Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]Cl)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[O:1][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 109.3 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzoic acid (4.5 g, 26.8 mmol), 3-morpholinopropyl chloride (9.5 g, 58.0 mmol), (prepared according to J. Am. Chem. Soc. 1945, 67, 736), potassium carbonate (8.0 g, 58 mmol), potassium iodide (1.0 g, 0.22 mmol) and DMF (80 ml) was stirred and heated at 100° C. for 3 hours. The solid was removed by filtration and the filtrate evaporated. The residue was dissolved in ethanol (50 ml), 2M sodium hydroxide (50 ml) was added and the mixture heated at 90° C. for 2 hours. After partial evaporation, the mixture was acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with a gradient of methanol (0 to 25%) in hydrochloric acid (pH2). Partial evaporation of the solvents and lyophilisation gave 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (8.65 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][C:20]=3[S:21][C:22]=2N(C)C)=[O:17])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH2:38]([O:45][CH2:46][C:47]1[CH:60]=[C:59](Br)[CH:58]=[CH:57][C:48]=1[O:49][CH2:50][CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([C:18]2[C:19]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:26][C:20]=3[S:21][C:22]=2[C:59]2[CH:58]=[CH:57][C:48]([O:49][CH2:50][CH2:51][N:52]3[CH2:53][CH2:54][CH2:55][CH2:56]3)=[C:47]([CH2:46][O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:60]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCOCC1
Reactant: Brc1ccc(OCCN2CCCC2)c(COCc2ccccc2)c1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(COCc4ccccc4)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCOCC1
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield by essentially following the procedures outlined in Example 81, Part E, from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methoxy-4-[(4-morpholinyl)methyl]phenyl ketone (Example 49, Part C) and 1-[2-(2-benzyloxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7]/[C:8](=[CH:12]\[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCC1CCCCC1)C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Yield: 99.2 %

Procedure:
A solution of (E)-2-[2-(teri-butoxy)-2-oxoethyl]-5-cyclohexyl-2-pentenoic acid (0.74 g, 2.5 mmol) and 1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (18 mg, 25 μmol) in methanol (2.5 ml) was stirred at 20-25° C. for 24 hours, under hydrogen (4 atmospheres, 60 p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (0.74 g, 98% conversion, enantiomeric excess=95%, 95% pure by NMR).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:15]=[CH2:16])[CH:5]=1)C.C(N(CC)CC)C.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[NH:1][CH2:2][C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[C:6]([CH:15]=[CH2:16])[CH:5]=2)=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: C=Cc1cc(C(C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 39.3 %

Procedure:
N-[4-(1-Amino-ethyl)-2-vinyl-phenyl]-methanesulfonamide (236.7 mg, 0.985 mmol) and triethylamine (274.6 μl, 1.970 mmol, 2 eq) were added in methylene chloride. The reaction mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (192.5 μl, 1.083 mmol, 1.3 eq.) was added into the mixture. The reaction mixture was stirred for 40 min. A reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (155.4 mg, 47%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:40])[C@@H:10]([NH:22][C:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:48]1([C:54](Cl)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)(Cl)Cl>[C:28]([O:27][C:25]([N:24]=[C:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:22][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:54]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:40])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-5-oxopentylcarbamate and triethylamine (170 mg) in chloroform (30 ml) was added triphenylmethyl chloride (470 mg), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (4S)-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (850 mg) as an oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH3:10].[B:11](OC)([O:14]C)[O:12]C.S(=O)(=O)(O)O>C1COCC1>[CH3:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[B:11]([OH:14])[OH:12]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(B(O)O)c1
Temperature: 25 °C

