Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]([NH2:18])[C:9]1=[O:19].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O.CCCCC>[CH3:6][O:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]([NH:18][C:2](=[O:3])[O:4][CH3:5])[C:9]1=[O:19]
Reactant: COC(=O)Cl
Reactant: CON1C(=O)[C@H](N)Cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCCCC
Product: COC(=O)N[C@@H]1Cc2ccccc2N(OC)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of methyl chloroformate (42.8 g, 0.453 mol) in chloroform (50 ml) was added to a mixture of (R)-1,2,3,4-tetrahydro-1-methoxy-2-oxo-3-quinolinamine 1 (M. Kawase, T. Kitamura, Y. Kilugawa, J. Org. Chem., 54, 1989 3394–3403)(0.15 mol) and sodium bicarbonate (50.4 g, 0.600 mol) in chloroform (250 ml) and water (100 ml) over a period of 10 minutes at 0° C. The mixture was stirred overnight at room temperature, diluted with pentane, and the layers were separated. The aqueous layer was extracted with diethylether, and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave an amber oil. Purification by flash chromatography (230–400 mesh silica gel, 35–40% ethyl acetate in hexane) gave the title compound as a light yellow oil (37.0 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:30][CH2:31][O:32][N:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH3:35])(=O)=O>>[F:48][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:34](=[N:33][O:32][CH2:31][CH2:30][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH:7]([O:6][C:5]4[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=4)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:19][CH:18]=3)[CH3:35])=[CH:37][CH:38]=2)=[CH:47][CH:46]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: CC(=NOCCOS(C)(=O)=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccc(F)cc3)cc2)cc1)Oc1ccc(F)cc1

Procedure:
The target compound (1.45 g) was obtained as a white powder by carrying out the reaction and the post-treatment according to Reference example 2 using ethyl 2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)propionate (1.8 g) obtained from Reference example 25(b), sodium hydride (55%, 271 mg), and 2-[[1-(4′-fluoro-4-biphenylyl)ethylidene]aminoxy]ethyl methanesulfonate (2.14 g) obtained from Reference example 26(b).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH2:21]([NH:6][C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:3][CH3:2])=[O:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1ccccc1)NCc1ccccc1
Yield: 72.6 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using D-phenylalanine methyl ester hydrochloride (2 gm, 9.2 mmol), THF (25 mL), MgSO4 (1.87 gm, 15.6 mmol), benzaldehyde (1.88 mL, 18.5 mmol), Et3N (1.28 mL, 9.2 mmol), sodium borohydride (699 mg, 18.5 mmol), and methanol (30 mL) to give 11g (1.8 gm, 72%) in FIG. 2. 1H NMR (500 MHz, CD3OD): δ 2.96 (2H, d, J=6.59 Hz), 3.53 (1H, t, J=7.08 Hz), 3.6 (3H, s), 3.63 (1H, d, J=12.93 Hz), 3.77 (1H, d, J=12.93 Hz), 7.13-7.18 (2H, m), 7.19-7.32 (8H, m). ESI-MS: 292.2 (M+23).
