Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:44])([Cl:43])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:42])[C@@H:14]([NH:34][C:35](OC(C)(C)C)=[O:36])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[C:66]([O:70][C:71]([NH:73][C@H:74](C(O)=O)[CH:75]([CH3:77])[CH3:76])=[O:72])([CH3:69])([CH3:68])[CH3:67].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]([Cl:44])([Cl:43])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:42])[C@@H:14]([NH:34][C:35](=[O:36])[C@@H:74]([NH:73][C:71]([O:70][C:66]([CH3:68])([CH3:67])[CH3:69])=[O:72])[CH:75]([CH3:77])[CH3:76])[CH2:15][O:16][Si:17]([C:30]([CH3:32])([CH3:31])[CH3:33])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To (S)-1-[(S)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.0 g, 1.46 mmol) in anhydrous dichloromethane (25 mL) at 0° C. and under an atmosphere of nitrogen was added trimethylsilyl trifluoromethanesulfonate (400 μL, 2.19 mmol). The reaction mixture was stirred at 0° C. for 2 h before adding N,N-diisopropylethylamine (1.0 mL, 5.84 mmol) and concentrating in vacuo. The residue was dissolved in anhydrous acetonitrile (15 mL) at room temperature and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (763 μL, 4.38 mmol), N-(tert-butoxycarbonyl)-L-valine, (317 mg, 1.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (777 mg, 2.04 mmol). Following 2 h at room temperature the reaction was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 2:1 to give the title compound (500 mg, 44%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 0.88-1.00 (m, 6H), 1.07 (s, 9H), 1.48 (s, 9H), 1.50-1.70 (m, 2H), 1.78-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.10-2.25 (m, 1H), 2.81-3.02 (m, 1H), 3.15-3.30 (m, 1H), 3.60 (d, J=10.7 Hz, 1H), 3.95 (br d, J=3.6 Hz, 2H), 3.98-4.06 (m, 1H), 4.19-4.30 (m, 1H), 4.59 (d, J=12.0 Hz, 1H), 4.90 (d, J=12.0 Hz, 1H), 5.10-5.20 (m, 1H), 5.36-5.47 (m, 1H), 6.77-6.88 (m, 1H), 7.36-7.50 (m, 6H), 7.56-7.70 (m, 4H). LCMS (m/z)=785.3 [M+H], Tr=4.25 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:2]=1>C(O)(C)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:2]=1
Reactant: OCCCCC#Cc1cccnc1
Agent: [Pd]
Solvent: CC(C)O
Product: OCCCCCCc1cccnc1

Procedure:
3-Pyridinehexanol was prepared by hydrogenation of 20.0 g of the crude 6-(3-pyridinyl)-5-hexyn-1-ol, prepared above in Example 105, dissolved in 200 ml of isopropyl alcohol over 2.0 g of 10% palladium on carbon at 1 atmosphere. The crude product obtained after filtration of the catalyst and evaporation of the solvent was evaporatively distilled to yield 15.8 g (89%) of 3-pyridinehexanol as a yellow oil, bp 120°-150° C./0.2 mm which was 90% pure by gas chromatography analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C@H:10]([CH3:22])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from Example 1, Step A (2.2 g, 7.33 mmol) in THF (30 mL) was added lithium hexamethyldisilazide (16.0 mL, 1M in THF, 16.0 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 min. Iodomethane (2.8 mL, 45.0 mmol) was then added. After stirring at −78° C. for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (30:70 hexanes/ethyl acetate) afforded the desired product (major diastereoisomer from the reaction).
Reaction SMILES: C(S([CH2:8][CH2:9][CH2:10][CH:11]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=O)(=O)=O)CCC.[OH-].[K+].CS(C)=O>C1(C)C=CC=CC=1>[C:11]12[CH2:10][CH2:9][CH:8]=[C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=2
Reactant: CCCCS(=O)(=O)CCCC1CCCCCCCCCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 84 %

