Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:24]N1C(=O)CCC1=O>CC(N(C)C)=O.ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:9]([Br:24])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2[nH]c(Br)c(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (302 mg) was dissolved in dimethylacetamide (10 ml) and dichloromethane (50 ml) and then treated with N-bromosuccinimide (178 mg) in dichloromethane (10 ml). The mixture was left stirring ambient temperature for 16 hours. The mixture was evaporated under reduced pressure and the residue was triturated with water to give a solid which was collected by filtration and dried to give 4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, m.p. 282-283° C.
Reaction SMILES: [C:1]([CH:5]1CCC(=O)CC1)(C)([CH3:3])[CH3:2].C(N(S(F)(F)[F:22])C1C=CC=CC=1)C.B(F)(F)F.CCOCC.[F:34][C:35]1[CH:40]=[CH:39][C:38](OC)=[CH:37][CH:36]=1>C(Cl)Cl>[F:34][C:35]1([F:22])[CH2:40][CH2:39][CH:38]([C:1]([CH3:5])([CH3:3])[CH3:2])[CH2:37][CH2:36]1
Reactant: CCN(c1ccccc1)S(F)(F)F
Reactant: COc1ccc(F)cc1
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) in CH2Cl2 (10.0 mL) was added to N-ethyl-N-phenylaminosulfur trifluoride (627 mg, 3.0 mmol ) at room temperature under N2. BF3.OEt2 (100 mL) was added and the mixture was stirred for 6 h at room temperature. The mixture was washed with saturated NaHCO3, dried (Na2SO4), filtered and evaporated in vacuo. Proton and Fluorine NMR with 4-fluoroanisole (2 mmol) as internal standard showed that a 99% yield of 1,1-difluoro-4-t-butylcyclohexane was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[N:18]1([CH2:24][CH2:25]O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH2:24][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(OCCN3CCOCC3)cc2)n1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (WO2005/110994, 0.462 g, 2 mmol), 2-morpholin-4-yl-ethanol (0.327 g, 2.5 mmol) and triphenylphosphine (1.05 g, 4 mmol) in THF (5 mL) under a nitrogen atmosphere was treated with diisopropyl azodicarboxylate (0.808 mg, 4 mmol). The reaction mixture was stirred at RT for 16 H, then diluted with diethyl ether. The organic layer was washed with water. The resulting aqueous layer was basified with potassium carbonate and extracted with EtOAc. The resulting organic layer was washed with aq. citric acid solution, and the resulting aqueous layer was basified with potassium carbonate, and extracted with EtOAc (three times). The resulting organic layer was dried (Na2SO4), evaporated to dryness then sonicated with diethyl ether (10 mL) and filtered to give the title compound (0.297 g, 43%) as a white solid. LCMS (Method 5): Rt 0.41, 2.16 min, m/z 345 [MH+]. 1H NMR (400 MHz, CDCl3): δ 7.46-7.39 (2 H, m), 6.98-6.93 (2 H, m), 5.50 (1 H, s), 4.15-4.08 (2 H, m), 3.75 (4 H, t, J 4.5), 3.63 (2 H, bs), 2.83-2.78 (2 H, m), 2.59 (4 H, t, J 4.3), 1.34-1.26 (9 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12](O)=O.S(Cl)(Cl)=O.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26].[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.CCOCC>[CH:25]([N:28]([CH2:12][CH2:11][CH:10]([C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C)cc1C(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C)cc1C(CCN(C(C)C)C(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
3-(2-Methoxy-5-methylphenyl)-3-phenylpropionic acid (12.8 g, 0.05 mol) (J. D. Simpson & H. Stehphen, J. Chem. Soc. 1956 1382) and thionyl chloride (50 ml) are heated on a water bath for 3 h. The excess of thionyl chloride is distilled off under reduced pressure. The remaining crude 3-(2-methoxy-5-methylphenyl)3-phenylpropionyl chloride is dissolved in 50 ml of dichloromethane and added dropwise to a stirred solution of diisopropylamine (20.2 g, 0.20 mol) in 200 ml of dichloromethane at about 0° C. The solution is left for 2 h, the solvent is distilled off and the remaining material is treated with water. The solid product consisting of N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropionamide is filtered off, dried and added in small portions to a stirred suspension of lithium aluminium hydride (6.0 g, 0.16 mol) in dry ether (700 ml). The mixture is refluxed for 2 days. Excess of hydride is destroyed by the careful addition of water, the ether layer is separated and dried with anhydrous sodium sulfate. After filtration the solution is added to a solution of excess fumaric acid in ether. The precipitated salt is collected and crystallized from 2-propanol. The hydrogen fumarate melts at 176° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6](O)[CH2:7][CH2:8][O:9][C:4]=2[N:3]=[CH:2]1.CC(C)(O)[C:13]#[N:14].P(CCCC)(CCCC)CCCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OC(C)C)(C)C>[S:1]1[C:5]2[CH:6]([C:13]#[N:14])[CH2:7][CH2:8][O:9][C:4]=2[N:3]=[CH:2]1
