Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 49.6 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (49 mg, 50% over 2 steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.22 (m, 2H), 8.12 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.70 (dd, J=9.2, 2.7 Hz, 1H), 7.34 (s, 2H), 7.13 (d, J=9.3 Hz, 1H), 4.52 (s, 1H), 4.02 (dt, J=13.0, 4.1 Hz, 1H), 3.35 (m, 2H), 2.85 (tt, J=7.8, 4.5 Hz, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.73 (q, J=9.8 Hz, 2H), 1.22 (m, 4H); ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 99.6% (AUC), tR=10.95 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([Cl:3])=[O:10]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(Cl)c1F

Procedure:
Thionyl chloride is metered at 70° C. to a suspension of 235 g (1.22 mol) of 3-chloro-2,4-difluorobenzoic acid in 800 ml of toluene and 3 ml of dimethylformamide until a clear solution has formed and evolution of gas is no longer observed. The toluene and excess thionyl chloride are then distilled off, and the product is subsequently obtained by distillation.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[CH:6][CH:7]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)c1nc(Br)ccc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1nc(-c2c(F)cccc2F)ccc1N
Yield: 47 %

Procedure:
A solution of methyl 3-amino-6-bromopicolinate (1.0 equiv.), 2,6-difluorophenyl-boronic acid (3.0 equiv), and Pd(dppf)Cl2-DCM (0.1 equiv.) in 3:1 DME/2M Na2CO3 (0.5 M) was subjected to microwave irradiation at 120° C. for 15 min intervals. The reaction was filtered and washed with EtOAc. The organic was partitioned with H2O (25 mL), was further washed with NaCl(sat.) (25 mL), was dried over MgSO4, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2,6-difluorophenyl)picolinate (47%). LCMS (m/z): 265.1 (MH+); LC Rt=2.70 min
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-].[K+].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH3:17][C:18](CC(C)C)=O>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:14][CH3:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)CC(C)C
Reactant: Oc1ccc(I)cc1
Agent: [I-]
Agent: [K+]
Product: COCCOc1ccc(I)cc1

Procedure:
A mixture of 4-iodophenol (1.0 g) 1-bromo-2-methoxyethane (0.7 g), potassium iodide (0.83 g), potassium carbonate (0.7 g) and methyl isobutylketone (10 ml) was refluxed for 18 h, diluted with ER (50 ml), filtered and evaporated. The residue was distilled to give the title compound (0.83 g). T.l.c. (cyclohexane-ER 1:1) Rf 0.6
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@H:13]1[C:33]([O:35][CH3:36])=[O:34])=O)C1C=CC=CC=1.N[C@@H]1CCN(CCN2C3C(=C(F)C=C(F)C=3)C=CC2=O)C[C@@H]1C(OC)=O>>[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@H:13]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1
Agent: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N

Procedure:
Methyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 39) (535 mg, 1.07 mmol) was hydrogenated as described for Intermediate 34 to give 391 mg (quantitative) of the product as a colorless hard foam.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][C:21]=1[Cl:34])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]=[O+][O-].CSC>ClCCl.CO>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:22][C:21]=1[Cl:34])[CH2:16][CH:17]=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: O=CC[C@@H](Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C

