Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)(C)(C)C.N1C=CC=CC=1.Cl.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([OH:33])[CH2:28][CH2:29][N:30]([S:2]([NH2:5])(=[O:4])=[O:3])[CH2:31][CH2:32]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OC1(c2ccccc2F)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: NS(=O)(=O)N1CCC(O)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 37.7 %

Procedure:
To a stirring solution of 4-(2-fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 4.06 mmol) in ethyl acetate (5 mL) was added hydrogen chloride (15 mL, 4N in 1,4-dioxane) and the resulting solution was stirred for 3 hours during which time a precipitate formed. The reaction mixture was concentrated at reduced pressure to give the crude product, 4-(2-fluoro-phenyl)-piperidin-4-ol hydrochloride, which was used in the next step without purification. To a solution of chlorosulfonyl isocyanate (0.35 mL, 4.06 mmol) in dichloromethane (10 mL) at 3° C. was added tert-butanol (0.39 mL, 4.06 mmol). After 25 minutes, pyridine (0.72 mL, 8.9 mmol) was added and the resulting mixture was stirred for 40 minutes during which time a precipitate formed. This slurry was added via pipette to a solution of crude 4-(2-fluoro-phenyl)-piperidin-4-ol hydrochloride (940 mg, 4.06 mmol) and triethylamine (0.62 mL, 4.47 mmol) in dichloromethane (6 mL) at 3° C. The resulting mixture was allowed to warm to ambient temperature over 4 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with dilute hydrochloric acid (40 mL, 0.1N) followed by saturated aqueous sodium chloride (30 mL). The organic layer was concentrated at reduce pressure. The resulting oil was dissolved in ethyl acetate (5 mL) and to this solution was added hydrogen chloride (15 mL, 4N in 1,4-dioxane) and the resulting solution was stirred for 5 hours. The reaction mixture was concentrated at reduced pressure and the resulting solid was purified by column chromatography through a silica gel cartridge (12 g) eluting with ethyl acetate/hexane (1:9 to 2:5) to give the product as a white solid (420 mg, 38% over 3 steps). 1H NMR (DMSO-d6) δ 7.65 (m, 1H,), 7.30 (m, 1H), 7.24-7.09 (m, 2H), 6.75 (s, 2H), 5.28 (s, 1H), 3.31 (m, 2H), 2.92 (m, 2H), 2.22 (m, 2H), 1.68 (m, 2H). MS (ES+)=275 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S@:25]([CH:33]2[CH2:35][CH2:34]2)(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S@:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH:33]1[CH2:34][CH2:35]1)=[O:26])=[O:29])[CH3:32]
Reactant: CCOC(=O)N=[S@](=O)(c1ccc(N)cc1)C1CC1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=[S@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (185 mg, 0.7 mmol) with (R)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-cyclo-propyl-sulfoximide (167 mg, 0.6 mmol) according to procedure 5a, the desired product is obtained in 26% yield (90 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1.[H][H]>C(O)C.C1COCC1.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(NCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(N)c1

Procedure:
262 mg (purity 66%, 0.55 mmol) of (+/−)-ethyl 2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclopropanecarboxylate were dissolved in 5 ml of ethanol/THF (1:1), 26 mg of palladium on carbon (10%) were added and the mixture was hydrogenated at RT using a hydrogen pressure of 1 bar for 24 h. The reaction mixture was then filtered through celite, the residue was washed with ethanol and the filtrate was concentrated. The crude product obtained in this manner was purified by preparative HPLC. This gave 87 mg (69% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2O)=[CH:4][C:3]=1[O:20][CH3:21].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:20][CH3:21])=[C:2]([F:1])[CH:11]=2)[CH:6]=[C:7]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:8]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1F
Temperature: 150 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
7-Fluoro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol (1.9 g), POCl3 (15 ml), were sealed in a process vial (20 ml). The mixture was heated at 150° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 5 ml MeOH. The mixture was stirred for 2 hours at room temperature, and the solid was collected and dried to give desired product (1.3 g, 64% yield). LC-MS: m/e 307 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)=[O:45])=[CH:39][CH:38]=2)[CH2:9][C:10]2[CH:35]=[CH:34][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22](=[O:33])[C@@H:23]([NH:28][C:29]([O:31][CH3:32])=[O:30])[C:24]([OH:27])([CH3:26])[CH3:25])=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.C(NCC)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22](=[O:33])[C@@H:23]([NH:28][C:29](=[O:30])[O:31][CH3:32])[C:24]([OH:27])([CH3:25])[CH3:26])=[N:16][C:12]=3[CH:11]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@H:46]3[CH2:50][CH2:49][CH2:48][NH:47]3)=[O:45])=[CH:39][CH:38]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4C(=O)OCC4c5ccccc5-c5ccccc54)cc3)c3ccc(F)cc3)ccc2[nH]1)C(C)(C)O
Solvent: CCNCC
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4)cc3)c3ccc(F)cc3)ccc2[nH]1)C(C)(C)O

