Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][F:20])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.[Pd]>[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]/[CH:18]=[CH:19]\[F:20])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C#CCF)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C/C=C\F)cc1
Yield: 99.3 %

Procedure:
cis-hydrogenation using Lindlar catalyst and pyridine: Stir a mixture of 533 mg, 2.51 mmoles of the title compound of Example 1 (recrystallized from dichloromethane-hexane), 211 mg, 2.67 mmoles of pyridine and 127 mg of Lindlar catalyst (palladium on calcium carbonate, poisoned with lead (obtained from Aldrich) in 25 mL of ethyl acetate under hydrogen at atomospheric pressure at 26° C. for 1 hr until the theoretical amount of hydrogen (62 mL) is consumed. Remove the catalyst by filtration and wash it with ethyl acetate. Wash the ethyl acetate solution successively with ice-cold 4% HCl solution, saturated NaHCO3 solution and water, and dry over anhydrous MgSO4. Evaporate solvent under vacuum to give the title compound as an oil (534 mg).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1C(OC(C)(C)C)=O)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].[C:28]([CH2:30][CH2:31][NH:32][C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)=[O:34])#[N:29]>>[C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([C:33](=[O:34])[NH:32][CH2:31][CH2:30][C:28]#[N:29])[CH:40]=2)=[CH:9][CH:10]=1)#[N:2]
Reactant: N#CCCNC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(I)cc1
Product: N#CCCNC(=O)c1cccc(-c2ccc(C[C@@H](C#N)NC(=O)[C@@H]3CCCCN3)cc2)c1

Procedure:
Prepared by a process analogous to that described in Method 2 Example 2 using (S)-tert-butyl 2-((S)-1-cyano-2-(4-iodophenyl)ethylcarbamoyl)piperidine-1-carboxylate and 3-(2-cyanoethylcarbamoyl)phenylboronic acid. NMR appeared to show the product was a free base.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[N:3]=1.[C:14](Cl)([Cl:16])=[O:15]>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([Cl:16])=[O:15])[N:3]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1nc(-c2ccccc2N)no1
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2NC(=O)Cl)no1
Reaction time: 17 h

Procedure:
A solution of 2-(5-methyl-1,2,4-oxadiazol-3-yl)benzeneamine (1.0 g) in dry dichloromethane (20 ml) was added dropwise to a solution of phosgene (14.1 ml) in dichloromethane (50 ml) at 0° under a nitrogen atmosphere. The opaque solution was then allowed to slowly attain room temperature and stirred for 17 h. The reaction mixture was concentrated under vacuo to give a pale yellow solid (1.3 g).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][C:31]=1[C:42]1[NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=2[N:43]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]([N:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:42]4[NH:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)[CH:32]=3)[CH2:37][CH2:38]2)=[O:28])[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1-c1nc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
CDI (0.047 g, 0.29 mmol) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.07 g, 0.29 mmol) in acetonitrile (2.50 mL). The resulting solution was stirred at room temperature for 5 hours. 2-(2-Fluoro-5-piperazin-1-yl-phenyl)-1H-benzoimidazole (0.10 g, 0.27 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added and reaction was heated at 65° C. overnight. Reaction was cooled to room temperature and solvent was removed under reduced pressure. DCM (2 mL) was added to the crude, organic solution was washed with water (2×4 mL) and with saturated Na2CO3 solution (2×4 mL) and concentrated. The crude reaction mixture was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to 100% AcOEt) to afford 0.08 g of the title compound (60%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([NH:1][N:2]2[N:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:13])=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: Cc1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: Cc1nn(NC(=O)Cc2cc(F)cc(F)c2)c(=O)c2ccccc12

Procedure:
The product from Example 28A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.58-11.61 (m, 1H), 8.32 (d, J=7.9 Hz, 1H), 8.00-8.02 (m, 2H), 7.90-7.93 (m, 1H), 7.09-7.21 (m, 2H), 7.02-7.05 (m, 1H), 3.74 (s, 2H), 2.55 (s, 3H); MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>C1(C)C=CC=CC=1>[C:15]1(=[O:25])[N:19]([CH2:2][C:3]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)Cc1ccc([N+](=O)[O-])cc1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)CN1C(=O)c2ccccc2C1=O
Reaction time: 4 h

