Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15](=[O:28])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][CH2:26][NH2:27])[N:24]=1)([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11].Cl[C:30]1[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1>>[C:10]([O:14][C:15](=[O:28])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][CH2:26][NH:27][C:30]2[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=2)[N:24]=1)([CH3:18])[CH3:17])([CH3:11])([CH3:13])[CH3:12]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 62.4 %

Procedure:
N,N-Diisopropylethylamine (13.1 g) was added to 2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (27.9 g) synthesized in Example 7 and 2-chloro-5-ethylpyrimidine (13.2 g), and the mixture was stirred at 130° C. for 20 hr. The reaction mixture was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (23.5 g) as a slightly yellow solid.
Reaction SMILES: ClC[C:3]([N:5]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]#[N:27])[CH:23]=2)[CH2:18]1)[CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C)=[O:4].CCO.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[O:4]=[C:3]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]#[N:27])[CH:23]=2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)NCCN(CC1Cc2ccc(C#N)cc2C1)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: N#Cc1ccc2c(c1)CC(CN1CCNCC1=O)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{(chloroacetyl)[(5-cyano-2,3-dihydro-1H-inden-2-yl)methyl]amino}ethyl)carbamate (350 mg, 0.9 mmol) in HCl/dioxane (20 mL) was stirred at RT for 12 hours and then concentrated to dryness. To the residue was added 20 mL EtOH and K2CO3 (500 mg, 3.7 mmol). The resulting mixture was heated to reflux for 4 hrs before cooled to RT and filtered. The filtrate was concentrate and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give 2-[(2-Oxopiperazin-1-yl)methyl]indane-5-carbonitrile. MS m/z: 256 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH:7]([NH:19]C(=O)OCC1C=CC=CC=1)[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[BrH:33].C(O)(=O)C>ClCCl>[BrH:33].[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH:7]([NH2:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1cccc(OCC(CNc2ccccc2[N+](=O)[O-])NC(=O)OCc2ccccc2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cccc(OCC(N)CNc2ccccc2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the compound obtained in Step 2 were added 30% hydrobromide/acetic acid (1 ml) and dichloromethane (2 ml), and the mixture was stirred at 0° C. for 2 hrs. The mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound as a crude product.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[F:11])[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: COc1ccc(F)c(B(O)O)c1
Product: COc1ccc(F)c(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 59 %

Procedure:
The title compound (70 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 2-fluoro-5-methoxyphenylboronic acid (98 mg, 0.58 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.30-7.24 (m, 2H), 7.17 (t, J 9.1, 1H), 7.02-6.97 (m, 1H), 6.90-6.84 (m, 1H), 5.61 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[NH:5]2.[CH3:14][C:15]([CH3:19])=[CH:16][CH:17]=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[N:5]2[CH2:17][CH:16]=[C:15]([CH3:19])[CH3:14]
Reactant: C[C@@H]1Nc2nc(Cl)ccc2NC1=O
Reactant: CC(C)=CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCN1c2nc(Cl)ccc2NC(=O)[C@@H]1C
Yield: 48.9 %

Procedure:
The compound of Example 2 (988 mg, 5.0 mmol) was suspended in 40 ml of anhydrous 1,2-dichloroethane. While stirring, 840 mg (10 mmol) of 3,3-dimethylacrolein and subsequently 1.9 ml (25 mmol) of trifluoroacetic acid were added. The mixture was cooled in an ice bath, 2.1 g (10 mmol) of sodium triacetoxyborohydride were introduced in portions, and the mixture was stirred at 0° C. for 1 h and at room temperature for a further 3 h. The reaction mixture was then added to about 150 ml of saturated aqueous sodium bicarbonate solution, the phases were separated, the aqueous was back-extracted three times with dichloromethane, and the combined organic extracts were dried (sodium sulfate) and concentrated. Chromatography on silica gel (ethyl acetate/heptane=1:2) provided 650 mg (49%) of the desired compound as a crystalline solid of melting point 136°-137° C.
Reaction SMILES: [Cr:1].O=O.O.[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=CC=1>>[CH:10]1([Cr:1][CH:5]2[CH:10]=[CH:9][CH:8]=[CH:11]2)[CH:5]=[CH:11][CH:8]=[CH:9]1
Reactant: [Cr]
Reactant: Cc1ccccc1
Agent: O=O
Solvent: O
Product: C1=CC([Cr]C2C=CC=C2)C=C1
Reaction time: 5 h

