Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[C:10]([F:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1ccc(O)c(F)c1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To the 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol (50 mL) was added thionyl chloride (0.55 mL, 7.3 mmol). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23]OC)[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1>C(O)=O.[Zn]>[CH:18]([OH:20])=[O:19].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[NH2:23])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: [Zn]
Solvent: O=CO
Product: Nc1nc(C(N)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Reaction time: 0.25 h
Yield: 184.7 %

Procedure:
Zinc powder (4.5 g) was added to a stirred solution of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer: 3 g) in 90% formic acid (150 ml) under ice-cooling over 5 minutes, and stirred at the same temperature for 15 minutes. After the resultant solution was filtered and washed with formic acid, the filtrate and the washings were combined and concentrated under reduced pressure to a volume of about 20 ml. The concentrate was dissolved in water (150 ml) and bubbled with hydrogen sulfide gas for 20 minutes under ice-cooling. The precipitating zinc sulfide was filtered off, and the filtrate was treated with activated charcoal and lyophilized to give 7-[2-(2-amino-4-thiazolyl)glycinamido]-3-cephem-4-carboxylic acid formate (2.9 g), pale yellow powder, mp>240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:27]=1[NH2:28].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:28][C:27]3[CH:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=[CH:32][C:26]=3[F:25])=[O:21])=[CH:23][CH:24]=2)[N:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: C[Al](C)C
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 36.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 2-fluoro-5-trifluoromethyl aniline (0.077 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.050 g of desired product. 1H NMR (DMSO-d6): δ 7.48-7.61 (m, 3H), 7.68-7.73 (m, 2H), 8.08-8.12 (m, 5H), 10.41 (br s, 1H), 12.78 (br s, 1H); MS (m/z): 493.09 [M−H]−.
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25].C(N(CC)CC)C.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:21][C:12]1[C:11]2[N:10]=[C:9]([CH2:22][O:23][CH2:24][CH3:25])[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][N:3]([O:2][CH3:1])[C:37]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:38])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Reactant: CC(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(=O)NC(C)C
Temperature: -8 °C
Reaction time: 8 h

Procedure:
The preparation of O-methyl-N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-hydroxylamine is described in Parts A-C of Example 20. Triethylamine (0.14 mL, 1.01 mmol) was added to a solution of O-methyl-N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyrdin-1-yl)butyl]hydroxylamine (0.29 g, 0.84 mmol) in dichloromethane (8 mL) and cooled to −8° C. Isopropyl isocyanate (0.08 mL, 0.84 mmol) was added dropwise to the reaction mixture, allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was then diluted with dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (30 mL) and the phases were separated. The aqueous phase was extracted with dichloromethane (20 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford a yellow solid. The material was then purified by HPFC (eluting with 0-25% CMA in chloroform) and crystallized from acetonitrile, filtered, dried at 80° C. in a vacuum oven over the weekend to afford 0.178 g of 1-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-3-isopropyl-1-methoxyurea as a white powder, mp 146-147° C. Anal. calcd for C21H31N7O3: C, 58.72; H, 7.27; N, 22.83. Found: C, 58.54; H, 7.27; N, 22.78.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[CH2:31][S:32][CH2:33][C:34]([F:37])([F:36])[F:35])[CH:7]=1)C.[OH-].[Li+]>CO.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:11]=[CH:10][C:9]=3[O:12][CH3:13])=[C:16]([CH2:31][S:32][CH2:33][C:34]([F:37])([F:35])[F:36])[CH:17]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSCC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)c2ccc(Cl)cc2)cc1CSCC(F)(F)F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To {3-[4-(4-chloro-benzoylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.47 mmol) in MeOH and H2O was added 1N aqueous lithium hydroxide. The reaction was stirred overnight at 65° C., and then acidified and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A suspension of t-butyl piperazine-1-carboxylate (2 g, 10.75 mmol, 2.00 equiv), 1-bromo-4-methoxybenzene (1 g, 5.38 mmol, 1.00 equiv), X-phos (257.2 mg, 0.54 mmol, 0.10 equiv), Pd2(dba)3 (248.4 mg, 0.27 mmol, 0.05 equiv), and NaOt-Bu (1.62 g, 16.88 mmol, 3.00 equiv) in toluene (15 mL) was placed in a 100-mL round bottom flask, stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via silica gel column (PE/EA (50:1)) yielded 1.412 g (81%) of t-butyl 4-(4-methoxyphenyl)piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.[CH3:27][O:28][CH2:29][CH2:30]Br>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:30][CH2:29][O:28][CH3:27])[C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 17.6 mg, 0.264 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (75 mg, 0.220 mmol) in N,N-dimethyl formamide (2 mL) at 0° C. After 5 min, 2-bromoethyl methyl ether (0.025 mL, 0.264 mmol) was added and the mixture was allowed to warm to ambient temperature. After 3 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 421 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([OH:18])=O)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:20][O:21][NH:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([N:22]([O:21][CH3:20])[CH3:23])=[O:18])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CNOC
Reactant: COc1ccc(N2CC(C(=O)O)CC2=O)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CC(C(=O)N(C)OC)CC2=O)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(3-fluoro-4-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid (5 g, 19.7 mmol), N-methoxymethanamine hydrochloride (2.18 g, 22.4 mmol), HOBt (4.0 g, 29.7 mmol) and Et3N (4.2 mL, 29.7 mmol) in 60 mL of DMF was added EDC (5.7 g, 29.7 mmol) at 0° C. The reaction was warmed to RT in 1 h and stirred at RT for 16 h. The mixture was diluted with 100 mL of EtOAc, and the resulted solution was washed with 50 mL of satd. NaHCO3 followed by 50 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was re-crystallized in 80% EtOAc/hexane to afford white solid. MS (ESI pos. ion) m/z: 297.3 (M+H). Calc'd Exact Mass for C14H17FN2O4: 296.29.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])O1.Cl[C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].CC#N>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.O>[OH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: CC(C)COC(=O)N1CCN(c2ccnc(Cl)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)N1CCN(c2ccnc(-c3ccccc3O)c2)CC1
Temperature: 120 °C

