Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[OH:6].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=1[OH:6]
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CO)ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a solution of methyl-5-formylsalicylate (Kadaba, J. Pharm. Sci. 1974, 63, 1333-1335) (1.80 g, 0.01 mol) in methanol (20 mi) at 0° C. was added sodium borohydride (0.38 g, 0.01 mol) in 4 portions during 0.5 h. The solution was further stirred at 0° C. for 2 h and then at room temperature for 0.3 h. It was neutralized with hydrochloric acid and concentrated under vacuum. The residue was passed through a column of silica gel using 1:1 ethyl acetate:hexane as the eluent to give 1.0 g (55%) of methyl-2-hydroxy-5-hydroxymethylbenzoate as a pale yellow powder, mp 66°-67° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]4)=[C:12]([C:31]([F:34])([F:33])[F:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].O1CCCC1.[Li+].[OH-].Cl>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]4)=[C:12]([C:31]([F:33])([F:32])[F:34])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)CC1CCc2cc(OCc3c(-c4ccc(CC)cc4)nsc3C(F)(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc3c(c2)CCC3CC(=O)O)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 2-(5-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dihydro-1H-inden-1-yl)acetate (220 mg, 0.45 mmol, 1.00 equiv), tetrahydrofuran (5 mL), water (4 mL), LiOH (97 mg, 4.05 mmol, 9.01 equiv). The resulting solution was stirred overnight at 30° C. The pH value of the solution was adjusted to 2 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×3 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (waters2767-16): Column, SunFire Prep C18,19*150 mm 5 umH PrepC-001(T)18600256819513816414 04; mobile phase, PhaseA:water with 0.05% NH4HCO3, PhaseB:CH3CN(50% CH3CN up to 100% in 10 min, hold 100% in 1.9 min, down to 50% in 0.1 min, hold 50% in 1.9 min); Detector, UV220&254 nm. This resulted in 18 mg (19%) of 2-(5-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dihydro-1H-inden-1-yl)acetic acid as light yellow oil. 1H NMR: (CDCl3, 400 MHz): δ 7.65 (d, J=8.0 Hz, 2H), 7.30 (d, J=4.8 Hz, 2H), 7.17 (d, J=8.0 Hz, 1H), 6.79-6.85 (m, 2H), 5.05 (s, 2H), 3.58-3.61 (m, 1H), 2.82-2.98 (m, 3H), 2.69-2.75 (m, 2H), 2.44-2.54 (m, 2H), 1.79-1.88 (m, 1H), 1.28 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H22F3NO3S, 460.1 (M−H). found 460.1.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCCC1>[CH:1]1([NH:6][C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CCCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1NC1CCCC1

Procedure:
Cyclopentanamine (2.7 g, 32 mmol) was added to a solution of 2-chloro-3-nitropyridine (5.0 g, 32 mmol) in tetrahydrofuran (200 mL), and the reaction mixture was stirred at reflux for 18 hours. After removal of solvent under reduced pressure, the residue was purified via silica gel chromatography to give the product as a yellow solid. Yield: 5.5 g, 26 mmol, 81%. 1H NMR (400 MHz, CD3OD) δ 8.42 (dd, half of ABX pattern, J=8.3, 1.8 Hz, 1H), 8.40 (dd, half of ABX pattern, J=4.5, 1.8 Hz, 1H), 6.69 (dd, J=8.3, 4.5 Hz, 1H), 4.51-4.59 (m, 1H), 2.07-2.17 (m, 2H), 1.62-1.85 (m, 4H), 1.51-1.62 (m, 2H)
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[Br:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.CN(C)C=CC1NC(=O)C=CC=1C#N.CN(C)C=O>O.[OH-].[Na+].CN1CCCC1=O>[Br:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[CH:18]=1
Reactant: Brc1c[nH]cn1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Agent: CN(C)C=Cc1[nH]c(=O)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2c(-n3cnc(Br)c3)nccc2[nH]1
Yield: 70.8 %

