Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2=[O:22])([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:7]2=[O:22]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (15.7 g, 51.3 mmol) in a mixture of ethyl acetate (400 ml) and MeOH (200 ml), 10% w/w Pd/C (0.900 g) was added, and the mixture was hydrogenated in a Parr apparatus at 30 psi for 2 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness affording tert-butyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (14 g, 50.7 mmol, 99% yield, MS/ESI+ 276.9 [MH]+). This product was used in the following step without any further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]([C:22]3[N:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]4=[N:24][CH:23]=3)=[O:21])[CH:13]=2)[N:8]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[C:7]([CH2:6][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[O:11][N:10]=2)=[CH:13][C:14]=1[NH:19][C:20]([C:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1)=[O:21]
Reactant: Cc1ccc(-c2noc(COS(C)(=O)=O)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(CN3CCOCC3)n2)cc1NC(=O)c1cnc2ccccn12

Procedure:
A solution of (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl methanesulfonate (44) (21.4 mg, 0.05 mmol), DIEA (13.0 mg, 0.1 mmol) and morpholine (13.0 mg, 0.15 mmol) in DMF (1 mL) was heated at 80° C. for 4 hours. The crude product was purified by preparative HPLC to yield N-(2-methyl-5-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F22). 1H NMR (400 MHz, CD2Cl2) δ 9.60 (d, J=6.8 Hz, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.45 (s, 1H), 8.06 (s, 1H), 7.89 (dd, J=2.0, 8.0 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.54 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.15 (m, 1H), 3.93 (s, 2H), 3.75 (m, 4H), 2.67 (m, 4H), 2.48 (s, 3H). MS m/z 419.2 (M+1)+. Note: if HCl salt of morpholine (0.15 mmol) was used, AgNO3 (0.15 mmol) was needed to avoid replacement of OMs group by Cl.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:43]1[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43]4[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][N:44]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2ccc(C#N)cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
A mixture of 59 mg (0.1 mMol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 120 mg of 2-chloro-5-cyanopyridine and 65 mg (0.2 mMol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 5 h. The mixture was diluted with ethyl acetate and extracted with water. Evaporation of the solvent and chromatography on silica gel (1:1 ethyl acetate-hexanes) gave the title compound (16 mg). 1H NMR: 0.88(6H,dd), 1.55-1.8(3H,m), 2.8-3.2(7h,m), 3.65(2H,m), 3.8(2H,m), 3.95(1H,m), 5.0(2H,m), 5.6(1H,d), 6.05(2H,s), 6.82(1H,d), 6.95(1H,d), 7.0(2H,d), 7.1-7.4(4H,m), 7.9(1H,d), 8.4(1H,bs). MS: 695(M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(N(C(C)C)C(C)C)C.C1N=CN([S:26](N2C=NC=C2)(=[O:28])=[O:27])C=1>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][S:26](=[O:28])(=[O:27])[O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(c1)OS(=O)(=O)N2
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-nitrophenol (7.7 g, 50 mmol) in acetonitrile (300 ml) is treated with N-ethyldiisopropylamine (18.7 ml, 110 mmol) and N,N′-sulfuryldiimidazole (10.8 g, 55 mmol) and boiled at reflux for 18 h. After cooling to RT, the solvent is distilled off under reduced pressure, the residue is taken up in 1 N HCl and the product is extracted with ethyl acetate. The product is then purified by flash chromatography (17:2:1, EtOAc/MeOH/H2O).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[P:62]([O-:67])([O:65]C)[O:63][CH3:64]>C(#N)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[C:12]([C:13]([CH3:30])([CH3:29])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:31]=[CH:32][C:2]([F:1])=[CH:3][C:4]=1[P:62](=[O:65])([OH:67])[O:63][CH3:64])=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: COP([O-])OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COP(=O)(O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 120 °C
Yield: 64.5 %

Procedure:
A solution of N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.200 g, 0.35 mmol) in acetonitrile (5 ml) was flushed with argon and then treated with N,N-diisopropylethylamine (0.25 ml, 1.4 mmol), triphenylphosphine (0.030 g), palladium(II) acetate (0.040 g). and dimethyl phosphite (0.10 ml, 1.06 mmol). The reaction mixture was then heated in a microwave oven at 120° C. for 40 min. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) gave 0.120 g (64% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.62 (6H, s, 2×CH3), 3.77 and 3.79 (3H, 2 s, OCH3), 3.95-4.05 (4H, m, 2×CH2), 4.75 (2H, d, J=4.6 Hz, NCH2), 5.32 (2H, s, OCH2), 7.22 (1H, m, aromatic), 7.3-7.35 (3H, m, aromatics), 7.38-7.42 (2H, m, aromatics), 7.48-7.54 (1H, m, aromatic), 7.55-7.62 (1H, m, aromatic), 8.54 (1H, broad t, NH). HRMS (ESI+) calculated for C25H28FN3O7P [M+H+]: 532.1649; found: 532.1642.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(OCC)(=O)C>[C:1]([NH:5][C:6]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h