Procedure:
A solution of bis(cyclopentadienyl)chromium in toluene was prepared, which solution was then added to a predetermined amount of silica (Grace· 532 product), dehydrated under an inert atmosphere at a temperature of 815° C. for 16 h, so that the final chromium content is 1% by weight. The toluene was then removed under reduced pressure. The bis(cyclopentadienyl)chromium was then sublimed under reduced pressure onto the silica support for 5 hours. Return to atmospheric pressure was carried out under dry nitrogen and the catalyst obtained was stored with oxygen and water excluded.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1c1ccc2ccccc2n1

Procedure:
A solution of 0.15 g (0.458 mmol) of tert.butyl 3-methyl-4-quinolin-2-yl-piperazine-1-carboxylate in 1 ml of trifluoroacetic acid and 20 ml of dichloromethane is stirred for ten hours at ambient temperature. Then the solution is concentrated by evaporation, the residue is taken up in water and made alkaline with dilute sodium hydroxide solution. The aqueous phase is extracted with dichloromethane and the organic phase is dried over sodium sulphate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:27][CH:29]1[CH2:30][O:31]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Reactant: ClCC1CO1
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1OCC1CO1

Procedure:
In analogy to Example 14, 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol is alkylated with epichlorhydrine to give (RS)-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-isobutyl-6-methyl-pyridine as a colourless oil; LC-MS: tR=1.00 min, [M+1]+=408.18.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1.C(N(C(C)C)CC)(C)C.[C:46](Cl)(=[O:48])[CH3:47].C(OCC)(=O)C>C(Cl)Cl>[CH2:30]([O:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:46](=[O:48])[CH3:47])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one in methylene chloride (5 mL) is added diisopropylethylamine (93 mg, 0.72 mmol) followed by acetyl chloride (36 mg, 0.458 mmol) and the mixture is stirred at RT for 24 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is purified by flash chromatography using a gradient of 25-75% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[CH:11][C:12]([S:14][CH3:15])=[CH:13][C:8]=2[CH:7](O)[C:6]([CH3:18])([CH3:17])[S:5]1(=[O:20])=[O:19])[CH:2]=[CH2:3].C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:17][C:6]1([CH3:18])[CH2:7][C:8]2[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:9]=2[N:4]([CH2:1][CH:2]=[CH2:3])[S:5]1(=[O:20])=[O:19]
Reactant: C=CCN1c2ccc(SC)cc2C(O)C(C)(C)S1(=O)=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1c2ccc(SC)cc2CC(C)(C)S1(=O)=O
Reaction time: 4 h

Procedure:
3,4-Dihydro-1-(prop-2-en-1-yl)-3,3-dimethyl-6-methylthio-1H-2,1-benzothiazin-4-ol 2,2-dioxide (1.8 g; 0.0053 m) was dissolved in trifluoroacetic acid (30 mL) and triethylsilane (15 mL) was added in one portion. After stirring for 4 hrs, the reaction was reduced to an oil under vaccuo and after the addition of saturated sodium bicarbonate, the product extracted with dichloromethane, dried, filtered and isolated as a colourless solid.(1.6 g; 93%)
Reaction SMILES: C([NH:4][C:5]1[C:17]([F:18])=[C:16]2[C:8]([C:9]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:23])[C:10]=3[C:24]([F:27])([F:26])[F:25])=[CH:7][C:6]=1[F:28])(=O)C.C(O)(=O)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:4][C:5]1[C:17]([F:18])=[C:16]2[C:8]([C:9]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:23])[C:10]=3[C:24]([F:27])([F:25])[F:26])=[CH:7][C:6]=1[F:28]
Reactant: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1cc(F)c(NC(C)=O)c(F)c1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1cc(F)c(N)c(F)c1C2
Temperature: 100 °C
Yield: 22.8 %

Procedure:
The crude 7-(acetylamino)-9a-butyl-6,8-difluoro-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one from step 2 (about 0.318 mmol) was treated with acetic acid (2 mL) and 6N HCl (2 mL). The resulting solution was stirred and heated in an oil bath at 100° C. for 2 hours. After cooling to room temperature, the mixture was poured into a slurry of solid Na2CO3 in CH2Cl2, dried over MgSO4, then filtered through a pad of silica gel and the product washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 25% EtOAc in hexanes, to afford 7-amino-9a-butyl-6,8-difluoro-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.026 g, 23%) as a yellow solid.
Reaction SMILES: ClC1C=CC=C2C=1N(C(C)C)C(=O)C(=O)N2.Cl[C:18]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=O)[C:19]=1[N:20]([C:24]([C:26](OCC)=[O:27])=[O:25])[CH:21]([CH3:23])[CH3:22]>C(Cl)Cl>[CH:21]([N:20]1[C:19]2[C:31](=[CH:32][CH:33]=[CH:34][CH:18]=2)[N+:35]([O-:37])=[C:26]([OH:27])[C:24]1=[O:25])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C(=O)N(c1c(Cl)cccc1[N+](=O)[O-])C(C)C
Agent: CC(C)n1c(=O)c(=O)[nH]c2cccc(Cl)c21
Solvent: ClCCl
Product: CC(C)n1c(=O)c(O)[n+]([O-])c2ccccc21

