Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:21])=[O:20]
Reactant: CCOC(=O)C1CC1CO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC1COS(C)(=O)=O
Reaction time: 8 h
Yield: 99 %

Procedure:
To a reaction solution of ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (4-1) (577 mg; 4.0 mmol) with Et3N (1.1 mL; 8.0 mmol) and DMAP (49 mg; 0.4 mmol) in 12 mL of CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.4 mL; 4.8 mmol). The resulting mixture of brown color suspension was stirred at 0° C. to room temperature under N2 for overnight. The reaction mixture was quenched with NaHCO3, then partitioned between CH2Cl2 (200 mL) and saturated NaHCO3 solution (50 mL); brine (50 mL). The organic layer was dried (Na2SO4), then filtered through silica gel pad, eluted with hexane:EtOAc/1:1. The filtrate was concentrated by vacuum to give 880 mg of ethyl 2-{[(methylsulfonyl)oxy]methyl}cyclopropanecarboxylate as a yellow oil (99% yield). 1H NMR (400 MHz, chloroform-D) δ ppm 0.91-1.02 (m, 1H) 1.26 (q, J=6.99 Hz, 3H) 1.29-1.36 (m, 1H) 1.63-1.74 (m, 1H) 1.79-1.92 (m, 1H) 3.02 (s, 3H) 3.99-4.24 (m, 4H).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([CH:27]=[O:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C>CN(C)C=O>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([CH:27]=[O:28])=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(C=O)o1
Agent: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Solvent: CN(C)C=O
Product: O=Cc1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 87 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole-5-carbaldehyde. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazole (122 mg, 0.327 mmol) and N,N-dimethylformamide following General Procedure K. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (114 mg, 87%): 1H NMR (CDCl3, 600 MHz) δ 9.77 (s, 1H), 7.78 (s, 1H), 7.27-7.25 (m, 2H), 7.17-7.15 (m, 3H), 4.86 (t, 1H, J=7.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 1.91-1.85 (m, 2H), 1.62-1.57 (m, 2H), 1.43-1.33 (m, 6H), 0.88 (s, 9H), 0.07 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 177.5, 170.8, 150.5, 143.6, 137.8, 129.2, 129.1, 126.5, 69.5, 37.2, 36.8, 32.2, 29.9, 29.9, 26.5, 25.8, 19.1, −4.2, −4.3.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](F)=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:14]([NH2:16])[CH3:15]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([NH:16][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN
Reactant: Fc1ncccc1-c1sccc1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNc1ncccc1-c1sccc1Br
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of 3-bromo-2-(2-fluoropyridin-3-yl)thiophene (0.47 g) and ethylamine (0.4 g) in dioxane (2 mL) in a sealed tube was heated at 100° C. for 2 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated to give 3-bromo-2-(2-ethylaminopyridin-3-yl)thiophene (0.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cc(F)ccc4F)cc3c2C1
Yield: 78.3 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 2,5-difluorobenzoyl chloride, 13.3 mg (78%) of the title compound were recovered as a beige solid.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]4[O:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34].C(OCC)C>O1CCOCC1>[ClH:34].[NH:23]1[CH2:24][CH2:25][O:26][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]([C:10]3[CH:9]=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)=[O:13])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4ccccc4)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1cnn(-c2ccccc2)n1
Temperature: 60 °C
Reaction time: 48 h
Yield: 93.2 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(2-phenyl-2H-1,2,3-triazole-4-carboxamido)phenyl)morpholine-4-carboxylate (30 mg, 66.7 μmol, Eq: 1.00) in dioxane (2 ml) was added 4 M HCl in dioxane (250 μl, 1.00 mmol, Eq: 15). The reaction mixture was stirred at 60° C. for 48 hours. To the mixture was added 2 ml of diethyl ether and stirred for 15 min at room temperature. The mixture was filtered and concentrated in high vacuum to give the expected HCl salt as a light-yellow solid (24 mg, 93.2%). MS (ISP): 350.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (319 mg, 78%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]#[CH:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([Li])CCC.IC>C1COCC1>[CH2:24]([C@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:14][C:13]([CH3:15])([CH3:16])[N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:25]#[C:26][CH3:27]
Reactant: C#CC[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC#CC[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
A solution of (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(prop-2-ynyl)oxazolidine-3-carboxylate (0.60 g, 1.6 mmol) in THF (5 mL) was cooled to −78° C. and butyllithium (0.75 mL, 1.9 mmol) was added dropwise. After 5 min, the mixture was re-cooled to −78° C. and iodomethane (0.15 mL, 2.3 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h and brought to RT and stirred for 15 h. The reaction mixture was quenched with sat NH4Cl, filtered, concentrated, and chromatographed on silica gel eluting with hexanes to afford a light yellow oil as (4S,5S)-tert-butyl 4-(but-2-ynyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.463 g, 74% yield). MS m/z: 298 (M+1).
Reaction SMILES: [C-]#N.[K+].[CH3:4][N:5](C=O)C.[C:9]([O:12][CH2:13][C:14]1([CH2:17]Br)[CH2:16][CH2:15]1)(=[O:11])[CH3:10].O>C1(C)C=CC=CC=1>[C:9]([O:12][CH2:13][C:14]1([CH2:17][C:4]#[N:5])[CH2:16][CH2:15]1)(=[O:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(=O)OCC1(CBr)CC1
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OCC1(CC#N)CC1
Temperature: 80 °C
Yield: 119.5 %