Procedure:
A mixture of 1-bromo-3-(4-nitrophenyl)acetone and potassium phthalimide (7.2 g.) in toluene (100 ml.) was heated under reflux with stirring for 4 hours. The mixture was filtered, the filtrate evaporated. The residue was purified by chromatography on silica gel using CH2Cl2 as eluant to give 1-phthalimido-3-(4-nitrophenyl)acetone, m.p. 184°.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(#N)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC#N
Product: CCCc1c(CNc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 6.8 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 14.9 g. of ethyl 4-aminobenzoate in 200 ml. of acetonitrile was heated to reflux for 48 hours. An additional 9.9 g. of ethyl 4-aminobenzoate were added and the reaction was refluxed an additional 120 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in methylene chloride. The organic solution was washed first with a saturated sodium carbonate solution and then with water. The organic solution was then dried over sodium sulfate and evaporated to dryness. Chromatography of the residue afforded 7.4 g. of the desired title product. NMR.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH:19]([F:21])[F:20])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[SH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl>[F:20][CH:19]([F:21])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:3]2[N:4]=[C:5]([S:8][CH3:9])[N:6]=[CH:7][C:2]=2[S:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CSc1ncc(Cl)c(C(=O)c2ccccc2OC(F)F)n1
Reactant: COC(=O)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2cnc(SC)nc2c1-c1ccccc1OC(F)F
Temperature: 60 °C
Yield: 97.9 %

Procedure:
A mixture of 303 mg of [5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanone 7, 107 mg of methyl sulfanylacetate, 253 mg of potassium carbonate and 5 ml of acetonitrile is microwave-heated in a sealed tube at 60° C. for 4 h. The mixture is diluted with a 0.5 N aqueous hydrochloric acid solution and extracted twice with ethyl acetate and once with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to obtain 343 mg of methyl 7-[2-(difluoromethoxy)phenyl]-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate 8 in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([CH3:15])[N:6]=1>CO.O>[Cl:11][C:9]1[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([CH3:15])[N:6]=[C:5]([O:2][CH3:1])[N:10]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Sodium methoxide (28% solution in methanol, 47.0 g, 244 mmol) was added dropwise to a stirred solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (48.3 g, 232 mmol) in methanol (600 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with water, concentrated, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-15% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (11.9 g, 58.5 mmol, 25%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:12]([NH:15][S:16](Cl)(=[O:18])=[O:17])([CH3:14])[CH3:13]>C1C=CC=CC=1>[CH3:13][CH:12]([NH:15][S:16]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:18])=[O:17])[CH3:14]
Reactant: COC(=O)c1cccnc1N
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)c1cccnc1NS(=O)(=O)NC(C)C

Procedure:
Methyl 2-amino-3-pyridine carboxylate (10.0 grams; 0.066 mole) and isopropyl sulfamoyl chloride (11.4 grams; 0.066 mole) were mixed with 300 ml of benzene and the resulting reaction mixture heated at reflux temperatures for a period of 48 hours. Following the reaction period, the reaction mixture was cooled and the solvent removed in vacuo. The oily residue thus obtained was extracted with 200 ml of cyclohexane and the extracts combined and cooled. The resulting precipitate was recovered by filtration and recrystallized from carbon tetrachloride. As a result of these operations, the desired title compound having a melting point of 121° C.-123° C. was obtained.
Reaction SMILES: [P:1](=[O:7])([NH2:6])([S:4][CH3:5])[O:2][CH3:3].[C:8](OC(=O)C)(=[O:10])[CH3:9]>S(OC)(OC)(=O)=O>[C:8]([NH:6][P:1](=[O:7])([S:4][CH3:5])[O:2][CH3:3])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: COP(N)(=O)SC
Solvent: COS(=O)(=O)OC
Product: COP(=O)(NC(C)=O)SC
Yield: 138.1 %