Procedure:
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (25/μL, 120 μmol), 3a (30 mg, 100 μmol), Pd(Ph3P)4 (12 mg, 10 μmol), K2CO3 (28 mg, 200 μmol), CH3CN (900 μL), and H2O (100 μL) were sealed in a microwave vessel and heated by microwave irradiation at 120° C. for 15 minutes. The reaction was filtered and purified by reverse phase HPLC to give compound 1. (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA). LCMS: m/z 356.1 (M+H)+ at 2.24 minutes (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH:20]([CH3:24])[CH:21]([OH:23])[CH3:22])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)O

Procedure:
A mixture of 4-amino-2-(2-butanon-3-yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide (obtained by treating 1.2 g, 3.1 mmoles, of the corresponding hydrochloride salt, prepared in Example 7C, with saturated sodium carbonate solution) and sodium borohydride (100 mg) in ethanol (20 ml) was heated under reflux for one hour. The solution was concentrated, diluted with water, acidified with 2N hydrochloric acid, and basified with saturated sodium carbonate solution. The mixture was extracted with methylene chloride to yield 1.16 g of foam. This material was chromatographed over deactivated silica using methylene chloride (100), methanol (2), ammonia (0.5) as the solvent system. The appropriate fractions were combined to yield the title compound (470 mg) as a foamy mixture of diastereoisomers. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.54 (bd, 1H); 8.2, 8.15 (2s, 1H); 6.32, 6.35 (2s, 1H); 4.36 (s, 2H); 4.24-4 (m, 1H); 4-2.12 (m, 3H); 2.8-2.52 (m, 6H); 1.41-0.96 (m, 12H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:11][C:12](=O)[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[N:18]=[C:17]2[C:29]1[N:34]=[C:33]([O:35][C@H:36]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][CH2:40][C:37]32[CH2:39][CH2:38]3)[CH:32]=[N:31][CH:30]=1)(C)(C)C>C1COCC1>[OH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[N:18]=[C:17]2[C:29]1[N:34]=[C:33]([O:35][C@H:36]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][CH2:40][C:37]32[CH2:39][CH2:38]3)[CH:32]=[N:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(CCO)cc34)n2)C1
Reaction time: 1 h