Procedure:
10 g (0.029 mole) of 2-(3-n-butylsulfonyl-prop-1-yl)-cyclododecanone in 40 ml of toluene were heated to reflux for 30 min. in the presence of powdered KOH, in accordance with the process of Example 1, letter (b). After addition of 6 ml of DMSO, heating to reflux for 12 further hours and usual treatments of extraction and distillation as previously described, the desired title compound was isolated in a 84% yield.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CNS(=O)(=O)c1cccc(N)c1
Product: CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-methyl-benzenesulfonamide [CAS 459434-40-3] according to general procedure II. Yellow solid. MS (ISP) 524.1 [(M−H)−]; mp 255° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH2:24][CH2:25][N:26]2C(=O)C3[C:28](=CC=CC=3)[C:27]2=[O:36])=[CH:7][CH:6]=1)[CH3:2].NN.C(OC(=O)C)(=O)C.O>CC(O)C>[CH2:1]([O:3][C:4](=[O:37])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH3:28])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(CCCc2c(CCN3C(=O)c4ccccc4C3=O)[nH]c3ccc(Cl)cc23)cc1
Agent: NN
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(CCCc2c(CCNC(C)=O)[nH]c3ccc(Cl)cc23)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
A stirred mixture of 4-(3-{5-chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid ethyl ester (415 g, 0.81 mol) and 55% hydrazine solution (141 g, 2.42 mol) in 2-propanol (4 L) is warmed to 80° C. for 3 h-4 h. The reaction is complete when the product/starting material ratio is greater than 99/1 by HPLC. The reaction mixture is cooled to room temperature. The byproduct is removed by filtration. The cake is washed with 2-propanol (400 mL×3). The filtrate and wash are combined and distilled to about half volume. Pyridine (830 mL×2) is added and the remainder of the 2-propanol is removed under reduced pressure. The stirred mixture is cooled to 5° C.-10° C. Acetic anhydride (90.4 g, 1.10 mol) is added dropwise to the reaction mixture at 5° C.-10° C. The reaction is complete when the product/starting material ratio is >99/1 by HPLC analysis. Water (5.0 L) is added to the reaction mixture, maintaining the temperature below 25° C. The reaction mixture is stirred at room temperature for 12 hours. The solid product is collected by filtration, washed with water (500 mL×3) and dried in vacuum oven (70° C.) to give 303 g (87.6%, 95.4% by HPLC) of 4-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester.
Reaction SMILES: ClCCCl.Cl.[NH2:6][C:7]12[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]1[CH2:12]3)[CH2:8]2.C(N(CC)CC)C.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39](Cl)=[O:40])=[CH:28][CH:27]=1>O>[CH:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:10]1)[C:7]([NH:6][C:39]([C:38]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[CH:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)=[O:40])([CH2:14]3)[CH2:8]2
Reactant: NC12CC3CC(CC1C3)C2
Reactant: COc1ccc(C(c2ccc(OC)cc2)c2cnccc2C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(C(c2ccc(OC)cc2)c2cnccc2C(=O)NC23CC4CC(CC2C4)C3)cc1
Reaction time: 7 h
Yield: 46.5 %

Procedure:
To 10 ml of 1,2-dichloroethane solution containing 2 g of 3-aminotricyclo[3.3.1.03,7 ]nonane hydrochloride and 10 ml of triethylamine was added 4.64 g of Compound c at room temperature. Then the mixture was stirred for 7 hours, followed by addition of water thereto to separate the organic layer. The aqueous layer was extracted with chloroform, then combined with the organic layer, washed with a saturated sodium chloride and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 2.5 g of the desired compound was obtained as a solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:42]=[CH:41][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:26]=[C:25]([N:27]4[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]4)[CH:24]=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)O1.Br[C:45]1[CH:46]=[N:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:34][C:32]([F:33])([F:35])[C:31]1[N:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:13][C:12]3[CH:11]=[CH:10][C:9]([C:45]4[CH:46]=[N:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=4)=[CH:42][CH:41]=3)[N:26]=2)[N:28]=[CH:29][C:30]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)nc4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a vial containing the title compound from Example 14 Step A (14.0 mg, 0.024 mmol) were added 3-bromo-6-trifluoromethylpyridine (6.4 mg, 0.028 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (1.7 mg, 0.0024 mmol). Acetonitrile (0.500 mL) and sodium carbonate (0.059 mL, 1.0 M in water, 0.059 mmol) were added, and the resulting mixture was degassed by a nitrogen sparge. The reaction vial was capped and placed in a pre-heated oil bath (70° C.). After 6 h, the reaction mixture was allowed to cool to room temperature, then was purified by flash chromatography on silica gel: LCMS m/z 613.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:10])[CH2:8][O:7][C:6](=[O:9])[NH:5]1.[Br:11][CH:12]([CH3:16])[C:13](Br)=[O:14].P([O-])(O)(O)=O.[K+]>O1CCCC1>[Br:11][CH:12]([CH3:16])[C:13]([N:5]1[C:4]([CH3:10])([CH3:3])[CH2:8][O:7][C:6]1=[O:9])=[O:14]
Reactant: CC1(C)COC(=O)N1
Reactant: CC(Br)C(=O)Br
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(Br)C(=O)N1C(=O)OCC1(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of sodium hydride (0.24 g; 10.0 mmol) in tetrahydrofuran (100 ml) was added 4,4-dimethyloxazolidin-2-one (1.15 g; 10.0 mmol) at 0° C., and the resultant suspension was stirred at room temperature for 5 hours. To the gelatinous reaction mixture was added 2-bromopropionyl bromide (1.05 ml) at 0° C. After stirring for 1 hour, a saturated aqueous solution of potassium dihydrogen phosphate was added to quench the reaction. An aqueous layer was extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a solid residue, which was purified by silica gel column chromatography (hexane:dichloromethane=1:1~0:1) to give 3-(2'-bromopropionyl)-4,4-dimethyloxazolidin-2-one (2.35 g, yield, 90%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[N:25]=1>>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[N:25]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2]
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3
Reactant: Fc1cccc(CBr)n1
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CCC(NC(=O)C2CC2)C1