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][C:6]([CH2:8][CH3:9])=[N:5][N:4]=1)[CH3:2].C(C1C=C(CC)NN=1)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:4]=1)[CH3:2]
Reactant: CCC1=NN=C(CC)C1
Reactant: CCOC(=O)CBr
Agent: CCc1cc(CC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(CC)cc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of 3,5-diethyl-4H-pyrazole (2.14 g, 17.2 mmol) (i.e. the product of Example 15, Step A) in N,N-dimethylformamide (10 mL) was added potassium carbonate (4.7 g) and ethyl bromoacetate (2.9 mL, 26.1 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solids were filtered off and the filtrate was diluted with ethyl acetate, washed with water and dried over MgSO4. The reaction mixture was concentrated under reduced pressure to give 2.79 g of the title compound.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Solvent: C1CCOC1
Product: OCc1cccc2c1Cc1ccccc1-2
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A solution of 1-fluorenecarboxylic acid (10.0 g, 47.6 mmol) in THF (150 mL) at 0° C. was charged With a 1M solution of BH3 -THF complex in THF (80 mL, 80 mmol). The reaction mixture was stored overnight at room temperature then quenched with 30 mL of 10% AcOH in methanol. After dilution with water (100 mL), the water layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with 10% potassium carbonate solution, water, brine, dried over magnesium sulfate and evaporated. The residue (white crystals) was washed with ether and dried to afford 1-fluorenemethanol (6.4 g, 68.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1.O>[CH2:28]([N:27]([CH3:26])[C:2]1[N:3]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:7]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNCc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and N-methylbenzylamine (76 mg, 0.625 mmol) in dioxane (5 mL) was heated to reflux for 5 min and cooled. The mixture was diluted with water to give a white precipitate, which was recrystallised from EtOH to give N-benzyl-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 147-150° C.; 1H NMR (CDCl3) (rotamers) δ 8.45 and 8.22 (2d, J=7.6 and 7.9 Hz, 1H), 7.90 and 7.85 (2d, J=8.3 and 7.7 Hz, 1H), 7.68 and 7.44 (2t, JHF=53.7 and 53.6 Hz, 1H), 7.43-7.25 (m, 7H), 4.92 and 4.90 (2s, 2H), 3.95-3.73 (m, 8H), 3.22 and 3.20 (2s, 3H); Anal. Calc. for C23H23F2N7O: C, 61.2; H, 5.1; N, 21.7. Found: C, 61.45; H, 5.2; N, 21.95%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.O1CCO[CH2:17][CH2:16]1>C(O)C.O.C(N(CC)CC)C>[CH2:16]([O:5][C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:6])[CH3:17]
Reactant: C1COCCO1
Reactant: O=C(O)c1cccnc1Cl
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccnc1Cl
Yield: 90 %

Procedure:
10 g (0.0635 mole) of 2-chloronicotinic acid, 4.86 ml (0.067 mole) of thionylchloride and 30 ml of dioxane are heated at 70° C. for 3 hours. 20 ml of ethanol is added and the mixture is heated for 2 hours. After cooling to room temperature 10 ml of triethylamine, 10 ml of water and 5 ml ethanol is added. The solvents are evaporated and the residue is extracted with ether and water. The ether is evaporated and the crude product is isolated. The yield is 10.3 g (95%). Distillation of the crude product at 8 mm Bp. 122°-123° C. yielded 9.4 g (90%) of the title compound (2b:l), b.p. 122°-123° C. at 8 mm Hg.
Reaction SMILES: [NH2:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1>CN(C1C=CN=CC=1)C.CCN(C(C)C)C(C)C.ClC(OC)=O.C(Cl)Cl>[CH3:34][C:2]([NH:1][C:8](=[O:10])[O:9][CH3:4])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)N)(c2ccccc2)OC1=O
Agent: CN(C)c1ccncc1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C)(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A CH2Cl2 (1 mL) solution of (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5 mg, 0.009 mmol) was treated with DMAP (5 mg, 0.04 mmol), i-Pr2NEt (10 drops), and methyl chloroformate (20 drops). The reaction was stirred overnight. The reaction solution was by prep HPLC affording methyl 2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-ylcarbamate (2.58 mg). LC-MS Method 1 tR=1.45 min, m/z=518 (M+1); 1H NMR (CDCl3) 7.66 (dd, 1H, J=9 Hz, 2 Hz), 7.48 (d, 1H, J=3 Hz), 7.35-7.27 (m, 5H), 7.15 (d, 2H, J=8 Hz), 7.01 (d, 2H, J=8 Hz), 6.87 (d, 1H, J=9 Hz), 5.67 (q, 1H, J=7 Hz), 3.69 (s, 3H), 2.2 (s, 3H), 1.54 (d, 3H, J=7 Hz), 1.46-1.36 (m, 2H), 1.30 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:15][CH2:14][C@H:13]2[NH:16][C@:10]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:15][CH2:14][C@H:13]2[N:16]([CH2:25][CH:24]=[CH2:23])[C@:10]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H]2CC[C@@]1(c1ccccc1)N2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCN1[C@@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of (1S,2S,5S)-2-(tert-butyldimethylsilyloxy)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 55; 237 mg), allyl bromide (0.4 ml), potassium carbonate (230 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was treated with diethyl ether, washed with water and brine, then dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-25%) to give the title compound (230 mg, 98% two steps).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:4].[OH-].[Na+].Cl>CO.O>[Br:11][C:9]1[C:8](=[O:12])[N:7]([CH3:13])[C:6]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)cc(Br)c1=O
