Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:41])[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:25]3)=[O:23])[C:17]1=[O:42])(=[O:14])=[O:13])[CH:6]=[CH:5]2>[Pd].C(O)C>[CH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:41])[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:25]2)=[O:23])[C:17]1=[O:42])(=[O:13])=[O:14]
Reactant: C[C@@H](C(=O)N1CCC[C@@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C(=O)N1CCC[C@@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C1=O
Reaction time: 17 h
Yield: 3 %

Procedure:
A mixture of benzyl (3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate (0.350 g), 10% palladium on carbon (0.035 g) and ethanol (1000 ml) was stirred under an atmosphere of hydrogen for 17 h. The reaction mixture was filtered through Harbolite™ and the filtrate was concentrated under reduced pressure to give an oil. The oil was partially purified using SPE (silica, eluting with methanol and then 10% aqueous ammonia in methanol) and then fully purified using mass directed preparative h.p.l.c. to give the title compounds (Example 403, 0.01 g; Example 404, 0.028 g), both as oils.
Reaction SMILES: C([O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C@@H:19]([C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[F:27][C:26]([F:28])([F:29])[C@H:19]([O:18][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:30])=[O:8])=[CH:11][CH:12]=1)=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(C(=O)OCc2ccccc2)cc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)c1ccc(C(=O)O)cc1)C(F)(F)F
Yield: 98.9 %

Procedure:
Then, 0.07 g of 5% palladium/carbon and 10 ml of a tetrahydrofuran solution containing 0.63 g of 4-((R)-1-trifluoromethylheptyloxycarbonyl)benzoic acid benzyl ester were stirred overnight at room temperature in a stream of hydrogen to decompose a benzyl protective group by hydrogenation. 5% palladium/carbon was removed using Celite as a filter aid, and the filtrate was concentrated. The concentrate obtained was purified by column chromatography to obtain 0.49 g of 4-((R)-1-trifluoromethylheptyloxycarbonyl)benzoic acid as a colorless liquid (gradually crystallized) (isolated yield: 98%).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:50][CH:49]=1)[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)=[O:25]>>[C:55]([O:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][C@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:37]=2[N:36]=[CH:35][CH:34]=[CH:33]3)=[O:25])=[CH:49][CH:50]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 85 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][CH2:33][CH3:34]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:32][CH2:33][CH3:34])[N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:27][CH:28]=1
Reactant: O=C(NCC=C1CCN(Cc2ccc(F)cc2)CC1)c1n[nH]c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCn1nc(C(=O)NCC=C2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
N-[2-(1-p-Fluorobenzyl-4-piperidylidene)ethyl]-1H-indazole-3-carboxamide (0.33 g) obtained in Example 9 was dissolved in DMF (5 ml), 60% sodium hydride (0.05 g) and 1-bromopropane (0.21 g) were successively added under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 ml), washed with water (20 ml×4), dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (0.15 g). Yield=41%.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[NH:23]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]4[C:3]=3/[C:4](=[CH:15]/[C:16]3[NH:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])/[C:5](=[O:14])[NH:6]4)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4[nH]ccc4c3)c21
Temperature: 90 °C

Procedure:
A solution of (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (112 mg, 0.31 mmol) (Starting Material 6), 5-indoleboronic acid (71 mg, 0.44 mmol) (from Example 40, Step A, supra) and sodium carbonate (110 mg, 1.03 mmol) were dissolved in 10 mL DMF and 5 mL water. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time, dichlorobis(triphenylphosphine) palladium(II) (11 mg) (Aldrich) was added, and the reaction was heated, under argon, at 90° C. for 2 days. Water (20 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with 5% MeOH/CHCl3 to give (Z)-1,3-dihydro-4-(5-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one as a red powder. (Yield 38 mg, 76%).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]O)=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:12]2[C:11]3[CH:23]=[CH:24][C:8]([Cl:7])=[CH:9][C:10]=3[O:14][C:13]=2[CH:15]=1
Reactant: OCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
11.9 g (0.15 mole) of pyridine were added to a suspension of 26.2 g (0.1 mole) of 2-(7-chlorodibenzofuran-3-oxy)-ethanol in 100 ml of dry toluene, and 17.9 g (0.15 mole) of thionyl chloride were then added dropwise at 3°-15° C. The mixture was stirred for 1 day at 40° C. and for a further 8 hours at 70° C. and cooled, and 150 ml of toluene and 200 ml of ice-water were added. The organic layer was washed with 100 ml of water, 50 ml of hydrochloric acid and 50 ml of 1 N sodium hydroxide solution in succession and finally with 100 ml of water, and was dried and concentrated. The solid residue was stirred with 40 ml of petroleum ether at +3° C. (ice-bath) for 30 minutes, filtered off with suction, washed with a little cold petroleum ether and dried. 22.8 g of 1-chloro-2-(7-chlorodibenzofuran-3-oxy)-ethane were obtained as colorless crystals of melting point 105°-107° C.; yield: 81% of theory.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11].CS(O)(=O)=O>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:10]([Cl:12])([Cl:11])[Cl:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)CCc1ccccc1
Yield: 8.7 %

