Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8]([C:18](=[O:36])[N:19]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH3:20])=[CH:7][N:6]=1)=[O:4].CO.O1CCOCC1.[OH-].[Na+]>O>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)[CH2:21][N:19]([CH3:20])[C:18]([C:8]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1)=[O:36]
Reactant: COC(=O)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cc(C(=O)O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.1 %

Procedure:
A mixture of 0.50 g (0.98 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid methyl ester (Example 6), 10 ml methanol, 10 ml dioxane and 10 ml 1N aqueous sodium hydroxide solution was stirred at room temperature for 17 h. Dilution with water was followed by washing with tert-butyl methyl ether. The aqueous layer was acidified to pH 2 with 1 M aqueous hydrochloric acid solution and extracted with four portions of dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate and concentrated to give 0.38 g (78%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:44]([O:46]CCCC)=[CH2:45].C1(N(C)C2CCCCC2)CCCCC1.Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:44]([C:2]1[N:10]2[C:5]([C:6]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[CH:4][CH:3]=1)(=[O:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(Br)ccc12
Reactant: C=COCCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc2n1-c1ccccc1OC21CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl 1′-bromospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (1.10 g, 2.60 mmol) and Pd2(dba)3.CHCl3 (543 mg, 0.525 mmol) in 1,4-dioxane (4.4 mL) was added tri-tert-butylphosphane (360 μL, 1.31 mmol), 1-vinyloxybutane (3.55 mL, 26.2 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (843 μL, 3.94 mmol). The mixture was heated at 80° C. for 5 hours. The mixture was cooled to room temperature before 1N HCl (3 mL) was added and the mixture was stirred for 1 hour. The mixture was poured into water and was extracted with ethyl acetate (4×). The organics were combined, washed with water (2×), brine and evaporated. The residue was purified by column chromatography (0-20% ethyl acetate in hexanes) to give tert-butyl 1′-acetylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (610 mg, 61%) as a yellow solid. ESI-MS m/z calc. 382.2. found 383.1 (M+1)+; Retention time: 1.97 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J=8.1, 1.3 Hz, 1H), 7.35 (d, J=4.1 Hz, 1H), 7.24-7.12 (m, J=9.4, 8.0, 1.6 Hz, 2H), 7.08-6.98 (m, 1H), 6.35 (d, J=4.1 Hz, 1H), 3.88 (d br, J=11.3 Hz, 2H), 3.13 (s br, 2H), 2.49 (s, 3H), 1.92-1.76 (m, 4H), 1.41 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:40][CH3:41])(=O)=O.O>CC(C)=O>[CH2:40]([O:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29])[CH3:41]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1c(O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 117.4 %