Procedure:
In a similar manner 8-chloro-1,2,3,4-tetrahydro-1-isopropyl-2,3-dioxo-quinoxaline was prepared from 2-chloro-N-ethoxalyl-N-isopropyl-6-nitroaniline by hydrogenation using methylene chloride as solvent. M.p. 228°-229° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH3:22][O:23][CH:24]=O.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C.O>[OH:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:14](=[CH:22]\[O:23][CH3:24])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(O)c1
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (0.558 g, 0.023 moles in DMF (20 ml) was added dropwise a solution of methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (2.0 g; 0.0077 mol) in DMF (10 ml) and methylformate (10 g; 0.167 mol). After stirring for 45 minutes, water (100 mls) was added and the mixture was extracted with ether (50 mls). The aqueous layer was acidified with hydrochloric acid to pH 3-4 and the mixture was extracted with ether (2×40 mls). The combined ether extracts were washed with water (3×30 mls) and saturated brine (1×30 ml), and then dried. The ether was evaporated off and the residue was dissolved in DMF (20 ml), and anhydrous potassium carbonate (0.649; 0.0046 moles) and dimethyl sulphate (0.559; 0.0044 moles) was added. The mixture was stirred at ambient temperature for 1 hour, then water (100 ml) was added, and the mixture was extracted with ether (2×40 ml). The combined ether extracts were washed with water (3×20 ml) and saturated brine (20 ml), dried, filtered, evaporate to dryness, then chromatographed using a mixture of ether and hexane as eluant to give (E)-methyl 2-[2-(3-hydroxyphenoxy)phenyl]-3-methoxypropenoate (E) as an amber gum which, on trituration with a mixture of hexane and dichloromethane, gave a white solid, [0.79, 30% yield from methyl 2-(3-hydroxyphenoxy)phenylacetate (D)]m.p. 115°-116° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:10]1[CH2:29][CH3:30])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:29]([C@H:10]1[C@H:9]([OH:8])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=1)[CH3:30]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-ethyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-(trifluoromethyl)benzonitrile (433.7 mg) in tetrahydrofuran (6 mL)-methanol (12 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/2) to give the title compound as a colorless solid (yield: 266.1 mg, 83%).
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[C@@H:3]([OH:18])[CH2:4][N:5]([CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH3:20][N:21]1[C:25]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=O)[O:34]C3C=CC=CC=3)[CH:29]=[CH:30][CH:31]=2)=[N:24][N:23]=[N:22]1>C(#N)C>[CH2:16]([N:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:4][C@H:3]([OH:18])[C@H:2]([NH:1][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:25]2[N:21]([CH3:20])[N:22]=[N:23][N:24]=2)[CH:27]=1)=[O:34])[CH3:19])[CH3:17]
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CCN(CCCc1ccc(F)cc1)C[C@H](O)[C@@H](C)N
Solvent: CC#N
Product: CCN(CCCc1ccc(F)cc1)C[C@H](O)[C@@H](C)NC(=O)Nc1cccc(-c2nnnn2C)c1
Yield: 78.5 %

Procedure:
The product of Step g (50 mg, 0.19 mmol, 1 eq.), phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate (55 mg, 0.19 mmol, 1 eq.) and acetonitrile (3 mL) were mixed at 25° C. under N2 overnight. Worked up by stripping off the solvents then purifying the residue over silica gel in 100% EtOAc to 4:1 EtOAc/MeOH. Obtained 70 mg of a white glass as product. NMR (300 MHz, CDCl3) δ 7.86 (s, 1H); 7.6 (d, 1H, J=7 Hz); 7.38 (t, 1H, J=7 Hz); 7.29 (d, 1H, J=7 Hz); 7.20-7.00 (m, 2H); 6.92 (t, 2H, J=7 Hz); 4.13 (s, 3H) 4.05-3.85 (m, 1H); 3.80-3.60(m, 1H); 2.80-2.40 (m, 8H); 1.85-1.60 (m, 2H); 1.18 (d, 3H, J=7 Hz); 1.00 (t, 3H, J=7 Hz).
Reaction SMILES: [SH:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)=O)=[CH:6][CH:5]=[C:4]([C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]2)[N:3]=1.C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:9]3[S:1][C:2]4[C:7]([N:8]=3)=[CH:6][CH:5]=[C:4]([C:20]3([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21]3)[N:3]=4)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=C(Nc1ccc(C2(c3ccccc3)CC2)nc1S)c1ccc2[nH]ccc2c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]ccc6c5)sc4n3)CC2)cc1
Temperature: 100 °C

