Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:44])[C@H:11]([N:20]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1)[S:21]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[CH:26][C:25]=1[CH3:33])(=[O:23])=[O:22])[CH2:12][O:13]C1CCCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][NH:9][C:10](=[O:44])[C@H:11]([N:20]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1)[S:21]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[CH:26][C:25]=1[CH3:33])(=[O:23])=[O:22])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)NOCc2ccccc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NOCc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionamide (1.7 g, 4.3 mmol) in methanol (100 mL) at 0° C. was added p-toluenesulfonic acid monohydrate (150 mg). After 12 h, the reaction mixture was warmed to room temperature and stirred for an additional 5 h. The reaction mixture was concentrated and the residue was chromatographed (Biotage 40M; 20% to 50% ethyl acetate-hexanes) to afford N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (1.60 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:7][N:6]=1)=N.O[Li].O.P(=O)(O)(O)[OH:35].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:35])=[N:6][CH:7]=3)=[N:12][C@H:13]3[C@@H:18]2[CH2:17][C@H:16]([OH:30])[CH2:15][CH2:14]3)=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: O=P(O)(O)O
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=N)OC)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Agent: O=P([O-])([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Analogously as described for Example 35 acidic acid (2R,4aR,10bR)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound 172) is converted in a first step into the corresponding imino ester 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester. In a second step, 443 mg (1.08 mmol) of 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg (2.16 mmol) LiOH—H2O is added and the solution stirred at 60° C. for 18 hrs. The pH is adjusted to 5 using phosphoric acid and Disodiumhydrogenphosphate. The solvent is removed and the solid residue extracted with chloroform/methanol. After filtering off and removing the volatiles 350 mg (82%) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:25]([O:28][C@@H:29]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:30]1O)(=[O:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:25]([O:28][C@@H:29]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:30]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)cc3)cs2)cc1OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3ccc(O[C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.3 %

Procedure:
In 45 ml of tetrahydrofuran were dissolved 1.5 g of 4-(4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole, 1.4 g of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose and 1.3 g of triphenylphosphine. Thereto was added, in small portions at 0° C., a solution of 0.9 g of diethyl azodicarboxylate dissolved in 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 14 hours. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: dichloromethane) and recrystallized from ethyl acetate-n-hexane to obtain 1.52 g of 4-[4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl]-2-(3,4-diethoxyphenyl)-thiazole.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][O:22][CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH3:27])[CH:9]=2)[CH:4]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:1][CH2:2][CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][O:22][CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH3:27])[CH:9]=2)[CH:4]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)(=[O:40])=[O:39]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(CO)C2c1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(COS(C)(=O)=O)C2c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of (1RS,2RS,3RS)-2-hydroxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (1.388 g, 2.82 mmol) in methylene chloride (10 ml) with TEA (1.2 ml) stirred under argon at 0° C. was added methanesulfonyl chloride (0.41 g, 3.5mmol). The cooling bath was removed and stirring continued for 1 h. The mixture was partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as an oil (1.52 g, 95%).
Reaction SMILES: [Cl-].C([NH+](CCCCCCCC)CCCCCCCC)CCCCCCC.C(N(CC)CC)C.C1C(O)=CC=C(C)C=1.ClCCl.[CH:45]12[CH2:51][CH:48]([CH2:49][CH2:50]1)[CH:47]=[CH:46]2.[CH:52]([O:54][CH3:55])=[O:53]>[Ru].[Co]>[C:45]12([C:52]([O:54][CH3:55])=[O:53])[CH2:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][CH2:46]2
Reactant: C1=CC2CCC1C2
Reactant: COC=O
Agent: [Co]
Agent: [Ru]
Agent: CCCCCCCC[NH+](CCCCCCCC)CCCCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C12CCC(CC1)C2
Temperature: 120 °C

