Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:29][C@@H:30]([CH2:39][CH3:40])[C@H:31]([OH:38])[C:32]([NH:34][CH:35]1[CH2:37][CH2:36]1)=[O:33].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:35]1([NH:34][C:32](=[O:33])[C@@H:31]([OH:38])[C@@H:30]([NH:29][C:24]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])(=[O:15])=[O:14])[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:26])[CH2:39][CH3:40])[CH2:37][CH2:36]1
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: Cc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(C)cc2C)CN1C(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,4-dimethylphenylsulfonyl)pyrrolidine-2-carboxylic acid (120 mg, 313 μmol, Eq: 1.00, prepared as described in U.S. Pat. Appl. US20100267722), (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride (99.7 mg, 407 μmol, Eq: 1.3), N,N-diisopropylethylamine (121 mg, 164 μA, 939 μmol, Eq: 3) and HATU (202 mg, 532 μmol, Eq: 1.7) were combined with DMF (2 ml) to give a light brown solution. The reaction was stirred overnight at RT. The crude material was purified by preparative HPLC (column: ymc C18 (120 A), 75×30 mm, acetonitrile/water (+0.1% formic acid)=95%-5% to 5%-95% in 8 min, flow: 25 ml/min). After evaporation of solvents, the title compound was obtained as a light brown foam (64.3 mg, 38.2%, MS (m/e)=538.3 [M+H+]).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][OH:19])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C(C)=CC=CC=1C.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12][CH2:11]1)[CH3:8])=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](C#CCO)CC1)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 8.16 g (29 mmol) of trans-[4-(3-hydroxy-prop-1-ynyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 230 ml methylenechloride was treated at 0° C. with 2.48 ml (31.9 mmol) of methanesulfonylchloride and 5.05 ml (43.5 mmol) of 2,6-lutidine. The reaction mixture was stirred over night to room temperature. The reaction was cooled (0° C.) and treated again with 0.68 ml (8.7 mmol) of methanesulfonylchloride and 1.68 ml (14.5 mmol) of 2,6-lutidine and stirred for 24 hours. Water (35 ml) was added and the reaction was stirred for 5 minutes. After extraction with aqueous saturated NaHCO3/ether (3×), the organic phases were washed with aqueous 10% NaCl, dried over sodium sulfate and evaporated to yield 12.5 g of crude trans-methanesulfonic acid 3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-prop-2-ynyl ester as brown oil, MS: 360 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH3:10]O>>[OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CO
Reactant: CC(C)C[C@H](O)C(=O)O
Product: COC(=O)[C@@H](O)CC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of (S)-2-hydroxy-4-methylpentanoic acid (3.0 g, 22.7 mmol) in methanol was added TMS CH2N2 (2M in hexanes, 34 mL, 17 mmol) dropwise, at 0° C., over 20 min The reaction mixture was stirred at 0° C. for 1 h. The solution was concentrated using a bath temperature of 20° C. and vacuum greater than 50 mm Hg. Purification via silica gel chromatography using 2-100% EtOAc in hexanes gave the ester as a yellow oil (2.14 g, 14.5 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ 5.13 (s, 1H), 4.1-4.0 (m, 1H), 3.81 (s, 3H), 1.6-1.5 (m, 1H), 2.35-2.20 (m, 2H), 1.05-0.84 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:21]N4CCOCC4)=[CH:15][N:16]3[CH2:19][CH3:20])=[C:12]([O:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:11]=2)=[CH:4][N:3]=1.Cl>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH3:21])=[CH:15][N:16]3[CH2:19][CH3:20])=[C:12]([O:28][S:29]([CH:32]([CH3:33])[CH3:34])(=[O:31])=[O:30])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CCn1cc(CN2CCOCC2)c2c(OS(=O)(=O)C(C)C)cc(Cc3cnc(N)nc3N)cc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCn1cc(C)c2c(OS(=O)(=O)C(C)C)cc(Cc3cnc(N)nc3N)cc21
Yield: 28.4 %