Procedure:
The product from Example 99G (0.115 g, 0.127 mmol) was dissolved in acetonitrile (2 mL) at ambient temperature and treated with diethylamine (1 mL) for 1 hour. The solution was concentrated to dryness to give the crude title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:27]=[CH:26][C:15]([O:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[C:14]([O:28][CH3:29])[C:13]=2[N+:30]([O-])=O)=[N:2]1.[Sn].Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:13]1[C:14]([O:28][CH3:29])=[C:15]([CH:26]=[CH:27][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)[O:16][CH2:17][C:18]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)=[O:19]
Reactant: COc1c(OCC(=O)N2CCOCC2)ccc(/C=C/c2n[nH]c3ccccc23)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(OCC(=O)N2CCOCC2)ccc(/C=C/c2n[nH]c3ccccc23)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
A solution of (E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxyacetyl}morpholine (0.2 g, 0.46 mmol) obtained in Step 4 in ethanol (4.0 mL) was ice-cooled and the solution was added with tin (0.16 g, 1.4 mmol) and concentrated hydrochloric acid (2.0 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture under ice-cooling, 6 mol/L sodium hydroxide was added to neutralize the mixture. Then, the obtained solid was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain (E)-4-{3-amino-4-[2-(1H-indazol-3-yl)vinyl]-2-methoxyphenoxyacetyl}morpholine (0.17 g, 93%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[N:10]1([C:16]2[C:21](=[O:22])[NH:20][CH:19]=[C:18]3[CH2:23][N:24]([CH2:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[C:25](=[O:26])[C:17]=23)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(#N)C.O>[CH2:8]([N:20]1[C:21](=[O:22])[C:16]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:17]2[C:25](=[O:26])[N:24]([CH2:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:23][C:18]2=[CH:19]1)[CH3:9]
Reactant: CCI
Reactant: O=C1c2c(c[nH]c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 60 °C
Yield: 35.4 %

Procedure:
Potassium carbonate (2.5 g, 18.09 mmol), iodoethane (0.103 ml, 1.281 mmol) and 7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (0.5 g, 1.281 mmol, see Example 15) were suspended in acetonitrile (30 ml). The suspension was heated in a three-neck round bottom flask at about 60° C. for about 2 h. After cooling to r.t. LC-MS analysis indicated complete conversion. The reaction mixture was diluted with water. The aqueous layer was extracted with DCM (2×100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow solid which was purified by preparative HPLC to give the title compound (190 mg, 0.454 mmol, 35.5 yield) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]([NH:38][C:35]2[CH:36]=[CH:37][C:30]3[CH2:29][CH2:28][CH:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:33][CH2:32][C:31]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
The title compound was prepared from 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to Example 179. Product was isolated as a tan solid (30 mg, 40%). LCMS (m/e) 521 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.65 (d, 1H, J=8.3 Hz), 8.04 (s, 1H), 7.52 (broad s, 1H), 7.50 (d, 1H, J=7.6 Hz), 7.43 (dd, 1H, J=8.1, 7.6 Hz), 7.37 (s, 1H), 7.29 (s, 1H), 7.09 (t, 1H, J=7.6), 7.04 (d, 1H, J=8.1 Hz), 6.16 (broad s, 1H), 3.71 (s, 4H), 3.52 (m, 3H), 2.63-2.85 (m, 4H), 2.58 (s, 4H), 2.8 (m, 2H), 1.42 (m, 2H), 1.27 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:21]([O:22][CH3:23])=[N:20][C:7]2[CH2:8][CH2:9][N:10](C(=O)C(F)(F)F)[CH2:11][CH:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([NH:3][C:4]1[C:21]([O:22][CH3:23])=[N:20][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCNc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCNc1cc2c(nc1OC)CCNCC2C
Yield: 86.7 %