Procedure:
A mixed solution of N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 135 (300 mg, 0.76 mmol), potassium carbonate (105 mg, 0.76 mmol) and diethyl sulfate (117 mg, 0.76 mmol) in acetone (15 mL) was refluxed with heating for 14 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to synthesize 378 mg (yield: 78%) of the title compound. Melting point: 174-175° C. (hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([NH:31][CH2:32][CH2:33]Br)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:33][CH2:32][NH:31][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[1-(4-chlorophenyl)cyclopropyl]-3,4-dihydroisoquinolin-7-ol (120 mg, 0.4 mmol) was added in several portions to a suspension of sodium hydrid (NaH, 1.3 mmol, activated by removal of oil) in dimethylformamide (DMF, 5 ml). 2-(Boc-amino)ethyl bromide was added after one hour and the resulting mixture stirred for 3 days at room temperature. DMF was evaporated, the residue diluted with ethylacetate and extracted with water. Removal of the solvents from the dried (Na2SO4) extract afforded an oil which was further purified by chromatography. Yield: 100 mg (0.23 mmol, 56%)
Reaction SMILES: [NH2:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(O)C.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=O)[C:25]([OH:27])=[O:26])[N:23]=1)=[O:17].[OH-].[Na+]>O1CCCC1.CCCCCC.O>[C:9]([O:8][C:6]([CH:5]=[CH:4][CH2:3][O:2][N:1]=[C:24]([C:22]1[N:23]=[C:19]([NH:18][CH:16]=[O:17])[S:20][CH:21]=1)[C:25]([OH:27])=[O:26])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)/C=C/CON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C=CCON=C(C(=O)O)c1csc(NC=O)n1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To tert-butyl 4-aminooxycrotonate (10.0 g) were added ethanol (150 ml) and water (150 ml), followed by gradually adding (2-formamidothiazol-4-yl)glyoxylic acid (11.0 g) with stirring. During the addition, the mixture was adjusted to pH 5 to 5.5 with 10% aqueous sodium hydroxide, and the stirring was continued at ambient temperature for 2 hours. After removal of the ethanol, to the remaining aqueous solution was added ethyl acetate, followed by adjusting to pH 7.5 with 10% aqueous sodium hydroxide. The aqueous layer was separated and washed with ethyl acetate. Thereto was further added ethyl acetate, followed by adjusting to pH 2.0 with 10% hydrochloric acid. The separated organic layer was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with n-hexane and tetrahydrofuran, and collected by filtration. To this substance were added ethanol (50 ml) and water (30 ml), followed by adjusting to pH 7.5 with 10% aqueous sodium hydroxide. The precipitated substance was collected by filtration, washed with a mixed solvent of water and ethanol (1:1 by volume), followed by addition of water and ethyl acetate, and adjusting to pH 2.0 with 10% hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with n-hexane and tetrahydrofuran to obtain 2-(3-t-butoxycarbonyl-2-propenyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (12.01 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[C:12]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1B1OC(C)(C)C(C)(C)O1.ClCCl.C(OCC)(=O)C>CO.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([CH3:10])[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[C:12]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: O=Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=O)n2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 32.4 g (113 mmol) of Na2CO3(H2O)10 in a mixture of 180 ml of methanol and 600 ml of water was added to a mixture of 8.37 g (45.0 mmol) of 6-bromopyridine-2-carbaldehyde, 18.1 g (45.0 mmol) of 2,4,6-trimethyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline and 2.65 g (2.30 mmol) of Pd(PPh3)4 in 600 ml of toluene by vigorous stirring at room temperature. The resulting mixture was stirred at 80° C. for 12 h. Thereafter, this mixture was cooled to room temperature, the organic layer was separated, dried over MgSO4, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-ethyl acetate=100:1 and then 10:1, vol.). Yield 10.7 g (63%). Anal. calc. for C26H24N2O: C, 82.07; H, 6.36; N, 7.36. Found: C, 82.24; H, 6.49; N, 7.18. 1H NMR (CDCl3): 10.12 (s, 1H, CHO), 8.06 (m, 1H, 3-H in Py), 7.90-7.99 (m, 3H, 5,7,8-H in naphthyl), 7.63 (d, J=8.3 Hz, 4-H in naphthyl), 7.54 (m, 1H, 5-H in Py), 7.49 (m, 1H, 4-H in Py), 7.39 (m, 1H, 6-H in naphthyl), 7.28 (d, J=8.3 Hz, 3-H in naphthyl), 6.74 (s, 2H, 3,5-H in mesityl), 3.98 (d, J=13.1 Hz, 1H, CHH′N), 3.89 (d, J=13.1 Hz, 1H, CHH′N), 3.37 (br.s, 1H, NH), 2.20 (s, 3H, 4-Me in mesityl), 2.04 (s, 6H, 2,6-Me in mesityl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]([CH3:50])[C:27]([C:29]1[N:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([C:48]#[N:49])([CH3:47])[CH3:46])=[CH:41][CH:40]=2)[C:32]2[N:33]=[C:34](Cl)[N:35]=[CH:36][C:31]=2[CH:30]=1)=[O:28]>>[C:48]([C:45]([C:42]1[CH:41]=[CH:40][C:39]([N:38]2[C:32]3[N:33]=[C:34]([NH:24][C:21]4[N:20]=[CH:19][C:18]([N:11]5[C:12](=[O:17])[CH2:13][CH:14]6[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:16][CH2:15]6)[CH2:10]5)=[CH:23][CH:22]=4)[N:35]=[CH:36][C:31]=3[CH:30]=[C:29]2[C:27](=[O:28])[N:26]([CH3:25])[CH3:50])=[CH:44][CH:43]=1)([CH3:47])[CH3:46])#[N:49]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1ccc(C(C)(C)C#N)cc1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1ccc(C(C)(C)C#N)cc1
Yield: 89 %

