Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:18])([F:17])[CH:14]([Cl:16])[F:15])=[CH:8][N:7]=1.[OH-].[K+].[ClH:21]>O>[Cl:21][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:18])([F:17])[CH:14]([Cl:16])[F:15])=[CH:8][N:7]=1
Reactant: Nc1ccc(OC(F)(F)C(F)Cl)cn1
Reactant: Cl
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: FC(Cl)C(F)(F)Oc1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 7.59 g (0.11 mol) of sodium nitrite in 15 ml of water was added dropwise with stirring to a solution of 22.6 g (0.1 mol) of 2-amino-5-(2-chloro-1,1,2-trifluoroethoxy)pyridine in 100 ml of concentrated HCl at 0° C. The mixture was stirred for one hour at 50° C., the pH was adjusted to 6.5 using 2N KOH, and the product was extracted three times with 100 ml of dichloromethane in each case. After drying over sodium sulfate and removal of the solvent by evaporation on a rotary evaporator, the residue was distilled at 6.5 mbar and 13 g of 2-chloro-5-(2-chloro-1,1,2-trifluoroethoxy)pyridine were obtained as a colorless liquid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Br)(Br)(Br)[Br:20].O>C(Cl)Cl>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCC(=O)N(CCCCCO)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCCCC(=O)N(CCCCCBr)C(C)C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
TPP (4.45 g, 9.34 mmol) was added to a 0° C. solution of alcohol 6 (2.00 g, 7.78 mmol) in dry CH2Cl2 (50 mL). After 10 min, CBr4 (3.10 g, 9.34 mmol) was added and the stirring was continued at 0° C. After 2 h, water (20 mL) was added and the reaction mixture was extracted with EtOAc (3×50 mL). The combined extracts were washed with water (2×20 mL), brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 30-35% ethyl acetate/hexane to afford 7 (2.20 g, 91%). TLC:EtOAc/hexanes (3:7), Rf˜0.40; 1H NMR (400 MHz, 45/55 mixture of rotamers) δ 4.60-4.70 and 3.96-4.10 (m, 1H, rotamers), 3.46 and 3.36 (t, J=5.8 Hz, rotamers), 3.02-3.10 (m, 2H), 2.30 and 2.22 (t, J=7.9 Hz, 2H), 1.80-1.97 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J=7.3 Hz, 6H, rotamers), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, rotamers) δ 172.79, 172.39, 48.17, 45.47, 43.32, 40.70, 33.89, 33.87, 33.49, 32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05, 25.84, 25.69, 25.54, 22.64, 21.47, 20.62, 14.17.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=3)[OH:53])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2].N1C=CC=CC=1.F>O1CCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=3)[OH:53])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4cccc(OC)c4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: *CC(*)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4cccc(OC)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-(3""-methyoxyphenyl)-2'"-hydroxyethyloxy-)3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetrone (29 mg in 0.6 mL tetrahydrofuran contained in a polypropylene vial) was added 80 μL of a solution of hydrogen fluoride-pyridine complex (40% in (2:1) tetrahydrofuran:pyridine) and the mixture stirred at room temperature. After 48 hours, the reaction was quenched by the careful addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were dried by passage through a magnesium sulfate plug, concentrated in vacuo and purified by flash chromatography (ethyl acetate:hexane (1:1)+1% methanol) to give the title compound (9.5 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[Cl:10].C(N(CC)C(C)C)(C)C.CO.[C:22]([O:25][CH2:26]C)(=[O:24])C>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:26][O:25][C:22](=[O:24])[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[Cl:10]
Reactant: CCOC(C)=O
Reactant: Cc1cc(Cl)c(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(C)cc1Cl
