Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1OC(C(O)=O)=CC=1.C(=O)(O)[O-].[Na+].F[B-](F)(F)F.Br[C:21]1[O:25][C:24]([F:26])=[CH:23][CH:22]=1.C([Li])CCC.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>CCCCC.O.CCCCC>[F:26][C:24]1[O:25][C:21]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:22][CH:23]=1
Reactant: Fc1ccc(Br)o1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: F[B-](F)(F)F
Agent: O=C(O)c1ccc(Br)o1
Agent: O=C([O-])O
Solvent: CCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(F)o1
Temperature: 25 °C

Procedure:
5-Bromo-2-furoic acid (300 mg, 1.57 mmol) and sodium bicarbonate (316 mg, 3.76 mmol) was stirred in 3.5 mL of pentane/water (2:5) at room temperature for 5 minutes. 1-Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis-(tetrafluoroborate (“Selectfluor®”) (668 mg, 1.88 mmol) was added, and the mixture was stirred for another hour at room temperature. The pentane layer containing 5-bromo-2-fluorofuran was separated from the mixture, dried (MgSO4), and used for next step directly. The pentane solution of 5-bromo-2-fluorofuran was diluted with 3 mL of anhydrous ether, and cooled to −78° C. under nitrogen. n-Butyllithium (1.6M, 0.25 mL, 0.39 mmol) was added, and the solution was stirred at −78° C. for 10 minutes. Tri-n-butylstannyl chloride (127 mg, 0.39 mmol) then was added, and the solution was allowed to warm to room temperature, and stirred for another 20 minutes. The mixture was quenched and washed with 1N sodium hydroxide, then the organic layer was separated, dried through MgSO4, and filtered, and then the solvent was evaporated to give the sub-title compound (155 mg) as a brown oil which was used without further purification for the next step.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:44]=[CH:43][S:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:44]=[CH:43][S:42][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccsc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccsc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 51.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 3-(chloromethyl)thiophene (0.27 g) as starting materials, 5-benzyloxy-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.48 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.39 g) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].[NH4+].[Cl-]>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:10]([CH3:11])[C:8](=[O:9])[C:7]2[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=[C:5]([S:4][CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[CH:6]=2)=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNS(C)(=O)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of 3-(2-aminoethylthio)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.12 g, 250 μmol, example 237) and DIPEA (64.7 mg, 87.4 μL, 501 μmol) in CH2Cl2 (2 mL) was added methanesulfonyl chloride (35.8 mg, 24.4 μL, 313 μmol) and the clear colorless solution was stirred at 0° C. for 2.5 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.121 g; 86%). MS (ESI): m/z=558.11 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:20])[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CNc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CNc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 52 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([CH2:19][OH:20])=[CH:7][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30](N)[N:29]=1>C1COCC1>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([CH2:19][OH:20])=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=2)[N:10]=1
Reactant: NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(CO)c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 70 °C

Procedure:
{2-[(2-aminoethyl)amino]-4-(2,4-dichlorophenyl)pyrimidin-5-yl}methan-1-ol was dissolved in 3 mL of anhydrous THF and 1.47 g (4.50 mmol) of anhydrous cesium carbonate was added. 2-chloro-5-nitro-6-aminopyridine (143 mg, 0.9 mmol) was added in one portion and the yellow suspension heated at 70° C. for 18 h. The reaction mixture was filtered, concentrated and the residue chromatographed (silica gel, 5% methanol/methylene chloride) to give [4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]methan-1-ol, 216 mg (53%), as a yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][NH:8][C:9]([C:11]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[C:25](=[O:31])[NH:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:19])[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:12]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:27]1([NH:26][C:25]([C@@H:21]2[CH2:22][CH2:23][CH2:24][N:20]2[C:18](=[O:19])[CH2:17][O:16][C:14]2[N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:38])=[O:5])=[O:10])[CH:15]=2)=[O:31])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 5 h

Procedure:
To a solution of 1.33 g ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid tert-butyl ester in 20 ml dichloromethane were added 3.8 ml TFA. After stirring for 5 h it was concentrated and codistilled twice with toluene to give the crude product. Yield: 1.58 g
Reaction SMILES: COCCOC.[CH2:7]([N:14]1[CH2:43][CH2:42][C:17]2[N:18]=[C:19](Cl)[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[C@H:24]([CH3:40])[CH2:23]3)[C:16]=2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][C:52]=2B2OC(C)(C)C(C)(C)O2)[N:47]([S:63]([C:66]2[CH:72]=[CH:71][C:69]([CH3:70])=[CH:68][CH:67]=2)(=[O:65])=[O:64])[CH:46]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([N:14]1[CH2:43][CH2:42][C:17]2[N:18]=[C:19]([C:52]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:53]=3[C:45]([CH3:44])=[CH:46][N:47]4[S:63]([C:66]3[CH:72]=[CH:71][C:69]([CH3:70])=[CH:68][CH:67]=3)(=[O:65])=[O:64])[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[C@H:24]([CH3:40])[CH2:23]3)[C:16]=2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(B4OC(C)(C)C(C)(C)O4)cccc32)cc1
Reactant: C[C@@H]1CN(c2nc(Cl)nc3c2CN(Cc2ccccc2)CC3)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(=O)(=O)c7ccccc7[N+](=O)[O-])[C@H](C)C6)n4)CN(Cc4ccccc4)CC5)cccc32)cc1
Temperature: 140 °C