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-[4-(cyano-dimethyl-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave tert-butyl 3-(6-(7-(4-(2-cyanopropan-2-yl)phenyl)-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (160 mg) in 89% yield. MS m/z 664.7
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH:19]([OH:22])[CH2:20][CH3:21])[C:12](=[O:23])[N:11]([CH3:24])[C:10]=3[N:9]=[C:8]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:34])[F:35])[CH:27]=2)=[CH:37][CH:38]=1
Reactant: CCC(=O)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(O)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(3-oxopentyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.273 mmol, example 20) in methanol (20 mL) was added sodium borohydride (40 mg, 1.05 mmol) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxypentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 33.5% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.63-7.58(t, 1H), 7.49(s, 1H), 7.44-7.42(m, 5H), 7.34-7.31(d, 1H), 5.44(s, 2H), 4.48-4.46(d, 1H), 4.08-4.01(m, 1H), 3.89-3.83(m, 1H), 3.42-3.37(m, 1H), 3.29(s, 3H), 1.63-1.55(m, 2H), 1.44-1.31(m, 2H), 0.87-0.84(t, 3H). LCMS retention time 3.372 min; LCMS MH+ 553.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:22])[C:19](Cl)=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>O.[Pd]>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc3ccoc23)C1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2ccc(O)cc2C(c2cccc3c2OCC3)C1
Temperature: 20 °C
Reaction time: 120 h

Procedure:
6.55 g, (0.020 mol) (+)-5-(benzofuran-7-yl)-8-chloro-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 1.0N sodium hydroxide (100 ml, 0.100 mol) and water (100 ml). 10% palladium-on-carbon (3.0 g) was added, and the resulting suspension was stirred under hydrogen at 20° C. and 100 kPa for 5 days. The reaction mixture was filtered and the filtercake was thoroughly washed with 0.3N hydrochloric acid (70 ml) and methanol (135 ml). The pH of the combined filtrate and washings was brought to 8.0 and the resulting suspension was filtered. The filtercake was washed with water/methanol (1/1) and dried in vacuo at 40° C. to give 3.45 g (76% of the theoretical yield) of the desired compound as white crystals.) M.p. 227°-30° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:41]1([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:46][CH2:45][NH:44][CH:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>C(N(CC)CC)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:44]1[CH2:45][CH2:46][N:41]([C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[CH2:42][CH:43]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Yield: 383.1 %

Procedure:
3-((6-Chloro-2-naphthyl)sulfonyl)propanoic acid (0.33 g), HOBt (2.30 g) and WSC (2.88 g) were added to acetonitrile (50 mL) and mixed for 15 minutes. Then, di-tert-butyl piperazine-1,3-dicarboxylate (2.99 g) and triethylamine (3.03 g) were added thereto, and the mixture was mixed at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and an aqueous potassium carbonate solution. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (2.40 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[Br:42][C:43]1[CH:51]=[CH:50][C:46]([CH2:47][NH:48][NH2:49])=[CH:45][CH:44]=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:11]([NH:49][NH:48][CH2:47][C:46]1[CH:50]=[CH:51][C:43]([Br:42])=[CH:44][CH:45]=1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: NNCc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NNCc1ccc(Br)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
N-(Methoxycarbonyl)-(L)-tert-leucine (J. Med. Chem., 41, 3387-3401, 1998) (1.74 g, 9.20 mmol) was dissolved in EtOAc (50 mL) and EDAC (1.94 g, 10.1 mmol), HOBT (1.37 g, 10.1 mmol), and NMM (1.11 mL, 10.1 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then 4-bromo-benzylhydrazine (prepared as described in Zh. Org. Khim., 28, 43-50, 1992) (2.31 g, 11.5 mmol) in EtOAc (20 mL) was added and the stirring was continued over night. The reaction mixture was washed with saturated NaHCO3 (aq.), H2O and brine and then the organic phase was dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (silica, CHCl3/MeOH, 100:0-96:4) yielding the title compound (1.85 g, 54%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:18]1[CH2:17][CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1(c2ccccc2Sc2ccc(F)cc2)CCNCC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccc(F)cc2)CC1