Procedure:
Reaction between styrene and trichlorosilane with platinum catalyst in the presence of a trimethylsilyl ester of methanesulfonic acid. 518 mg Styrene and 694 mg trichlorosilane were introduced into a glass tube, and 42 mg of a trimethylsilyl ester of methanesulfonic acid were added. 2.5 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) were added. The tube was sealed with Teflon tape and a rubber septum and placed in a 50° C. oil bath where it was heated for 30 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 11% and a phenethyltrichlorosilane yield of 8.7%. The ratio between the phenethyltrichlorosilane and the (α-methylbenzyl)trichlorosilane was 390:1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH:5]=[CH:6][C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C:8]=3[CH2:9][CH2:10][C@@H:11]2[OH:22])=[CH:3]1.C(O[C:27](=[O:29])[CH3:28])(=O)C>N1C=CC=CC=1>[C:2]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][O:21][C:20](=[O:21])[CH3:17])[C:4]([CH:5]=[CH:6][C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C:8]=3[CH2:9][CH2:10][C@@H:11]2[O:22][C:27](=[O:29])[CH3:28])=[CH:3]1)(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3C(=C1CC[C@@H]2O)C=CC1=C[C@@H](O)CC[C@@]13CO
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C=C1C=CC1=C3CC[C@H](OC(C)=O)[C@@]3(C)CC[C@@H]12
Reaction time: 16 h

Procedure:
A mixture of 500 mg of 3β,17β,19-trihydroxyandrosta-4,6,8(14)-triene, 1.0 ml of pyridine and 0.5 ml of acetic anhydride was left to stand at room temperature for 16 hours in an atmosphere of nitrogen. Dilution with water, followed by extraction with ether and concentration at reduced pressure gave 3β,17β,19-triacetoxyandrosta-4,6,8(14)-triene as a white crystalline product.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[CH3:19][C:16]1[O:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: Cc1cnc(C2=CCN(Cc3ccccc3)CC2)o1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cnc(C2CCNCC2)o1
Yield: 91.8 %

Procedure:
25 g 1-benzyl-4-(5-methyl-oxazol-2-yl)-1,2,3,6-tetrahydro-pyridine and 6 g palladium charcoal in 200 mL tetrahydrofuran and 200 mL ethanol were stirred at RT for 12 h under hydrogen atmosphere (30 psi). The mixture was filtered and the filtrate concentrated to yield 15 g of the desired product. Rf: 0.05 (petrolether/ethyl acetate=1/1), (M+H)+: 167
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([CH:18]2[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:19]12[CH2:24][CH:22]([CH2:21][CH2:20]1)[CH2:23][CH:18]2[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:17]
Reactant: CCOC(=O)C1(NC(=O)C2CC3CCC2C3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
2-[(Bicyclo[2.2.1]heptane-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (148 mg, 0.45 mmol) is dissolved in EtOH (8 mL), and solid KOH (600 mg, 10 mmol) and water (0.8 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (273) as white solid (105 mg, 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)=[O:13])[O:9][N:8]=2)[CH:2]=1.[OH-].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)=[O:13])[O:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(C(=O)O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
) A mixture of compound (56) (0.001 mol) in methanol (100 ml) was cooled to 0° C. NaOH 1N (0.0288 mol) was added and the reaction mixture was stirred overnight at RT. The reaction mixture was re-cooled to 0° C. 1 N HCl (30 ml) was added and this mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was crystallized from ethanol. The precipitate was filtered off, washed with ethanol, and dried, yielding 0.2 g (5.2%) (±)4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-α-phenylbenzeneacetic acid (compound 406).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22](=[O:31])[N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22](=[O:31])[N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CNCCC3c3ccc(O)cc3)cc21
Reactant: O=COCc1ccccc1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21