Reactant: OC1CCOc2ncsc21
Reactant: CC(C)(O)C#N
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: N#CC1CCOc2ncsc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6,7-dihydro-5H-pyrano[2,3-d]thiazol-7-ol (0.65 g, 4.14 mmol), acetone cyanohydrin (880 mg, 10.3 mmol) and (n-Bu)3P (1.67 g, 8.27 mmol) in THF (79 mL) was added at 0° C. 1,1′-(azodicarbonyl)dipiperidine (2.09 g, 8.27 mmol). The mixture was stirred at 0° C. for 30 min, then, it was allowed to warm to RT and was stirred for 2 h. Subsequently, the reaction mixture was diluted with diisopropyl ether, filtrated and the filtrate was conc. in vacuo. Purification by means of CC (5-70% EtOAc/Hept) provided a yellow solid.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH2:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][C@H:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][C@H:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1)[CH3:14]
Reactant: C[C@@H](O)CN
Reactant: CCc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
A solution of 2.02 g of (RS)-2-(2-oxoethyl)-6-ethyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.7 g (71%) of (R)-1-(7-ethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: OO.NC(N)=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:20][C:21]1[CH:34]=[CH:33][C:32]2[O:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[N+:35]([O-:37])=[O:36])[C:24](=[O:38])[C:23]=2[CH:22]=1>C(Cl)Cl>[Br:20][C:21]1[CH:34]=[CH:33][C:32]2[O:31][C:30]3[C:25](=[N+:26]([O-:5])[CH:27]=[CH:28][C:29]=3[N+:35]([O-:37])=[O:36])[C:24](=[O:38])[C:23]=2[CH:22]=1
Reactant: NC(N)=O
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])ccnc12
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc[n+]([O-])c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of urea hydrogen peroxide (58.6 mg, 0.623 mmol) in 5 mL of CH2Cl2 at 0° C. was added dropwise trifluoroacetic anhydride (87 μL, 0.623 mmol). After stirring for 5 min at 0° C., a solution of 8-bromo-4-nitro-10H-chromeno[3,2-b]pyridin-10-one (80 mg, 0.249 mmol) in CH2Cl2 (5 mL) was added and the resulting reaction was stirred at rt for 1.5 h. The mixture was carefully quenched with saturated NaHCO3 and extracted with ethyl acetate (5×5 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=10:1 to 5:1) gave 8-bromo-4-nitro-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide as an light yellow solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CO>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:23][C:24]3[CH:25]=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=3)=[N:3][CH:4]=[C:5]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:6]=2)[N:9]=1
Reactant: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 77.3 %

Procedure:
To a stirred solution of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.0602 g, 0.198 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, step 2, 0.0494 g, 0.223 mmol) in DMF (1 mL) in a 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 0.80 mL, 0.80 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aq phase was acidified to a pH of about 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue. Upon addition of MeOH to the residue, a tan precipitate came out. The solid was collected via filtration and washed with MeOH to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(morpholinomethyl)pyridin-2-ylamino)-2-chloropyridin-3-yl)methanesulfonamide (0.0774 g, 77% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.26 (s, 1H) 9.66 (br. s., 1H) 8.76 (s, 1H) 8.67 (t, J=2.45 Hz, 2H) 8.31 (d, J=1.56 Hz, 1H) 7.74-8.01 (m, 2H) 3.43-3.66 (m, 6H) 3.14 (s, 3H) 2.38-2.48 (m, 7H). m/z (ESI, pos. ion): 505.9 (M+H)+.