Procedure:
The N-tert-butyl-3-(chloromethyl)benzamide was placed under an argon atmosphere and treated with a solution of tert-butyl 1-piperazine-carboxylate (2.96 g, 15.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.53 mL, 31.7 mmol) in dimethyl sulfoxide (15 mL) at room temperature. The reaction mixture was stirred overnight, diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (×5). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give a crude oil. This oil was purified by iterative rounds of silica chromatography (20-70% ethyl acetate in n-hexanes, followed by 0-6% methanol in dichloromethane) to give the intermediate tert-butyl 4-(3-(tert-butylcarbamoyl)benzyl)piperazine-1-carboxylate (5.04 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:19]([C:21]1([CH2:25]O)[CH2:24][O:23][CH2:22]1)[CH3:20].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCCCCCC.C(OCC)(=O)C>[CH2:19]([C:21]1([CH2:25][C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[CH2:24][O:23][CH2:22]1)[CH3:20]
Reactant: CCC1(CO)COC1
Reactant: O=C(O)c1ccc(-c2cc(F)c(F)c(F)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCC1(Cc2cc(C(=O)O)ccc2-c2cc(F)c(F)c(F)c2)COC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 107.2 %

Procedure:
In step (c -2), 3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid (10.0 g, 37.0 mmol), 3-ethyl-3-hydroxymethyloxetane (5.9 g, 37 mmol), 4-dimethylaminopyridine (4.5 g, 37 mmol), and 100 ml of dichloromethane were mixed under nitrogen atmosphere and cooled to 0° C., and then 50 ml of a dichloromethane solution including 8.0 g (39 mmol) of dicyclohexylcarbodiimide was added dropwise thereto at 0° C., and the resulting mixture was stirred at room temperature for 15 hours. The mixture was filtrated by celite to collect a filtrate. The filtrate was condensed under a reduced pressure, followed by column chromatography (volume ratio of ethyl acetate:heptane=1:4) to obtain 13.9 g of (3-ethyloxetane-3-yl)methyl 3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[N:19]([C:20](=[O:22])[CH:21]=1)[CH:18]=[C:17]([CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:16]=[CH:15]2)=[O:11])(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:24][CH2:23][C:17]1[CH:16]=[CH:15][C:14]2[N:19]([C:20](=[O:22])[CH:21]=[C:12]([C:10]([NH:9][CH2:8][CH:7]([NH:32][S:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)(=[O:34])=[O:35])[C:6]([OH:42])=[O:5])=[O:11])[CH:13]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)cc(=O)n2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc2cc(C(=O)NCC(NS(=O)(=O)c3ccccc3)C(=O)O)cc(=O)n2c1
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (S)-2-Benzenesulfonylamino-3-{[7-(tert-butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid tert-butyl ester (21.2 mg, 0.035 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred overnight, evaporated to dryness and triturated in ether (3×) and dichloromethane (1×). The solid was dried and characterized to yield 62% (10 mg, 0.022 mmol) of the title compound which was characterized by 1HNMR (400 MHz, CD3OD) δ: 9.03 (s, 1H), 7.93-7.83 (m, 3H), 7.64 (dd, 1H, J=9, 1.5 Hz), 7.55-7.45 (m, 3H), 7.26 (s, 1H), 6.92 (d, 1H, J=1.5 Hz), 4.29 (s, 2H), 4.22 (dd, 1H, J=7.5, 5 Hz), 3.81-3.77 (dd, 1H, J=13.5, 5 Hz), 3.55-3.45 (m, 1H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][C:15]([F:18])([F:17])[F:16]>O>[F:7][C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH:22]([CH:2]=[O:4])[CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][C:15]([F:18])([F:17])[F:16]
Reactant: O=C1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=CC1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To dried MTP 10.0 g (29.2 mmol), THF 100 ml was added, and potassium-t-butoxide 3.30 g (29.4 mmol) was added. The mixture was stirred for about one hour. To the reactant, a Th solution (50 ml) of the above 4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanone 6.0 g (23.1 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 150 ml was added to the reactant, the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). The resulting purified material was stirred in mixture solvent of 3N-hydrochloric add 200 ml and acetone 200 ml for 5 hours, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanecarboaldehyde 3.6 g (13.3 mmol). The yield was 57.6% from 4-(3-fluoromethoxy phenyl)cyclohexanone.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[O:24]CC2C=CC=CC=2)=[C:11]([F:32])[CH:10]=1)[CH2:5][CH2:6][CH2:7][NH2:8])(=[O:3])[CH3:2].O1CCCC1>CO>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[OH:24])=[C:11]([F:32])[CH:10]=1)[CH2:5][CH2:6][CH2:7][NH2:8])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(O)c1
Yield: 90.2 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for N-acetyl-N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (70 mg, 0.16 mmol) and tetrahydrofurane for methanol (15 mL), the title compound (50 mg, 91%) was obtained as a brown liquid, after purification on silica gel (dichloromethane/ethyl acetate: 5/5)
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13](=[O:19])[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.[BH4-].[Na+].[H-].[Na+].[H][H].[CH3:28]I>CO.O1CCCC1>[CH3:17][C:15]1([CH3:18])[CH2:14][CH:13]([O:19][CH3:28])[C:12]2[CH:20]=[CH:21][C:9]([OH:8])=[CH:10][C:11]=2[O:16]1
Reactant: [H][H]
Reactant: CI
Reactant: CC1(C)CC(=O)c2ccc(OCc3ccccc3)cc2O1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC1CC(C)(C)Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
7-Benzyloxy-2,3-dihydro-2,2-dimethyl-4-oxobenzopyran synthesized as in Referential Example 22 was dissolved in 60 ml of methanol, and reduced with 1.0 g of sodium borohydride at room temperature. The product was dissolved in 10 ml of tetrahydrofuran, and the solution was added dropwise to a mixture of 1.0 g of 60% sodium hydride and 5 ml of tetrahydrofuran. After generation of hydrogen ceased, 4.3 g of methyl iodide was added dropwise, and the mixture was further stirred for 2.5 hours at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was concentrated, and the residue was dossolved in 30 ml of ethanol and hydrogenated at room temperature for 8 hours in the presence of 5% palladium-carbon catalyst. The crude product was purified by column chromatography to give 2.2 g (yield 58%) of the desired product as a pale brown liquid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:17][C:18]([F:26])([F:25])[C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21]>>[F:17][C:18]([F:26])([F:25])[CH:19]([CH2:24][N:11]1[CH2:12][CH2:13][O:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: FC(F)(F)c1cccc(C2CNCCO2)c1
Reactant: C=C(C(=O)OC)C(F)(F)F
Product: COC(=O)C(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
In a 5 mL round-bottomed flask, 2-(3-(trifluoromethyl)phenyl)morpholine (650 mg, 2.81 mmol) was combined with methyl 2-(trifluoromethyl)acrylate (650 mg, 4.22 mmol; added slowly) to give a colorless solution and stirred at room temperature for 50 min. The crude reaction mixture was concentrated in vacuo to give an oil. The crude material was purified by flash chromatography (silica gel, 40+S, 0% to 30% ethyl acetate in hexanes) to afford 850 mg (78%)(methyl 3,3,3-trifluoro-2-((2-(3-(trifluoromethyl)phenyl)morpholino)-methyl)propanoate as a clear liquid. MH+=386.
Reaction SMILES: C1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])C=CC=CC=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl>[C:22]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[CH:7]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:21])[NH2:23]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCCCCC/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was dissolved in methylene chloride (20 ml), and sodium cyanate (0.50 g, 7.7 mmoles) and trifluoroacetic acid (5 ml) were added. The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was shaken with potassium carbonate (1 g), water (20 ml) and methylene chloride (50 ml), and the organic layer was separated, washed with water, dried and concentrated. Recrystallization of the residue from isopropyl ether gave 1-carbamoyloxy-(E)-7-(3-pyridyl)-6-heptene (1.82 g, 79%) (Compound Id-23).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1.[CH2:12](O)[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCOCC>[CH:5]1([CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(O)CC1CC1
Reactant: CCCCO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC1CC1
Reaction time: 64 h
Yield: 49.8 %

