Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16](OC)(=[O:27])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C[O-].[Na+].Cl>O.CN(C)C=O>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([C:16](=[O:27])[CH2:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:15])=[CH:18][CH:19]=1)=[O:22]
Reactant: CCCCCOc1ccc(C(C)=O)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.6 %

Procedure:
Dimethylformamide (600 ml), p-pentyloxyacetophenone (60.0 g) and dimethyl terephthalate (73.5 g) were charged in 1-liter three-necked flask and stirred. To this mixture was added 28% methanolic solution (84.2 g) of sodium methoxide and, after that, a reaction was carried out at the inner temperature of 35 to 40° C. for 48 hours. After completion of the reaction, the reaction solution was added to a mixed solution of water (3,000 ml) and 1N hydrochloric acid (600 ml) to separate the crystals. The mixture was stirred at room temperature for 1 hour, and then the separated crystals were filtered. The wet crystals and methanol (1,000 ml) were charged in a 2-liter three-necked flask, heated to reflux for 2 hours and cooled down to room temperature, and the crystals were filtered. The crystals were washed with methanol (200 ml). The crystals were dried overnight in vacuo to give 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)-propane-1,3-dione (66.0 g).
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].Br[C@H:7]([CH3:11])[C:8]([OH:10])=[O:9].O.C(O)(=O)C>CCO>[C:2]([S:5][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:1]
Reactant: C[C@@H](Br)C(=O)O
Reactant: CC(C)(C)S
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@H](SC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 483 mg of Na in 10 mL of EtOH was added 10 mL of tert-butylthiol with stirring at room temperature under nitrogen. After 10 min a solution of 1.53 g of (2R)-2-bromopropanoic acid in 3 mL of EtOH was added and the stirring was continued at room temperature for 3 h. The reaction mixture was poured into water and was acidified with acetic acid and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and was evaporated under water aspirator vacuum using a trap containing bleach to give 1.48 g of (2S)-2-(tert-butylthio)propanoic acid as an oil at 92% yield. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ3.44 (q, J=7 Hz, 1H), 1.49 (d, J=7 Hz, 3H), 1.37 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].[OH-].[Na+]>ClCCl>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1)=[O:33]
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(=O)c2ccc3ccccc3c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.0 g (20.7 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 2.1 g (20.7 mmol) TEA are dissolved in 30 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 3.95 g (20.7 mmol) 2-naphthoyl chloride are dissolved in 40 ml absolute dichloromethane and added dropwise under ice cooling. The mixture is stirred for two hours at RT without further cooling. Subsequently, the batch is made alkaline with 10% sodium hydroxide solution and washed twice with a small amount of water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatographically purified over silica gel with CHCl3/CH3OH (96/4). Yield of colorless resin 5.4 g (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:36]1[CH2:41][CH2:40][CH2:39][C@H:38]([O:42][C:43]2[C:44]3[CH:51]=[CH:50][NH:49][C:45]=3[N:46]=[CH:47][N:48]=2)[CH2:37]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[N:46]1[C:45]2[NH:49][CH:50]=[CH:51][C:44]=2[C:43]([O:42][C@H:38]2[CH2:39][CH2:40][CH2:41][N:36]([C:11](=[O:13])[CH2:10][NH:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:37]2)=[N:48][CH:47]=1
Reactant: O=C(O)CNc1cc(F)cc(Cl)c1
Reactant: c1nc(O[C@H]2CCCNC2)c2cc[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CNc1cc(F)cc(Cl)c1)N1CCC[C@H](Oc2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a cooled solution of 2-(3-chloro-5-fluorophenylamino)acetic acid (139 mg, 0.68 mmol) at 0° C. in DMF (5 mL) was added HOBt (136 mg, 0.10 mmol), EDCI (197 mg, 0.10 mmol), (S)-4-(piperidin-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (150 mg, 0.7 mmol) and Et3N (0.2 mL, 1.37 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3×20 mL). The combined EtOAc layer was dried over Na2SO4 and concentrated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (45 mg, 17%) the titled compound. 1H NMR (400 MHz, DMSO-d6): δ 12.08 and 12.05 (2s, 1H), 8.41 and 8.39 (2s, 1H), 7.35 (s, 1H), 6.62-6.25 (m, 4H), 5.39-5.24 (m, 1H), 4.05-3.62 (m, 5H), 3.55-3.42 (m, 2H), 1.89-1.45 (m, 4H). LC-MS: m/z [M+1]=404.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([O:23][CH3:22])[CH:28]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: COc1cc(CN)on1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)on1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (120 mg, 0.4 mmol) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) (60.16 mg, 0.47 mmol) as starting materials; off white solid (32 mg, 19.6%). MS (ESI): 414 (M+H)+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH:20]=[CH2:21].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH:20]1[O:9][CH2:21]1
Reactant: C=CCc1ccccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccccc1CC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
MCPBA (826 mg, 3.83 mmol) was added portionwise to an ice-cold solution of 2-chloro-1-allylbenzene (487 mg, 3.19 mmol) in CH2Cl2 (20 mL). The mixture was stirred at room temperature for 16 h. Aqueous 10% Na2CO3 solution (10 mL) and CH2Cl2 (100 mL) were added. The solution was successively washed with aqueous 10% Na2S2O3 (2×40 mL) and brine (40 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 8:2) to give the title compound (512 mg, 95% yield).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CI>O1CCCC1.O.C(OCC)C.CCCCCC>[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([CH3:1])[C:15]=1[C:16]([OH:18])=[O:17]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1c(F)c(F)c(C)c(C(=O)O)c1F
Reaction time: 0.25 h