Procedure:
A 12 L 4-neck round bottle flask was equipped with mechanical stirrer, a thermometer, a condenser, a nitrogen inlet and an additional funnel. To the flask was charged 1335 mL of and 667 g of potassium cyanide and kept stirring to complete dissolution. 1417 g of DMF and 1417 g of crude [1-(bromomethyl)cyclopropyl]methyl acetate were added from the addition funnel over 30 min. When the addition was complete, the reaction mixture was heated to 80° C. with stirring about 1 hour. The resulting mixture was cooled to about 20˜25° C. 3500 mL of water and 3500 mL of toluene were added to the reaction mixture with stirring over 30 min. The layers were separated and the aqueous layer was back extracted with 3500 mL of toluene. Combined the organic layer and then concentrated to obtain 1253 g dark brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)=[C:11]=[O:12]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(Br)cc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.5 %

Procedure:
A 0° C. solution of 4-bromo-2-fluoroaniline (1 g, 5.26 mmol) in dichloromethane (10 mL) was treated dropwise with 1-isocyanato-3-methylbenzene (0.71 mL, 5.26 mmol), warmed to room temperature, stirred for 18 hours, and filtered. The filter cake was washed with dichloromethane and dried to provide 0.62 g of the desired product. MS (ESI(−)) m/e 321 (M−H)−.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:32]=[C:31]([O:33][CH3:34])[C:25]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[C:24]([O:35][CH3:36])[CH:23]=1)CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:32]=[C:31]([O:33][CH3:34])[C:25]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[C:24]([O:35][CH3:36])[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1N(C)C(C)=O

Procedure:
A mixture of 3.24 g. of sodium methylate, 8.75 g. of β-anilino-propionitrile and 14.9 g. of 4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2',6'-dimethoxy-N-methyl-acetanilide in 60 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 4 hours with the exclusion of moisture. The solution was poured into 600 ml. of water. The resulting emulsion was extracted with two 400 ml. portions of ethyl acetate. Thereafter, the ethyl acetate extracts were washed with two 150 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-N-methyl-acetanilide having a melting point of 202°-204° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.I[CH3:31]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:11]=[C:10]3[N:27]([CH3:31])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc3[nH]ncc3c(-c3ccc(Cl)nc3)c2-c2ccncc2)cn1
Reactant: CI
Product: Cn1ncc2c(-c3ccc(Cl)nc3)c(-c3ccncc3)c(-c3ccc(Cl)nc3)nc21

Procedure:
Following a similar procedure to that described in examples 73 and 74, but using 4,6-bis(6-chloropyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 40) instead of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and iodomethane instead of 2-bromo-1,1-diethoxyethane, the title compounds were obtained.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CC(C)=O.[OH-].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19]>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH:17]2[CH:1]([OH:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:4]2)=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1Oc2ccccc2C1O

