Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][C:15]1[S:16][C:17]2[C:26]3[C:25](=O)[CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:14][C:15]1[S:16][C:17]2[C:26]3[C:25](=[CH:3][C:1]#[N:2])[CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1nc2ccc3c(c2s1)C(=O)CC3
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2s1)C(=CC#N)CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a suspension of diethyl cyanomethylphosphonate (393 mg, 2.22 mmol) in tetrahydrofuran (6 mL) was added 65% sodium hydride (66.0 mg, 1.79 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Thereto was added a solution of 2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-one (300 mg, 1.48 mmol) in tetrahydrofuran (6 mL), and the mixture was stirred at room temperature for 2 hr. To the mixture were added diethyl cyanomethylphosphonate (131 mg, 0.74 mmol) and 65% sodium hydride (16.0 mg, 0.43 mmol), and the mixture was further stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (181 mg, yield 54%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=1>O.Cl>[F:12][C:10]1[CH:9]=[CH:8][C:7]2[N:13]([C:14]3[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[N:1]=[N:5][C:6]=2[CH:11]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(F)cc2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(Oc1ccc(-n2nnc3cc(F)ccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.1 of sodium nitrite in 25 ml of water was added drop-by-drop to a stirred solution of 6.7 g of 7B in 150 ml of 12% hydrochloric acid at 2° C. The resulting mixture was stirred at room temperature for 12 hours, then was filtered. Recrystallization of the filter cake from ether/hexane gave 7, as a solid, m.p.: 164°-166° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18](O)[CH2:17][CH2:16]2)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2].CS(Cl)(=O)=O.C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19]([CH:18]=[CH:17][CH2:16]2)=[CH:20][CH:21]=1)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CC=C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
In 5 ml of pyridine was dissolved 1.0 g of 1-acetoxy-1-[(1-hydroxy)indan-5-yl]-2-[2-(N,N-dimethylamino)ethoxy]ethane. To the solution was added 0.3 ml of methanesulfonyl chloride at room temeprature. The resulting mixture was stirred at the same temperature overnight. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The resulting mixture was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=10/1) to obtain 80 mg of oily 1-acetoxy-1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethane (compound No. 297).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH:63]=[CH2:64])[CH2:45]2)[CH:7]([CH3:66])[CH2:6][CH2:5][C:4]1=[O:67])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH2:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH2:6][CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (20 mg) (EXAMPLE 31) in ethyl acetate (500 μl) was added rhodium on carbon (5 mg). The flask was filled with hydrogen, and the mixture was stirred at room temperature. After 1.5 hours the mixture was filtered through Celite then the solvent was removed in vacuo to give the title compound (20 mg). MASS (FAB) 940 (M+Li); Partial 1H NMR δ: 7.18 (s,1H); 7.16 (d, J=9 Hz, 1H); 6.96 (d, J=3 Hz, 1H); 6.92 (dd, J=9,3 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.55 (brd, J=4 Hz, 1H); 3.72 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:28]I>CN(C=O)C.[Ag]=O>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[N:5]([C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH3:28]
Reactant: CI
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COCCC1(C(=O)N(C)[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (2.73 mmol, 1.03 g) and silver oxide (10.9 mmol, 2.53 g) in DMF (25 mL) was added methyl iodide (160 mmol, 10 mL) at room temperature. The suspesion was stirred for 2 days at room temperature at which time TLC analysis of the mixture indicated the presence of starting material. An additional 10 mL (160 mmol) of methyl iodide and 2 g (8.6 mmol) of silver oxide were added, respectively. The suspension was stirred for 24 h and the solid was filtered through a pad of celite and was washed with ethyl acetate (30 mL) and methanol (30 mL). The filtrate was concentrated and the residue was extracted with ethyl acetate (3×30 mL).The organic layer was washed with water (20 mL) and brine solution (20 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude compound which was purified by silica gel column chromatography to obtain 530 mg (50%) as a light brown oil. HR MS (C20H28N2O6): Obs. mass, 392.1940. Calcd. mass, 392.1947 (M+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:9][C:10](=[O:25])[N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[CH2:12]1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:7][CH:8]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:9][C:10]([N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[CH2:12]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2ccnc2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(CC(=O)N1Cc2ccccc2-n2ccnc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of [3-oxo-3-(4H,6H-3,5,10b-triaza-benzo[e]azulen-5-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) in DCM (3 mL), was added trifluoroacetic acid (0.18 nit, 3 mL/mmol)). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 3-amino-1-(4H,6H-3,5,10b-triaza-benzo[e]azulen-5-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one (30 mg, 98%).
Reaction SMILES: [O:1]1[CH2:5][CH:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:1]1[CH2:5][CH:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[N:33][C:34]=4[NH2:36])[N:29]([C@H:37]4[CH2:38][CH2:39][C@@H:40]([N:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)[CH2:41][CH2:42]4)[N:28]=3)=[CH:11][CH:12]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: CC1(C)OB(c2ccc(NC3COc4ccccc43)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC5COc6ccccc65)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 20.2 %