Procedure:
Propane-2-sulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-3-morpholin-4-ylmethyl-1H-indol-4-yl ester (Example 10d; 270 mg, 0.55 mmol) was dissolved in methanol (50 mL) and 1 M aqueous hydrochloric acid solution (0.6 mL) and hydrogenated at room temperature and atmospheric pressure for 16 h in the presence of palladium on activated charcoal (10%, 170 mg). The catalyst was removed by filtration through filter aid and the filtrate was concentrated. The residue was dissolved in water (10 mL) and the pH set to ≈9 with 25% aqueous ammonia solution. The precipitate was collected by filtration and purified by preparative HPLC to afford the title compound (63 mg, 28%). Off-white solid.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:12][CH:11]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:12][CH:11]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CC(OC(=O)c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CC(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of benzoic acid 3-tert-butoxycarbonylaminocyclobutyl ester (100 mg, 0.34 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hrs and then concentrated under reduced pressure. The residue was partitioned between EtOAc (20 mL) and saturated aqueous sodium hydrogenocarbonate solution (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give benzoic acid 3-aminocyclobutyl ester as a colorless oil (62 mg, yield: 94%).
Reaction SMILES: [F:1][C:2]1[C:10](F)=[C:9]([C:12](O)=[O:13])[C:8]([F:15])=[C:7](F)[C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1.CCOCC>[OH:5][CH2:4][C:3]1[CH:7]=[C:8]([F:15])[C:9]([CH2:12][OH:13])=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCc1cc(F)c(CO)cc1F
Temperature: 10 °C

Procedure:
A solution of 63.2 g (0.265 mols of 2,3,5,6-tetrafluoroterephthalic acid (m.p. 268 - 271° C., obtainable from Pierce-Chemical, Rockford, Ill., U.S.A., in 450 ml of tetrahydrofuran are introduced in the course of 1 hour into a solution of 40.3 g (1.06 mols) of lithium aluminium hydride in 1200 ml of tetrahydrofuran. The reaction mixture is refluxed for 24 hours, then cooled to 10° C. and treated carefully with 40 ml of 15% sodium hydroxide solution and finally with 120ml of water. The white precipitate is filtered off, washed with 500 ml of tetrahydrofuran, and the clear filtrate concentrated at 60° C. under vacuum. 37.9 g of slightly yellow-colored crystals are obtained. This-layer chromatography reveals them to be a mixture of at least three substances. To isolate a unitary substance, the batch is dissolved in 500 ml of ether, 2.8 g of insoluble constituents are removed by filtration, and the ethereal solution concentrated to one-third its volume. It is then treated with 35 ml of pentane and cooled to 10° C., white crystals precipitating. After two recrystallizations from ether+pentane, 3.4 g of fine needles are obtained which melt at 107-109° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
At −10° C. and under N2 atmosphere, to a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 10.7 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (5.4 g, 26.8 mmol), and PPh3 in anhydrous THF were slowly added DIAD over one hour. The resulting reaction mixture was subsequently warmed up to room temperature and stirred for additional 2 hours. Once the yellow precipitation was generated, the reaction mixture was cooled back to −5° C. and stirred overnight. While the solution was still cold, the yellow precipitation was quickly filtrated and washed with cold THF (30 mL) to afford tert-Butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (62) (1.77 g, 36%) as a white solid. LC-MS (ESI): m/z (M/M+2) 463.1/465.1.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][NH2:13]>O>[CH3:12][NH:13][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4]
Reactant: CN
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: O
Product: CNc1ccc([N+](=O)[O-])cc1N

Procedure:
12.5 g (0.079 mol) of 2-fluoro-5-nitroaniline and 100 ml methylamine (40% in water) are stirred for 48 hours at ambient temperature. The precipitated product is diluted with water, suction filtered, washed and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:3][CH:2]=1>C(O)(=O)C.[Pt](=O)=O>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:15][CH2:16][CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:19]3)[CH2:11][CH2:10]2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCC2(CC1)CCN(CCC1CCNCC1)CC2

Procedure:
0.17 g (0.5 mmol) of the compound from Example 22 were dissolved in 25 ml 90% acetic acid followed by addition of 30 mg platinum(IV) oxide. The mixture was filled into an autoclave and hydrogenated for 4 h at room temperature and a pressure of 20 atm. The catalyst was removed by filtration and the solvent evaporated under reduced pressure. The residue was treated with water and neutralized with sodium carbonate followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to leave the pure title compound.
Reaction SMILES: O[CH:2]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[C:8]=1[Cl:17].OS(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:17][C:8]1[C:7]2[CH2:6][CH2:5][NH:4][CH2:3][CH:2]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[C:10]([O:13][CH3:14])[C:9]=1[O:15][CH3:16]
Reactant: COc1ccc(C(O)CNCCc2ccc(OC)c(OC)c2Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCCc3c2cc(OC)c(OC)c3Cl)cc1
Reaction time: 4 h
Yield: 83.5 %

