Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[CH:9]=2)=[CH:4][C:3]=1[CH3:18].[O:19]1COCO[CH2:20]1.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2[CH:20]=[O:19])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(C2=CC(C)(C)CC(C)(C)C2)ccc1F
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(C2=C(C=O)C(C)(C)CC(C)(C)C2)ccc1F
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 200 g of glacial acetic-acid, 200 g of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene and 35.4 g of 1,3,5-trioxane, a catalytic quantity (4.0 g) of concentrated sulfuric acid was added and the batch was heated to 106°-110° C. for 11/4 hours. The mixture was then cooled to 30° C. and partitioned between 100 ml of water and 200 ml of heptane. The bottom layer was discarded and to the remaining solution 100 ml of methanol was added. A solution of 96 g of 85% potassium hydroxide in 100 ml of water was then added and the reaction mixture was heated to 68°-72° C. for 13/4 hours. The batch was then cooled to 30° C. and the phases were allowed to separate. The bottom layer was discarded and the top layer was concentrated in vacuo until 25% of the total volume was distilled off. The remaining solution was diluted with 100 ml of heptane and 182 g of triethylamine. To the resulting mixture, a solution of 324 g of sulfur trioxide/pyridine complex in 535 g of dimethyl sulfoxide and 78.3 g of triethylamine was added at 30°-35° C. The batch was stirred at 30°-35° C. for 1/2 hour, then cooled to about 20° C. and quenched with 600 g of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was diluted with 100 ml of methanol and 50% sodium hydroxide solution (90 g) was added. The reaction mixture was stirred for 11/2 hours at 30°-34° C. Water (100 ml) was added and the phases were allowed to separate at room temperature. The bottom layer was discarded and the top solution was concentrated in vacuo to remove the solvent. The residue was dissolved in 200 ml of ethanol, the solution was cooled to about 3° C., seeded and the product was allowed to crystallize overnight. The solids were filtered off, washed with 80 ml of cold ethanol and dried to constant weight. Yield: 100 g of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OCC)C.CC(N=NC(C#N)(C)C)(C#N)C>[Br:21][CH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(CBr)cc1OC
Yield: 70.2 %

Procedure:
To a solution of methyl 2-methoxy-4-methylbenzoate (10.00 g, 55 mmol) in CCl4 (150 mL) were added NBS (11.8 g, 66 mmol) and AIBN (0.100 g). The reaction mixture was refluxed for 18 h. The reaction mass was diluted with diethyl ether and washed with 25% NaOH solution. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 10.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.77 (m, 6H), 4.68 (s, 2H), 7.06 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.61 (d, J=7.8 Hz, 1H); MS (m/z): 259.13 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:18]1(O)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OC1CCCC1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCCC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, cyclopentanol (49 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with cyclopentanol (49 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol). The mixture was heated under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to give the title compound (77 mg, 88%) as a white solid. The resulting solid was washed with hexane-ether and collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [C:1]12([C:11]3[C:12](=[O:17])[NH:13][NH:14][C:15]=3[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:19][CH2:20][CH2:21]Br.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:1]12([C:11]3[C:12](=[O:17])[N:13]4[CH2:19][CH2:20][CH2:21][N:14]4[C:15]=3[CH3:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Cc1[nH][nH]c(=O)c1C12CC3CC(CC(C3)C1)C2
Reactant: BrCCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)n2n1CCC2
Temperature: 100 °C
Yield: 20 %

Procedure:
Into a sealable pressure vessel was placed 4-adamantan-1-yl-5-methyl-1,2-dihydro-pyrazol-3-one (3.5 g) (as described in example 48) along with 1,3-dibromopropane (6.1 g) and DMF (40 mL) and one equivalent of solid potassium carbonate. The reaction vessel was sealed and the solution was heated to 100° C. for 20 hours. The reaction was then allowed to cool and diluted with EtOAc and saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The obtained residue was purified via ISCO Combiflash chromatography (over silica column, eluting with EtOAc/heptane) to afford 2-adamantan-1-yl-3-methyl-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one (0.821 g) as a white solid. MS (ESI+): 273.0 [M+H]+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19].[C:25]([O:29][CH3:30])(=[O:28])[CH2:26][SH:27].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:19][C:18]1[C:17]2[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])=[CH:23][CH:22]=[CH:21][C:20]=2[S:27][C:26]=1[C:25]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CS
Reactant: N#Cc1c(F)cccc1OCCCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1sc2cccc(OCCCN3C(=O)c4ccccc4C3=O)c2c1N