Procedure:
A mixture of 0.7 g of 4-[2-(4-fluorophenylthio)phenyl]piperidine-4-carboxylic acid and 0.83 ml of acetic anhydride in 4.2 ml of pyridine is stirred at reflux for 4 hours. Thereafter, the excess pyridine is removed by rotary evaporation and the residue is taken up in 10 ml of water, where it is treated with 10 ml of 1 N hydrochloric acid. The acidic mixture is extracted thrice with 20 ml portions of an ether-benzene (1:1) mixture and the combined extracts are successively washed twice with 40 ml portions of water, washed once with a 15 ml portion of a saturated sodium chloride solution and dried. The resulting residue is recrystallized from an acetone-ether (1:4) mixture providing 1-acetyl-4-[2-(4-fluorophenylthio)phenyl]piperidine-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:3].CC([O:21][C@@H:22]1[C@@H:27]([O:28]C(C)=O)[C@@H:26](Br)[O:25][C@H:24]([C:33]([O:35]C)=[O:34])[C@H:23]1[O:37]C(C)=O)=O.[OH-].[Li+]>CO.O>[CH3:3][N:2]([CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH:26]1[O:25][CH:24]([C:33]([OH:35])=[O:34])[CH:23]([OH:37])[CH:22]([OH:21])[CH:27]1[OH:28])[CH3:1]
Reactant: COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)C[C@@H]1CCCC[C@H]1c1cccc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C[C@@H]1CCCC[C@H]1c1cccc(OC2OC(C(=O)O)C(O)C(O)C2O)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.33 g (10 mmol) (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, 3.58 g (9 mmol) acetobromo-α-D-glucuronic acid methyl ester and 0.23 g (9.5 mmol) lithium hydroxide in 23 ml dry methanol was first stirred at 20° C. for 30 minutes, a solution of 0.65 g lithium hydroxide in 25 ml water was then added and the mixture was stirred again for 30 minutes. It was extracted with ethyl acetate and the aqueous phase was adjusted to a pH of 3.5 by addition of acetic acid and extracted again with ethyl acetate. The aqueous phase was evaporated in vacuo and the residue was purified by HPLC. 0.85 g (23% of theory) of the title compound was obtained in this manner in the form of a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:6]([C:5]1[NH:4][N:3]=[N:2][N:1]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
The compound of the formula (11) is prepared using tri alkyl tin azide. Ortho tolyl benzonitrile (OTBN of the formula (8) is reacted with trialkyl tin azide followed by hydrolysis to give tetrazole derivative of the formula (9). The tetrazole derivative is reacted with trityl chloride to give trityl tetrazole derivative of the formula (10), which on radical bromination gives compound of the formula (11). The reaction sequence is given in the Scheme 6.
Reaction SMILES: [N:1]1([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[N:1]1([C:8]([CH3:12])([CH3:11])[CH:9]([NH2:10])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C#N)N1CCCCCC1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Solvent: CO
Product: CC(C)(C(N)c1ccccc1)N1CCCCCC1
Yield: 83 %

Procedure:
The title compound (3.7 g; 83%) was prepared from 2-(hexahydro-1H-azepin-1-yl)-2-methylpropanenitrile D41 (3 g; 18 mmol) and phenyllithium in dibutylether (18 ml of a 2M solution; 36 mmol) in THF (100 ml), followed by reaction with sodium borohydride (2.13 g, 54 mmol) in methanol (100 ml) in a similar manner to that described in D5. 1H NMR (CDCl3) δ 0.78 (3H, s), 0.98 (3H, s), 1.55-1.70 (8H, m), 1.83 (2H, br s), 2.67-2.79 (4H, m), 4.18 (1H, s), 7.20-7.30 (3H, m), 7.40-7.42 (2H, m).