Procedure:
1,2-Dimethoxyethane (6.75 mL) was added to a 20 mL microwave vial containing a mixture of (R)-6-benzyl-2-chloro-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.1 g, 2.03 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (0.92 g, 2.23 mmol). Then 2M aqueous Na2CO3 was added and the reaction mixture was degassed via three argon/vacuum cycles, then charged with Pd(Ph3P)4 (0.234 g, 0.203 mmol). The vial was sealed and heated via microwave irradiation at 140° C. for 90 minutes. The mixture was then cooled to room temperature and diluted with Et2O and water. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography [55-75% ethyl acetate (containing 2% EtOH)/heptanes] to afford (R)-6-benzyl-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 792.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[C:23]([F:22])([F:32])[F:33])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1ccccc1C(F)(F)F
Solvent: CCO
Product: O[C@H](CNCc1ccccc1C(F)(F)F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 2-(trifluoromethyl)benzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=96%, [M+H]+=461.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:30]([CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH3:31]>>[CH2:30]([CH:32]1[CH2:37][CH2:36][CH:35]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:34][CH2:33]1)[CH3:31]
Reactant: CCC1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-ethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([N:7]([CH2:15][CH:16]=[O:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH2:6].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].N12CCC(CC1)CC2>CO>[C:10]([O:9][C:8]([N:7]([C@@H:4]([CH:5]=[CH2:6])[CH2:3][O:2][CH3:1])[CH2:15][CH:16]([OH:17])[C:19](=[CH2:20])[C:18]([O:22][CH3:23])=[O:21])=[O:14])([CH3:12])([CH3:13])[CH3:11]
Reactant: C=C[C@@H](COC)N(CC=O)C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Agent: C1CN2CCC1CC2
Solvent: CO
Product: C=C[C@@H](COC)N(CC(O)C(=C)C(=O)OC)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of (S)-tert-butyl 1-methoxybut-3-en-2-yl(2-oxoethyl)carbamate (Intermediate 252, 1.475 g, 6.06 mmol) and methyl acrylate (0.82 ml, 9.09 mmol) in MeOH (0.2 ml) under nitrogen at room temperature was added quinuclidine (0.337 g, 3.03 mmol). The reaction mixture was stirred at that temperature overnight. Another 100 mg of quinuclidine was added and the reaction was stirred for another 24 hours. The reaction mixture was then partitioned between water and ethyl acetate. The layers were separated and the organics were washed with water and brine, then dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-30% ethyl acetate/hexanes) afforded the title compound as a clear oil (1.28 g, 65%). The product is a mixture of two diastereomers.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:55])[C:51]([F:54])([F:53])[F:52])=[CH:46][CH:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([C:50](=[O:55])[C:51]([F:53])([F:54])[F:52])=[CH:46][CH:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:14][CH2:13]1)=[O:17]
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (250 mg, 0.40 mmol) is coupled to 4′-bromo-2,2,2-trifluoroacetophenone (120 mg, 0.48 mmol) using Method B to give the title compound.
Reaction SMILES: [N:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30](O)=[O:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30]([N:4]1[CH2:3][CH2:2][N:1]([N:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3=[O:13])[CH2:6][CH2:5]1)=[O:31])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C1CCCCN1N1CCNCC1
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCN(N2CCCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.8 %

Procedure:
1-(piperazin-1-yl)piperidin-2-one (0.44 g) obtained in Example 8b), (2S)-3-[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.76 g), HOBt (0.37 g) and triethylamine (0.34 mL) were dissolved in DMF (10 mL), WSC (0.46 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was washed with an aqueous sodium bicarbonate solution and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1), and recrystallized form ethyl acetate to obtain the title compound (0.32 g, 28%) as a colorless powder.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([Br:22])[N:19]=[CH:18][C:17]=2[NH2:23])=[CH:12][CH:11]=1>C(OC(OCC)OCC)C>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:16]3[CH:21]=[C:20]([Br:22])[N:19]=[CH:18][C:17]=3[N:23]=[CH:1]2)=[CH:24][CH:25]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNc2cc(Br)ncc2N)cc1
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Cn2cnc3cnc(Br)cc32)cc1
Temperature: 100 °C
Yield: 108.8 %