Procedure:
19.1 Grams of dimethyl sulfate were gradually added to 296 g (purity 86.3%) of O,O-dimethylphosphoramidothioate at 40° C. in 30 min and to the resultant were further added 1180 g of O,O-dimethyl phosphoramidothioate and 76.1 g of dimethyl sulfate at the same temperature over 2 hours separately. The resultant reaction mixture was further maintained at the temperature for 8 hours to obtain 1562 g of O,S-dimethyl phosphoramidothioate(purity: 79.1%). To 1562 g of obtained O,S-dimethyl phosphoramidothioate was added 1218 g of acetic anhydride and 41 g of dimethyl sulfate at 40° C. over an hour. The resultant was maintained at the temperature for an hour to complete the reaction to give 2799 g of crude O,S-dimethyl N-acetylphosphoramidothioate (purity: 49.13%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[S:9][C:8]([C:10](O)=[O:11])=[CH:7][C:6]=2[CH:13]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[S:9][C:8]([C:10]([N:17]([O:18][CH3:19])[CH3:16])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2s1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2cc(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-difluoro-1-benzothiophene-2-carboxylic acid (synthesized by the method of WO2003/055878, 1.95 g, 9.10 mmol), N,O-dimethylhydroxyamine hydrochloride (977 mg, 10.0 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g, 10.0 mmol) and N-hydroxybenzotriazole (1.35 g, 10.0 mmol) in dichloromethane (20 mL) was added triethylamine (1.90 mL, 13.7 mmol) at room temperature. The mixture was stirred at room temperature overnight, and then to the reaction solution was added 10% hydrochloric acid solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a crude 5,7-difluoro-N-methoxy-N-methyl-1-benzothiophene-2-carboxamide (2.48 g) as a colorless solid. The resultant was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][C@H:3]2[CH2:7][C:8]3[C:13]([C@@H:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C=O)C>[CH2:18]([N:1]1[C:5](=[O:6])[CH2:4][C@H:3]2[CH2:7][C:8]3[C:13]([C@@H:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:17]=[CH2:16]
Reactant: O=C1C[C@H]2Cc3ccccc3[C@H]2N1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1C(=O)C[C@H]2Cc3ccccc3[C@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of (3aR,8bS)-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (1.00 g, 5.77 mmol) in DMF (10 mL) was added at 0° C. sodium hydride (60% in mineral oil, 0.254 g, 6.35 mmol). The solution was stirred for 1 h at 0° C. and allyl bromide (1.41 g, 2 equiv., 1.01 mL, 11.5 mmol) was added. The solution was stirred for 18 h at room temperature and water was added. The mixture was extracted with ethyl acetate and washed with water and brine. The solvents were removed in vacuo and the residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (50:50) to give (3aR,8bS)-1-allyl-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one F22 (0.910 g, 0.910 g, 4.27 mmol, 73.9% Yield) as a colourless oil. LCMS (method A) 1.51 min; ES+: 214 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:19])[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:19][C:2]1([F:1])[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Reactant: FC1(F)CNC12CCN(c1ncnc3[nH]ccc13)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CC(F)(F)C12CCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 1.25 h
Yield: 83.1 %