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 1-bromo-2-chloro-5-fluoro-4-methylbenzene (70 g) dissolved in ethyl acetate (400 mL) was added N,N-diisopropylethylamine (161 mL), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.15 g) and methanol (120 mL). The resulting mixture was stirred at 90° C. for 24 h under carbon monoxide (4 bar) in a 1.5 L autoclave. Further dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (2.57 g) was added and the reaction heated at 90° C. for a further 3 h. The cooled reaction mixture was evaporated to dryness and the residue purified by silica chromatography, eluting with 50% dichloromethane in iso-hexane to give the subtitle compound (57.7 g).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:17][C:16]([NH:18][C:19]2[N:20]=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][C:14]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([NH:18][C:16]2[S:17][C:13]([NH:12][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)=[C:14]([C:29]([NH2:31])=[O:30])[N:15]=2)[N:20]=1
Reactant: NC(=O)c1nc(Nc2cc3ccccc3cn2)sc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2sc(Nc3cc4ccccc4cn3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To a mixture of p-anisoyl chloride (0.4 mL, 3.0 mmol) in pyridine (2 mL) was added dropwise a solution of 5-amino-2-(isoquinolin-3-ylamino)-thiazole-4-carboxamide (0.20 g, 0.70 mmol) in pyridine (3 mL), and the mixture was stirred overnight at rt. The solvent was evaporated. The residue was triturated with MeOH, and the resulting solids were collected to give 42 mg (28% yield) of the titled compound.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].[CH3:28][C:29]1[C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][NH:31][N:30]=1>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[C:29]([CH3:28])=[N:30][NH:31][CH:32]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1c[nH]nc1C
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3c[nH]nc3C)nc21

Procedure:
The title compound (mp 113°-115° C.) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-methyl-4-(tributylstannyl)pyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][S:28]([CH2:31][C:32]([O:34]C)=[O:33])(=[O:30])=[O:29])=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][S:28]([CH2:31][C:32]([OH:34])=[O:33])(=[O:29])=[O:30])=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: COC(=O)CS(=O)(=O)Nc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NS(=O)(=O)CC(=O)O)nc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethanol (1.00 mL) and aqueous sodium hydroxide (1 M, 0.075 mL, 0.075 mmol) were added to methyl {[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]sulfamoyl}acetate (TFA salt, 20.0 mg, 0.034 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (10-80% acetonitrile in water+0.1% TFA) to give {[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]sulfamoyl}acetic acid (TFA salt) as a colorless solid. MS APCI calc'd for C19H17F3N5O4S [M+H]+ 468. found 468. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J=5.2 Hz, 1H), 8.54-8.21 (m, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.27 (d, J=5.1 Hz, 1H), 7.14 (s, 2H), 4.38-3.68 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:11][C:10]=12)=[O:5])C.[OH-].[K+].O>C(O)(=O)C>[F:17][C:15]([F:16])([F:18])[C:14]1[N:9]2[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[N:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CCOC(=O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A mixture of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.6 g, 13.9 mmol), 2M potassium hydroxide solution (111 mL) and water (55 mL) was stirred at room temperature for 5 h, cooled (ice-water), and acetic acid (30 mL) was added. The mixture was evaporated, acetic acid (150 mL) was added and the stirred solution was heated under reflux conditions for 20 min. The reaction mixture was evaporated, water (150 mL) was added followed by extraction with ethyl acetate (2×300 mL). The combined organic layers were washed with brine (2×150 mL), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane 1:1) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (1.93 g, 37%) as a yellow solid. MS (ISN) 374.3 [(M−H)−]; mp 231° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[C:21]([O:35][C:36]2[CH:37]=[CH:38][C:39]([C:42](OCC)=[O:43])=[N:40][CH:41]=2)=[CH:22][C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[NH:25][C:24]=2[CH:34]=1)(=[O:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[C:21]([O:35][C:36]2[CH:37]=[CH:38][C:39]([CH2:42][OH:43])=[N:40][CH:41]=2)=[CH:22][C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[NH:25][C:24]=2[CH:34]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(CO)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