Procedure:
Magnesium turnings (30.3 g; 0.55 mol) are placed ina baked-out apparatus flushed with argon, covered with about 30 ml of THF and treated with a few crystals of iodine. A few drops of bromo-p-xylene (cf. Example A1 a)) were subsequently added to the static solution. The Grignard reaction commenced very quickly and the remaining bromo-p-xylene (total amount: 92.5 g; about 70 ml; 0.5 mol) was subsequently added dropwise while stirring. The mixture was refluxed for 4 hours, then cooled. The Grignard solution was then transferred in a countercurrent of protective gas into a 500 ml dropping funnel and added dropwise at −70° C. to a solution of trimethyl borate (62.4 g; 67 ml; 0.6 mol) in 350 ml of THF while stirring (time: about 1 hour). During this addition, a precipitate was formed. The reaction mixture was allowed to warm to RT overnight and was then poured while stirring into a mixture of 700 g of ice and 20 ml of concentrated sulfuric acid. The organic phase was separated off, the aqueous phase was extracted three times with chloroform and the combined organic phases were evaporated. The crude product was recrystallized from chloroform/hexane.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:8]([S:10]([C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([C:19]2[C:20]3[CH:29]=[N:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]=3[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)[CH:18]=1)(=[O:12])=[O:11])[CH3:9]>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])=[CH:18][C:17]=2[C:19]2[C:20]3[CH:29]=[N:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:21]=3[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Cyclopropylmethanol (0.018 g, 0.25 mmol) in dioxane (0.75 mL) was treated with sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol) and stirred at ambient temperature for 10 minutes. A solution of Example 322e (0.0683 g, 0.147 mmol) in dioxane (0.75 mL) was added and the mixture was stirred at 60° C. for 8 hours and then at ambient temperature for 16 hours. Additional cyclopropylmethanol (0.018 g, 0.249 mmol) and sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol) were added and the mixture was heated at 70° C. for 9 hours. The reaction mixture was cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in dichloromethane) to provide the title compound (0.0685 g, 90%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:16][CH2:15]1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccccn3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(N2CCC3(CCNC3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 ml) was added to a solution of tert-butyl 8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.47 mmol, 1.0 eq.) in methylene chloride (3 ml) at 0° C. and the reaction mixture was stirred at 25° C. for 1 h. When the reaction was complete (TLC), the solvent was removed in vacuo in order to obtain the desired amine (AMN-20).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1>C(OCC)C.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:19])=[CH:12][CH:13]=1
Reactant: NC(=O)CCCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCCc1ccc(Cl)cc1
Reaction time: 0.13 h
Yield: 61 %

Procedure:
To a stirred suspension of lithium aluminum hydride (1.84 g, 48.6 mmol) in diethyl ether (50 mL) at ambient temperature was added a solution of 4-(4-chlorophenyl)butanamide in tetrahydrofuran (25 mL), dropwise over 8 minutes. Stirring was continued at ambient temperature for a further 4 hours. The reaction mixture was carefully quenched by sequential slow addition of water (2 mL), 10M sodium hydroxide (0.75 mL), and water (7 mL). After stirring the mixture for 20 minutes, it was extracted with diethyl ether (50 mL). The organic layer was dried over sodium sulfate and concentrated to afford 4-(4-chlorophenyl)butan-1-amine as a light yellow oil (1.36 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:14])(=[O:13])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][C:28](=[O:31])[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1

Procedure:
The title compound was prepared from (4-chlorosulfonyl-phenoxy)-acetic acid methyl ester (Chem. Pharm. Bull. 1995, 43, 1132) and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a grey solid; MS (ES) m/z: 418.9 (MH+); HRMS Calcd. for C20H23N2O6S(MH+): 419.1271. Found: 419.1271.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[F:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:15][C:16]1[C:24]([O:25][CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[O:6][CH:7]=2)=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19]
Reactant: Cc1ccc(-c2nc(CCl)co2)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)co2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a solution of 4-Chloromethyl-2-p-tolyl-oxazole (0.10 g, 0.50 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.08 g, 0.50 mmol) and potassium carbonate (0.233 g, 1.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.03 g, 18%). 1H NMR (DMSO-d6, 400 MHz): δ 2.37 (s, 3H), 5.13 (s, 2H), 7.11 (m, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.41 (m, 1H), 7.88 (m, 3H), 8.12 (br s, 1H) and 8.29 (s, 1H). MS ES+ (345.24), HPLC (method I) Rt=16.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19](Cl)=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:19]([C:17]2[S:18][C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)([C:26]([F:27])([F:29])[F:28])[O:13][N:12]=3)=[C:15]3[CH2:25][CH2:24][CH2:23][CH2:22][C:16]=23)=[O:20])=[CH:32][CH:33]=1)(=[O:36])[NH2:37]
Reactant: O=C(Cl)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Reactant: NC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: NC(=O)c1ccc(NC(=O)c2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3c2CCCC3)cc1
Yield: 61.8 %

Procedure:
Stir a mixture of 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carbonyl chloride (48 mg, 0.1 mmol) and 4-aminobenzamide (27 mg, 0.2 mmo) in pyridine (3 mL) at ambient temperature overnight. After removal solvent under vacuum, purify the residue by preparative HPLC to afford N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide as a white solid (36 mg, 62.0%). MS (m/z): 582.1 (M+1). 1H NMR (CDCl3, 400 MHz) δ 7.84 (d, J=8.4 Hz, 2H), 7.65-7.63 (m, 3H), 7.49 (s, 2H), 7.44 (s, 1H), 6.03 (s, 1H), 5.61 (s, 1H), 4.09-4.05 (d, J=16 Hz, 1H), 3.72-3.68 (d, J=16 Hz, 1H), 3.07 (s, 2H), 2.94 (s, 2H), 1.76 (s, 4H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[ClH:6].[CH3:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][S:17][C:11]=2[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1>>[ClH:4].[Cl:6][C:16]1[S:17][C:11]2[CH:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9][N:8]([CH3:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: CN1CCc2ccsc2C(c2ccccc2)C1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Product: CN1CCc2cc(Cl)sc2C(c2ccccc2)C1