Procedure:
In a pressure reactor made of stainless steel and having an internal volume of 50 ml, 0.025 mmol of [Ru(CO)3Cl2]2 as a ruthenium compound, 0.025 mmol of Co2(CO)8 as a cobalt compound, 0.25 mmol of trioctylammonium chloride as a halide salt, 2.0 mmol of triethylamine as a basic compound, 0.25 mmol of p-cresol as a phenolic compound, and 0.25 mmol of dichloromethane as an organic halide were introduced and mixed at room temperature, and thus a catalyst system was obtained. 5.0 mmol of norbornene and 5.0 mL of methyl formate were added to this catalyst system, subsequently the reactor was purged with nitrogen gas at 0.5 MPa, and the system was maintained for 15 hours at 120° C. Thereafter, the reactor was cooled to room temperature, and the pressure was released. A portion of the remaining organic phase was withdrawn, and the components of the reaction mixture were analyzed by using gas chromatography. According to the analysis results, the amount of methyl norbornane monocarboxylate produced by the reaction was 8.60 mmol (yield in terms of norbornene 86.0%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OCC[C@@H](O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: OC[C@H](O)CCOc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 71.6 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(3R)-(3,4-dihydroxybutan-1-yl)oxy]quinazoline (4.23 g) in methanol (40 ml) is added 10% palladium/carbon (634 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 18.5 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure, and the residue is washed with acetone to give 4-[(3R)-(3,4-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (2.13 g) as crystals. A part of the product is recrystallized from ethanol to give a product having the following physical properties.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=CC=CC=1.C1CCCCC=1.C([OH:41])C>[Pd]>[C:27]([Si:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][CH:2]2[CH2:7][O:41]2)=[CH:32][CH:31]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: CCO
Reactant: CC(C)(C)[Si](Oc1ccc(OCc2ccccc2)cc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
(4-Benzyloxy-phenoxy)-tert-butyl-diphenyl-silane (32.5 g, 67 mmol) was dissolved in ethanol. 10% Palladium on carbon (3.0 g) was added followed by cyclohexene (100 mL). The mixture was heated at reflux for 16 hours. The reaction was cooled to room temperature and filtered through Celite. The solvent was removed in vacuo to yield the title compound (22.0 g, 63 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[H-].[Na+].I[CH3:22].O>O1CCCC1>[CH3:18][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][N:7]([CH3:22])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CN(C)C(=O)CCNC(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)CCN(C)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Benzyl [2-(dimethylcarbamoyl)ethyl]carbamate (I-139) (0.69 g, 2.76 mmol) was dissolved in tetrahydrofuran (10 ml), and with cooling with ice, sodium hydride (oily, about 55%, 0.15 g, 3.44 mmol) was added, followed by stirring for 10 minutes. Iodomethane (0.26 ml, 4.18 mmol) was added, followed by stirring at room temperature for 18 hours, and water was added. After extraction with ethyl acetate and drying over anhydrous sodium sulfate, the solvent was evaporated away, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain a colorless oil (0.63 g, 86%).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13]
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NOCc2ccccc2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NO)c(C)c1
Reaction time: 0.75 h
Yield: 97.6 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (3.0 g, 5.39 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (160 mL) was added 10% Pd—C (1.3 g), and the resulting mixture was hydrogenated at atmospheric pressure for 45 min. The reaction mixture was degassed under argon and the slurry was filtered over Celite. The Celite cake was washed with ample 80% ethanol-methylene chloride and the filtrate was concentrated to almost dryness forcing the mixture to crystallize. The slurry was filtered, washing with 50% diethyl ether-hexanes to afford N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (2.38 g) as a white solid.
Reaction SMILES: [S-2].[Na+].[Na+].[Cl-].[NH4+].[Cl:6][C:7]1[C:8]([O:31][CH3:32])=[CH:9][C:10]2[CH:16]([C:17]3[C:25]4[O:24][CH2:23][CH2:22][C:21]=4[CH:20]=[C:19]([N+:26]([O-])=O)[CH:18]=3)[CH2:15][N:14]([CH3:29])[CH2:13][CH2:12][C:11]=2[CH:30]=1>C(O)CC>[Cl:6][C:7]1[C:8]([O:31][CH3:32])=[CH:9][C:10]2[CH:16]([C:17]3[C:25]4[O:24][CH2:23][CH2:22][C:21]=4[CH:20]=[C:19]([NH2:26])[CH:18]=3)[CH2:15][N:14]([CH3:29])[CH2:13][CH2:12][C:11]=2[CH:30]=1
Reactant: COc1cc2c(cc1Cl)CCN(C)CC2c1cc([N+](=O)[O-])cc2c1OCC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCCO
Product: COc1cc2c(cc1Cl)CCN(C)CC2c1cc(N)cc2c1OCC2
Reaction time: 16 h