Procedure:
To N-(2-mercapto-6-(1-phenylcyclopropyl)pyridin-3-yl)-1H-indole-5-carboxamide (360 mg, 0.934 mmol) was added toluene (9.3 mL) and camphor sulfonic acid (195 mg, 0.841 mmol) before it was heated to 100° C. for 16 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 1 time with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after after flash chromatography. MS (ESI) m/z: Calculated: 367.1; Observed: 368.1 (M++H).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[CH:21]2[C:22]3[C:27]([CH2:28][CH2:29][N:20]2[CH2:19][CH2:18][NH:17]1)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>CN(C)C=O>[CH2:16]1[CH:21]2[C:22]3[C:27]([CH2:28][CH2:29][N:20]2[CH2:19][CH2:18][N:17]1[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1ccc2c(c1)CCN1CCNCC21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN3CCc4ccccc4C3C2)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
2-Chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (332 mg, 1.5 mmol) was added to the solution of 1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline (292 mg, 1.55 mmol), triethylamine (0.223 ml, 1.6 mmol) in N,N-dimethylformamide (8 ml) and the mixture was stirred for 6 hours and stood overnight ice-water. After addition of ice-water the solution was partitioned between water and ethyl acetate, and the organic layer was washed with brine and dried with magnesium sulfate. The solvents were removed under reduced pressure and purification by silica gel column chromatography (eluent; dichloromethane/methanol=95/5) afforded title compound (530 mg, 95%). Treatment with 4N hydrogen chloride in ethyl acetate yielded corresponding hydrogen chloride salt (495 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12]C)=[O:11]>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccccc1Cl

Procedure:
Methyl 3-(2-chlorophenyl)propionate was refluxed in 10% aqueous sodium hydroxide (1 l.) for two hours and the reaction mixture was cooled, acidified and filtered. The filter cake was dissolved in hot aqueous sodium bicarbonate and filtered. The filtrate was acidified and filtered to yield 3-(2-chlorophenyl)propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10][CH2:11][C:12]([CH3:14])=O>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[S:10][CH:11]=[C:12]([CH3:14])[C:4]=2[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)CSc1cc(F)c(F)cc1Br
Solvent: Clc1ccccc1
Product: Cc1csc2c(Br)cc(F)c(F)c12
Temperature: 140 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A polyphosphoric acid (1.86 g) was suspended in chlorobenzene (8 mL), and a solution (8 mL) of the compound (730 mg, 2.60 mmol) of Step 1 of Example 51 in chlorobenzene was added thereto at 120° C., and stirred at 140° C. overnight. After further stirred at 155° C. two nights, the resultant was returned to room temperature, and the reaction solution was concentrated under reduced pressure, and diluted with ethyl acetate. To the mixture liquid, a 1 N sodium hydroxide aqueous solution was added under ice-cooling for the neutralization, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane) to thus obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:17]=[C:16]([OH:18])[C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c2nc(C3CC3)n(C)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)C(=O)c1cc(O)c2nc(C3CC3)n(C)c2c1
Yield: 91.8 %

Procedure:
A solution of 15.4 g (42.0 mmol) 7-benzyloxy-2-cyclopropyl-3-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide in 200 ml ethanol and 3.6 ml acetic acid was hydrogenated over 3.4 g 10% Pd/C in autoclave (5 bar H2) at 50° C. for 16 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from diisopropyl ether to afford 10 g (92%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH2:29][OH:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH2:29][O:30][C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:8][CH:9]=3)=[O:12])[CH:20]=[CH:19][C:18]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CO)ccc21
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Product: C=CCOC(=O)c1ccc(C(=O)OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manruer similar to Example 4(c), by reaction of 2.06 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.18 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyimethanol, 2.8 g (70%) of allyl ester are obtained in the form of a translucent oil.