Procedure:
A mixture of N-(2,3-dihydrobenzo[b]furan-3-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.080 g, 0.000237 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.087 g, 0.000198 mol), tetrakis-(triphenylphosphine)palladium (0.014 g, 0.000012 mol) and sodium carbonate monohydrate (0.061 g, 0.000495 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1 M ammonium acetate over 25 min, 21 mL/min). Subsequently, the crude product was dissolved in dichloromethane, loaded onto Trikonex column (7 cm) and eluted with dichloromethane (5 mL). The desired band was cut, the product was extracted with a mixture of dichloromethane/methanol/triethylamine in a ratio of 90:5:5 (10 mL) and the solvents were removed under reduced pressure. The residue was triturated in diethyl ether and the precipitate was collected by filtration and dried to yield cis-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.021 g, 0.00004 mol) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:19]1[C:24]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[NH:11][C:10]4[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=4[N:8]=3)[CH2:5][CH2:6]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: Clc1nccnc1Cl
Reactant: N#Cc1ccc2[nH]c(C3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4Cl)CC3)nc2c1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
The mixture of 2-piperidin-4-yl-1H-benzoimidazole-5-carbonitrile (2 g, 8.8 mmol), 2,3-dichloro-pyrazine (1.43 g, 9.7 mmol) and K2CO3 (2.4 g, 17.6 mmol) in CH3CN (20 mL) was heated to 80° C. for 10 h, then it was concentrated and partitioned between DCM and H2O. The organic layer was dried over Na2SO4 and concentrated to give the desired compound (1.5 g, 65%). The crude product was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.C[O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]#N)=[CH:16][C:15]=1[CH3:23]>>[C:2]1([C:1]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH:7]=[CH:6][C:5]([CH2:21][S:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([OH:10])=[O:24])=[C:15]([CH3:23])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(SC#N)cc1C
Reactant: Cc1ccccc1O
Product: Cc1cc(SCc2ccc(-c3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in a manner analogous to Example 1B from 2-methylphenol. 400 MHz 1H NMR (DMSO-d6) δ 10.09 (s, 1H), 7.36 (s, 1H), 7.30 (d, 1H, J=8.1 Hz), 6.83 (d, 1H, J=8.1 Hz), 2.08 (s, 3H); MS m/z 166 (M+1). Step 2. Preparation of (2-Methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester (Compound 2B)
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]2)=[N:24][CH:25]=1>>[OH:31][CH:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][N:22]=2)[CH2:27]1
Reactant: Nc1cnc(N2CCC(O)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1cnc(N2CCC(O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C19H16F3N5O3 m/e 419.37, obsd 420.0 (ES, M+H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:33])=[C:5]1[C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3cccc(C(F)(F)F)c3)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 149.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (55 mg, 0.12 mmol), β-alanine (863 mg, 9.7 mmol) and NaOMe solution (14.5 mL, 7.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 46 mg of the title compound. MS: (+) m/z 512.27 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]2[C:6]([C:7](O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[N:12]2
Reactant: CCc1ccc2c(O)ccnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ccc2c(Cl)ccnc2n1
Yield: 83 %

Procedure:
The product from Example 8e (200 mg, 1.14 mmol) was treated with POCl3 following the procedure from Example 7d giving the title compound as a brown solid (183 mg, 83%).
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:4][CH3:5])[CH3:2].[CH2:18]([O:20][CH2:21][C:22](Cl)=[O:23])[CH3:19]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:6]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[C:22](=[O:23])[CH2:21][O:20][CH2:18][CH3:19])[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CCN(C=Cc1cccc(C(F)(F)F)c1)CC
Solvent: c1ccncc1
Product: CCOCC(=O)C(=CN(CC)CC)c1cccc(C(F)(F)F)c1