Procedure:
Lithium aluminum hydride in THF (181 μL, 0.181 mmol) was added to a solution of (4R)-tert-butyl 4-(6-(5-(2-tert-butoxy-2-oxoethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (56 mg, 0.090 mmol) in THF (904 μL) at 0° C.; the reaction was stirred for 1 h. The crude was quenched with EtOAc and was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 40% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(5-(2-hydroxyethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate as a pale yellow oil. MS (ESI, pos. ion) m/z: 550.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH3:29]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:28]([CH3:29])[CH3:27])[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Solvent: CC#N
Product: CN(C)CCn1cc(Br)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
Add 4-[4-bromo-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.2 g; 0.023 mol; 1.0 equiv), dimethyl amine (40% aqueous solution, 22 mL; 0.18 mol; 8.0 equiv) in ACN (100 mL) and stir at 100° C. for 3 h. Concentrate, quench the reaction with saturated NaHCO3 solution and extract with EA. Concentrate the organic layer; purify over a silica gel column with EA/hexane to give the title compound (7.5 g; 83.33%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][C@@H:8]2[N:10]([CH2:11][C:12]3[NH:17][C:16]([C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[N:15][C@@H:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[Cl:30])[C:13]=3[C:31]([O:33][CH3:34])=[O:32])[C@@H:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.C(N(CC)CC)C.Cl[S:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:45])=[O:44]>C(Cl)Cl>[C:49]([O:48][C:47]([NH:46][S:43]([NH:1][CH:2]1[CH2:3][C@@H:4]2[N:10]([CH2:11][C:12]3[NH:17][C:16]([C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[N:15][C@@H:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[Cl:30])[C:13]=3[C:31]([O:33][CH3:34])=[O:32])[C@@H:8]([CH2:7][O:6][CH2:5]2)[CH2:9]1)(=[O:45])=[O:44])=[O:53])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(NS(=O)(=O)NC(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of methyl (4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 60b (60 mg, 0.12 mmol) and triethylamine (0.17 mL, 1.2 mmol) in DCM (5 mL) was added a 0.05 M solution of tert-butyl N-chlorosulfonylcarbamate in DCM (2.5 mL, 0.125 mmol) dropwise at 0° C. The mixture was allowed to warm to room temperature while stirred for 16 h, and then concentrated in vacuo. The residue was purified by silica gel chromatography to afford 0.08 g of methyl (4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylsulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 63a as a yellow oil (yield was 97%). MS: calc'd (MH+) 684, measured (MH+) 684.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: OC(c1ccc(C2CCCCC2)cc1)c1ccccn1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.0 g of chromium trioxide are added in portions at 5° C, whilst stirring and with exclusion of moisture, to a solution of 15.8 ml of pyridine in 200 ml of absolute methylene chloride, behind a protective shield. After the completion of the addition the mixture is stirred for a further 30 minutes at room temperature, 2.8 g of crude 2-[(p-cyclohexylphenyl)-hydroxymethyl]-pyridine, dissolved in 10 ml of methylene chloride, are then added all at once and the mixture is stirred for a further 20 minutes at room temperature. The mixture is decanted off from the brown resin which is formed and is partitioned at 0° C between 50 ml of methylene chloride and 2 lots of 50 ml of saturated sodium bicarbonate solution. The organic phase is washed successively with twice 50 ml of 0.1 N hydrochloric acid and twice 50 ml of water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 200 g of silica gel, using chloroform as eluant, and fractional crystallisation from cold ethanol, yields 2-[(p-cyclohexylphenyl)-oxomethyl]-pyridine of the formula ##STR13## of melting point 44°-45° C (boiling point 185°-190°/0.35 mm).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[S:18][CH:17]=3)[CH:12]=[C:11]([O:25][C:26]3C=C(C(F)(F)F)SC=3)[N:10]=2)=[CH:5][CH:4]=1.O(C)[Na].CO.Cl>CN(C)C=O>[CH3:26][O:25][C:11]1[CH:12]=[C:13]([O:15][C:16]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[S:18][CH:17]=2)[N:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:35])([F:1])[F:36])=[CH:8][CH:7]=2)[N:10]=1
Reactant: FC(F)(F)c1ccc(-c2nc(Oc3csc(C(F)(F)F)c3)cc(Oc3csc(C(F)(F)F)c3)n2)cc1
Agent: CO[Na]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(Oc2csc(C(F)(F)F)c2)nc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 60 °C
Yield: 51 %

Procedure:
A solution of 2-(α,α,α-trifluoro-p-tolyl)-4,6-di{[5-(trifluoromethyl)-3-thienyl]oxy}pyrimidine (1.50 g, 2.70 mnol) in dimethylformamide is treated with 25% NaOCH3 in methanol (0.58 g, 2.70 mmol), heated to 60° C. for 1.5 hours, cooled to room temperature, poured onto water and acidified to pH 5 with 6N HCl. The resultant reaction mixture is extracted with ether. The ether extracts are combined, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a solid residue. The residue is chromatographed (silica gel, ethyl acetate/hexanes, 3/97) to afford the title product as a white solid, 0.58 g (51% yield), mp 91-93° C., identified by 1HNMR, 13CNMR, 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: [CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@H:7]([C:18]([O:20]C)=[O:19])[NH:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@H:7]([C:18]([OH:20])=[O:19])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H]1N[C@@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 79.4 %

Procedure:
In the same manner as described in Reference Example 2-(1) using methyl (1RS,3SR)-trans-1-butyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.0 g), 1N NaOH (8.2 ml) and methanol (35 ml), there is obtained the title compound (1.51 g, 79%) as colorless needles, m.p. 204°-205° C.
Reaction SMILES: [C:1]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:12]=1)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[C:1]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:12]=1)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)/C=C/c2ccccc2)c2ccccc21
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: O=C(O)CCCn1cc(C(=O)/C=C/c2ccccc2)c2ccccc21

Procedure:
The procedure of Ex. 16 was repeated except that (E)-ethyl 4-(3-cinnamoyl-1-indolyl)butyrate obtained in Ex. 60 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give (E)-4-(3-cinnamoyl-1-indolyl)butyric acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[I-].[Na+]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCI
Reactant: O=Cc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Product: CC(C)CCOc1ccc(C=O)cc1
Yield: 92.6 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and 1-iodo-3-methylbutane (649 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-(isopentyloxy)benzaldehyde (292 mg, quant. crude) as a dark yellow oil that was used without further purification or characterization.