Procedure:
70 ml of 1.69M n-hexane solution of n-butyllithium was added dropwise to solution of 18 ml of diisopropylamine in 75 ml of tetrahydrofuran at −65 ° C. under nitrogen stream, and the mixture was stirred at the same temperature for 15 minutes. To the solution was added dropwise solution of 9.5 g of 2,4,5-trifluoro-3-methylbenzoic acid in 75 ml of tetrahydrofuran at −60° C., and the mixture was stirred at the same temperature for 15 minutes. To the solution was added dropwise 9.5 ml of methyl iodide at −70° C., and the mixture was stirred at the same temperature for 30 minutes and overnight at room temperature. Diethylether and water were added for separation, and the aqueous layer was collected. The aqueous layer was acidified by adding conc. hydrochloric acid, and extracted with diethylether. The organic layer was dried over ahnydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C[O:12][C:13](=[O:42])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:31]1[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=1[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:42])=[O:12])=[C:17]([CH3:41])[CH:18]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccccc1F
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3F)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-fluorophenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 132 mg (68%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H22O4F4 510, found 511 (M+1, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@:32]12([CH2:42][S:43](O)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]>CC(C)=O.CO>[C@@:32]12([CH2:42][S:43]([O:22][C@@:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([C@H:14]([C:11]3[S:12][CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=3)[CH3:31])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: CC(C)=O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OS(=O)(=O)C[C@@]12CCC(CC1=O)C2(C)C)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (10 g) in acetone (ca. 200 ml) a solution of (1R)-10-camphorsulfonic acid (3.9 g) in methanol (50 ml) was added and the mixture was heated shortly under reflux until a clear solution was obtained. The solution was then slowly cooled to rt, seeded with crystals of the desired enantiomeric salt and let overnight. The solid precipitate was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This salt was then taken up in methylenechloride and water and basified with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride. The organic phases were combined, dried with sodium sulphate, filtrated and the solvent removed under reduced pressure. The crude product was then dissolved in ethanol, the slurry heated for 20 min, small amount of water was added, the solution slowly cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with cold ethanol and dried under reduced pressure to provide the title enantiomerically pure compound (3.9 g, 39% yield, 96% ee). The analytical date were identical with published in U.S. Pat. No. 6,300,353 B1 and WO 99/45008.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])=[O:6].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:18][O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:5]([N:4]1[CH2:3][CH2:2][O:1][C:21]1([CH3:23])[CH3:22])=[O:6]
Reactant: COc1ccc2ccccc2c1C(=O)NCCO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ccccc2c1C(=O)N1CCOC1(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Example 175A in anhydrous N,N-dimethyl formamide (10 mL) was added 2,2-dimethoxypropane (0.62 mL, 5.0 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol). The resulting mixture was stirred under a N2 atmosphere at 60° C. for 16 h. Additional 2,2-dimethoxypropane (0.3 mL, 2.4 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) were added, and the mixture was stirred at 60° C. for 6 h. The mixture was partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (3×50 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using a solvent gradient of 50-65% ethyl acetate in hexane. The title compound was obtained as a colorless, crystalline solid (0.44 g, 62% for two steps). 1H NMR (300 MHz, CDCl3) δ 1.83 (s, 3 H), 1.88 (s, 3 H), 3.13 (m, 1 H), 3.40 (m, 1 H), 3.92 (m, 2 H), 3.98 (s, 3 H), 7.28 (m, 1 H), 7.37 (m, 1 H), 7.49 (m, 1 H), 7.71 (m, 1 H), 7.80 (m, 1 H), 7.86 (m, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][P:16]([CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])([O:20][CH2:21][CH3:22])=[O:23])[CH3:19]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1c(C)oc2c([N+](=O)[O-])cccc12)OCC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (226 mg) and triethyl phosphite (0.52 ml) was stirred at 100° C. for 6 hours. The reaction mixture was cooled and concentrated in vacuo and to the residue was added toluene. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from diisopropyl ether to give 3-(diethoxyphosphorylmethyl)-2-methyl-7-nitrobenzo[b]furan (93 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])=[CH:13][N:12]=1)[CH3:2]>CO.[Pd]>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:13][N:12]=1)[CH3:10]
Reactant: CCC=C(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OC

