Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:17])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH:4]=[O:17])=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)CCC(C)(C)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CCC=O)c1ccc(F)cc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-fluoro-phenyl)-4-methyl-pentanoic acid methoxy-methyl-amide (3.90 g) in tetrahydrofuran (70 ml) at −30° C. was added dropwise over 10 min a suspension of lithium aluminum hydride in tetrahydrofuran (15.4 ml, 1 M suspension). The mixture was stirred for a further 30 min at −30° C. and then cooled to −78° C. The mixture was quenched by dropwise addition of acetone (25 ml) and the mixture was then allowed to warm to room temperature. The mixture was then diluted with water and taken up in ethyl acetate. The mixture was washed sequentially with 1 N aq. hydrochloric acid and with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield a colourless oil, (1.62 g, 54%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH:9]([OH:13])[C:10]([OH:12])=[O:11]>>[C:1]([O:13][CH:9]([C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([Br:5])[CH:7]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=C(O)C(O)c1cccc(Br)c1
Reactant: CC(=O)Cl
Product: CC(=O)OC(C(=O)O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl Chloride (1.5 mL) was added to 3-bromomandelic acid 1 (1.00 g, 4.33 mmol) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to provide compound 2 which was used in the next reaction without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:31]=[N:32][C:33]([NH:36][C:37]([NH:39][CH:40]4[CH2:42][CH2:41]4)=[O:38])=[CH:34][CH:35]=3)[CH:21]=2)=[CH:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=O)C.[OH-].[Na+]>CO>[CH:40]1([NH:39][C:37](=[O:38])[NH:36][C:33]2[N:32]=[CH:31][C:30]([O:29][C:26]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:21]=[C:20]([C:17]5[N:16]=[CH:15][C:14]([CH2:13][N:8]([CH2:9][CH2:10][O:11][CH3:12])[C:6](=[O:7])[CH2:5][OH:4])=[CH:19][CH:18]=5)[S:28][C:27]=34)=[CH:35][CH:34]=2)[CH2:41][CH2:42]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 30 (from the previous step) in MeOH/THE (15/5 mL) was added 1N NaOH (2.6 mL). The reaction mixture was stirred at RT overnight, concentrated and diluted with water. The resultant suspension was shaken for 15 min. The solid was collected by filtration, rinsed with water and air-dried. The residue was purified by Biotage (SiliaSep 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV) to produce a material that upon trituration with methanol afforded the title compound 31 (79 mg, 0.144 mmol, 72% over 2 steps) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 9.23 (bs, 1H), 8.56-8.49 (m, 2H), 8.38-8.20 (m, 3H), 7.84-7.70 (m, 3H), 7.66 (bd, J=9.0 Hz, 1H), 6.73-6.67 (m, 1H), 4.82-4.57 (m, 3H), 4.23 and 4.13 (2d, J=6.0 Hz, 2H), 3.52-3.39 (m, 4H), 3.23-3.21 (2s, 3H), 2.65-2.57 (m, 1H), 0.74-0.60 (m, 2H), 0.53-0.37 (m, 2H). MS (m/z): 549.6 (M+H).
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4]([O-:6])=[O:5].Br[CH:12]([CH2:14][CH2:15][CH2:16][CH3:17])[CH3:13]>C(O)C>[CH3:13][CH:12]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCCCC(C)Br
Agent: [Na]
Solvent: CCO
Product: CCCCC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
Under argon atmosphere, to a solution of sodium metal (70.6 g, 3.07 mol) in absolute ethanol (900 ml) was added ethyl malonate (510 g, 3.18 mol) with stirring. Further, 2-bromohexane (475 g, 2.88 mol) was added dropwise gradually and, after sodium bromide was precipitated, in such a rate that ethanol was slowly refluxed. After addition reflux was continued for 4 hours. After cooling the mixture to room temperature 50% aqueous potassium hydroxide solution (843 g) was added dropwise and the reaction mixture was refluxed for 5 hours. Ethanol was distilled off and the residue was neutralized with concentrated hydrochloric acid (600 ml). The resulting solution was then extracted with ether (one liter×3) and the extracts were dried over anhydrous sodium sulfate. After concentration, the residue was heated at 130° C. for 2 hours and at 180° C. for 2.5 hours. The distillation of the residue under reduced pressure gave dl-3-methylheptanoic acid (310 g, 2.15 mol, 75%, b.p.: 124°-125° C./25 mmHg).