Procedure:
To a solution of 15.3 g. (0.125 mol.) of salicylaldehyde in 100 ml. of acetone was added 7.0 g. (0.125 mol.) of potassium hydroxide dissolved in a minimum amount of water. α-Bromo-p-chloroacetophenone (29.16 g., 0.125 mol.) was added dropwise with stirring and cooling (ice bath). After addition, the reaction mixture was stirred at 25° for 12 hours. The precipitate was collected by filtration, washed with water and combined with the residue remaining after concentration of the filtrate to give 2-(4'-chlorobenzoyl)-3-hydroxycoumaran which was immediately dehydrated in the presence of p-toluenesulfonic acid to yield 2-(4'-chlorobenzoyl)benzofuran.
Reaction SMILES: [Cl-].[Li+].[Cu]C#N.[Cl-].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Zn+])=[CH:10][CH:9]=1.B(F)(F)F.CCOCC.[C:25]1([S:31]([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][CH:38]([C:37]2[CH:36]=[CH:35][C:34]([S:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)(=[O:32])=[O:33])=[CH:41][CH:40]=2)[OH:39])=[CH:10][CH:9]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: N#C[Cu]
Agent: FB(F)F
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(C(O)Cc2ccc(F)cc2)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Lithium chloride (0.57 g, 13.5 mmol, dried at 140° C. under vacuum) and copper(I) cyanide (0.605 g, 6.8 mmol) were dissolved in tetrahydrofuran (5 mL) and cooled to −40° C. under nitrogen. 4-Fluorobenzylzinc chloride (0.5M in tetrahydrofuran, 15 mL) was added dropwise and the solution cooled to −20° C. for 5 minutes then to −78° C. Boron trifluoride diethyl etherate (1.7 mL, 13.5 mmol) and 4-(phenylsulfonyl)benzaldehyde (Example 113 Step 1, 300 mg, 1.2 mmol) in tetrahydrofuran (5 mL) were added and the reaction stirred at −78° C. for 30 minutes then warmed to 25° C. and quenched with saturated ammonium chloride solution. Ethyl acetate was added and the mixture stirred for 10 minutes then the layers separated. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, to give the title compound as a white solid (0.386 g, 90%). δH (360 MHz, CDCl3): 7.94–7.88 (4H, m), 7.58–7.43 (5H, m), 7.10–7.02 (2H, m), 6.99–6.93 (2H, m), 4.92–4.88 (1H, m), 2.99–2.85 (2H, m), 2.01 (1H, d, J=3.2 Hz).
Reaction SMILES: C1(S(O)(=O)=[O:8])C=CC=CC=1.[CH:11]([C@:14]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:18][CH2:17][C@@H:16]([NH:19][C@H:20]2[CH2:25][CH2:24][O:23][CH2:22][C@H:21]2[O:26][CH3:27])[CH2:15]1)([CH3:13])[CH3:12].[C:44]([O-:47])([O-:46])=O.[K+].[K+]>O>[C:24]([OH:8])(=[O:23])[CH2:25][CH2:20][C:44]([OH:47])=[O:46].[CH:11]([C@:14]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:18][CH2:17][C@@H:16]([NH:19][C@H:20]2[CH2:25][CH2:24][O:23][CH2:22][C@H:21]2[O:26][CH3:27])[CH2:15]1)([CH3:13])[CH3:12]
Reactant: O=S(=O)(O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)(C(C)C)C1
Agent: [K+]
Solvent: O
Product: O=C(O)CCC(=O)O
Reaction time: 0.25 h

