Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][C@@H:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:7]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([F:33])[CH:24]=2)[CH:5]=1.[NH2:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1>>[F:33][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:31])=[O:30])[O:22][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH:11]([CH3:21])[CH2:12][OH:13])[CH:7]=1)[C:3]([NH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=[O:2]
Reactant: Nc1nccs1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Product: CC(CO)Oc1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)cc(C(=O)Nc2nccs2)c1

Procedure:
The compound of Production Example 42 was obtained as a colorless oil using the obtained 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(3-fluoro-4-methanesulfonyl-phenoxy)-benzoic acid methyl ester and 2-amino-thiazole, by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1

Procedure:
A solution of 4-nitro 1,2-phenylene diamine(1.53 g, 10.0 mmol) in DMF was treated with phenyl sulfonyl chloride(1.76 g, 10.0 mmol) and triethyl amine(1.01 g) in DMF for 12 h at 23° C. The reaction mixture was partitioned between saturated NH4Cl and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized (EtOH) to afford desired (0.275 g, 9%). 1H NMR(DMSO) 9.5(s, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74(d, 2H, J=8 Hz), 7.76(t, 1H, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7.55(d, 1H, J=2 Hz), 6.79 (d, 1H, J=8 Hz), 6.5(s, 2H, br)
Reaction SMILES: C(O[C:9](=O)[N:10]([CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C)C1C=CC=CC=1>CO.[Pd]>[Si:15]([O:14][CH2:13][CH2:12][NH:10][CH3:9])([C:28]([CH3:30])([CH3:31])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 67.1 %

Procedure:
A solution of N-[2-(t-butyldiphenylsilyloxy)-ethyl]-N-methyl-carbamic acid benzyl ester (5.7 g, 12.7 mmol) (obtained as described in Reference Example 40(1)) in methanol (285 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (5.7 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (19:2)→ethyl acetate:methanol (1:1) as the eluant to afford [2-(t-butyldiphenylsilyloxy)ethyl]methylamine (2.67 g, yield 69%) as a transparent oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[I:17][CH2:18][C:19](Cl)=[O:20].Cl>O>[I:17][CH2:18][C:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CI
Reactant: NC(=O)c1cc(N)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc(NC(=O)CI)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To an ice-cooled, stirred solution of 5-Aminosalicylamide (10.0 grams, 0.073 tool), in 300 mL of water containing NaHCO3 (42.0 grams, 0.5 tool), iodoacetyl chloride (18.4 grams, 0.09 mol) is added dropwise over 15 min. After stirring at 0°-5° C. for 1 hr., the solution is acidified with cold 6N HCl. The precipitate is collected and dried in vacuo over NaOH pellets, to afford 21.3 grams (96% yield) of crude 5-(iodoacetamido)salicylamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:4](N)[CH:3]=1.C(ON=O)CC(C)C.C[Si](C)(C)[Br:25]>BrCBr>[Br:25][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: C[Si](C)(C)Br
Reactant: Nc1cc(Cl)nnc1OCC(F)(F)F
Agent: CC(C)CCON=O
Solvent: BrCBr
Product: FC(F)(F)COc1nnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
To a suspension of 2.30 g 6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazin-4-ylamine in 23 mL dibromomethane was added 5.11 g isoamylnitrite at once and drop wise 4.642 g trimethylbromosilane at ambient temperature (during ca 10 min). A moderate exotherm was observed and a dark brown solution was obtained. The mixture was stirred at ambient temperature for 18 h. The solvents were evaporated and the residue was purified (3×) by chromatography on silica gel using a gradient of heptane to dichloromethane to yield 0.70 g of the title compound as white crystalline solid, MS 292 (M+H)+.
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[NH:6][CH:7]=1.[OH-].[NH4+:24]>>[C:2]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[NH:6][CH:7]=1)#[N:24]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(F)(F)F)c[nH]2)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C#N)c[nH]2)CC1
Temperature: 60 °C
Yield: 83 %