Procedure:
A mixture of EXAMPLE 14A (0.5 g, 1.54 mmol), methyl thioglycolate (217 μL, 2.31 mmol), and sodium carbonate (653 mg, 6.16 mmol), was heated in methanol (7.7 mL) at 70° C. for 21 hours. The mixture was cooled, diluted with water, and the precipitate filtered and dried. The crude product was purified by flash chromatography on silica gel using a gradient of 0-2% methanol in dichloromethane to provide the title compound as an 85% pure mixture with unreacted EXAMPLE 14A. 1H NMR (DMSO-d6) δ 7.79-7.88 (m, 5H), 7.33-7.44 (m, 2H), 6.97 (s, 1H), 6.86 (dd, J=7.8, 1.0 Hz, 1H), 4.23 (t, J=5.8 Hz, 2H), 3.80 (t, J=6.8 Hz, 2H), 3.77 (s, 3H), 2.17 (quin, J=6.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH:12][CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[S:14](N)(N)(=[O:16])=[O:15]>COCCOCCOC>[CH3:13][N:12]1[C:11]2=[CH:10][C:9]3[C:4]([CH:3]=[C:2]2[NH:1][S:14]1(=[O:16])=[O:15])=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: CNc1cc2ccccc2cc1N
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Product: CN1c2cc3ccccc3cc2NS1(=O)=O
Temperature: 160 °C
Yield: 69.7 %

Procedure:
A solution of 2-amino-3-methylamino-naphthalene (168 mg, 0.98 mmol) and sulfamide (44 mg, 0.98 mmol) in anhydrous diglyme (2 mL) was added dropwise over 5 minutes to a flask heated in a 160° C. oil bath. The reaction mixture was heated at 160° C. for an additional 30 minutes, then cooled to room temperature and evaporated under vacuum. The residue was partitioned between ethyl acetate (20 mL) and 2N hydrochloric acid (10 mL). The organic phase was washed with 2N hydrochloric acid (10 mL) and brine (10 mL), dried over magnesium sulfate, and evaporated under vacuum to afford the title compound (160 mg) as a solid.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16]([CH2:18][C@H:19]([NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:37])=[O:36])[C:20]([N:22]2[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24][CH:23]2[C:29]([O:31]CC)=[O:30])=[O:21])=[O:17])[CH2:9]1)(=[NH:7])[NH2:6].[OH-].[Na+]>>[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:17])[CH2:18][C@@H:19]([C:20]([N:22]2[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24][CH:23]2[C:29]([OH:31])=[O:30])=[O:21])[NH:34][S:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)(=[O:37])=[O:36])[CH2:9]1)(=[NH:6])[NH2:7]
Reactant: CCOC(=O)C1C[C@H](C)CCN1C(=O)[C@H](CC(=O)NC[C@@H]1CCCN(C(=N)N)C1)NS(=O)(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[C@@H]1CCN(C(=O)[C@H](CC(=O)NC[C@@H]2CCCN(C(=N)N)C2)NS(=O)(=O)c2ccc3ccccc3c2)C(C(=O)O)C1