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (Preparation 69) (10.0 g, 35.8 mmol) and 2-bromomethyl-6-fluoro-pyridine (Preparation 44) (7.49 g, 39.4 mmol) by essentially following procedures as described in Preparation 45 to obtain 4.30 g (31%) of a salmon colored solid. Resolve the enantiomers using chiral chromatography essentially as described for Example 194, but using 0.2% DMEA/EtOH eluent. (R)-Isomer is first to elute. Slurry the solid in EtOAc and filter to give the title compound. m.p.=243-245° C.; MS (ES): m/z 389 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[N:19](S(C3C=CC=CC=3)(=O)=O)[CH:18]=2)[CH:3]=1.[OH-].[Na+].CO>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[NH:19][CH:18]=2)[CH:3]=1
Reactant: O=C(Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3nccnc23)cc(Cl)n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1cc(-c2c[nH]c3nccnc23)cc(Cl)n1)c1ccccc1
Yield: 48.8 %

Procedure:
A mixture of EXAMPLE 17A (40.0 mg, 0.082 mmol) and 20% sodium hydroxide (0.1 mL) in dioxane (1.5 mL) was heated at 50° C. for 2 h. The mixture was concentrated and the residue treated with water, sonicated, filtered, and washed with water. The solids were dissolved in 6 mL hot 1:1 dimethylsulfoxide/methanol. After cooling, a precipitate formed and additional methanol was added. The solids were filtered, washed with methanol, and dried to give 14.0 mg (32%) of the title compound. 1H NMR (300 MHz, DMSO-D6) 7.41-7.67 (m, 3H), 7.95-8.16 (m, 3H), 8.39 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.8 Hz, 1H), 8.77 (s, 1H), 9.08 (d, J=1.2 Hz, 1H), 10.98 (s, 1H), 12.74 (s, 1H). MS (ESI) m/z 350.5 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)cc1-c1ccnn1C
Yield: 100.2 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.198 mmol) in 6N sodium hydroxide (2.397 ml, 1.198 mmol) and tetrahydrofuran (5.992 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg, 1.2 mmol, 100% yield) as a yellow oil; LCMS (ES) m/z=236 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH:10]=1)[CH2:8]Br.[C-:14]#[N:15].[Na+]>CCO.O>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH2:8][C:14]#[N:15])[CH:10]=1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C

Procedure:
A solution of 5-trifluoromethyl-2-iodobenzyl bromide (55 g, 0.15 mol) in EtOH (200 mL) is stirred at room temperature and a solution of sodium cyanide (16 g, 0.33 mol) in water (60 mL) is added. The reaction mixture is heated to reflux temperature for 3 hours and then cooled to room temperature. Most of the ethanol is removed by rotary evaporator and the residue partitioned between EtOAc (500 mL) and water (200 mL). The organic layer is washed with brine (250 mL), dried (MgSO4) and the solvent is removed by rotary evaporator. The residue is purified using flash chromatography (1:9 EtOAc/hexanes) to give 5-trifluoromethyl-2-iodophenylacetonitrile as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([OH:17])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].S(OCC)(O[CH2:26][CH3:27])(=O)=O>CN(C=O)C>[CH2:26]([O:17][C:16]1[N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[N:13]=[N:14][C:15]=1[C:18]([O:20][CH3:21])=[O:19])[CH3:27]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2O)cc1
Reactant: CCOS(=O)(=O)OCC
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2OCC)cc1
Yield: 33 %