Procedure:
A mixture of 2-(2,6-diethyl-phenyl)-4-methoxy-5-(1-propyl-but-1-enyl)-pyridine (20 mg) and 10% Pd/C (20 mg) in MeOH (1 mL) is hydrogenated at 50 psi overnight. The mixture is filtered through celite and washed with MeOH. The filtrate is concentrated to give 2-(2,6-diethyl-phenyl)-4-methoxy-5-(1-propyl-butyl)-pyridine. 1H NMR (CDCl3) 8.29 (s, 1H), 7.26 (d, 1H), 7.13 (d, 2H), 6.71 (s, 1H), 3.81 (s, 3H), 3.00 (m, 1H), 2.37 (m, 4H), 1.65 (m, 4H), 1.23 (m, 4H), 1.07 (t, 6H), 0.86 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].I[C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.[Cu]I.N[C@@H]1CCCC[C@H]1N>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cc[nH]n2)cc1Br
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccn(-c3cccc(C(F)(F)F)c3)n2)cc1Br
Temperature: 100 °C

Procedure:
To a stirred solution of 3-(3-bromo-4-methylphenyl)-1H-pyrazole (i.e. the product of Step B) (5.0 g, 21.09 mmol) in p-dioxane (19 mL) under a nitrogen atmosphere was added 3-iodobenzotrifluoride (5.75 g, 21.11 mmol), copper(I) iodide (0.05 g, 0.262 mmol), trans-1,2-diaminocyclohexane (253.5 μL, 2.10 mmol) and potassium carbonate (6.1 g, 44.14 mmol). The reaction mixture was heated at 100° C. overnight, cooled to room temperature and diluted with water and ethyl acetate. The resulting mixture was separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with hydrochloric acid (1N), saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide a solid (9 g). Hexanes were added to the solid, and the mixture was filtered to obtain the title compound as a solid (6.4 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Na][Na].[SH:16][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[C:18]([OH:20])=[O:19]>C(O)CCC>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:16][C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH3:21])[C:18]([OH:20])=[O:19])[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: CCOc1ccc2nc(Cl)sc2c1
Reactant: CC(S)(C(=O)O)c1ccccc1
Agent: [Na][Na]
Solvent: CCCCO
Product: CCOc1ccc2nc(SC(C)(C(=O)O)c3ccccc3)sc2c1
Reaction time: 4 h