Procedure:
Dissolve (R)-4-Benzyl-3-[(S)-2-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-pent-4-enoyl]-oxazolidin-2-one (1.95 mmoles; 1.00 g) in dichloromethane (10 ml) and methanol (1 mL). Cool the mixture to −78° C. in a dry ice acetone bath and add ozone subsurface to the reaction with an exotherm to −71° C. The reaction turns blue, and then sweep with nitrogen to a clear color. Add dimethyl sulfide (2 mL; 27.20 mmoles) dropwise at −78° C. Warm the solution to ambient temperature and then test with KI starch paper (test is negative). Remove the solvents under vacuum, extract with MTBE, wash with pH=7 buffer, water, and brine. Concentrate the organics under vacuum to give a white non-crystalline solid (0.81 g). LCMS (M+1=515.39).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([NH:19][CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23][O:24][C:25](=[O:33])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C)C=O>[CH3:23][O:24][C:25](=[O:33])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1)[CH3:20]
Reactant: COC(=O)COCCCCBr
Reactant: CNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCCCCN(C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
Under an argon atmosphere, to a solution of 763 mg of 5,6-diphenyl-2-(methylamino)pyrazine in 4 ml of N,N-dimethylformamide, 140 mg of 60% sodium hydride was added, followed by stirring at 80° C. for 30 minutes. The reaction solution was ice-cooled and a solution of 657 mg of 2-(4-bromobutyloxy)acetic acid methyl ester in 2 ml of N,N-dimethylformamide was slowly added. After an ice bath was removed, the mixture was stirred at room temperature for 14 hours. The reaction solution was combined with ice water and extracted with ethyl acetate and, after the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 240 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:11]2[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:12]2)[CH2:9][CH2:8][CH:7](O)[CH2:6][CH2:5]1)#[N:2].CS(Cl)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+].CN(C=O)C.O>[N:32]([CH:7]1[CH2:6][CH2:5][C:4]([N:11]2[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[C:13]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:12]2)([CH2:3][C:1]#[N:2])[CH2:9][CH2:8]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCC(O)CC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCC(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[1-(cyanomethyl)-4-hydroxycyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (75 mg, 0.21 mmol) in DCM (2 mL) at ambient temperature was added TEA (0.059 mL, 0.42 mmol), and methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture was stirred at ambient temperature for 10 minutes. The mixture was diluted with saturated aqueous NaHCO3, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude residue (90 mg, 0.207 mmol) was diluted in DMF (1.0 mL), NaN3 (27 mg, 0.41 mmol) was added and the mixture was heated at 90° C. for 16 hours. The mixture was cooled to ambient temperature, diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 30-100% EtOAc/hexanes) to give the title compound as a mixture of two diasteromers (ratio 1:3), which was used without further purification.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[F:6][C:7]([F:12])([F:11])[C:8](O)=O.P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1.O>[NH2:5][C:3]1[S:4][C:8]([C:7]([F:12])([F:11])[F:6])=[N:1][N:2]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NNC(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(C(F)(F)F)s1
Temperature: 20 °C
Yield: 72.1 %

Procedure:
A three-liter reaction flask fitted with a mechanical stirrer, heating mantle, dropping funnel, thermometer and water-cooled condenser connected to a caustic trap was charged with 228 g (2.5 mole) of thiosemicarbazide, 1260 ml of 1,4-dioxane and 285.1 g (2.5 mole, 193 ml) of trifluoroacetic acid. The dropping funnel contained 383.8 g (2.5 mole, 229 ml) of phosphorus oxychloride which was added to the reaction flask over a period of 30 minutes. The resulting thick slurry was heated slowly to reflux with rapid evolution of hydrogen chloride gas. The slurry thinned with separation of the product as a heavy syrup. Total reflux time required about four hours until the gas evolution ceased. The dioxane was decanted and then 1700 ml of water was added to the residue. The mixture was cooled to 20° C. and made basic with 50% sodium hydroxide (~225 ml) to pH 9. The slurry was cooled to 10° C. and collected on a filter funnel. The cake was washed with cold water and dried in the oven. There was obtained 305 g, Mp 219°-220.5°, yield 72.1%. The proton NMR recorded in Me2SO-d6 consisted of a peak at 7.9∂ (NH2) with respect to tetramethylsilane.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][N:2]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CNc1nc(-c2ccccc2)cs1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of N-methyl-4-phenyl-1,3-thiazol-2-amine (1.67 g, 8.8 mmol) in N,N-dimethylformamide (25 mL) was added 60% sodium hydride (350 mg, 8.8 mmol), and the mixture was stirred for 30 min. Methyl 4-(bromomethyl)benzoate (2.1 g, 9.2 mmol) was added and the mixture was stirred at room temperature for 1.5 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (2.6 g, yield 86%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:31][CH2:32][CH2:33][CH3:34])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][CH:27]=O)=[C:21]([O:29][CH3:30])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1>[CH2:14]([N:18]([CH2:31][CH2:32][CH2:33][CH3:34])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][CH:27]=[CH:5][C:3]#[N:4])=[C:21]([O:29][CH3:30])[CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC=CC#N)c(OC)c1
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To 200 mg (8.3 mmol) of sodium hydride, 14 ml of tetrahydrofuran was added. To this mixture, 1.47 g (8.3 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling, and the mixture was stirred for 20 minutes. Next, 1.02 g (3.52 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal in tetrahydrofuran was added dropwise. After stirred for 30 minutes, the reaction mixture was poured into 100 ml of water and subjected to extraction with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 1.0 g of an orange oily matter (yield: 91.2%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([C:22](Cl)=[O:23])[CH2:16]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)(Cl)=O.O>O1CCOCC1>[OH:2][CH2:1][CH2:3][NH:4][C:22]([CH:17]1[CH2:16][C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:5](=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:14]=2)[CH2:18]1)=[O:23]
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1ccc2c(c1)CC(C(=O)Cl)C2
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc2c(c1)CC(C(=O)NCCO)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.2 g (0.084 mole+20%) of monoethanolamine dissolved in 30 cm3 of dioxane is placed in a 250 cm3 reaction vessel equipped with a stirrer, a cooler, a dropping funnel and a thermometer. At a temperature of between 15° and 20° C., a solution of 12.2 g (0.042 mole) of 5-benzoyl-indan-2-carboxylic acid chloride (prepared in conventional manner by reacting thionyl chloride with the corresponding acid) in 30 cm3 of dioxane is slowly added. The reaction mixture is stirred for one hour at ambient temperature and then poured into iced, acidified water. A whitish oil separates and finally crystallizes. Upon recrystallization from acetone, a solid which melts at 106°-107° C. (capillary tube) is obtained.
Reaction SMILES: [C:1]([C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Si](C)(C)C)[CH:15]=[CH2:16].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:2]1([C:1]2([C:9]([OH:11])=[O:10])[CH2:16][CH2:15][CH2:14][O:8]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:16][CH:15]=[CH2:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CC[Si](C)(C)C
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(O)(C(=O)OCC)c1ccccc1
Product: O=C(O)C1(c2ccccc2)CCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
The title compound was prepared according to a literature procedure (T. Akiyama, K. Ishikawa and S. Ozaki, Chemistry letters 1994, 627). To a solution of ethyl benzoylformate (2.5 g, 14.0 mmol) and allyl trimethylsilane (2.7 ml, 16.9 mmol) in 31 ml of methylene chloride (anhydrous) at −78° C. was added 1.6 ml of tin chloride (14.28 mmol) dropwise. The cooling bath was removed after the addition was complete. After the reaction mixture was stirred at room temperature for 5 min., TLC showed the reaction was complete. Triethylamine (3.5 ml) and water (150 ml) were added to quench the reaction. Extraction with ethyl acetate was complicated by the emulsion which was broken up by filtration through celite. The extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography with methylene chloride/hexane=2.5:97.5 to afford 2-hydroxyl-2-phenyl-4-pentenoic acid, ethyl ester as an oil (1.2 g). 400 MHz 1H NMR (CDCl3): δ 7.59 (m, 2H); 7.29 (m, 3H); 5.79 (m, 1H); 5.13 (m, 2H); 4.23 (m, 2H); 2.96 (m, 1H); 2.74 (m, 1H); 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[CH2:9][S:8]1)=[O:6].Cl>CO.O>[CH3:18][O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH:7]([C:5]([OH:6])=[O:4])[S:8][CH2:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)C1Cc2ccc(OC)cc2CS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CSC(C(=O)O)C2
Temperature: 60 °C
Yield: 87.3 %