Procedure:
Combine tert-butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1.50 g, 4.70 mmol) and ammonium hydroxide (90 mL). Heat the reaction mixture at 60° C. for two days. Let cool to room temperature, then filter via Buchner funnel Wash the solids with water and hexanes to give the title compound as a white solid (1.08 g, 83%). MS (ES) m/z=221 [M]+.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Cl:14][C:15]1[N:20]=[C:19]([CH:21](O)[CH3:22])[CH:18]=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([CH:21]([F:11])[CH3:22])[CH:18]=[CH:17][N:16]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(O)c1ccnc(Cl)n1
Solvent: ClCCl
Product: CC(F)c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (7.70 g, 17.4 mmol) was added drop wise to a solution of 1-(2-chloropyrimidin-4-yl)ethanol (2.30 g, 14.5 mmol) in dichloromethane (20 mL) at 0° C. and the mixture was stirred at 0° C. for 15 minutes. The mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/Hexane) to afford 2-chloro-4-(1-fluoroethyl)pyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=5.0 Hz, 1H), 7.45 (d, J=5.0 Hz, 1H), 5.65-5.51 (m, 1H), 1.71-1.65 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C@:13]1([CH3:20])[C@H:17]([CH3:18])[NH:16][C:15](=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:16]2[C:15](=[O:19])[CH2:14][C@@:13]([OH:12])([CH3:20])[C@@H:17]2[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: C[C@@H]1NC(=O)C[C@]1(C)O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(N2C(=O)C[C@](C)(O)[C@@H]2C)ccc(C#N)c1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
A solution of 2-chloro-4-iodo-3-methylbenzonitrile (1.29 g), (4S,5S)-4-hydroxy-4,5-dimethylpyrrolidin-2-one (500 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (343 mg), tris(dibenzylideneacetone)dipalladium(0) (177 mg) and cesium carbonate (1.86 g) in 1,4-dioxane (4 mL) was tightly sealed, and the mixture was stirred at 120° C. for 3 hr using microwave reactor. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=30→70%, basic silica gel eluent:ethyl acetate/hexane=30→80%), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as colorless crystals (yield: 603 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:3]=12.Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC
Temperature: 95 °C
Yield: 43.7 %

Procedure:
A suspension of 1 g of 4-chloro-2-(5,6-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.655 g of 4-(2-chloroethyl)morpholine hydrochloride and 1.11 g of potassium carbonate in 10 ml of dimethylformamide is heated at around 95° C. for approximately 3 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is run into 20 ml of water, and extracted with three times 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (90/10 by volume)]. 0.54 g of 4-chloro-2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:28][CH2:29][CH2:30][CH3:31])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCCCN
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Product: CCCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Yield: 56 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (4.5 g) in anhydrous dimethylformamide (100 cc), N,N'-carbonyldiimidazole (2 g) and butylamine (0.73 g). After recrystallization in acetonitrile, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-butylacetamide (2.35 g), m.p. 170° C., is obtained.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: FCCOc1ccccc1
Product: O=S(=O)(Cl)c1ccc(OCCF)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
At 0° C., (2-fluoro-ethoxy)-benzene (20 mmol) was added slowly to chlorosulfonic acid (200 mmol). The reaction mixture was stirred for 20 min at 0-5° C. and then warmed to room temperature, and finally stirred at 45° C. for 2 h. Then the reaction mixture was cautiously (!) added to ice water. The precipitate was filtered, washed with water and dried in a vacuum oven at 30° C. to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]3=[CH:12][S:13][C:14](=S)[N:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:16].C(I)C.C(#N)C.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(N(CC)CC)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]3=[CH:12][S:13][C:14](=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])[N:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:16]
Reactant: Fc1ccc2c(c1F)OCc1csc(=S)n1-2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCI
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)=C1SC=C2COc3c(ccc(F)c3F)N21
Reaction time: 5 h
Yield: 63.8 %