Procedure:
Purification from Benzenesulfonate Salt: The resulting oil from the Example 1 was dissolved in IPA (1.54 L) and transferred to crystallization flask. An IPA (2×385 mL) rinse was added to the batch. The solution was warmed to 56° C. at which point benzenesulfonic acid (283 g, 1.79 mol) was added which resulted in an increase in temperature to 71° C. The solution was cooled to 60° C. and benzenesulfonate salt seed (1 g) was added. The thin slurry was aged for 30 min to develop a thick seed bed after which heptane (4.62 L) was added over 50 min. After aging at 55 to 65° C. for 2 h the slurry was cooled to ambient temperature overnight. The slurry was filtered and the wet cake was washed with 2:1 heptane/IPA (2×2.3 L). The off-white solid was dried under N2/vacuum to give the benzenesulfonate salt (875 g, 98.3 wt %) as a tan solid (84% adjusted yield). Water (11.1 L), IPAc (32 L), and ((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine benzenesulfonate salt (1.645 kg) were added to a solution of K2CO3 (6.58 kg) in water (18.3 L). The mixture was aged 15 min. The layers were separated and the organic layer was washed with water (16 L). The IPAc solution of ((1R,3S)-3-Isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine free base (60.5 kg containing 1.16 kg free base) was concentrated to an oil. The resulting oil was diluted with ethanol (3.785 L) and reconcentrated to an oil. The dilution and concentration were repeated three more times.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.C(OC(=O)[CH2:16][CH2:17][C:18]1[N:27]([CH2:28][C:29]([O:31]C(C)(C)C)=O)[C:21]2=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=[C:20]2[CH:19]=1)C>C1COCC1.[Cl-].[Na+].O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]2[CH:19]=[C:18]3[N:27]([C:21]=2[N:22]=1)[CH2:28][C:29](=[O:31])[CH2:16][CH2:17]3
Reactant: CCOC(=O)CCc1cc2ccc(Cl)nc2n1CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCc2cc3ccc(Cl)nc3n2C1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
2.5 ml of 1M KOtBu THF solution was added to 20 mL of THF and the solution was cooled at −10° C. A solution of 3-(1-tert-butoxycarbonylmethyl-6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-propionic acid ethyl ester (0.73 g) in 4 mL of THF was added over 2 min. After stirring for 15 min at −10° C., 3 mL of 1 N HCL was added, followed by 10 mL brine. The mixture was extracted with 40 mL of EtOAc, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in 30 mL of toluene and added 1 g of silica gel, and the resulting mixture was heated to reflux for 3 h. After cooling, the reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography eluted with 40% EtOAc/hexane to give 0.3 g of the title product as beige solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>C1COCC1.C1(C)C=CC=CC=1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:33])[N:2]([CH3:1])[C:3]2[N:8]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[N:6]=[CH:5][N:4]=2)=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCN1CCN(c2ccc(Nc3ncnc(NC)n3)cc2)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(Nc3ncnc(N(C)C(=O)Nc4ccc(F)c(C(F)(F)F)c4)n3)cc2)CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of N-methyl-N′-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (24 mg, 0.077 mmol) in 1.5 ml THF and 2.5 ml toluene, 4-fluoro-3-trifluoromethyl-phenyl-isocyanate (25 μl, 0.17 mmol) is added and the mixture is stirred for 5 h at 100° C. Workup analogously as described in Example 171 gives the title compound: ESI-MS: 519 [MH]+; tR=4.3 min (purity: 100%, gradient J); TLC: Rf=0.43 (DCM/MeOH 9).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([C:18]1([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17].O>C1C=CC=CC=1>[C:16]([C:18]1([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:20][C:21]2([O:4][CH2:1][CH2:2][O:3]2)[CH2:22][CH2:23]1)#[N:17]
Reactant: OCCO
Reactant: N#CC1(c2cccs2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N#CC1(c2cccs2)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
Ethylene glycol (9.08 g) and p-toluenesulfonic acid (0.0139 g) were added to a solution of 4-cyano-4-(thiophen-2-yl)cyclohexanone (15 g) in benzene (120 ml) and the reaction mixture was boiled under reflux for 4 hours at 110° C. on a water separator (Dean-Stark apparatus). The reaction mixture was cooled to RT and the organic phase was washed with aqueous sodium bicarbonate solution (1×150 ml), water (1×150 ml) and saturated NaCl solution (1×150 ml). After drying over Na2SO4, the solvents were removed under reduced pressure.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:19]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: NCc1ccccc1Cl
Product: Clc1ccccc1Cn1cnnc1-c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 2-chlorobenzylamine (0.5 ml) as described above; yield: 0.089 g (28.8%);
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[N:10]=[CH:9][NH:8][C:7](=[S:11])[CH:6]=1.Br[CH2:15][CH2:16][CH:17]([F:22])[C:18]([Br:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:21][C:18]([F:20])([F:19])[CH:17]([F:22])[CH2:16][CH2:15][S:11][C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:12])[F:13])[N:10]=[CH:9][N:8]=1
Reactant: FC(CCBr)C(F)(F)Br
Reactant: FC(F)(F)COc1cc(=S)[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(CCSc1cc(OCC(F)(F)F)ncn1)C(F)(F)Br
Temperature: 25 °C
Reaction time: 7 h
Yield: 53.5 %

Procedure:
6-(2,2,2-trifluoroethoxy)-4(3H)-pyrimidinethione (see Example 1B) (3 g) and 1,4-dibromo-3,4,4-trifluorobutane (see Example 3A) (3.86 g) were added to acetone (50 cm3) containing potassium carbonate (1.97 g) and the mixture stirred at ambient temperature for 7 hours. After standing for a further 16 hours, tlc showed the reaction to be incomplete, so the mixture was heated to reflux for 5 hours. The reaction was then allowed to cool, inorganic solids were filtered off and washed with more acetone. Evaporation of the combined organic layers at reduced pressure afforded a brown oil which was chromatographed on silica gel, eluting with 1:4 ethyl acetate:hexane. This gave the title pyrimidine (3.05 g). M+ =399; 1H NMR (CDCl3): δ2.2-2.4(2H,m); 3.25-3.50(2H,m); 4.68-4.95(1H,m); 4.8(2H,q); 6.73(1H,s); 8.58(1H,s); (oil).