=O)C=C(OCC)C=1[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:25])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=3)[CH2:12][CH2:13]2)[CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 257) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 523.3 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[O:58])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (0.70 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloro-perbenzoic acid (70%, 0.38 g) in dichloromethane (10 ml) and the mixture was stirred at −78° C. for 1 hour. To the reaction system was added an aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The resultant was concentrated under reduced pressure, the residue was separated and purified with column chromatography (basic silica gel, ethyl acetate→ethanol: ethyl acetate 1:19), followed by recrystallization (ethyl acetate-diisopropyl ether) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocin-5-carboxamide (490.1 mg) as yellow crystals (Compound 47).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH2:3]1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:15][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2]([CH3:14])([CH3:1])[CH2:3][C:4]2([CH3:13])[CH3:12]
Reactant: Cc1ccc2c(c1)C(C)(C)CC2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(C)(C)c2cc(CBr)ccc21
Temperature: 0 °C
Yield: 97.3 %

Procedure:
10.0 g of 1,1,3,3,5-pentamethylindane were dissolved in 125 ml of carbontetrachloride and were added to the resulting solution, 9.92 g of N-bromosuccinimide and 35 mg of 2,2′-azobisisobutyronitrile (AIBN). The reaction mixture was heated to reflux for 5 hours. The reaction was cooled to 0° C. and the succinimide was filtered off. The resulting solution was concentrated in vacuo and the residue (14.7 g) was further dissolved in 150 ml of hexane. The precipitate was again removed by filtration and the solution was concentrated in vacuo, giving 13.8 g of 5-bromomethyl-1,1,3,3-tetramethylindane as a yellow oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:45]=[C:44]([F:46])[C:19]([NH:20][C:21]([O:23][CH2:24][CH2:25][CH:26]([CH3:43])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:42])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:22])=[N:18][C:16]1=[O:17])(=O)C.[OH-].[Na+].Cl>CO>[F:46][C:44]1[C:19]([NH:20][C:21]([O:23][CH2:24][CH2:25][CH:26]([CH3:43])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:42])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:22])=[N:18][C:16](=[O:17])[N:15]([CH:45]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(NC(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)nc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O)[C@H]2O)cc1F
Temperature: 4 °C
Yield: 67.7 %

Procedure:
The obtained crude compound 7a (16.70 g, 24.89 mmol) was dissolved in MeOH (50 ml) and cooled down on an ice bath. NaOH (24 ml, 8M) solution was added dropwise to maintain the reaction temperature at 4° C. Then the pH of the reaction mixture was immediately adjusted to 7 by dropwise addition of HCl solution (2.3M). The organic layer was separated and washed with water, dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was further purified by silica column chromatography using hexane-ethyl acetate from 60:40 to 0:100 with 10% increment as the eluent. The pure title compound (9.6 g, 67.7% yield) was obtained as a waxy solid with light yellow colour. 1H NMR(CDCl3): δ0.83, 0.85, 0.86, 0.88 (4s, 12H, CH3), 0.91 (d, 3H, J=6.1 Hz, CH3), 0.95-1.84 (m, 28H, CH2+CH+OH), 1.40 (d, 3H, J=6.4 Hz, H-5), 3.91 (t, 1H, H-3), 4.15-4.38 (m, 4H, COOCH2+H-2+H-4), 5.69 (d, 1H, J=4.2 Hz, H-1), 7.79 (br s, 1H, N—CH═C—F). MS (APCI): MW: 570.21. 13C NMR(CDCl3, 100 MHz): δ [19.64, 19.71, 22.59, 22.68, 24.27, 24.30, 24.45, 24.77, 27.93, 29.68, 32.76, 35.45, 35.54, 37.25, 37.30, 37.38, 37.42, 37.48, 39.33](CH3+CH2+CH+C5), 65.33 (OCH2), [74.94, 75.12 (br), 80.75](C2,C3,C4), 92.00 (br)(C1), 124.3-128.0 (br), 135.0-138.0 (br), 153.11 (NHCOO). Elemental Analysis: calculated: C, 63.24; H, 9.20; N, 7.38; F, 3.30. Found: C, 63.59; H, 9.32; N, 7.11; F, 3.29.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(OCc2ccccc2)c(CO)c1Br
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)n1nc(OCc2ccccc2)c(C=O)c1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
3-Benzyloxy-5-bromo-4-hydroxymethyl-1-isopropyl-1H-pyrazole (3.0 g) was dissolved in dichloromethane (30 mL), and manganese dioxide (4 g) was added to the stirred solution at room temperature. The mixture was stirred at 50° C. for 1 hour. After the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure to give the title compound (2.7 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]1([NH2:10])[CH2:9][CH2:8]1>CO>[CH2:2]([NH:10][CH:7]1[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: NC1CC1
Solvent: CO
Product: C=CCCCNC1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.3 %

Procedure:
Using an addition funnel, a solution of 5-bromopentene (15.75 g, 106 mmol) in 50 mL of methanol was added over the course of 5 min to a solution of cyclopropylamine (20.6 g, 361 mmol) in 200 mL of methanol. This solution was allowed to stir at rt for 72 h at which time is was refluxed for 1 h. The methanol and excess cyclopropylamine were removed by distillation. The residue, hydrobromide salt of the product, was partitioned between ether and 4 N NaOH. The aqueous phase was washed with ether (2×). The combined ether extracts were dried (MgSO4), filtered, and concentrated to give 8 g (60%) of N-(pent-4-enyl)cyclopropanamine as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.31-0.36 (m, 2H) 0.40-0.46 (m, 2H) 1.53-1.63 (m, 2H) 1.87 (brs, 1H) 2.05-2.10 (m, 2H) 2.10-2.14 (m, 1H) 2.69 (t, J=7.32 Hz, 2H) 4.91-5.07 (m, 2H) 5.72-5.88 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[S:10](=[O:14])(=[O:13])[CH:11]=[CH:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:9]2[S:10](=[O:14])(=[O:13])[CH2:11][CH2:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2c1S(=O)(=O)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2c1S(=O)(=O)CC2
Yield: 80.1 %

Procedure:
7-Nitrobenzo[b]thiophene-1,1-dioxide (19 g, Example 17) was hydrogenated in 200 ml of ethyl acetate over 1.0 g of 10% palladium-on-charcoal catalyst at 500 pounds-per-square-inch of pressure and 100° C. until no more hydrogen gas was absorbed. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The solid residue was recrystallized from 1-chlorobutane to yield 13.2 g of the title compound; m.p. 117°-119° C.