Procedure:
An enaminoketone was formed from 4.86 g. of N,N-diethyl-3-trifluoromethylstyrylamine and 2.44 g. of ethoxyacetyl chloride in the presence of 1.6 g. of pyridine. The desired enaminoketone, 1-diethylamino-4-ethoxy-2-(3-trifluoromethylphenyl)-1-buten-3-one was formed. To the unpurified enaminoketone in 75 ml. of anhydrous tetrahydrofuran at 0° C. was added 3.2 g. of sodium methoxide, and the mixture was stirred for 15 minutes. To this mixture was added 4.4 g. of ethyl formate dropwise. The mixture was stirred for three hours, and 50 ml. of a 40 percent methylamine solution in water was added followed by 5 g. of methylamine hydrochloride. The reaction mixture was stirred overnight at ambient temperature, and was then evaporated to dryness under vacuum. The residue was taken up in dichloromethane, and the solution was washed with water and dried over magnesium sulfate. The dry solution was filtered, and evaporated under vacuum to obtain a dark residue which was triturated in cold diisopropyl ether. The solids were removed by filtration and recrystallized from diisopropyl etherdichloromethane to obtain 1.6 g. of 3-ethoxy-1-methyl-5-(3-trifluoromethylthylphenyl)-4(1H)-pyridone, m.p. 131°-133° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[C:25]([F:28])([F:27])[F:26])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>ClCCl.[Cu]I>[CH3:29][C@H:12]1[N:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:30]3[CH:34]=[N:33][CH:32]=[N:31]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[C:25]([F:27])([F:28])[F:26])[CH2:13]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(-n2cncn2)c1
Temperature: 166 °C

Procedure:
A mixture of 4-{(3R)-4-[(3-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluoromethyl)benzonitrile (349 mg, 0.82 mmol), 1,2,4-triazole (112.6 mg, 1.64 mmol), K2CO3 (226.7 mg, 1.64 mmol), and CuI (15.6 mg, 0.082 mmol) were charged to a microwave vial. NMP (3 mL) was introduced under nitrogen atmosphere and the reaction mixture was heated at 166° C. for 3 hr in an oil bath. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via prep HPLC under neutral condition to yield 4-((3R)-3-methyl-4-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile as a light tan color solid (176.8 mg, 45.3% yield). HRMS: calcd for C21H19F3N6O2S+H+, 477.13150. found (ESI-FTMS, [M+H]1+), 477.13303.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([O:31][Si](C)(C)C)=[C:28]([CH3:30])[CH3:29]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:28]([CH3:30])([CH3:29])[C:27]([O:26][CH3:25])=[O:31])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
(1-(4-Fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (16.0 g, 50 mmol) was dissolved in 400 mL of dry THF and TiCl4 (60 mL of 1.0 M DCM solution, 60 mmol) was added portionwise and then stirred 30 min. The flask was put on a rotary evaporator until the THF began to distill to degas the HCl and then the reaction was treated with 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (17.4 g, 100 mmol). The reaction was quenched with aqueous sodium bicarbonate and extracted 2× EtOAc, the organic layers dried over MgSO4, filtered, concentrated, and then chromatographed using DCM to give 16.2 g (81% yield) of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate. MS found: (M+H)+=403.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:8]([O:20][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCO
Reactant: O=C1C=CC(=O)O1
Product: CCCCCCCCCCCCOC(=O)/C=C\C(=O)O

Procedure:
Into an autoclave, were charged 295 parts of maleic anhydride and 560 parts of lauryl alcohol. The mixture was reacted at 60° C. for 5 hours under sealed condition, to obtain maleic acid monolauryl ester, containing 1.3% unreacted maleic anhydride. After adding to the mixture, 275 parts of allyl chloride and 375 parts of triethyl amine, an atmosphere was substituted with nitrogen. The mixture was reacted at 80° C. for 8 hours, and cooled to a room temperature. The mixture was rinsed by 90 parts of 10% hydrochloric acid aqueous solution, to obtain 960 parts of lauryl allyl maleate of 92.7% purity and of Gardner Color more than 10. A molar ratio of maleic anhydride:lauryl alcohol was 1:1, and maleic acid monolauryl ester:allyl chloride:triethyl amine was 1:1.19:1.23.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[F:15][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:17]2[C:16]([F:15])=[N:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1cccnc1F
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1cccnc1F

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-fluoronicotinic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-fluoropyridine-3-carboxamide. MS (Q1) 328.1 (M)+.