Procedure:
7.87 g of N-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-(2-chloro-3,4-dimethoxyphenyl)ethylamine was dissolved in 59 ml of CF3COOH. 1.7 ml of concentrated H2SO4 was added to the solution and the reaction was conducted for 4 hours. After the completion of the reaction followed by concentration under reduced pressure, 100 ml of CHCl3 and 50 ml of 10% NaOH were added to the residue to conduct extraction. The extract was washed with water, dehydrated over MgSO4 and concentrated to dryness under reduced pressure to obtain 6.25 g (yield: 83.5%) of 6-chloro-2,3,4,5-tetrahydro-7,8-dimethoxy-1-(4-methoxyphenyl)-1H-3-benzazepine.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:5](=[N:15]/O)/[C:4]=2[CH:3]=1.BrC1C=CC2C(C=1)=NC([OH:32])=C1C=2C=CC=C1>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:4](=[C:5]([OH:32])[N:15]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH:3]=1
Reactant: Oc1nc2cc(Br)ccc2c2ccccc12
Reactant: O/N=C1/c2ccccc2-c2ccc(Br)cc21
Solvent: O
Product: Oc1nc2ccccc2c2ccc(Br)cc12
Temperature: 185 °C

Procedure:
To the solid product from Step 1, (9Z)-2-bromo-9H-fluoren-9-one oxime (106 mg, 0.387 mmol) was added polyphosphoric acid (5 g). The mixture was then heated to 185° C. for 2 h. After cooling to r.t., water was added and the resulting solid was collected by filtration to give a 1:1 mixture of the title compounds and the regioisomeric 3-bromophenanthridin-6-ol. LRMS (M+H)+=274.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].[CH:17](OCC)=[O:18]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:17][OH:18])[C:5]2=[O:16]
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Reactant: CCOC=O
Solvent: O
Product: CCC(=O)N1CC(=CO)C(=O)c2cc(Cl)ccc21
Temperature: 55 °C
Reaction time: 7 h
Yield: 75.1 %

Procedure:
A mixture of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (200.5 g) and 1,5-diazabicyclo[5,4,0 ]undecene-5 (384.9 g) in ethyl formate (400.9 g) was heated at 55° C. with stirring for 7 hours and then diluted with cold water (450 ml). The mixture was washed successively with diisopropyl ether and ethyl acetate and then the aqueous layer was acidified with hydrochloric acid under ice cooling. The resultant precipitate was collected by filtration and dried to give 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (168.29 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)cc1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.447 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-methoxyphenylboronic acid (0.302 g) in ethanol (1 ml). The mixture was heated under reflux for 2.75 hours, then left at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) were added and the mixture heated under reflux for 3 hours. The cooled reaction mixture was then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as an off-white crystalline solid, m.p. 222° C. with softening at 192° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2C)=[CH:13][C:12]([I:22])=[N:11][CH:10]=1.[F:34]C(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(C)C(=O)C1C(C2C=CC(F)=CC=2)=CC(Cl)=NC=1>>[F:29][C:28]([F:30])([F:31])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:32])([F:1])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:34])=[CH:19][CH:20]=2)=[CH:13][C:12]([I:22])=[N:11][CH:10]=1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(Cl)cc1-c1ccc(F)cc1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(I)cc1-c1ccc(F)cc1

Procedure:
The title compound is prepared according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) using N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-4-(4-fluoro-phenyl)-N-methyl-nicotinamide (Example 36) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][CH:12]=[CH2:13])[C:3]=1[OH:14].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][CH2:12][CH3:13])[C:3]=1[OH:14]
Reactant: [H][H]
Reactant: C=CCc1cc2c(c(C)c1O)CCO2
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc2c(c(C)c1O)CCO2

Procedure:
A solution of 37 (0.500 g, 2.63 mmol) in absolute ethanol (25 mL) was hydrogenated over 5% palladium on carbon (0.060 g) at 3 atmospheres pressure. After hydrogen uptake was complete (30 minutes) the catalyst was removed by filtration through celite. The filter cake was washed with an additional portion of ethanol (30 mL) and the combined filtrate and washings concentrated to a white crystalline solid. Recrystallization from hexane gave 38. 38: mp 72°-73° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3]>C(O)(=O)C>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCCC(C)CCO
Solvent: CC(=O)O
Product: CC(C)=CCCC(C)CC=O
Reaction time: 8 h