Reaction SMILES: CN.CO.[S:5]1[CH:9]=[C:8]([CH:10]=O)[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2.CC(O)=O.[BH3-][C:21]#[N:22].[Na+]>>[CH3:21][NH:22][CH2:10][C:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5][CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1csc2ccccc12
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2 M methylamine in methanol (75 mmole, 150 mmole) was added benzo[b]thiophen-3-carboxaldehyde (5.3 g, 33 mmole) and HOAc (4.3 mL, 75 mmole). The reaction was stirred at RT for 1 h, then NaBH3CN (2.1 g, 33 mmole) was added portionwise over 5 minutes. The reaction was stirred for an additional 16 h then was concentrated under vacuum. The residue was taken up in Et2O (300 mL) and washed with 1.0 N NaOH (300 mL) then with brine, dried (Na2SO4), and concentrated. Purification by flash chromatography on silica gel (5% (5% NH4OH/MeOH)/CHCl3) gave the title compound (2.81 g, 48%) as a brownish oil: 1H NMR (400 MHz, CDCl3) 6-7.87 (2d, 2H), 7.40 (m, 2H), 7.32 (s,1H), 4.02 (s, 2H), 2.56 (s, 3H), 1.5 (br s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[OH-].[Na+].Cl.[NH:19]1[CH2:24][CH2:23][C:22](O)([OH:25])[CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: OC1(O)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCC(=O)CC2)cc1C(F)(F)F
Yield: 91.7 %

Procedure:
A solution of 4-methoxy-3-(trifluoromethyl)benzoyl chloride (4.00 g, 16.8 mmol) in toluene (16 mL) and a solution of NaOH (3.8 mL of 4.0 M, 15 mmol) were contemporaneously added drop-wise to a solution of piperidine-4,4-diol hydrochloride (2.30 g, 15.2 mmol) in NaOH (7.6 mL of 2.0 M, 15 mmol) at 25° C. The mixture was stirred for 90 min before the toluene was removed in vacuo. The alkaline phase was extracted with dichloromethane (3 times). The organics were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to provide 1-(4-methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one (4.2 g, 91%). ESI-MS m/z calc. 301.3, found 302.2 (M+1)+. Retention time: 0.95 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=1.9 Hz, 1H), 7.70 (dd, J=8.6, 2.1 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 4H), 2.55 (s, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH:18]1([C@H:24]([NH2:26])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>CN1CCCC1=O>[CH:18]1([C@H:24]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: C[C@@H](N)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2ccccc2)c2ccccc12)C1CCCCC1
Yield: 75.5 %

Procedure:
722 mg (3.0 mmol) of 1-chloro-4-phenylphthalazine and 1.15 g (9.0 mmol) of (R)-(-)-1-cyclohexylethylamine were added to 2 ml of N-methylpyrrolidone, and the resultant mixture was stirred at 120° to 130° C. for 6 hours under heating. After the end of the reaction, the mixture was cooled. 20 ml of an aqueous 5% NaOH solution was added to the mixture and the solution was extracted with chloroform. The organic layer was dried over MgSO4, concentrated, purified by silica gel chromatography (eluent: ethyl acetate:hexane:chloroform=1:3:1) and recrystallized from ether-chloroform, thereby obtaining 751 mg of (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)#[N:26]>>[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)#[N:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: N#Cc1ccccc1B(O)O
Product: N#Cc1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 2.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-cyanophenylboronic acid (available from Aldrich Chemical Company, Inc.; 59 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (2 mg, 1%). The compound of Example 111 has the same formula as the compound of Example 112. LCMS analysis indicated that the material was ˜94% pure, as measured by UV at 214 nm. LRMS m/z 450.8 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.CO.[NH3:17]>>[Cl:1][C:2]1[CH:11]=[C:10]([NH2:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: N
Solvent: CO
Product: COc1ccc2nc(Cl)cc(N)c2c1
Temperature: 150 °C
Yield: 55 %

Procedure:
A suspension of 2,4-dichloro-6-methoxyquinoline (5.00 g, 22.0 mmol) in NH3 (g)/MeOH (saturated, 40 mL) was heated to 150° C. for 16 hours in a sealed tube. The solvent was removed and the residue was diluted with MeOH (20 mL). The mixture was filtered off and the filtrate was concentrated to give the crude product. Purification by column chromatography on silica gel (PE/EtOAc=2/1) gave product (7.50 g, yield: 55%) as a solid.