Procedure:
A stirred mixture containing 11.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 16.6 g of 4-bromo-1H-imidazole and 100 ml of N-methylpyrrolidinone was heated in an oil bath at 135°-140° C. for 22 hours. The reaction mixture was cooled and diluted with 200 ml of water. The resulting precipitate was collected, washed with water, air-dried, combined with 1.5 g of 5-(4-bromo-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one prepared in another run starting with 1 58 g of 5-bromo-1,6-naphthyridin-2(1H)-one, recrystallized twice from dimethylformamide and dried in an Abderhalden drying pistol at 90° for 22 hours, after which the sample still contained 0.2 mol of dimethylformamide per mol of product. The material was then dissolved in 100 ml of 5% aqueous sodium hydroxide solution, the solution filtered and the filtrate solidified with acetic acid. The cottony solid that crystallized out was collected, washed with distilled water and dried in an oven at 100° C. over the weekend to produce 10.3 g of 5-(4-bromo-1H-imidazol-1-yl)- 1,6-naphthyridin-2(1H)-one, m.p. 278°-280° C.
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[F:14][C:15]([F:31])([F:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=O)[N:24]=[CH:23]1.CCN(CC)CC>C(Cl)Cl>[F:30][C:15]([F:14])([F:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:26]=[C:25]([C:27]#[N:29])[N:24]=[CH:23]1
Reactant: NC(=O)c1cn(-c2ccccc2C(F)(F)F)cn1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cn(-c2ccccc2C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
TFAA (2.5 mL, 17.7 mmol) was added at 0° C. to a stirred mixture of 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carboxamide (3.97 g, 8.177 mmol), Et3N (5 mL, 35.87 mmol), and dry DCM (100mL), the resulting mixture was stirred at 0° C. for 2 h. The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to give 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbonitrile as a pale-yellow to white solid (3.13 g, 82%). MS (ESI) 468 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3[C:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]=3)[CH2:11]2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[ClH:43].O1CCOCC1>C(OCC)C>[ClH:43].[NH:33]1[CH2:32][CH:31]=[C:30]([C:21]2[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=2[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH2:19][N:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:8])=[O:9])[CH2:11]3)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2C2=CCNCC2)C1
Temperature: 80 °C

Procedure:
A vial charged with tert-butyl 4-(2-(2-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.305 g, 0.491 mmol) was treated with HCl 4N in dioxane (3.07 ml, 12.26 mmol) then was heated to 80° C. for one hour. The reaction mixture was cooled to room temperature and was diluted with diethyl ether. The resulting white solid was filtered off and dried yielding 5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride (0.242 g, 0.434 mmol). [M+H]+=522.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.81 (br. s., 2H), 8.35-8.44 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.18-7.28 (m, 2H), 7.02 (d, J=6.6 Hz, 1H), 5.72 (br. s., 1H), 4.22-4.36 (m, 2H), 3.31-3.52 (m, 4H), 3.26 (m, 2H), 2.83-3.08 (m, 2H), 1.91-2.20 (m, 2H)
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:5])#[N:2].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.O>CN(C=O)C>[C:1](/[C:3](=[CH:23]\[C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)/[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:5])#[N:2]
Reactant: O=Cc1ccco1
Reactant: N#CCC(=O)Nc1nnc(-c2ccccc2)s1
Solvent: O
Solvent: CN(C)C=O
Product: N#C/C(=C\c1ccco1)C(=O)Nc1nnc(-c2ccccc2)s1
Temperature: 150 °C

Procedure:
312 mg of 2-cyano-N-(5-phenyl-1,3,4-thiadiazol-2-yl)acetamide and 150 uL of furan-2-carbaldehyde were mixed in 2.5 mL of DMF and heated in a microwave at 150° C. for 15 min. 5 ml of H2O was added and the resulting precipitate was collected and washed with water (4×) to give the crude product. Recrystallization from ethanol gave 180 mg of pure product as a brown solid. MS (M+H, 323); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 6.82 (m, 1H)), 7.43 (d, 1H), 7.49 (m, 4H), 7.87 (m, 2H), 8.15 (s, 1H), 8.22 (br, s, 1H).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[C:11](=[C:13]1[CH2:22][C:21](=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1)=[O:12].[F:24][C:25]([F:38])([F:37])[S:26]([O:29]S(C(F)(F)F)(=O)=O)(=[O:28])=[O:27]>>[F:24][C:25]([F:38])([F:37])[S:26]([O:29][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]1=[C:11]=[O:12])(=[O:28])=[O:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C=C1CC(=O)c2ccccc2N1
Solvent: c1ccc2ncccc2c1
Product: O=C=C1C=Cc2ccccc2N1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
Compounds of Formula I in which ring A is a quinoline can be prepared from a carbonyl-quinolin-1-one (XLM) via the method depicted in Scheme IXb. The carbonyl-quinolin-4-one (XLI) is converted to a triflate group by adding about 1.1 eq. to about 1.5 eq. trifluoromethanesulfonic anhydride (Tf2O) to a basic solution of the carbonyl-quinolin-1-one (XLIII) which is maintained at about 0° C. The reaction is complete in about 1 h to about 3 h to form a 1-trifluoromethanesulfonyloxy-carbonyl-quinoline (LXX). The triflate group can be reacted with a substituted phenylboronic acid (X) via the method depicted in Scheme I to form a (substituted phenyl)-carbonyl-quinoline (LXXI). The carbonyl group of the (substituted phenyl)-carbonyl-quinoline (LXXI) can be converted to an α,β-unsaturated carboxylic ester by adding the (substituted phenyl)-carbonyl-quinoline (LXXI) to a solution of 2-lithio-1,1-diflouroethene (prepared by combining an alkyl lithium with 1,1-difluoroethene at about −78° C.) while maintaining a temperature below −78° C. The resulting alcohol is isolated and immediately treated with methanol and H2SO4 to give a compound of Formula I in which ring A is a quinoline (LXXII).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:25]([CH3:27])[CH3:26])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH:25]([N:11]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[O:16][C:15]2([CH3:24])[CH3:23])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1ccc(N(c2ccc3c(c2)C(C)(C)OC3(C)C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Temperature: 55 °C
Yield: 90 %