Procedure:
200 ml of an agar plate medium (pH 6.0) composed of 5 g of peptone, 3 g of malt extract, 1 g of magnesium sulfate, 40 g of glucose, 20 g of agar and 1 liter of distilled water was poured into a Petri dish made of glass and having a diameter of 21 cm. Using Conradi's rod, this agar medium was inoculated with 2 ml of a one-day culture of Hansenula saturnus IFO 0809. After the microorganism was grown overnight in standing culture, 70 ml of a 2% citronellal solution in decane was placed over the agar medium and a fermentation-transformation test was carried out in shaking culture for 5 days. As a result of gas chromatographic analysis of the decane layer, the microbial esterification reaction of citronellol formed by microbial reduction of citronellal with acetic acid formed by acetic acid fermentation was observed, and an accumulation of citronellyl acetate in the decane layer was recognized from one day after the start of the reaction. In consequence of the fermentation-transformation test carried out for 5 days, the accumulation concentration of citronellyl acetate in the decane layer reached 19 g/l.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:29])([CH3:28])[CH2:11][C@:12]([CH2:18][NH:19][C@@H](C3C=CC=CC=3)C)([OH:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1>CCO.[Pd]>[NH2:19][CH2:18][C@:12]([OH:17])([CH2:11][C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([CH3:29])[CH3:28])[C:13]([F:15])([F:16])[F:14]
Reactant: C[C@@H](NC[C@](O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C[C@@](O)(CN)C(F)(F)F)c1cccc2c1OCC2

Procedure:
(2R)-4-(2,3-Dihydro-1-benzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-({[(1R)-1-phenylethyl]amino}methyl)-2-pentanol (Intermediate 23, (480 mg, 1.178 mmol) was dissolved in EtOH (13 mL) and hydrogenated over 10% palladium on charcoal (119 mg) at 50 psi and room temperature for 5 hours. Catalyst was removed by filtration through a microfibre filter pad and Celite. The Celite was washed several times with EtOH. The filtrate was evaporated in vacuo to give the title compound as a pale grey solid (330 mg).
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH:13]([C:17]#[N:18])[C:14]([NH2:16])=[S:15].C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:16][C:14]1[S:15][C:6]2[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:4]([Cl:3])[C:5]=2[C:13]=1[C:17]#[N:18]
Reactant: N#CC(C(N)=S)c1ccc([N+](=O)[O-])cc1Cl
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(N)sc2cc([N+](=O)[O-])cc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9.2 ml (0.18 mol) of bromine in 72 ml of methylene chloride is added dropwise at room temperature to a suspension of 46 g of 2-chloro-4-nitrophenylcyanothioacetamide (0.18 mol) and 30 g of sodium hydrogencarbonate (0.36 mol) in 650 ml of methylene chloride. This was followed by 2 hours of stirring at room temperature, filtering off with suction and repeated washing of the yellow residue with water.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][CH:5]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[O:7].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:1]([O:4][CH:5]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[O:7])[CH3:2]
Reactant: C#CCOc1ccc(CCNC(=O)C(O)CCc2ccccc2)cc1OC
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(CCc2ccccc2)OCC)cc1OC
Reaction time: 16 h

Procedure:
Ethyl iodide (1.5 g, 10 mmol) is added slowly at room temperature to a mixture of 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-4-phenyl-butyramide (3.0 g, 8.2 mmol), 30% sodium hydroxide solution (7.0 ml, 41 mmol) and catalytic amounts of tetrabutylammonium bromide (50 mg) in 30 ml of dichloromethane. The reaction is stirred for 16 hours at +40° C. Subsequently the mixture is evaporated and the residue is diluted with water and dichloromethane. The phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated. The remaining oil is purified by chromatography on silica gel (ethyl acetate/hexane 1:1) to yield 2-ethoxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-4-phenyl-butyramide (Compound E1.02).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1>>[Br:1][C:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[NH:9][N:10]=1
Reactant: c1cnc2cn[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Product: Brc1n[nH]c2cccnc12
Yield: 68.6 %

Procedure:
750 mg of N-bromosuccinimide was reacted on 0.5 g of 1H-pyrazolo[4,3-b]pyridine in the similar method as described in Production example 87, to afford 570 mg of the title compound as a colorless powder.