Procedure:
By treating the product from Example 68 with methanolic sodium hydroxide solution there is obtained (2RS,4R)-1-[N4 -[[(S)-1-amidino-3-piperidinyl]methyl]-N2 -(2-naphthylsulfonyl)-L-asparaginyl]-4-methyl-2-piperidinecarboxylic acid (epimers 1:1), FAB-MS: 587 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([CH3:25])[C:19]3=[O:26])[C:11]1=[O:27])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.[CH3:34][C:35](OC(C)=O)=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:35]([O:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([CH3:25])[C:19]3=[O:26])[C:11]1=[O:27])[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])(=[O:36])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CN1Cc2ccc(N3CCO[C@H]([C@@H](O)C(=O)OC(C)(C)C)C3=O)cc2C1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of compound 70-2 (80 mg) in CH2Cl2 (2 ml) at 0° C. was added pyridine (26 μL), Ac2O (30 μl), and DMAP (4 mg). The mixture was stirred for 1 hour at 0° C., warmed to rt, and stirred for an additional 12 h. The mixture was diluted with EtOAc and the organic layer was washed sequentially with sat. aq. CuSO4 solution, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford compound 70-3 (85 mg) as a light yellow semisolid. LC-MS: M+H=419. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[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]>[CH2:1]([O:8][C:9]1[C:10]([C:27]2[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=2[F:25])=[N:11][CH:12]=[C:13]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)c(OCc2ccccc2)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
Under an argon atmosphere, to a solution of 3-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridine (2.53 g) in toluene (20 mL) were added 2-fluoro-5-methoxyphenylboronic acid (1.77 g), tris(dibenzylideneacetone)dipalladium(0) (255 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (457 mg) and 2.0 M aqueous sodium carbonate solution (10.4 ml), and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was filtered through celite, and water was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.81 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2].[Cl:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[O:11][CH2:18][CH2:17][CH2:16][Cl:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1O
Reactant: ClCCCBr
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1OCCCCl
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g, 40 mmol), K2CO2 (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol) and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford 6.5 g of an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel with ethyl acetate as eluent. Concentration of the appropriate fractions afforded 2.8 g of a solid. The solid was recrystallized from toluene and then from ethanol-water to yield 2.2 g (51%) of a solid, m.p.=124°-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:27])[C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(Nc2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N(C)c2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Yield: 66.4 %

Procedure:
Following general procedure F and using 4-[(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 17, 0.043 g, 0.127 mmol), potassium carbonate (0.139 g, 1 mmol) and iodomethane (0.144 g, 1 mmol) in 1 mL of anhydrous N,N-dimethylacetamide, the title compound (0.031 g, 70%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 2H, J=9.0 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.70 (d, 1H, J=2.1 Hz), 6.55 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.20 (s, 2H), 3.24 (s, 3H), 3.01 (heptet, 1H, J=7.0 Hz), 1.28 (t, 3H, J=7.1 Hz), 1.25 (s, 6H), 1.15 (d, 6H, J=7.0 Hz).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[CH:6]=1)C.[OH-].[Na+]>CO>[CH3:24][C:23]1[N:19]([CH2:18][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:30])=[O:3])[CH2:12][CH2:13]2)=[O:29])[N:20]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid ethyl ester (4.35 g, 10.27 mmol) in methanol (50 mL) was added aq. solution of sodium hydroxide (2 M, 7.7 mL, 15.41 mmol) at RT. After stirring 4 h at RT, the solvent was removed, and the residue was dissolved in THF (30 mL), and aq. solution of lithium hydroxide (121 mg in 5 mL of water) was added at RT. After stirring overnight at RT, the solvent was removed and the residue was dissolved in ethylacetate (50 mL) and the reaction mixture was acidified with 2M aq. solution of HCl until pH 1-2. After separation of phases, the aq. layer was re-extracted with ethylacetate (20 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure to give 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (2.40 g, 59%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.45-1.55 (m, 1H), 1.65-1.1.79 (m, 1H), 1.80-1.91 (m, 2H), 2.22 (s, 3H), 2.67-2.78 (m, 1H), 2.89-2.95 (m, 1H), 3.17-3.24 (m, 1H), 3.95-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.21-5.38 (dd, 2H, diastereotopic), 6.50 (s, 1H), 7.47 (t, 1H), 7.55 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H). MS: m/z=396 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][C:12]([F:15])([F:14])[CH3:13])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:19]([O:18][C:16]([N:6]1[CH2:7][CH:8]([CH2:10][CH2:11][C:12]([F:14])([F:15])[CH3:13])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)C1CC(CCC(C)(F)F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)CCC1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 84.5 %