Temperature: 60 °C
Yield: 72.5 %

Procedure:
To a suspension of 5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.030 g, 0.069 mmol) in methanol (1 mL) was added 1 M NaOH (0.346 mL, 0.346 mmol). The reaction mixture was heated to 60° C. for 12 hours. The reaction mixture was diluted with H2O and the pH was adjusted with 1 M HCl until 1-2. Solids precipitated out of solution, which were collected, washed with H2O and dried under vacuum to yield 0.021 g (72%) pure desired product as a pale yellow solid. MS ESI (+) m/z 421, 423 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 13.3 (br s, 1H), 9.93 (s, 1H), 8.21 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.05 (t, 1H), 3.18 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:11]2[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:12]2)[CH2:9][CH2:8][CH:7](O)[CH2:6][CH2:5]1)#[N:2].CS(Cl)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+].CN(C=O)C.O>[N:32]([CH:7]1[CH2:6][CH2:5][C:4]([N:11]2[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[C:13]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:12]2)([CH2:3][C:1]#[N:2])[CH2:9][CH2:8]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCC(O)CC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCC(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[1-(cyanomethyl)-4-hydroxycyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (75 mg, 0.21 mmol) in DCM (2 mL) at ambient temperature was added TEA (0.059 mL, 0.42 mmol), and methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture was stirred at ambient temperature for 10 minutes. The mixture was diluted with saturated aqueous NaHCO3, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude residue (90 mg, 0.207 mmol) was diluted in DMF (1.0 mL), NaN3 (27 mg, 0.41 mmol) was added and the mixture was heated at 90° C. for 16 hours. The mixture was cooled to ambient temperature, diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 30-100% EtOAc/hexanes) to give the title compound as a mixture of two diasteromers (ratio 1:3), which was used without further purification.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[C:14]#[N:15].Cl>CS(C)=O>[C:14]([C:13]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=1[O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)#[N:15]
Reactant: Oc1cccc(O)c1
Reactant: N#Cc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1cc(Cl)ccc1Oc1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
66 g of resorcinol are added to 220 ml of dimethyl sulphoxide. With stirring, 37.4 g of potassium hydroxide (powder) are added, whereupon the temperature rises to 55° C. The mixture is kept for 30 minutes at 60° C. and the 51.6 g of 2,5-dichlorobenzonitrile are added in portions. The reaction mixture is then stirred for 7 hours at 90° C. and, after cooling, poured into ice-water. The pH is adjusted to 6 with conc. hydrochloric acid and initially a brown oil precipitates, which soon becomes crystalline. Crystallisation from ethanol/-water yields 49.6 g of 3-(2'-cyano-4'-chlorophenoxy)-phenol with a melting point of 118°-120° C.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]2=[O:32])[CH2:10]1)C1C=CC=CC=1.Cl.CN1C2C=CC=CC=2N(CC2OCCNC2)C1=O.[C:52]([OH:59])(=[O:58])/[CH:53]=[CH:54]\[C:55]([OH:57])=[O:56]>C(O)(C)C>[C:52]([OH:59])(=[O:58])/[CH:53]=[CH:54]\[C:55]([OH:57])=[O:56].[C:26]1([N:18]2[C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[N:16]([CH2:15][CH:11]3[O:12][CH2:13][CH2:14][NH:9][CH2:10]3)[C:17]2=[O:32])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1n(CC2CN(Cc3ccccc3)CCO2)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Agent: Cn1c(=O)n(CC2CNCCO2)c2ccccc21
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Product: O=c1n(CC2CNCCO2)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
30 g of 4-benzyl-2-(1-phenyl-6-chloro-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine hydrochloride are treated as in part (a) of Example 2. After evaporation of the solvent under reduced pressure, 20 g of an oily product are obtained and are dissolved in hot isopropyl alcohol. A hot solution of maleic acid in isopropanol is added. The salt precipitates slowly, 19 g of 2-(1-phenyl-6-chloro-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine maleate are obtained, m.p. 234° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][C:4]([CH3:7])([NH2:6])[CH3:5].[C:9](ON1C(=O)CCC1=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(O)(C)C.O>[CH3:1][N:2]([CH3:8])[CH2:3][C:4]([NH:6][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:5]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(C)CC(C)(C)N