20 mg of lithiumaluminium hydride was added to a tetrahydrofuran (2 ml) solution of 90 mg of ethyl 5-((6-(1-acetylpyrrolidin-2-yl)-2-pyridin-2-yl-1H-benzimidazol-5-yl)oxy)pyridine-2-carboxylate obtained in Example 495 with cooling with ice, and the reaction liquid was stirred at 0° C. for 30 minutes. The reaction liquid was diluted with chloroform, washed with aqueous saturated ammonium chloride, aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [Br:1][C:2]([OH:12])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Br:1][C:2]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: CC(O)(Br)CCC1CCC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(Br)(CCC1CCC(=O)N1)O[Si](C)(C)C(C)(C)C
Yield: 98.4 %

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-(3-bromo-3-hydroxy-butyl)-pyrrolidin-2-one (6.76 g, 21.6 mmol) was reacted with tert-butyldimethylsilyl chloride (3.59 g, 23.8 mmol). Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) provided 5-[3-bromo-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (7.45 g). 1H NMR (CDCl3) δ7.30 (m, 2H), 7.12 (m, 1H), 7.04 (m, 1H), 5.71 (m, 1H), 3.81 (m, 1H), 3.56 (m, 1H), 2.66 (m, 2H), 2.32-2.17 (m, 3H), 1.70-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.24 (d, 3H); MS 426.2, 428.2 (M+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16](=O)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1.[OH-].[Na+].[BH4-].[Na+].C([O:34]C(C)C)(C)C>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[OH:34])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(C)OC(C)C
Reactant: O=C(Cc1ccc(Cl)cc1Cl)CN1CC=C(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCN1CC=C(c2ccc(Cl)cc2)CC1)c1ccc(Cl)cc1Cl

Procedure:
After adding 12.93 g (0.03 mol) of 3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(2,4-dichlorophenyl)propanone hydrochloride to a solution of 1.2 g (0.03 mol) of sodium hydroxide in 50 ml of methanol, 1.17 g of sodium borohydride are portionwise added to the above mixture over 1 hour. After terminating the addition, the reaction mixture is boiled under reflux for 3 hours, then the reaction mixture is poured into 150 ml of water. The major part of methanol is distilled off from the so-obtained oily precipitate, which is then twice extracted with 50 ml of ethyl acetate each. After evaporating the solvent, 12.3 g of evaporation residue are obtained to give a crystalline product on addition of 50 ml of diisopropyl ether. In this way 8.32 g of title product are obtained, which is recrystallized from 28 ml of isopropanol to obtain 6.3 g of title compound, m.p.: 96°-98° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:17]=2)[N:12]=[C:11]([C:29]([O:31][CH3:32])=[O:30])[CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[N:17]=2)[N:12]=[C:11]([C:29]([O:31][CH3:32])=[O:30])[CH:10]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(O)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 18 g of methyl 4-(benzyloxy)-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridine-2-carboxylate dissolved in 200 ml of methanol with 200 ml of tetrahydrofuran was charged with 1.8 g of 20% palladium hydroxide on carbon catalyst, and the mixture was stirred at room temperature for 2 hours under hydrogen atmosphere at 1 atm. The reaction mixture was filtered and concentrated to give crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[S:33][CH:34]=[CH:35][C:31]=4[CH3:30])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1ccsc1C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2sccc2C)c1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 μmol) and 3-methyl-2-thiophenecarboxylic acid (28 mg, 200 μmol). Yield 43 mg (98%).