Procedure:
Acetic anhydride (1.28 mL, 13.6 mmol) was added to a solution of N4-(4-methoxybenzyl)-6-bromopyridine-3,4-diamine (1.05 g, 3.41 mmol) in triethylorthoformate (13 mL). The mixture was heated at 100° C. for 18 hours and then concentrated to give the title compound as a brown oil (1.18 g, quantitative). 1H NMR (d6-DMSO, 400 MHz) δ 8.75 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 7.35 (d, 2H, J=8.8 Hz), 6.90 (d, 2H, J=8.8 Hz), 5.45 (s, 2H), 3.70 (s, 3H). LCMS (2) Rt=2.27 min; m/z (ESI+) 318, 320 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[CH2:25]1COCC1.C[Mg]Br.C(OCC)C>O>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[O:16][C:15]([CH:17]([OH:18])[CH3:25])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC(O)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-pyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde (0.4 g, 0.0012 mol) and THF (15 mL) were added and cooled to 0-5° C. To the flask was slowly added 3.0 M methyl magnesium bromide in diethyl ether (0.6 mL, 0.0036 mol). The resulting reaction mixture was stirred at room temperature for 2 h. To the reaction mass, water was added and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced to get the crude product. The crude product was purified by column chromatography using 1% MeOH in chloroform [0.17 g, 40%]. LC-MS (ESI): Calculated mass: 360.1; Observed mass: 361.1(RT: 1.29 min).
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([Cl:12])[CH:5]=1)[CH:2]=C.C[OH:14]>C(Cl)Cl>[Cl:12][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[O:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CO
Reactant: C=CCc1ccc(C#N)c(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-Allyl-2-chlorobenzonitrile (265 mg, 1.5 mmol) in DCM (2 mL) and methanol (2 mL) was cooled to −78° C. Then O3 was bubbled into for 10 minutes. Then dimethylsulfide (1 mL) was added and the mixture was stirred at RT for 5 hours. The mixture was concentrated in vacuo to give the title product.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][NH:4][N:3]=1.O1CCCC1.C(=O)(O)[O-].[Na+].[F:20][C:21]([F:31])([F:30])[CH2:22][CH2:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH2:23][CH2:22][C:21]([F:31])([F:30])[F:20])=[CH:5][NH:4][N:3]=1
Reactant: O=C(Cl)CCSCCC(F)(F)F
Reactant: CCNc1c[nH]nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(C(=O)CCSCCC(F)(F)F)c1c[nH]nc1Cl
Temperature: 5 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A 500-mL 3-neck flask was charged with 3-chloro-N-ethyl-1H-pyrazol-4-amine (3.25 g, 22.3 mmol), tetrahydrofuran (80 mL) and water (80 mL). The resulting suspension was cooled to 5° C. and sodium bicarbonate (3.75 g, 44.6 mmol) was added, followed by dropwise addition of 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (5.42 g, 24.56 mmol) at <5° C. The reaction mixture was stirred at <10° C. for 3 hours. The reaction mixture was poured into water (100 mL) and the mixture was extracted with dichloromethane (150 mL×3). The combined organics were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to afford crude product as a light brown oil, which was purified by flash column chromatography using 0-5% methanol/dichloromethane as eluent. The fractions containing pure product were concentrated to give the desired product as a white solid (3.60 g, 48%): mp 67-68° C.; 1H NMR (400 MHz, CDCl3) δ 11.55 (bs, 1H), 7.65 (s, 1H), 3.73-3.68 (dd, J1=7.2, J2=14.0, 2H), 2.86-2.82 (t, J=7.2, 2H), 2.67-2.63 (t, J=8.0, 2H), 2.45-2.30 (m, 4H), 1.16-1.12 (t, J=7.2, 3H); 13C NMR (101 MHz, CDCl3) δ 171.87, 137.89, 128.40, 125.97 (q, J=277.4 Hz), 120.81, 44.01, 34.31 (q, J=27.3 Hz), 33.97, 27.30, 24.08 (q, J=3.4 Hz), 12.77; ESIMS m/z 330 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[CH2:2][N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])[O:10][CH:9]([C:13]([F:16])([F:15])[F:14])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: CNC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(CN(C)C(C)C)cc2OC1C(F)(F)F
Reaction time: 3 h

Procedure:
The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (01597/1 PR) (1.0 g, 2.5 mmol) was dissolved in DMF (5 mL). The solution was cooled at ice bath under nitrogen and the isopropyl(methyl)-amine (0.26 mL, 2.5 mmole) was added into the solution followed by addition of potassium carbonate (0.345 g, 2.5 mmol). After the mixture was stirred at r.t for 3 hr, LCMS indicated that the product was formed. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 and filtered. The filtrate was concentrated to afford the crude product. The ester was of suitable purity to use without further purification.