Procedure:
An optically-active compound of 4-(3,3-difluoro-1,6-diazaspiro[3,4]oct-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (170 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (209 mg), N,N-diisopropylethylamine (117 μl) and 1,4-dioxane (3.4 ml), and the mixture was stirred at 100° C. for 75 minutes. The mixture was cooled to room temperature. Thereto was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate twice again. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=2/1, followed by chloroform/methanol=92/8 to 3/1). The mixture was concentrated under reduced pressure, and the resulting residue was slurry-washed with a mixed solvent of n-heptane/ethanol (3/1) to give the titled compound (177 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c1
Yield: 66 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxyphenylboronic acid in 66% yield using method F; δH [2H6]-DMSO 13.55,(1H, s), 12.57,(1H, s), 8.35,(2H, m), 8.27-8.10,(5H, m), 7.65,(1H, s), 7.37,(1H, t), 7.03-6.93,(4H, m), 3.83,(3H, s); MS 371 (MH)+; HPLC retention time (system 1) 4.08 minutes.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH2:3]1.CCN(C(C)C)C(C)C.[N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]2=[C:34]([C:41](Cl)=[O:42])[CH:33]=1>C1COCC1>[F:22][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:11]=[CH:10][C:9]=2[NH:21][C:41]([C:34]2[CH:33]=[N:32][N:36]3[CH:37]=[CH:38][CH:39]=[N:40][C:35]=23)=[O:42])[CH2:3]1
Reactant: O=C(Cl)c1cnn2cccnc12
Reactant: C[Si](C)(C)COCCn1ncc(N)c1N1CCCC(F)(F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)COCCn1ncc(NC(=O)c2cnn3cccnc23)c1N1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine (1.2 g, 3.61 mmol) in 30 mL THF was added DIPEA (1.3 mL, 7.22 mmol) and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (720 mg, 3.97 mmol) in THF (50 mL) at 0° C. After addition was complete, the mixture was warmed to room temperature, then stirred overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatogaphy (hexanes:EtOAc=3:1 to 1:1) to afford 1.0 g (60%) of N-(5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=478.2; 1H NMR (400 MHz, CDCl3) δ: 9.49 (s, 1H), 8.87 (dd, 1H), 8.75 (s, 1H), 8.71 (dd, 1H), 7.94 (s, 1H), 7.10 (dd, 1H), 5.40 (s, 2H), 3.67 (m, 6H), 2.06 (s, 2H), 1.93 (m, 2H), 0.95 (m, 2H), 0 (s, 9H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:7]([NH:8][C:44]([C:40]1[CH:39]=[C:38]2[C:43](=[CH:42][CH:41]=1)[N:35]([CH2:34][C:31]1[CH:30]=[CH:29][C:28]([C:23]3[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:33][CH:32]=1)[C:36]([CH3:48])=[C:37]2[CH3:47])=[O:45])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(c3ccccc3)c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using diphenylmethanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:26])[CH2:24]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:24][C:23]([O:22][CH3:21])=[O:26])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Product: COC(=O)CON1C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O

Procedure:
Employing 8-tert-butyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.56 g) and methylbromoacetate (190 μl), reaction was conducted in the same manner as in Example 40 to obtain an oily compound. This was separated by column chromatography (eluent; dichloromethane) to obtain 0.67 g of a coloress oily compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:31](=[O:32])[N:30]([CH3:33])[C:12]3[N:13]([CH3:29])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][C:17]([C:20]2[NH:21][N:22]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:24]=2)=[CH:16][CH:15]=4)=[CH:5][CH:4]=1.Br[C:35]1C=CC(C2C(=O)N(C)C3N(C)C4C(C=3C=2)=CC(C2C=C(COCC)NN=2)=CC=4)=CC=1.IC>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:31](=[O:32])[N:30]([CH3:33])[C:12]3[N:13]([CH3:29])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[N:22]([CH3:35])[N:21]=2)=[CH:16][CH:15]=4)=[CH:5][CH:4]=1
Reactant: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)[nH]n1
Reactant: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)n[nH]1
Agent: Cl
Solvent: CI
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, with the compound from Example 84, 3-(4-bromophenyl)-6-(5-ethoxymethyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:2]>ClCCl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOc1cc(CO)ccc1-c1ccc(F)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)ccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of (2-ethoxy-4′-fluoro-biphenyl-4-yl)-methanol (0.43 g, 1.75 mmol, 1.0 equiv) in dichloromethane (20 mL) was added activated MnO2 (3.04 g, 34.92 mmol, 20.0 equiv) and the reaction mixture stirred vigorously for 3 h at ambient temperature. The reaction mixture was filtered over a pad of Celite, rinsed generously with dichloromethane and evaporated to dryness under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (4:1) to yield 0.33 g (77%) of the title compound as white crystals. MS (EI): 244.1 [M]+.