Procedure:
6,7-Difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (0.4 g) prepared in Reference Example 18 and ethyl iodide (1.9 g) were added to acetonitrile (10 ml) and the mixture was stirred at 75° to 78° C. for 5 hours. Then diethyl malonate (0.5 g) and triethylamine (0.62 g) were added and the mixture was refluxed for 24 hours. After the reaction mixture was evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica-gel column chromatography (Silica gel 60, 230-400 meshes, made by Merck Co., 130 g, eluent; chloroform) under medium pressure and recrystallized from a mixed solvent of hexane - ethyl acetate to give the title compound (0.38 g) as pale yellow crystals. The compound had physical properties identical to those of diethyl (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxain-1-ylidene)malonate prepared in Reference Example 6.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH:6]1[C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:35]([O:37][C:38](=[O:43])[CH2:39]C([O-])=O)[CH3:36].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.O.CC(OC)(C)C>[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:11]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:7]1)=[O:13])[CH3:36]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1cc(F)c(F)cc1F
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(F)cc2F)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
1-(Methoxycarbonyl)-2-(2,4,5-trifluorophenyl)piperidine-4-carboxylic acid (2.388 g, 7.53 mmol) (reference compound 27) was dissolved in methyl THF (50 mL) and di(1H-imidazol-1-yl)methanone (1.831 g, 11.29 mmol) added. The suspension was stirred at room temperature under nitrogen for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.306 g, 13.55 mmol) was suspended in methyl THF (50.0 mL) and magnesium chloride (1.290 g, 13.55 mmol) added. The suspension was stirred at 50° C. under nitrogen for 5.5 h using an oversized stirring bar (flask 2). The suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE and water added. The phases were separated and the organic phase washed with water, satd NaHCO3 and water and was evaporated. Traces of water were azeotropically removed by MeCN to yield a yellow oil. The residue was purified on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (1.877 g, 64%) was isolated as colorless oil. 1H NMR (600 MHz, cdcl3) δ 1.19-1.29 (m, 3H), 1.49-2.19 (m, 3H), 2.22-2.29 (m, 1H), 2.82-2.91 (m, 1H), 3.34 (ddd, 1H), 3.39-3.48 (m, 2H), 3.62 (s, 3H), 4.05-4.20 (m, 3H), 5.00-5.06 (m, 1H), 6.85-7.00 (m, 2H). MS m/z 388 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: N#Cc1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([Cl:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[CH:3][C:4]=2[Cl:23])[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(Br)cc1Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(-c2ccccn2)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 30 step ii) (0.20 g) which was dissolved in dry dioxane (10 ml). 2-pyridyl tributyl tin (0.181 g) and palladium (0) tetrakistriphenylphosphine (0.028 g) were added and the mixture was heated at 80 C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 0.20 g.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1Br
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1N1CCNCC1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in 1,4-dioxane (100 ml) at room temperature, were added piperazine (15.3 g, 178 mmol) and K2CO3 (4.92 g, 35 mmol). The resulting mixture was heated to reflux for 7 days after which the reaction mixture was cooled to room temperature and the solvent and the excess piperazine were removed in vacuo and heating with a hot water bath. The residue was dissolved in 1N NaOH solution and extracted with CH2Cl2 (6×30 ml), dried over Na2SO4. The solvent was removed in vacuo to obtain 1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0 g, 26%).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][S:7]([NH2:10])(=[O:9])=[O:8]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]1([CH:4]=[N:10][S:7]([CH3:6])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: O=CC1CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N=CC1CC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopropanecarbaldehyde (0.374 mL, 5 mmol) and methanesulfonamide (0.523 g, 5.5 mmol) in toluene (15 mL) was added titanium(IV) isopropoxide (2.93 mL, 10 mmol), and the mixture was heated to 100° C. for 1 day. The mixture was cooled to room temperature and concentrated in vacuo. The residue was placed under high vacuum for 30 min to give a biphasic mixture. The top layer was discarded. The residue was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:17]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: SC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(SC2CCCC2)c(Br)c1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
A solution of 3-bromo-4-fluorobenzaldehyde (517.4 mg) in DMSO (8 ml) was added with potassium carbonate (514.9 mg) and cyclopentanethiol (250 μl, TCI), and stirred at 90° C. for 17 hours. The reaction mixture was extracted with ethyl acetate (50 ml), and the organic layer was washed successively with water and saturated brine, and dried. Then, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=8:1) to obtain the title compound (Intermediate S-23, 644.7 mg).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:8]([O:15][CH2:16][CH:17]1[O:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[CH2:1]([O:5][CH2:18][CH:17]([OH:19])[CH2:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: c1ccc(COCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCC(O)COCc1ccccc1
Temperature: 80 °C
Yield: 48.2 %

Procedure:
n-Butanol (2.5 ml, 27 mmol) is added to a suspension of sodium hydride (50% in mineral oil; 1.3 g, 27 mmol) in DMF (5 ml) and the mixture is then heated to 80° C. for 1.0 hours when all the sodium hydride is consumed. A solution of 2,3-epoxypropyl benzyl ether (benzyl glycidylether*) (4.52 g, 27 mmol) in DMF (5 ml) is added slowly to the n-butoxide solution. The mixture is then heated to 80° C. for 16 hours, diluted with water and extracted with ether. The ether layer is dried and concentrated to give an oil which is distilled to provide the desired product (3.1 g), bp 125°-130°/0.8-0.5 mm.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:11](B(O)O)=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[C:18]([F:29])[CH:17]=1>>[CH:1]1([O:5][C:6]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=4)=[C:18]([F:29])[CH:17]=3)=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccnc1OC1CCC1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3cccnc3OC3CCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-(cyclobutoxy)pyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C19H17FN4O, 336.14; m/z found, 337.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.57 (m, 1H), 8.17-8.10 (m, 2H), 8.01-7.92 (m, 1H), 7.66 (dd, J=1.9, 7.4, 1H), 7.52-7.43 (m, 2H), 7.00-6.93 (m, 1H), 5.38-5.22 (m, 1H), 4.67 (s, 2H), 2.57-2.37 (m, 2H), 2.26-2.05 (m, 2H), 1.90-1.61 (m, 2H).