Solvent: O
Solvent: CC(C)O
Product: CN(C)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.3 %

Procedure:
N1,N1,2-Trimethylpropane-1,2-diamine (5.68 g, 48.8 mmol) was dissolved into isopropanol/water (1:1, 150 mL). To this solution was added CbzOSu (12.2 g, 1 equiv, 48.8 mmol) in one portion. The reaction was left to stir at room temperature overnight for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (300 mL) and water (100 mL). The layers were separated and the organic layer extracted with water (2×100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to an oil. The crude oil was purified on an ISCO purification system with gradient elution from 2% methanol in DCM to 30% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (8.95 g, yield: 73.2%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI+) for C14H22N2O2 (250.2); Found: 251 (MH+).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:42][C:43]([N:45]1[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]1([CH3:54])[CH3:53])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]2([CH3:54])[CH3:53])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.9 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.C(N([CH2:18][CH3:19])CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:19]2[CH2:18][CH2:1][O:2][CH2:3][CH2:4]2)=[CH:7][CH:6]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cc1ccc(S)cc1
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(SC2CCOCC2)cc1
Reaction time: 0.25 h
Yield: 159.4 %

Procedure:
(4-Mercapto-phenyl)-acetic acid methyl ester (1.8 g, 9.89 mmol) was dissolved in DMF (20 ml) at 0° C. Triethylamine (1.5 g, 14.83 mmol) was added and stirred for 15 minutes followed by addition of 4-iodo-tetrahydropyan (3.14 g, 14.83 mmol). The reaction mixture was stirred overnight at room temperature. Solvent was removed under reduced pressure, the resulting residue was taken into water and extracted with ethyl acetate (50 ml×2) washed with water and brine (50 ml each) dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by column chromatography over silica gel using 15% ethyl acetate in hexanes as eluent to provide [4-(Tetrahydro-pyran-4-ylsulfanyl)-phenyl]acetic acid methyl ester (2.1 gm).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][C:30]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[S:17])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1)Nc1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carbothioamide and phenyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:30][C:31]([CH3:33])=O.[BH3-]C#N.[Na+].C(OCC)(=O)C>CO>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:24](=[O:27])[CH2:25][NH:26][CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:29]
Reactant: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CN)CCc3ccccc3C2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CNC(C)C)CCc3ccccc3C2)cc1
Yield: 23 %

Procedure:
The amine from Example 13A was dissolved in 1 M pH4 MeOH buffer (82 g NaOAc/L MeOH, add HOAc to pH 4.5) and acetone (12 mg, 0.2 mmol) and NaBH3CN (13 mg, 0.2 mmol) were added. Following stirring for 2 hours ethyl acetate (30 mL) was added and the resulting solution was washed with aqueous NaOH (1N, 2×10 mL). The organic phase was dried over MgSO4, concentrated, and purified by HPLC to provide the titled compound (30 mg, 23% over 3 steps). 1H NMR (300 MHz, DMSO-D6) δ 9.21 (s, 1H), 7.83 (s, 1H), 7.32 (d, J=9.3 Hz, 2H), 7.10 (m, 4H), 6.61 (d, J=9.0 Hz, 2H), 3.28 (q, J=6.9 Hz, 4H), 3.22 (d, J=18.9 Hz, 1H), 3.11 (d, J=18.9 Hz, 1H), 3.07 (s, 2H), 2.77 (m, 2H), 2.45 (m, 2H), 2.09 (m, 1H), 1.05 (t, J=7.2 Hz, 6H), 0.81 (d, J=6.3 Hz, 3H), 0.73 (d, J=6.3 Hz, 6H). MS (ESI) positive ion 437 (M+H)+; negative ion 435 (M−H)−.
Reaction SMILES: [CH:1]([C:3]([OH:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]>[Pd].C1CCCCC1>[CH2:1]([C:3]([OH:16])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: C=CC(O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCCCC1
Product: CCC(O)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 21 g. of α-vinyl-benzhydrol and 84 ml. of cyclohexane is refluxed in the presence of palladium catalyst. When the reaction is over, as evidenced by thin layer chromatography, the mixture is cooled, the catalyst is filtered off, and the filtrate is evaporated under reduced pressure. 21.2 g. of crystalline α-ethyl-benzhydrol, melting at 93°-94° C., are obtained as residue.