Procedure:
A mixture of 21.4 g of 2-chloro-6-ethoxybenzothiazole, 22.6 g of the disodium salt of 2-mercapto-2-phenylpropionic acid and 200 ml of n-butanol is boiled for 4 hours and is evaporated and worked up in the customary manner to give 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid, m.p. 152°-153°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[C:32]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:39]3[CH:40]=[CH:41][C:36]([NH:35][C:32](=[O:34])[CH3:33])=[CH:37][CH:38]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 22.6 %

Procedure:
To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (3.5 ml), ethanol (1.75 ml) and water (1.75 ml), 4-Acetamidophenyl boronic acid (0.237 g, 1.32 mmoles) and sodium carbonate (0.211 g, 1.99 mmoles) were added and the system is degassed for 30 min Palladium tetrakis triphenylphosphine (0.038 g, 0.033 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.080 g, 24% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 10.12(s,1H), 8.06(s,1H), 8.04(dd, J=8.0,1.4 Hz, 1H), 7.85(m,1H), 7.74(d, J=8.5 Hz, 2H), 7.68(d, J=8.2 Hz, 1H), 7.58(m,3H), 7.32(m,1H), 7.06(dt, J=8.2,2.4 Hz, 1H), 6.82(m,2H), 6.02(q, J=7.0 Hz, 1H), 2.06(s,3H), 1.89(d, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1
Product: CCOC(=O)CNc1ccccc1
Reaction time: 18 h
Yield: 70 %

Procedure:
To a 250 mL round-bottom flask equipped with addition funnel and argon inlet was added 50 mL of aniline III which was stirred mechanically at 0° C. under argon atmosphere Ethyl bromoacetate, 25 mL (224 mmol) was added in dropwise fashion over 60 min. The mixture slowly solidified and was allowed to stand unstirred at -25° C. for 18 hours. The solid was chipped from the flask and partitioned between dichloromethane (CH2Cl2) and water. The aqueous layer was made basic with 20 mL 50 NaOH solution and extracted with CH2Cl2. The combined organic layers were washed well with H2O, dried over MgSO4 and concentrated. The residue was crystallized from hexane containing a trace of CH2Cl2. Total yield was 28 g (156 mmol, 70% yield) based on ethyl bromoacetate used. mp. 54°-55° C., 'H-NMR (CDCl3) ppm δ7.19 (t, 2 H, J= 7 Hz), 6.76 (t,1 H, J=7 Hz), 6.60 (d, 1 H, J=7 Hz), 4.24 (q, 2 H, J=7 Hz), 3.89 (S,2 H), 1.29 (t, 3 H, J=7 Hz; IR (KBr) 3420, 1742, 1610, 1520, 1220 cm-1.
Reaction SMILES: [CH:1]1([C:4]2[N:5](COCC[Si](C)(C)C)[N:6]=[C:7]3[C:12]=2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]3[CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH:1]1([C:4]2[C:12]3[C:7](=[C:8]([CH2:17][O:18][CH2:19][C:20]4([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(C4CC4)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]nc(C3CC3)c2c1

Procedure:
tert-Butyl 4-(((3-cyclopropyl-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (18 mg, 0.03 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 9 mg (77%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.92 (s, 1H), 7.31-7.45 (m, 5H), 7.22-7.33 (m, 1H), 4.67 (s, 2H), 3.52 (s, 2H), 2.95-2.99 (m, 2H), 2.76-2.81 (m, 2H), 2.15-2.24 (m, 3H), 1.89-1.95 (m, 2H), 1.04-1.02 (m, 4H). Mass spec.: 430.16 (MH)+. Accurate mass spec.: m/z 430.2097 [MH]+, Δ=2.1 ppm.