Reaction SMILES: [Na].C([S:9][C:10]1[CH:47]=[CH:46][CH:45]=[CH:44][C:11]=1[CH2:12][NH:13][CH2:14][C:15]([CH3:43])([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]CC1C=CC=CC=1)C1C=CC=CC=1.N>>[SH:9][C:10]1[CH:47]=[CH:46][CH:45]=[CH:44][C:11]=1[CH2:12][NH:13][CH2:14][C:15]([CH3:43])([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=1)[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]
Reactant: CC(CNCc1ccccc1SCc1ccccc1)(CNCc1ccccc1SCc1ccccc1)Cc1ccc([N+](=O)[O-])cc1
Agent: N
Agent: [Na]
Product: CC(CNCc1ccccc1S)(CNCc1ccccc1S)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Sodium was added to a solution of 1.24 g [70] (2.0 mmol) in 30 ml liquid ammonia until the colour became permanently blue. After thirty minutes the excess sodium was destroyed by adding ammonium chloride. After the ammonia evaporated, the residue was dissolved in water and extracted with chloroform. After drying and removal of the solvent, a white residue was left.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24].O>CCOCC>[CH3:26][S:23]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 232 mg of alcohol 16b in 10 ml of ether was added 1 ml of triethyl amine, followed at 0° C. by 80 μl of mesyl chloride. The mixture was stirred at ambient temperature for 1 hr and then poured into water and extracted into ether. The organic extract was washed with water, dried and concentrated, to give 320 mg of 16c as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:8]([CH:17]([OH:26])[CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:7]=[CH:6][N:5]2[C:27]=1[CH3:28].C(OC(C)C)(C)C>ClC(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:8]([C:17](=[O:26])[CH:18]=[CH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:7]=[CH:6][N:5]2[C:27]=1[CH3:28]
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)c(C(O)C=Cc3ccccc3)ccn2c1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: Cc1nc2c(NC(=O)C(C)(C)C)c(C(=O)C=Cc3ccccc3)ccn2c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
A solution of 35.5 g of 2,3-dimethyl-7-(3-phenyl-1-hydroxy-2-propenyl)-8-pivaloylaminoimidazo[1,2-a]pyridine in 900 ml of trichloromethane is treated with 60 g of manganese dioxide and stirred vigorously at room temperature for 20 h. The mixture is then filtered, the filtrate is concentrated to dryness in vacuo and the oil obtained is treated with a little diisopropyl ether. The crystals obtained in this process are filtered off with suction. 31.5 g of the title compound of melting point 108-10° C. are obtained.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:2][C:3](=[O:5])[CH3:4])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc(C)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
40.7 g (0.44 mole) of chloroacetone are added dropwise at room temperature, with stirring, over a period of 30 minutes to a suspension of 61.25 g (0.4 mole) of 4-methyl-3-nitrophenol, 60.8 g (0.44 mole) of ground potassium carbonate, 39.9 g (0.267 mole) of sodium iodide and 900 ml of dimethylformamide. After a further 3 hours at room temperature, the whole is filtered with suction and the residue is washed with dimethylformamide. The organic solution is concentrated by evaporation in vacuo and the resulting crude product is partitioned between methylene chloride and water. The residue remaining after drying and removal of the methylene chloride is chromatographed over silica gel with petroleum ether/methylene chloride. Subsequent recrystalliation from methylene chloride/petroleum ether yields 1-(4-methyl-3-nitrophenoxy)-2-propanone having a melting point of 84°-86°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)C>[CH:9]1([N:8]([CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:25](=[O:26])[O:27][CH3:28])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: COc1cccc(CCNC2CCCC2)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)N(CCc1cccc(OC)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of N-(3-methoxyphenethyl)cyclopentanamine (1.31 g, 6 mmol) in diethyl ether (50 mL) was added triethylamine (1.3 mL, 9 mmol) and methyl chloroformate (0.7 mL, 9 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. Filtration and removal of solvent under reduced pressure followed by silica gel column chromatography using hexanes/ethyl acetate afforded methyl cyclopentyl(3-methoxyphenethyl)-carbamate as a pale yellow liquid (1.41 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.19 (t, 1H, J=7.6 Hz), 6.78-6.73 (overlapping doublets and singlet, 3H), 4.27-4.24 (m, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.28 (t, 2H, J=7.9 Hz), 2.80 (t, 2H, J=7.9 Hz), 1.68-1.67 (m, 2H), 1.53-1.50 (m, 6H). LC-MS (ESI) Calcd for C16H23NO3 [M+H]+: 278.17. Found: 278.00.