Procedure:
A solution of 4-[i-propyl-(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 86, 0.007 g) in 5 mL of ethanol was treated with 2 mL of 5M sodium hydroxide solution and the resulting solution was heated at 55° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was acidified using hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to a residue which was subjected to preparative reverse phase HPLC, using 10% water in acetonitrile as the mobile phase, to afford the title compound (0.0064, 90%) as a white solid. 1H NMR (300 MHz, acetone-d6): δ 7.78 (d, 2H, J=8.9 Hz), 7.32 (d, 1H, J=7.8 Hz), 7.04 (dd, 1H, J=7.8 J=1.8 Hz), 7.00 (d, 1H, J=1.7 Hz), 6.56 (d, 2H, J=9.0 Hz), 4.46 (heptet, 1H, J=6.5 Hz), 1.50 (s, 6H), 1.47 (s, 6H), 1.15 (d, 6H, J=6.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27]>C(Cl)Cl.CO>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:25])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c4cccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 580.1 [M+H]+; tR=3.80 min (System 1); TLC: Rf=0.27 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)(C)(C)C.[ClH:23]>C(OCC)(=O)C>[ClH:23].[ClH:23].[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[CH2:13][N:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(F)c(F)c2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CCN(Cc2ccc(F)c(F)c2)C1
Temperature: 25 °C

Procedure:
To an ethyl acetate solution (5 mL) of (3S)-(1-(3,4-difluorobenzyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (1.55 g), an ethyl acetate (5 mL) solution of 4N hydrochloric acid was added, and the reaction solution was agitated at room temperature. Deposited substances in the reaction solution was separated by filtering after 10 hours, and 904 mg of the title compound was obtained by further washing with ether. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([OH:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:12][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1cc2ccccc2c(O)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 70 %

Procedure:
3-Methyl-2-phenyl-1-naphthalenol (86) (0.11 g, 0.48 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.12 g (70%) of the title compound (87) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 6.71 (d, J=8.8 Hz, 2H), 7.10-7.16 (m, 2H), 7.20-7.30 (m, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.2 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 9.80 (s, 1H). LCMS (ESI): m/z 339 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Yield: 97.6 %