Procedure:
To a mixture of 4-(3,3-difluoro-butyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (92.7 mg, 0.23 mmol, 1 equiv) in THF (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (49 mg, 1.17 mmol, 5 equiv). The reaction mixture was stirred at rt overnight the THF was removed under vacuum. The residue was diluted with water, washed with ether. The aqueous layer was taken up in ethyl acetate, partitioned with 10% citric acid. The organic layer was washed with water (1×), brine (1×), dried and concentrated to give a white solid, 4-(3,3-difluoro-butyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (59.7 mg, 83%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC(C(N)C)=CC=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34][NH2:35])=[CH:30][CH:29]=1>C(Cl)Cl>[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34][NH:35][C:14]2[CH:15]=[C:10]([NH:9][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[N:11]=[CH:12][N:13]=2)=[CH:30][CH:29]=1
Reactant: NCCOc1ccc(F)cc1
Reactant: C[C@H](Nc1cc(Cl)ncn1)c1ccccc1
Agent: CC(N)c1ccc(Cl)cc1
Solvent: ClCCl
Product: C[C@H](Nc1cc(NCCOc2ccc(F)cc2)ncn1)c1ccccc1
Temperature: 150 °C
Yield: 54.2 %

Procedure:
4-[(1S)-(1-phenylethyl)amino]-6-chloropyrimidine, (Intermediate III, Compound of Example 6), (234 mg, 1.0 mmole) and [2-(4-fluorophenoxy)ethyl]amine (357 mg, 2.3 mmole) were combined in a 2 mL pressure vial which was then securely capped. The vial was heated at 150° C. for 20 hours. After cooling, the solid mass was dissolved in CH2Cl2 (25 mL) and extracted with saturated sodium carbonate (25 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from CH2Cl2 (5 mL) to afford the titled compound as a white solid (191 mg, 54%). 1H NMR (CDCl3) δ 1.54 (d, J=6.6 Hz, 3H), 3.54 (q, J=5.5 Hz, 2H), 3.94 (t, J=5.5 Hz, 2H), 4.59 (p, J=6.6 Hz, 1H), 5.05 (broad m, 1H), 5.08 (s, 1H), 5.34 (broad d,1H), 6.77 (m, 2H), 6.95 (t, J=9.1 Hz, 2H), 7.23 (m,1H), 7.32 (d, J=4.4 Hz, 4H), 8.09 (s, 1H), LC/MS (MH+) m/e 353.79 obs.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18]CC)=[O:17])=[CH:10]2>[OH-].[Na+]>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc(Oc3cccc(C(F)(F)F)c3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2cc(Oc3cccc(C(F)(F)F)c3)ccc2[nH]1

Procedure:
Ethyl 5-(3-trifluoromethylphenoxy)indole-2-carboxylate (0.8 g, 2.29 mmol) was hydrolysed in methanolic NaOH (3.2M, 4.0 mL) at reflux, for 1 hr. After work-up the product: 5-(3-trifluoromethylphenoxy)indole-2-carboxylic acid was obtained as an almost white solid, 0.73 g (ca 100%).
Reaction SMILES: CO[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15](SC)[C:4]=1[C:5]([NH:7]C1CCCCC1=O)=[O:6].C(O)(=O)C.N1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[F:20][C:19]([F:21])([F:22])[C:17]1[CH:18]=[CH:3][C:4]([C:5]([NH2:7])=[O:6])=[CH:15][CH:16]=1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
2-Methoxy-6-methylsulfanyl-N-(2-oxo-cyclohexyl)-4-trifluoromethyl-benzamide (intermediate B, 380 mg, 1.05 mmol) was dissolved in 10 mL tetrahydrofurane. Acetic acid (145 mg, 2.4 mmol) and pyrrolidine (97 mg, 1.4 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (290 mg, 1.4 mmol) was added and stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-2-methoxy-6-methylsulfanyl-N-2-pyrrolidin-1-yl-cyclohexyl)-4-trifluoromethyl-benzamide as a light yellow solid (125 mg, 28%), MS: m/e=417.3 [(M+H)+] and trans-2-methoxy-6-methylsulfanyl-N-2-pyrrolidin-1-yl-cyclohexyl)-4-trifluoromethyl-benzamide as a light yellow solid (28 mg, 6%), MS: m/e=417.3 [(M+H)+].