Reaction SMILES: C(OC([N:8]1[C:12]([CH3:32])([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[NH2:8][C:12]([C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=2)=[CH:16][N:17]=1)([CH3:32])[CH2:11][OH:10]
Reactant: CCCCCCCCc1ccc(-c2cnc(C3(C)COC(C)(C)N3C(=O)OC(C)(C)C)[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCCCCCCc1ccc(-c2cnc(C(C)(N)CO)[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a flame dried round bottom flask equipped with a magnetic stirbar under an inert atmosphere was added 6 (973 mg, 2.07 mmol) followed by MeOH (20 mL) and p-TsOH.H2O (1.22 g, 6.42 mmol). This mixture was then heated to reflux, stirred 3 hours, cooled to 0° C., and quenched by slow addition of saturated aqueous NaHCO3 (20 mL). This solution was then diluted with EtOAc (30 mL) and the aqueous layer was discarded. The organic phase was washed with saturated aqueous NaHCO3 (1×20 mL), washed with 1M NaOH (1×20 mL), dried over sodium sulfate, and concentrated to an orange oil. To this oil was added Et2O which produced VPC24241 (408 mg, 60%) as a white precipitate which was collected by filtration.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:28])[CH3:27])[CH:23]=4)[N:18]([CH3:33])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(O[Si](C)(C)C(C)(C)C)cc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(O[Si](C)(C)C(C)(C)C)cc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
In a round-bottomed flask, 2-[5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (100 mg, 0.168 mmol) was dissolved in dichloromethane (0.8 ml) and trifluoroacetic acid (0.52 ml, 6.75 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.8 ml) and ethylenediamine (0.68 ml, 10.1 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate to afford 55 mg (70%) of 2-[5-(tert-butyl-dimethyl-silanyloxy)-1-methyl-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.CO.Cl>CCO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH2:10])=[C:4]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: COC(=O)COc1cc(N)nc(C)c1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)COc1cc(N)nc(C)c1CN
Reaction time: 48 h

Procedure:
Methyl 2-(6-amino-3-cyano-2-methylpyridin-4-yloxy)acetate (215 mg, 0.972 mmol) was dissolved in EtOH (16 ml), MeOH (8 ml) and HCl 1M (5 ml), then Palladium on carbon (310 mg, 0.292 mmol) was added and the reaction mixture was stirred at it under H2 pressure during 48 h. After filtration over celite, washing with MeOH and evaporation of the solvent, the title compound was obtained. MS (Method D): [M+H]+226.0/451.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2)=[NH:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:19]=[C:18]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)[N:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: N=C(NO)c1ccc2[nH]ccc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1OCC
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a solution of 3,4-diethoxybenzoic acid (0.11 g; 0.52 mmol), and the product of Example 7, Step C (0.09 g; 10.52 mmol) in anhydrous THF (2 ml), PyBroP (0.25 g; 0.53 mmol) was added, followed by DIPEA (0.21 ml; 1.2 mmol), with stirring, at room temperature under N2. After overnight stirring, the mixture was diluted to 15 ml with EtOAc, washed with saturated NH4Cl (3×5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2, EtOAc) to give the coupling product. This was suspended in anhydrous toluene (3 ml) and 1M TBAF was added. The resulting mixture was refluxed for 1 h under N2, cooled to room temperature and diluted to 15 ml with EtOAc, washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness. The residue was purified by crystallization from MeOH, to give the title compound (0.096 g; 53%), as a colourless solid. 1H-NMR (CDCl3) 1.5 (m, 6H); 4.19 (m, 4H); 6.66 (s, 1H); 6.98 (d, 1H, J=8.4 Hz); 7.26 (m, 1H); 7.47 (d, 1H, J=8.5 Hz); 7.71 (d, 1H, J=1.8 Hz); 7.8 (dd, 1H, J=1.8, 8.5 Hz); 8.0 (dd, 1H, J=1.3, 8.5 Hz); 8.37 (broad s, 1H); 8.5 (s, 1H).