Procedure:
Analogously to Example 10f, 0.190 g of 7-[4-(4-hydroxyphenyl)piperidin-3-yloxymethyl]-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one and 0.070 ml of benzyl formate are reacted. The title compound is obtained as a white foam. Rf=0.19 (2:1 EtOAc-heptane); Rt=6.03.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>O1CCCC1.O>[C:17]1(=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCCCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C1CCCCCCC1
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (969 mg) in tetrahydrofuran (50 mL) was added ethyl diethylphosphonoacetate (5.48 mL) dropwise under ice cooling. After stirring the solution under ice cooling for 30 minutes, a solution of cyclooctanone (2.52 g) in tetrahydrofuran (70 mL) was added dropwise to the solution under ice cooling. The resulting solution was stirred under ice cooling for 2 hours and at room temperature for 40 hours. Water and 3N hydrochloric acid were then added to the solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=9:1) to give the title compound (1.96 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:26][CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[CH3:22])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CC(C)(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(NCCC(C)(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 86.4 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and 3,3-dimethylbutylamine (0.21 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give light yellow solid (0.54 g, 87%): GCMS ml/z 405.00 (M+). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 7.08 (s, 1H), 6.22 (s, 1H), 5.64 (q, 1H, J=7.0 Hz), 4.26 (m, 2H), 3.16 (m, 2H), 1.57 (m, 2H), 1.33 (m, 3H), 0.98 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:22])[CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([F:21])([F:20])[F:19])[C:11]=3[N:10]=2)[CH2:2]1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.ClCCl>[O:23]1[CH2:28][CH2:27][CH:26]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:22])[CH2:8][C:9]3[NH:10][C:11]4[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:2]2)[CH2:25][CH2:24]1
Reactant: O=C1CCOCC1
Reactant: O=C(Cc1nc2c(C(F)(F)F)cccc2[nH]1)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Cc1nc2cccc(C(F)(F)F)c2[nH]1)N[C@@H]1CCN(C2CCOCC2)C1
Reaction time: 16 h

Procedure:
To a solution of N-[(3R)-pyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide (1.0 equiv) in methanol (0.500 M) at room temperature was added tetrahydro-4H-pyran-4-one (1.25 equiv.) followed by sodium triacetoxyborohydride (4 equiv); the reaction mixture was stirred for 16 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[(3R)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]-2-[7-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide as a white solid. 1H-NMR (CD3Cl3) δ: 1.45-1.74 (m, 5H), 2.14-2.22 (m, 2H), 2.33 (m, 1H), 2.60 (m, 2H), 2.83 (m, 1H), 3.34 (m, 2H), 3.91 (m, 2H), 3.95 (s, 2H), 4.39 (m, 1H), 7.27 (t, J=8.0 Hz, 1H), 4.45-7.54 (m, 2H). MS m/z: 397 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:34]=[N+:35]=[N-:36])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCOCCOCCCl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OCCOCCOCCN=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 4a (3.85 g, 7.71 mmol), sodium azide (2.51 g, 38.58 mmol) and nBu4NI (5.7 g, 15.43 mmol) in anhydrous DMF (20 mL) was stirred at 90° C. for 24 hrs. The solution was cooled to r.t. then diluted with EtOAc (300 mL). The organic layer was washed with water (3×200 mL), dried (Na2SO4), filtered and evaporated under reduced pressure. The oily residue was purified by flash silica gel column chromatography (PE then PE/EtOAc 1:1) to afford 4 (3.29 g, 85%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH3:32]>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:30][CH2:31][CH3:32])[N:19]=3)=[O:17])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: O=C(NCCN1CCN(Cc2ccc(F)cc2)CC1)c1n[nH]c2ccccc12
Product: CCCn1nc(C(=O)NCCN2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21

Procedure:
The title compound was synthesized by using N-[2-(4-p-fluorobenzyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 11 and 1-bromopropane according to the same process as in Example 12.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH2:26])[C:9]1=[O:27])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44](O)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH:26][C:44](=[O:45])[C@@H:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:9]1=[O:27])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)CN2c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
Under argon atmosphere, 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (4.75 g) obtained from Step 2 of Example 95 was dissolved in anhydrous N,N-dimethylformamide (40 ml), N-tert-butoxycarbonyl-L-phenylalanine (3.80 g), 1-hydroxybenzotriazole (1.93 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.74 g) and triethylamine (3.65 ml) were added under ice-cooling, the mixture was stirred for 5 minutes at same temperature, and subsequently the resultant mixture was allowed to come to room temperature, stirred for 2 hours. Ice-water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 8.06 g of the titled compound (Yield: 100%).