Procedure:
A stirred mixture of 2.50 g (0.011 mole) sodium sulfide and 0.60 g (0.011 mole) ammonium chloride in 10 ml n-propanol was warmed to reflux temperature and a solution of 0.44 g (0.0011 mole) 8-chloro-5-(5-nitro-2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was added dropwise and reflux was continued for 16 h. The solvent was removed in vacuo and the residue was redissolved in dichloromethane. The solution was washed with 0.1N NaOH, water and brine. Evaporation yielded 8-chloro-5-(5-amino-2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as a foam.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[CH3:8])=[CH:4][F:5].S(=O)(=O)(O)[OH:16]>O>[F:5][CH2:4][C:3]([OH:16])([C:6]([F:11])([F:12])[C:7]([F:10])([F:9])[CH3:8])[C:2]([F:13])([F:14])[F:1]
Reactant: O=S(=O)(O)O
Reactant: CC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Solvent: O
Product: CC(F)(F)C(F)(F)C(O)(CF)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol may be prepared by fluorinating commercially available 2,3-pentanedione to form 2,2,3,3-tetrafluoropentane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-pentene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-pentene to form 2-trifluoromethyl-1,3,3,4,4-pentafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[CH:15]=[CH:14][NH:13][C:9]2=[N:10][C:11]=1[NH2:12])=[O:5])C.[OH-].[Na+].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:52]([C:59]1[S:63][C:62]([CH2:64][NH2:65])=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(O)C.[Cl-].[Na+].O>[O:52]([C:59]1[S:63][C:62]([CH2:64][NH:65][C:4]([C:6]2[CH:7]=[C:8]3[CH:15]=[CH:14][NH:13][C:9]3=[N:10][C:11]=2[NH2:12])=[O:5])=[CH:61][CH:60]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CCOC(=O)c1cc2cc[nH]c2nc1N
Reactant: NCc1ccc(Oc2ccccc2)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc2[nH]ccc2cc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 98 °C
Reaction time: 15 h
Yield: 18.5 %

Procedure:
To a solution of 6-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester described in Preparation Example R-2 (95 mg, 0.46 mmol) in ethanol (10 mL) was added an aqueous solution of 1N sodium hydroxide (5 mL, 5 mmol), which was then heated for 3 hours in an oil bath at 98° C. After cooling the reaction solution, the reaction solution was concentrated until it reached ⅓ of its volume, neutralized with 1N hydrochloric acid, and further concentrated. The resulting crude product was suspended in N,N-dimethylformamide (5 mL), triethylamine (0.096 mL, 0.69 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (153 mg, 0.35 mmol) and C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation Example 26 (71 mg, 0.35 mmol) were added thereto, followed by stirring at room temperature for 15 hours. After the reaction was completed, the reaction solution was poured into brine, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (31 mg, 0.085 mmol, 18.5%) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:37][CH:38]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[S:37][CH:38]=2)[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (262 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (601 mg, yield: 85%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].CO>CN(C)C=O.O>[CH:22]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[CH:23][CH3:24]
Reactant: C=CCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC=COc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 136 h
Yield: 71.6 %

Procedure:
5.0 grams (25.0 mmole, 1.0 eq.) of 4-benzyloxyphenol was dissolved in 100 ml of N,N-dimethylformamide. 10.4 grams (75.0 mmole, 3.0 eq.) of potassium carbonate and 3.25 ml (37.5 mmole, 1.5 eq.) of allyl bromide were added to the reaction and it was stirred at 80° C. for 3 hours and at room temperature for another 136 hours. The reaction mixture was diluted with water and extracted 3× with 60 ml of ethyl acetate. The combined organics were dried over sodium sulfate, filtered, evaporated and pumped on high vacuum overnight. The title compound (4.3 grams, 72% yield) was isolated by recrystallization from methanol.
Reaction SMILES: N([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1)N.S(Cl)([Cl:19])=O>>[Cl:19][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NNc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 50 °C

Procedure:
49.4 g of 2-hydrazino-6-trifluoromethoxybenzothiazole are added over one hour to 97.9 g of thionyl chloride heated to 50° C. The mixture is then heated for one hour at this same temperature and then cooled to 0° C. After addition of 200 g of an ice/water mixture (1/1 by weight), the precipitate is filtered off and washed with twice 50 cm3 of water. 54.5 g of 2-chloro-6-trifluoromethoxybenzothiazole are thus obtained, melting at 50° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[N:27][C:28]=1[Cl:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:30][C:25]1[CH:26]=[N:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1

Procedure:
To a solution of 80 mg of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 50 mg 5,6-dichloro-3-pyridine methanol and 73 mg triphenyl phosphine in 3 ml of dry THF 56 mg of diisopropylazodicarboxylate were added. After 16 h at room temperature the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 96 mg of 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester were obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([CH:22]2[CH2:24][CH2:23]2)[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1>O1CCCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]([CH:22]2[CH2:23][CH2:24]2)[CH:17]([F:35])[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C[C@@H](c1ccc(Cl)cc1)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(F)[C@@H](c1ccc(Cl)cc1)C1CC1
Temperature: -78 °C

Procedure:
To a stirred solution of lithium diisopropyl amide (30 mmol) in dry tetrahydrofuran (125 ml) under nitrogen at −78° C. is added dropwise a solution of methyl (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoate (6.5 g, 27.2 mmol) in dry tetrahydrofuran (50 ml). The reaction mixture is allowed to warm to 0° over 5 minutes, re-cooled to −78° C., and N-fluorobenzenesulfonimide (19.1 g, 60.6 mmol) is added.