Reaction SMILES: [C:1]([C:6]1[C:7]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.[C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH3:28]>>[OH:5][C:1]([C:6]1[C:7]([NH:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[N:8][CH:9]=[CH:10][CH:11]=1)([CH:2]([CH3:4])[CH3:3])[CH2:28][C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)c1cccnc1NC(=O)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)C(O)(CC(=O)OC(C)(C)C)c1cccnc1NC(=O)C(C)(C)C

Procedure:
A solution of N-(3-isobutyrylpyridin-2-yl)pivalamide (3.10 g, 12.5 mmol), LDA (1.5 M, 17.50 mL, 2.1 eq) and t-butyl acetate (3.5 mL, 2.1 eq) were reacted as outlined in Scheme 1 to give tert-butyl 3-hydroxy-4-methyl-3-(2-pivalamidopyridin-3-yl)pentanoate which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([O:11][CH2:10][C@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]1[O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:43])=[O:42]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]([C@@H](C=O)OCc3ccccc3)O[C@@H]2S1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@H](COS(C)(=O)=O)OCc3ccccc3)O[C@@H]2S1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of 102 (1.2 g, 2.2 mmol) (Prepared according to the synthesis of Examples 151 and 152, step 1) in dichloromethane (30 mL) was added TEA (664 mg, 6.6 mmol) and MsCl (499 mg, 4.4 mmol) at 0° C. After kept 2 hours at room temperature, the reaction was quenched by water (100 mL) and extracted with dichloromethane (3×30 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrates were concentrated to give a residue, which was purified by silica gel column with 10%-30% ethyl acetate in petroleum ether to give the title compound (1.1 g, 80%) as brown syrup; (ES, m/z): [M+H]+ 627.0; 1H NMR (300 MHz, CDCl3) δ 7.22-7.45 (m, 15H), 6.35 (d, J=6.3 Hz, 1H), 5.03-5.15 (m, 2H), 4.61-4.80 (m, 4H), 4.47-4.53 (m, 2H), 4.25-4.36 (m, 1H), 4.08-4.12 (m, 1H), 3.89-3.92 (m, 1H), 3.46-3.78 (m, 2H), 3.06 (s, 6H), 3.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][C:3]=1[F:24].[NH3:25]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:25])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][C:3]=1[F:24]
Reactant: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C21N=C(C)C(=S)N1
Reactant: N
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C21N=C(C)C(N)=N1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
6′-Bromo-5′-fluoro-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 14, 0.500 g, 1.22 mmol) and ammonia (7 M in MeOH) (16.5 mL, 115 mmol) were mixed in a MW vial. The vial was sealed and the reaction was heated at 100° C. for 30 min in a MW reactor (fixed hold time). The mixture was concentrated and the residue was dissolved in new ammonia (7 M in MeOH) (16.5 mL, 115 mmol) and heated once more at 100° C. for 30 min in a MW reactor. 4 cycles of concentration, addition of ammonia and heating were performed in total. After evaporation of the solvent, the residue was partitioned between EtOAC and 2 M citric acid (10 mL). The phases were separated and the organic layer was re-extracted with 2 M citric acid (10 mL). The organic layer was discarded while the combined aqueous phases were basified to pH 12 by addition of 50% aq. NaOH and then extracted with EtOAc. The combined organic layers were dried over magnesium sulfate and concentrated, to give the title compound (0.354 g, 74% yield) as a diastereomer mixture in the ratio ˜4:1 (established by HPLC). 1H NMR (500 MHz, DMSO-d6, contains both isomers) δ ppm 0.88-0.99 (m, 1 H) 1.09-1.28 (m, 4 H) 1.32-1.52 (m, 3.8 H) 1.58-1.72 (m, 1 H) 1.81 (d, 2 H) 2.16 (s, 3.8 H) 2.88-3.07 (m, 3.7H) 3.12 (s, 0.8 H) 3.18 (s, 3 H) 6.60 (br. s., 2.6 H) 6.75 (d, 1.21 H) 7.32 (d, 1.26 H); MS (ES+) m/z 394, 396 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:18]=2)[N:13]=1)([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2[C:49]([F:52])([F:51])[F:50])N=1)(C)CO.C(O)(C(F)(F)F)=O>>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[C:18]=2[C:49]([F:52])([F:51])[F:50])[N:13]=1)([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC(C)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
{1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-2-hydroxy-1-methyl-ethyl}-carbamic acid tert-butyl ester Enantiomer 1 was synthesized as per {1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-2-hydroxy-1-methyl-ethyl}-carbamic acid tert-butyl ester Enantiomer 1 (Example 28) in 95% yield using 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propan-1-ol Enantiomer 1 as starting material (bis-TFA salt).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.O.[OH-].[Na+]>C(O)(C)C>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: ClCc1csc(-c2ccc(Cl)cc2)n1
Temperature: 20 °C
Reaction time: 10 h

Procedure:
171.65 g (1.0 mol) of 4-chlorothiobenzamide are dissolved in 550 ml of isopropyl alcohol and 133.3 g (1.05 mol) of 1,3-dichloroacetone are added at a temperature of a maximum of 30° C. over a period of 3hours. The mixture is subsequently stirred at 40° C. for 5.5 hours and at 20° C. for 10 hours. In order to complete the reaction the mixture is then heated to 55° C. for 7.5 hours. The product is isolated by cooling to 10° C. and adding 950 ml of water. The pH value is adjusted to 4 to 5 using sodium hydroxide solution and the product is filtered off with suction.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)Nc1ccccc1C(=O)Nc1cccnc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCCNC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 83.8 %

Procedure:
Step 1): A mixture of 2-(N'-n-heptylureido)-N-(pyridin-3-yl)benzamide obtained in the Example 34 (5.0 g, 14 mmol) and PtO2 in acetic acid (70 ml) was stirred at 40° C. under hydrogen atmosphere (50 psi) for 17 hours and then filtered. The filtrate was neutralized with 30% NaOH solution, extracted with ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (20% methanol and 0.8% NH4OH in dichloromethane) to give 2-(N'-n-heptylureido)-N-(piperidin-3-yl)benzamide (83.8%): mp 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[N:10]([CH3:17])[N:9]=1.[I:18](O)(=O)=O.II>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([I:18])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[N:10]([CH3:17])[N:9]=1
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)Nc1cc(-c2ccccc2Cl)nn1C
Agent: II
Solvent: CCO
Product: CC(=O)Nc1c(I)c(-c2ccccc2Cl)nn1C
Temperature: 50 °C
Reaction time: 18 h
Yield: 379.8 %

Procedure:
To a solution of N-(3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)acetamide (526 mg, 2.12 mmol) in ethanol (16 mL) were added iodic acid (93 mg, 0.53 mmol) and iodine (294 mg, 1.16 mmol). The reaction was stirred for 18 h at 50° C. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with a 2 N Na2SO3 solution. The organic phase was dried over MgSO4, filtered and evaporated to give N-(3-(2-chlorophenyl)-4-iodo-1-methyl-1H-pyrazol-5-yl)acetamide as a light orange solid (756 mg), which was used as such in the subsequent step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=1.Br[C:13]1C=CC(C=C)=C(CC)C=1.B1C2CCCC1CCC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH2:11][CH3:13])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CCO
Reactant: C=Cc1ccc(Br)cc1CC
Agent: B1C2CCCC1CCC2
Product: CCc1cc(Br)ccc1CCO
Yield: 81 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 36A (1.98 g, 5.1 mmol) was heated in a pressure vessel with 9-BBN at 100° C. for 15 h to yield 36B (0.95 g, 81%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.58 Hz, 3 H) 2.66 (q, J=7.58 Hz, 2 H) 2.87 (t, J=6.82 Hz, 2 H) 3.83 (t, J=6.82 Hz, 2 H) 7.06 (d, J=8.08 Hz, 1 H) 7.25-7.31 (m, 1 H) 7.32-7.37 (m, 1 H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]1([C:14]#[N:15])[CH2:13][CH2:12]1.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[C:14]([C:11]1([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)#[N:15]
Reactant: N#CC1CC1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2(C#N)CC2)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Solid KHMDS (6.82 g, 34.3 mmol) is dissolved in THF (60.0 mL) and cooled to −40° C. Cyclopropanecarbonitrile (2.30 g, 34.3 mmol) is added, and the resulting solution is stirred for 30 minutes. A solution of 4-fluorobenzonitrile (4.15 g, 34.3 mmol) in THF (20.0 mL) is added, and the mixture is stirred for 20 minutes at −40° C. followed by 2 hours at room temperature. A saturated solution of NaHCO3 (50.0 mL) is added, and the aqueous phase is extracted with EtOAc (4×40.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 70% EtOAc) (743 mg, 4.42 mmol, 13%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.60-1.67 (m, 2H) 1.84-1.90 (m, 2H) 7.49 (d, J=8.59 Hz, 2H) 7.85 (d, J=8.79 Hz, 2H).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:19][C:20]1[S:24][C:23]([C:25](OCC)=[O:26])=[CH:22][CH:21]=1.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:25]([C:23]1[S:24][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:26])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 68 %

Procedure:
A 0.25M THF solution of tert-butyl acetate (2.90 g, 25 mmol) is added dropwise to a cold (−78° C.) solution of potassium bis(trimethylsilyl)amide (100 ml of a 0.5M toluene solution) and ethyl 5-chlorothiophene-2-carboxylate (Lancaster)(4.77 g, 25 mmol) in 50 ml of THF. The reaction is allowed to warm to 0° C. over one hour. After stirring an additional hour at 0° C., the reaction is poured into 100 ml of a 1M HCl solution. The organic layer is extracted with brine and evaporated in vacuo. The crude residue is purified by flash column chromatography eluting with 5% ethyl acetate/hexane to provide the product (4.54 g, 17 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7,53 (d, 1H), 6.98 (d, 1H), 3.78 (3, 2H), 1.50 (s, 9H).