Procedure:
A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-3-amine (455 mg, 1.5 mmol), acetaldehyde (253 μl, 4.50 mmol) and 5% Pd/C (23.0 mg) in EtOH (18 ml) was subjected to H2 (50 psi) for 16 h at room temperature. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography to provide 280 mg (56%) of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H NMR (CDCl3) δ 6.47 (1H), 4.03 (0.5H), 3.88 (5H), 3.71 (0.5H), 3.43 (1H), 3.64 (3H), 2.98 (2H), 1.20 (6H) ppm. A mixture of of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (331 mg, 1.00 mmol), K2CO3 (415 mg, 3.00 mmol), MeOH (13 ml) and H20 (2.7 ml) was stirred for 16h at room temperature. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 204 mg (87%) of N-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 6.48 (s, 1H), 3.87 (s, 3H), 3.80 (br s, 1H), 3.10-2.70 (m, 9H), 2.48 (br s, 1H), 1.26 (d, 3H), 1.24 (t, 3H) ppm.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C(=O)(O)[O-].[Na+].[Br:27][CH2:28][C:29](Cl)=[O:30]>C1C=CC=CC=1>[Br:27][CH2:28][C:29]([O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3)=[O:30]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)CBr

Procedure:
To a solution of 2.884 g (0.01 mol) of testosterone in 30 ml of dry benzene was added 1.008 g (0.012 mol) of sodium bicarbonate; then, while stirring, there were introduced dropwise 1.888 g (0.012 mol) of bromoacetyl chloride over a 5 minute period. The reaction mixture was then stirred under reflux for 6 hours until no testosterone could be traced by TLC. (Plates of Silica Gel G and a CHCH3 /CH3OH system were used.) The inorganic residue was filtered while hot, the filtrate was evaporated in vacuo and the residue was recrystallized from methanol, m.p. 144°-145° C., yield 3.2 g (78%). IR (KBr) 1735 (C=O), 1660 (C=O) cm-1. PMR as expected. The product has the formula: ##STR1520##
Reaction SMILES: CO[C:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C([Br:14])(=O)C>O>[Br:14][C:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2
Reactant: COC12CCC(CC1)CC2
Reactant: CC(=O)Br
Solvent: O
Product: BrC12CCC(CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a stirred mixture of 1-methoxybicyclo[2.2.2]octane (4.0 g, 28 mmol) and acetyl bromide (6.2 g, 50.4 mmol) was added 10 drops of stannic chloride at 0° C. After stirring for 0.5 h, the temperature was allowed to rise to 20-25° C. and stirring was continued at the same temperature for 3 h. After cooling to 0° C., water (30 mL) was added and the mixture was stirred for 10 min. Then the mixture was poured into water (150 mL) and extracted with ether (100 mL×3). The ether layers were combined, washed with aqueous sodium bicarbonate and water, and dried over sodium sulfate. The solvent was removed under reduced pressure to produce 1-bromobicyclo[2.2.2]octane (4.0 g, 75%), which was used for next step without purification. 1H NMR (CDCl3) δ 2.23 (m, 6H), 1.95 (m, 1H), 1.81-1.63 (m, 6H), 1.52 (m, 1H).
Reaction SMILES: [S:1](Cl)([N:4]=C=O)(=[O:3])=[O:2].CC(O)(C)C.[NH2:13][C@@H:14]([CH2:25][C:26]1[O:27][C:28]([CH2:31][C:32]2[S:33][C:34]3[CH:40]=[C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:38]=[CH:37][C:35]=3[N:36]=2)=[N:29][N:30]=1)[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl>[C:41]1([C:39]2[CH:38]=[CH:37][C:35]3[N:36]=[C:32]([CH2:31][C:28]4[O:27][C:26]([CH2:25][C@H:14]([NH:13][S:1](=[O:3])(=[O:2])[NH2:4])[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:16])=[N:30][N:29]=4)[S:33][C:34]=3[CH:40]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: NS(=O)(=O)N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a solution of Compound 45a (460 mg, 0.81 mmol) in DCM (5 mL) was added TFA (5 mL) and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with toluene (3×) and DCM, then dried under high vacuum to give (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 100% yield) as a yellow solid. LCMS=1.90 min using analytical method (B), 471.0 (M+H). In a separate flask, to a solution of sulfurisocyanatidic chloride (170 mg, 1.2 mmol) in DCM (2 mL) was added 2-methylpropan-2-ol (90 mg, 1.2 mmol) in DCM (2 mL) and the reaction mixture stirred for 20 min. The resulting solution was then added to a mixture of (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 0.81 mmol) and TEA (0.56 mL, 4.0 mmol) in DCM (5 mL) and the reaction mixture stirred for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with 1 N HCl solution and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (6 mL) and treated with TFA (3 mL) then stirred for 1 h. The mixture was concentrated under reduced pressure, co-evaporated under reduced pressure with toluene and DCM, and the residue purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give Compound 45b (380 mg, 86% yield) as a yellow solid. LCMS=2.00 min using analytical method (B), 550.2 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.15-8.08 (m, 1H), 8.06-8.00 (m, 1H), 7.76-7.70 (m, 1H), 7.66-7.58 (m, 2H), 7.50-7.44 (m, 2H), 7.42-7.27 (m, 7H), 5.65-5.58 (m, 1H), 5.23-5.19 (m, 1H), 5.16-5.09 (m, 2H), 4.73-4.61 (m, 3H), 3.53-3.30 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:32])[CH3:31])=[CH:4][C:5]2[N:9](COCC[Si](C)(C)C)[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:7][C:6]=2[CH:24]=1.[C:33]([C:35]1[CH:36]=[C:37](Br)[CH:38]=[CH:39][CH:40]=1)#[N:34]>>[C:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[C:3]1[C:2]([O:1][C:39]2[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=2)[C:33]#[N:34])=[CH:24][C:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:9][C:5]=2[CH:4]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Reactant: N#Cc1cccc(Br)c1
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1cccc(C#N)c1