Procedure:
Sulphuryl chloride (0.16 ml) was added to a stirred solution of 6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine hydrochloride (0.49 g free base converted to hydrochloride salt with ethanolic hydrogen chloride) at room temperature. After 2 hours the mixture was evaporated and the solid residue recrystallised twice from ethanol (5 ml) to give the title product as white crystals (m.p. 198°).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=O)[NH:7][CH:8]=1)[CH3:2].[Cl:11]C1NC(=O)C(C)=C(C)N=1>>[Cl:11][C:6]1[NH:5][C:4](=[O:10])[C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: CCc1c[nH]c(=O)[nH]c1=O
Reactant: Cc1nc(Cl)[nH]c(=O)c1C
Product: CCc1cnc(Cl)[nH]c1=O
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield from 5-Ethyl-1H-pyrimidine-2,4-dione utilizing a method analogous to the preparation of 2-chloro-5,6-dimethyl-3H-pyrimidin-4-one (see Lee, et al., WO 9605177). 1H NMR (400 MHz, DMSO-d6): δ13.21 (br s, 1H), 7.90 (br s, 1H), 2.39 (q, 2H, J=7.6 Hz), 1.08 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for C6H7N2OCl, 159, 161; found 159, 161.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(phenylsulfonyl)benzene. MS (ESI): mass calcd. for C22H16FN3O2S, 405.09; m/z found, 406.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.29 (dd, J=6.7, 2.5, 1H), 8.03 (d, J=1.4, 1H), 7.80-7.66 (m, 3H), 7.58 (m, 1H), 7.41-7.28 (m, 5H), 6.84 (dd, J=8.0, 1.6, 1H), 6.78-6.66 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:8][C:7](S(CC3C=CC=CC=3)(=O)=O)=[N:6][C:5]=2[N:32]=1.[Cl:33][C:34]1[C:35]([F:42])=[C:36]([CH2:40][SH:41])[CH:37]=[CH:38][CH:39]=1.C(O)C.[BH4-].[Na+]>CS(C)=O>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:8][C:7]([S:41][CH2:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[C:35]=3[F:42])=[N:6][C:5]=2[N:32]=1
Reactant: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(S(=O)(=O)Cc2ccccc2)nc2nc(N)sc12
Reactant: Fc1c(Cl)cccc1CS
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2cccc(Cl)c2F)nc2nc(N)sc12
Temperature: 50 °C

Procedure:
To a mixture of the product from example 25 step f) (1.2 g), the product from example 25 step g) (1.6 g) in a mixed solvent of ethanol (30 ml) and DMSO (5 ml) was added sodium borohydride (100 mg) and the mixture heated at 50° C. for 2 hours. The ethanol was removed by rotary evaporation and the crude product extracted into ethyl acetate and washed with water. The subtitle compound was obtained by purification (SiO2, 1:1)dichloromethane:ethyl acetate as eluant) to give (1.95 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:17]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 100 °C
Yield: 44.2 %

Procedure:
10 g of methyl 4-hydroxybenzoate and 20.5 g of 4-(2-chloroethyl)morpholine were dissolved in 100 ml of dimethylformamide and, after the addition of 38 g of potassium carbonate heated to 100° C. for 1 hour. The reaction mixture obtained was poured on to ice-water, extracted with ethyl acetate, dried and evaporated. The oily, slightly brown residue was saponified with potassium hydroxide in water/ethanol and, after acidification and recrystallization from hexane/ethyl acetate, gave 7.3 g of p-(2-morpholinoethoxy)benzoic acid in beige crystals, m.p. 112°-114° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([CH3:49])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([CH3:49])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(Cc4ccccc4)CC3)CC2)cc(C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc(C)c1O
Temperature: 25 °C

Procedure:
A solution of 54 mg (0.08 mmol) of (R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 78) in 5 mL MeOH were combined with 20 mg of 10% Pd/C and shaken at RT and 3 bar hydrogen until the reaction stopped. The catalyst was suction filtered and the solvent evaporated down i.vac. The residue was triturated with DIPE, suction filtered and dried under a high vacuum.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[C:12]([S:13]([C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[N:27][NH:11]2
Reactant: O=N[O-]
Reactant: Nc1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cccc(OCCCl)c12
Temperature: 3 °C

Procedure:
A mixture of 3-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.78 g, 2.1 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.15 g, 2.2 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles).