Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[BrH:10].[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CCCCCC.C(OCC)(=O)C.CS(C)=O>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([CH3:9])[C:2]=1[F:1]
Reactant: Br
Reactant: Cc1c(N)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc(Br)c1F
Temperature: 10 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
To a stirred solution of 3-fluoro-2-methylaniline (25 g, 200 mmol) in acetic acid (140 mL) at 0-5° C. was added hydrogen bromide (100 mL, 200 mmol) then dimethyl sulfoxide (72 mL) was added slowly dropwise (reaction is exothermic and at temperature higher than 5-15° C. produces dibromoisomer). The mixture was stirred at 5-15° C. for 12 h (mixture became clear solution). The resulting solution was cooled to 0° C. and neutralized with sodium hydroxide then with sodium bicarbonate to pH 7. The mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. Flash chromatography (0-10% ethyl acetate in hexane) gave the desired product as a white solid (23.3 g, 114 mmol, 57% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.11 (t, J=8.20 Hz, 1H), 6.35 (d, J=8.98 Hz, 1H), 3.72 (br. s., 2H), 2.07 (d, J=1.95 Hz, 3H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[C:30]([O:34][C:35]([NH:37][C@:38]([C:47]1[O:51][C:50]([C:52]2[CH:53]=[C:54]([N:59]([CH3:64])[S:60]([CH3:63])(=[O:62])=[O:61])[CH:55]=[C:56](Br)[CH:57]=2)=[N:49][N:48]=1)([CH3:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([O:34][C:35]([NH:37][C@:38]([C:47]1[O:51][C:50]([C:52]2[CH:53]=[C:54]([N:59]([CH3:64])[S:60]([CH3:63])(=[O:62])=[O:61])[CH:55]=[C:56]([C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:6]=3)[CH:57]=2)=[N:49][N:48]=1)([CH3:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CN(c1cc(Br)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Product: CN(c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-1-trityl-1H-imidazole (Preparation described in Jetter, M. C., Boyd, R. E., Reitz, A. B. Org. Prep. Proced. Int. 1996, 28(6), 709-710; 87 mg, 0.20 mmol) in 2 mL TF was added ethylmagnesium bromide (1.0 M solution in THF, 0.24 mL, 0.24 mmol) dropwise. The reaction was stirred at rt for 0.5 h and zinc chloride (0.5 M solution in THF, 0.8 mL, 0.4 mmol) was added. After stirring for 1 h, 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-bromo-N-methyl-N-(methylsulfonyl)benzenamine (100 mg, 0.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.8 mg, 0.018 mmol) were added. The mixture was heated in a microwave oven to 80° C. for 0.5 h, quenched with saturated ammonium chloride and extracted with EtOAc. The combined organic layers were washed with water and brine. Drying, solvent evaporation and flash chromatography (15-65% EtOAc/hexanes) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(methylsulfonyl)-5-(1-trityl-1H-imidazol-4-yl)benzenamine. 1H NMR (CDCl3) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.54 (d, J=0.8 Hz, 1H), 7.40-7.00 (m, 21H), 3.56 (d, J=12 Hz, 1H), 3.44 (d, J=12 Hz, 1H), 3.39 (s, 3H), 2.92 (s, 3H), 1.72 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(=O)(O)[O-]>[CH3:1][O:2][C@H:3]([CH3:9])[C@H:4]([NH:5][C:11]([O:13][CH3:14])=[O:12])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)Cl
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Agent: O=C([O-])O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
A solution of O-methyl-L-threonine (1.01 g, 7.59 mmol) in saturated bicarbonate solution (93 mL) was treated dropwise with methyl chloroformate (900 μL, 1.10 g, 11.61 mmol), followed by stirring at RT for 24 h. The mixture was extracted methyl t-butyl ether and cooled to 0° C. The mixture was adjusted to pH 1-2 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×) and the combined extracts were extracted with saturated sodium chloride solution and dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound (1.31 g, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.44 (d, J=8.7 Hz, 1H), 4.39 (dd, J=8.7, 2.3 Hz, 1H), 4.00 (dd, J=6.2, 2.4 Hz, 1H), 3.71 (s, 3H), 3.36 (s, 3H), 1.21 (t, J=7.2 Hz, 3H). MS (+ESI) m/z (rel abundance) 192 (60, M+H), 209 (100, M+NH4).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH3:13][C:3]1[C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH2:25]2)=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccnc(Cl)c1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOC(=O)c1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C

Procedure:
Step (i) of Example 106 was repeated, except that the compound prepared in step (a) of Example 109 was used instead of 3-bromo-7,8-dihydro-6H-1,6-naphthyridin-5-one and 1-tert-butoxycarbonylpiperazine was used instead of 3,3-diphenyl-1-propylpiperazine. Thus, ethyl 3-methyl-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]isonicotinate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+].Cl>C(O)C.O.O>[OH:14][CH2:13][C@H:12]([NH:11][C@@H:10]([CH3:16])[C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[OH:17])[CH3:15]
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](CO)N[C@@H](C)[C@H](O)c1cc(F)cc(F)c1
Temperature: 0 °C

Procedure:
The hydrobromide salt of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (0.023 mole) (U.S. Pat. No. 5,104,870) is dissolved in a 50:50 mixture of ethanol/water (150 mL) and chilled to 0° C. while being stirred under a nitrogen atmosphere. A solution of sodium borohydride (0.093 mole) in water (25 mL) is added dropwise, and the solution is allowed to warm to room temperature while being stirred overnight. The solution is cooled to 0° C., and concentrated hydrochloric acid (25 mL) is carefully added dropwise. The mixture is concentrated under reduced pressure to remove ethanol and then diluted with water to dissolve the solids. This solution is cooled with an ice bath, made basic by treatment with 40% aqueous sodium hydroxide and extracted three times with diethyl ether. The combined ether extracts is washed with a saturated sodium chloride solution, dried over sodium sulfate and spin evaporated in vacuo to give the free base of (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol (21). A sample of the free base is treated with ethereal hydrogen chloride to give a solid that may be recrystallized from ethanol/ether to give the hydrochloride salt of (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol. See eg., Boswell et al., J. Heterocyclic Chem., (1996) 33:33.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].C(=O)=O.[F:31][C:32]([F:37])([F:36])[C:33](Cl)=[O:34].Cl>[C]=S>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:33](=[O:34])[C:32]([F:37])([F:36])[F:31])=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)cc2)CC1
Reactant: O=C(Cl)C(F)(F)F
Agent: Cl
Agent: O=C=O
Agent: [Al+3]
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)C(F)(F)F)cc3)cc2)CC1
Reaction time: 6 h

Procedure:
0.5 mol of 4-(trans-4-pentylcyclohexyl)biphenyl, 500 ml of carbon sulfide and 0.5 mol of aluminium chloride are introduced into a three-neck flask fitted with a dry-ice reflux condenser. After the mixture has been cooled to -30°, 0.5 mol of trifluoroacetyl chloride are condensed in. The mixture is then allowed to warm to 0° and stirred at this temperature for 6 hours then at room temperature for 14 hours. The reaction mixture is poured onto a mixture of ice and dilute hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted by shaking with dichloromethane (2×50 ml). The organic phases are combined, the solvents removed by distillation and the product is recrystallized twice from ethanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=O.C(=O)(O)[O-].[Na+]>CCO>[CH3:7][C:5]1[N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[N:1]=[C:2]2[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1csc2nc(-c3ccc([N+](=O)[O-])cc3)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A mixture of 2-amino-4-methylthiazole (0.24 g, 2.11 mmol) and 2-bromo-4′-nitroaceto phenone (0.5 g, 2.05 mmol) in EtOH (20 ml) was heated under reflux for 16 h. The reaction mixture was allowed to cool and sodium bicarbonate (200 mg, 2.38 mmol) was added and heating was continued for 1 h. On cooling to room temperature, the solvent was removed under reduced pressure and DCM (75 ml) was added to the residue. The insoluble material was collected by filtration and purified by flash chromatography (50:1 DCM/MeOH) to give the title compound (0.266 g, 50%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:22]1([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[C:8]([O:28][CH2:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:9]=1
Reactant: OCC1CCCC1
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(F)cc(Br)cc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (7.5 g, 34.4 mmol) in dry THF (50 mL) at 0° C. was added a mixture of sodium bis(trimethylsilyl)amide (1.0 M, 34 mL, 34 mmol) and cyclopentanemethanol (3.4 g, 34 mmol) in THF (100 mL). The reaction was allowed to warm up to room temperature and stirred overnight. Water (50 mL) was added to the reaction and the product was extracted by CH2Cl2 (2×50 mL). The solvent was washed with brine and dried over Na2SO4. The solvent was removed to give 4-bromo-2-cyclopentylmethoxy-6-fluorobenzonitrile (4.5 g, 43.9%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:8][N:7]1[C:3]([CH2:2][O:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6]1
Reactant: COC(=O)c1cc(CO)n(C)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(COS(C)(=O)=O)n(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of methyl 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylate (0.60 g, 3.51 mmol) and triethylamine (1.22 mL, 8.77 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.41 mL, 5.26 mmol). The reaction mixture was stirred at this temperature for 15 minutes and the coolant removed. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][O:31][CH2:32][CH2:33]Br>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:33][CH2:32][O:31][CH3:30])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COCCBr
Product: COCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-methoxyethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-bromoethyl methyl ether following General Procedure H.
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.CO>[CH3:1][C:2]1[C:10]([O:11][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1c(O)ccc2c1cnn2C1CCCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc([N+](=O)[O-])cc2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Under nitrogen, 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (200 mg, 0.861 mmol) was dissolved in N,N-dimethylformamide (5 ml), followed by adding thereto 4-fluoronitrobenzene (100 μl, 0.947 mmol) and potassium carbonate (179 mg, 1.29 mmol), and the resulting mixture was stirred at 50° C. for 1 hour. After the reaction solution was cooled to room temperature, a 1N-aqueous hydrochloric acid solution (6 ml) and methanol (3 ml) were added thereto and the resulting mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 9 with a saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate/toluene=3/1. The combined extract layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain 4-methyl-5-(4-nitrophenoxy)-1H-indazole (192 mg, yield 82.8%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 108 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[2-ethyl-5-(2-methylpropanoyl)thiophen-3-yl]methyl}amino)benzoate (268 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred with heated under reflux for 2 hr. To the reaction mixture was added 1N hydrochloric acid (10 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (280 mg, quantitative) as a pale-brown solid.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[C:38]=3[Cl:47])[CH2:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:12]=2)[CH2:7][CH2:6]1.O.[OH-].[Li+].Cl>C1COCC1.O>[ClH:47].[Cl:47][C:38]1[C:39]([C:43]([F:45])([F:44])[F:46])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:21]([CH2:22][CH:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]([OH:48])=[O:2])[CH2:10][CH2:9]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 169.6 %

Procedure:
To a stirring solution of [4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-acetic acid methyl ester (99 mg, 0.146 mmol) in a mixture of THF and water (3:1; 12 ml) was added lithium hydroxide monohydrate (8 mg, 0.192 mmol). The resulting mixture was stirred at room temperature for 18 hours and then acidified with 1 M aqueous HCl (0.2 ml). The mixture was concentrated in vacuo, water (5 mL) was added, and the crude material was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over sodium sulfate, and filtered. The organic layer was concentrated, and the crude amine was treated with 1 M HCl (Et2O). The resulting precipitate was dried under vacuum to afford the title compound as a solid (87 mg, 97%). MS(ES) m/e 666.0 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:35][CH:34]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2SCC(=O)N(NC(=O)c2ccccc2)C(C)C)cc1
Yield: 73 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml)/2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 4-methoxyphenylboronic acid (75 mg, 0.49 mmol) and Pd[PPh3]4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (78 mg, 72%). MS m/e 435.24 (M+H+)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1cccc(Cl)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 12 and 3-chlorobenzen sulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: CC(C)CC(C1C=CC(C)=CC=1)=O.[Br:14][CH2:15][C:16]1(CBr)[CH:21]=[CH:20][C:19]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][CH2:17]1>>[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:27])[CH2:23][CH:24]([CH3:25])[CH3:26])=[CH:18][CH:17]=1
Reactant: CC(C)CC(=O)C1=CCC(CBr)(CBr)C=C1
Agent: Cc1ccc(C(=O)CC(C)C)cc1
Product: CC(C)CC(=O)c1ccc(CBr)cc1

Procedure:
Add NBS (1.6 g, 9.2 mmol) to a solution of 3-methyl-1-p-tolyl-butan-1-one (1.5 g, 8.4 mmol) and AIBN (1.4 g, 8.4 mmol) in carbon tetrachloride (30 mL) and heat to reflux for 18 h. Cool the reaction mixture to room temperature and pour into water (500 mL). Extract with EtOAc (3×100 mL), wash the combined organic extracts with brine (300 mL), dry over Na2SO4 and concentrate in vacuo to obtain 2.9 g of a brown oil, consisting of the desired intermediate with a small amount of unreacted 3-methyl-1-p-tolyl-butan-1-one and 1-(4,4-dibromomethyl-phenyl)-3-methyl-butan-1-one. Use this mixture in the next step without additional purification. MS (APCI+) m/z: 255 (M+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:45]=[CH:44][C:28]([CH2:29][O:30][C:31]2[C:36]([N:37]3[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]3)=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:27][CH:26]=1>ClCCl>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][O:30][C:31]2[C:36]([N:37]3[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]3)=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:44][CH:45]=1
Reactant: COc1ccc(COc2ncccc2N2CCC(O)CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(COc2ncccc2N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of Dess-Martin periodinane (9.19 g, 21.67 mmol) in dichloromethane (95 ml) at room temperature was treated with a solution of 2′-(4-Methoxybenzyloxy)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ol (5.68 g, 18.06 mmol) in dichloromethane (60 ml) and the reaction mixture was stirred at room temperature (a mild exotherm was observed). After 1 hour, the reaction mixture was washed with sat'd Na2S2O3(aq.), sat'd NaHCO3(aq.), sat'd NaCl(aq.), dried over MgSO4, filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 7:3 hexanes:EtOAc to 3:2 hexanes:EtOAc) gave the title compound as a yellow, viscous oil (4.01 g, 71%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21])(=O)C.[OH-].[Na+].CO>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.14 G. 1-acetamido-2-nitro-4-benzylsulfinylbenzene is treated with 4 ml. 5N sodium hydroxide and 12 ml. methanol, on steam bath for 30 minutes, diluted with water, and filtered to give 1-amino-2-nitro-4-benzylsulfinylbenzene.