Procedure:
The entitled compound was obtained as an oily substance in the same method as in Example 121 (step 11), (step 12) or in accordance with the method or by combining it with an ordinary method but using 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 121 (step 10) and 3-cyanobromobenzene.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:20][C:17]([O:16][C:14](=[O:15])[NH:13][C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH2:3][OH:2])([CH3:18])[CH3:19]
Reactant: COC(=O)C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a solution (R)-β-[[(1,1-Dimethylethoxy)carbonyl]amino]-benzenebutanoic acid methyl ester (1.5 g, 5.1 mmol, J. Med. Chem. 1985, 28, 434) in THF (10 mL), was added lithium borohydride (218 mg, 10 mmol), followed by ethanol (10 mL), dropwise. After stirring at rt for 18 hours, an additional lithium borohydride (218 mg 10 mmol) was added and stirring continued for 6 hours. The reaction mixture was ice cooled and adjusted to pH 4 by the addition of a 10% citric acid solution. Organic solvents were removed and the resulting cloudy aqueous solution was extracted with dichloromethane. The extracts were combined, dried (MgSO4) and concentrated in vacuo to afford a clear colorless oil residue which was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes to yield (1.2 g, 89%) of the title compound as a clear colorless oil. MS; (M+H)+=266
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl>C(C(C)=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2cccc(Cl)c2)cc1
Yield: 88.2 %

Procedure:
18.3 g of p-hydroxybenzaldehyde is dissolved in 200 ml of methyl ethyl ketone, and then 22.8 g of potassium carbonate and 24.2 g of m-chlorobenzyl chloride are added thereto. The resulting mixture is refluxed for 8 hours in a stream of nitrogen. Insoluble substances produced are removed by filtration, and then the solvent is distilled away. The resulting residue is distilled under reduced pressure to obtain 32.6 g of 4-(3-chlorobenzyloxy)benzaldehyde in the form of white crystal.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(O)(C)C.[NH2:13][NH2:14]>C(OC)(C)(C)C.[Cl-].[Na+].O>[CH3:8][C:4]1[N:3]=[C:2]([NH:13][NH2:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(F)n1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: Cc1cccc(NN)n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A jacketed reaction flask was equipped with mechanical stirrer, nitrogen inlet, and reflux condenser and the jacket was cooled to 10° C. The reactor was programmed to automatically cool to 0° C. if at any point the internal temperature exceeded 80° C. The reactor was purged with a steady stream of nitrogen gas. To the reactor was charged 25 g (0.225 mol) of 2-fluoro-6-methylpyridine followed by 100 ml of isopropanol and the jacket temperature was adjusted to 73° C. (corresponding to an internal temperature of 70° C.). To the reactor was charged 44 g (0.90 mol) of 65% aqueous hydrazine and the mixture was stirred overnight with the jacket set at 70° C. The reactor contents were diluted with 125 ml of methyl t-butyl ether (MTBE) and 13 ml of saturated brine to give two layers which were separated. The aqueous layer was extracted with 2×60 ml of MTBE. The combined organic layers were combined and dried over sodium sulfate (anhydrous). The drying agent was removed by filtration and the organic filtrate was concentrated by rotary evaporation. The resulting oil solidified upon standing to give the desired product (21.1 g) as a white solid.