Reaction SMILES: N1C=CC=CC=1.O[C:8]1[C:9]([CH3:24])=[C:10]([CH3:23])[C:11]2[O:16][C:15]([CH3:20])([C:17]([O-:19])=O)[CH2:14][CH2:13][C:12]=2[C:21]=1[CH3:22].C([Cl:28])(=O)C.C(=O)([O-])O.[Na+].C1C[O:37][CH2:36][CH2:35]1>O>[C:36]([C:8]1[C:9]([CH3:24])=[C:10]([CH3:23])[C:11]2[O:16][C:15]([CH3:20])([C:17]([Cl:28])=[O:19])[CH2:14][CH2:13][C:12]=2[C:21]=1[CH3:22])(=[O:37])[CH3:35]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)[O-])O2
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 1 liter round bottom flask with an atmosphere of di-nitrogen was added dry pyridine (10.00 g, excess mole) and dry THF solvent to dissolve 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-1-benzopyran-2-carboxylate (24.9 g). The temperature was reduced to 0° C. and acetyl chloride (15 ml) slowly added with agitation. The solution was observed to be yellow. The solution was allowed to warm up to ambient temperature and then refluxed for 1 hour. The solution was cooled, reduced in volume (100 ml) and water added with a sodium hydrogen carbonate (1 g). The solution was extracted three times with DCM, the DCM dried (sodium sulphate) and evaporated to dryness. The hydroxy acetyl was redissolved in dry THF (100 ml) and oxalyl chloride (10% solution 50 ml, excess) was slowly added at 10° C. under an atmosphere of di-nitrogen. The solution was allowed to warm to ambient temperature and stirred for 12 hours. The clear solution was evaporated to dryness at 50° C. and 10 mbar to give 3,4-dihydro-6-acetyl-2,5,7,8-tetramethyl-1-benzopyran-2-carbonyl chloride. The solid was washed with saturated sodium bicarbonate and vacuum dried. A carbon 13 NMR clearly showed the aromatic ring and the acetyl functionality.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1([CH2:18][O:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([N:26]3[C:31](=[O:32])[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]4[N:51]=[C:52]([CH3:54])[N:53]=[C:27]34)[CH2:22][CH2:21]2)[CH2:17][CH2:16][CH2:15]1>O.C(OCC)(=O)C>[OH:13][C:14]1([CH2:18][O:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([N:26]3[C:31](=[O:32])[C:30]([CH2:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:46]5[NH:3][C:4](=[O:7])[O:5][N:47]=5)=[CH:38][CH:39]=4)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]4[N:51]=[C:52]([CH3:54])[N:53]=[C:27]34)[CH2:24][CH2:25]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CCC3)CC2)c2nc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CCC3)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogen carbonate (0.29 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[(1-hydroxycyclobutyl)methoxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.098 g) was added, and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 38 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.028 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.031 mL) were added, and the mixture was stirred at room temperature for 30 min. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.034 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=[O:35])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:74][C:75]([CH3:79])([CH3:78])[CH2:76]N>C(Cl)Cl>[OH:74][C:75]([CH3:79])([CH3:78])[CH2:76][O:35][C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])[CH:32]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OCC(C)(C)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich, 104 mg, 0.27 mmol) was added followed by the addition of DIPEA (0.41 mmol) and 2-hydroxy-2-methyl-propylamine (Matrix, 24 mg, 027 mmol). The mixture was stirred at rt 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 75 mg.