Procedure:
A solution of methyl 1-{4-[(ethylamino)carbonyl]phenyl}-5-hydroxy-1H-1,2,3-triazole-4-carboxylate (580 mg, 2 mmol) obtained in Example 1211a) and diethyl sulfate (339 mg, 2.2 mmol, 1.1 eq.) in DMF (5 ml) was stirred at 90° C. for 15 hr. The reaction mixture was concentrated to dryness, and chloroform (20 ml) and water (10 ml) were added to the residue. After partitioning, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a white powder (210 mg, 33%).
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7]1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.Br[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[C:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c2ccccc2c(=O)n1C(c1ccccc1)c1ccccc1
Yield: 37.6 %

Procedure:
A mixture of 1,2-dihydro-1-carboethoxy-3H-indazol-3-one (G. Heller and P. Jacobsohn, Chem. Ber, 1921, 54B, 1107; 2.06 g), triethylamine (1.01 g) and bromodiphenylmethane (2.5 g) in chloroform (60 ml) was heated under reflux for 4 hours. The reaction mixture was then washed successively with water, M hydrochloric acid and then with water, dried (MgSO4) and evaporated. The residue was dissolved in methylene chloride and purified by column chromatography using an increasing gradient of ether in methylene chloride as eluant to give (from the later fractions) 1,2-dihydro-1-carboethoxy-2-diphenylmethyl-3H-indazol-3-one as a solid (1.4 g), m.p. 115-118° C.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:3].[C:12]([OH:15])(=[O:14])[CH3:13]>[Pd]>[C:12]([OH:15])(=[O:14])[CH3:13].[CH:2]([C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cccnc1C#N
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)c1cccnc1CN

Procedure:
To a solution of 3-(prop-1-en-2-yl)picolinonitrile in acetic acid was added 10% Pd/C. The Parr shaker bottle was evacuated/H2 purged 3×, and then shaken at 50 psi until starting material was consumed (typically <1 h). The reaction was filtered through diatomaceous earth and concentrated to yield (3-isopropylpyridin-2-yl)methanamine acetic acid salt which was used without further purification. To the crude salt in THF was added aq 1M NaOH, followed by BOC2O (2 eq). The reaction was allowed to stir at rt overnight. After ˜16 h, the reaction mixture was transferred to a seperatory funnel, diluted with EtOAc, and water, and the layers were separated. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound as a clear oil. 1H NMR (CDCl3, 400 MHz) δ 8.4 (m, 1H), 7.5 (m, 1H), 7.2 (m, 1H), 4.5 (s, 2H), 3.1 (s, 1H), 1.4 (s, 9H), 1.2 (d, J=3.5 Hz, 6H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[C:11]([CH3:24])[CH:10]=2)[N:3]=1.[CH3:25][O:26][C:27]([C@H:29]1[CH2:34][CH2:33][C@@:32]([C:36]2[S:37][C:38](Br)=[CH:39][N:40]=2)([OH:35])[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>CC1CCCO1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][O:26][C:27]([C@H:29]1[CH2:34][CH2:33][C@:32]([OH:35])([C:36]2[S:37][C:38]([C:13]3[CH:14]=[C:9]([NH:8][C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[CH:10]=[C:11]([CH3:24])[CH:12]=3)=[CH:39][N:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28]
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(Br)s2)CC1(C)C
Reactant: Cc1cc(Nc2nccc(C)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC1CCCO1
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(C)cc(Nc4nccc(C)n4)c3)s2)CC1(C)C
Temperature: 70 °C
Yield: 65.7 %

Procedure:
To a mixture of (4-methyl-pyrimidin-2-yl)-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine (20.0 g, 56.9 mmol), (1S,4R)-4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2,2-dimethyl-cyclohexanecarboxylic acid methyl ester (19.8 g, 56.9 mmol), and PdCl2(dppf)2 (2.33 g, 2.85 mmol) in degassed 2-methyltetrahydrofuran (237 mL), was added sodium carbonate (2 M in H2O, 56.9 mL, 114 mmol). The reaction flask was purged with nitrogen and then heated to 70° C. for 5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered over celite. The solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. Purification by chromatography on silica gel (Isco CombiFlash 100:0 to 40:60, hexanes:ethyl acetate), then by Chromatography on silica gel (2:98, methanol:dichloromethane) provided 17.5 g (37.4 mmol 66%) of (1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-1,3-thiazol-2-yl}-cyclohexanecarboxylic acid methyl ester as a light tan foam.