Procedure:
To a stirred mixture of ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)valerate (26.8 g), tetrahydrofuran (200 ml) and sodium borohydride (13.4 g) is added dropwise methanol (40 ml) for 1.5 hours at 70°-80° C. After the addition is complete, the mixture is refluxed for 2 hours with stirring. After evaporation of solvent, the residue is diluted with water (300 ml) and extracted with ethyl acetate (300 ml). The extract is washed successively with 1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 5-(1-benzyloxycarbonyl-4-piperidyl)pentanol (23 g) as a colorless oil.
Reaction SMILES: C(OC(=O)[CH2:5][NH:6][CH2:7][C@H:8]([NH:12][C:13]([O:15]CC1C=CC=CC=1)=O)[CH:9]([CH3:11])[CH3:10])C.[H][H]>CO.[Pd]>[CH:9]([C@H:8]1[NH:12][C:13](=[O:15])[CH2:5][NH:6][CH2:7]1)([CH3:11])[CH3:10]
Reactant: [H][H]
Reactant: CCOC(=O)CNC[C@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H]1CNCC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a Parr vessel charged with (R)-(2-benzyloxycarbonylamino-3-methyl-butylamino)-acetic acid ethyl ester (4.2 g, 13.0 mmol) in MeOH (130 mL) is added Pd-on-C (10%, 396 mmol). The reaction vessel is pressurized with 40 PSI hydrogen pressure and shaken for 4 h at ambient temperature. The reaction mixture is then filtered through celite and the filtrate is concentrated to provide 1.77 g (95%) of (R)-6-isopropyl-piperazin-2-one as an off-white solid which is used without further purification. 1H NMR (300 MHz, CDCl3) δ0.93 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.68 (sept, J=6.7 Hz, 1H), 2.67 (dd, J=12.8, 8.9 Hz, 1H), 3.09-3.22 (m, 2H), 3.46 (ABq, ΔAB=34.3 Hz, JAB=17.5 Hz, 2H), 5.97 (br s, 1H) ppm.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(C#N)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A mixture of 10 g (0.025 mol) of 4-(3-cyanophenyl)-2,6-dimethyl 1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester, obtained as described in A), and 91 g (0.076 mol) of pyridinium chlorochromate adsorbed on alumina, was suspended on 250 ml of CH2Cl2, and the suspension was stirred at room temperature for 5 hours. The remaining solid was separated by filtration, and the organic solution was washed with water (3×150 ml), dried with anh. Na2SO4, and concentrated to dryness at reduced pressure. The product was obtained as an oil, which was purified by column chromatography (Silicagel, n-hexane:EtAcO, 8:2) with a yield of 78%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17]>CN(C)C(=O)C>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])#[N:17]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: COc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Sc3ccccc3OC)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 231.2 %

Procedure:
2-Methoxythiophenol (0.0322 g, 0.230 mmol) and potassium carbonate (0.158 g, 1.14 mmol) were stirred in N,N-dimethylacetamide. 3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.248 g, 0.571 mmol) was added to the reaction mixture portion-wise and the mixture stirred under a nitrogen atmosphere at ambient temperature for 2 hours. The reaction was quenched with a 1M aqueous solution of sodium hydroxide (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was separated and washed with water (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by silica gel column chromatography (ethyl acetate elution) to afford the title compound (0.295 g, 93%) and this was used without further purification.
Reaction SMILES: N=C=N.[C:4]1([CH3:21])[CH:9]=[CH:8][C:7]([S:10]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[NH2:22][CH:23]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:24]([OH:41])[CH:25]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:37]([O:36][C:34]([NH:33][CH:25]([CH:24]([OH:41])[CH:23]([NH:22][C:18](=[O:20])[C@H:14]([CH:15]([CH3:16])[CH3:17])[NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:21])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Agent: N=C=N
Product: Cc1ccc(S(=O)(=O)N[C@H](C(=O)NC(Cc2ccccc2)C(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)C(C)C)cc1

Procedure:
According to the carbodiimide coupling procedure of Example 55, N-(p-toluenesulfonyl)valine was coupled to the resultant compound of Example 11 to give the desired compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]#[CH:20]>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:20][C:19]#[CH:18])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCBr
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Solvent: CCO
Product: C#CCSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Yield: 65.2 %

Procedure:
6 g (25 mmoles) of 5-benzyl-benzimidazoline-2-thione, 2.3 ml of propargyl bromide and 40 ml of ethanol are refluxed for 3 hours. The reaction mixture is concentrated, the crystalline substance thus obtained is worked up according to the method of Example 2. The dichloromethane extract is concentrated and the residue is crystallized from 20 ml of toluene. 4.53 g (65.2%) of title product are obtained melting at a temperature of 109° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15]C)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>O>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([OH:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(Cc2ccccc2)n1
Agent: Br
Solvent: O
Product: Oc1ccc(Br)c(Cc2ccccc2)n1
Reaction time: 4 h
Yield: 92.7 %

Procedure:
A mixture of 72.5 g of 2-benzyl-3-bromo-6-methoxypyridine and 300 ml of 47% hydrobromic acid was heated under stirring for 4 hours in an oil bath kept at 100° C. After cooling as it was, 500 ml of water was added thereto. The resulting crystals were collected by filtration, washed with water and diethyl ether, air-dried and then dried under heating under reduced pressure, to give 63.8 g of the target compound.