Procedure:
Thionyl chloride (10.7 g, 90 mmol) was added to cyclopropaneacetic acid (9.0 g 90 mmol) [J. Med. Chem. 27, 1291 (1984); Chem. Lett., 1273 (1983); J. Org. Chem. 43. 3496 (1978)]. After stirring for 64 hours the liquid was dissolved in ether and added to a solution of butanol (6.7 g, 90 mmol) and triethylamine (9.1 g, 90 mmol) in 100 mL of diethyl ether at 0° C. The mixture was stirred for 16 hours and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was distilled at 46° C. at 2 mm of Hg to give 7 g of the title compound. MS(CI): m/e =156 for M+ of C9H16O2.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][CH:14]=3)[C:9](=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.[W]>[Br:27][C:8]1[C:9](=[O:26])[C:10]2[C:15]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:11]=2
Reactant: O=C1C=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Yield: 59.8 %

Procedure:
3-Phenyl-6-(3-phenyl-propoxy)-indene-1-one (200 mg, 0.586 mmol) obtained in Step 1 was dissolved in carbon tetrachloride, and N-bromosuccinimide (313 mg, 1.75 mmol) and 2,2′-azobisisobutyronitrile (9.7 mg) were added thereto. The mixture was refluxed for 1 hr under the irradiation of a 375 W tungsten lamp. Upon the completion of the reaction, the mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate:hexane=1:5) to obtain 147 mg of the titled compound (yield: 60%) as a red solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:32][C:33](Cl)=[O:34].O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C)C=O>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:32][C:33]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:34])[CH2:40][CH2:39]1
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(C(=O)Nc5cccc(C(F)(F)F)c5)c4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.7 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[3-(trifluoromethyl)phenyl]benzamide (429 mg, 1.0 mmol) produced in Example A29(v) and chloroacetyl chloride (225 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 6 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1) to give a colorless oil. This was dissolved in N,N-dimethylformamide (5 mL), 1-methylpiperazine (400 mg, 4.0 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel chromatography (eluent:ethyl acetate/methanol=10:1), and triturated with diethyl ether to give the title compound (340 mg, 60%) as a white solid.