Procedure:
Potassium hydroxide (0.80 g, 14.3 mmol) was added to a solution of 7-methoxy-isothiochroman-3-carboxylic acid methyl ester (0.34 g, 1.43 mmol) in MeOH (50 mL). The solution was heated at 60° C. for 2 h, cooled to room temperature, and diluted with H2O (100 mL). The solution was made acidic with 6 M HCl and extracted with EtOAc (3×100 mL). The organic extracts were combined, dried (MgSO4) and concentrated to give 7-methoxy-isothiochroman-3-carboxylic acid (0.28 g, 88%) as a pale yellow solid. The solid was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].NCC([OH:14])C.[C:15](#[N:22])[C:16]1C=CC=C[CH:17]=1>>[OH:14][CH2:17][CH2:16][CH2:15][NH:22][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(O)CN
Reactant: N#Cc1ccccc1F
Reactant: N#Cc1ccccc1
Product: N#Cc1ccccc1NCCCO

Procedure:
The aromatic aldehyde which is used in the methods of the present invention can be prepared by any number of reaction schemes. For instance, the aromatic aldehyde can be formed from reacting an indole with ozone in an organic solvent followed by addition of at least one reducing agent to form a formyl aromatic aldehyde. The formyl aromatic aldehyde can be reacted with a base or acid in the presence of water and/or an organic solvent to yield the starting aromatic aldehyde. Alternatively, the aromatic aldehyde can be formed by starting with a benzonitrile which is reacted with a reactant that permits the attachment of desired substituents on the benzonitrile. For instance, fluorobenzonitrile can be reacted with 1-amino-2 propanol in the presence of an organic solvent to yield the desired 2-(hydroxypropyl) aminobenzonitrile. The benzonitrile can then be reacted with a hydrogen source and a catalyst to form the desired aromatic aldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][Br:9])=[CH:4][C:3]=1[N+:12]([O-])=O.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1.[Pd]>[O:21]=[C:20]1[N:1]=[C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][Br:9])=[CH:4][C:3]2=[N:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1N=c2ccc(OCCBr)cc2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
A solution of 2-(4-amino-3-nitrophenoxy)ethyl bromide (980 mg, 7.59 mmol) in dry THF (20 mL) was shaken over 5% Pd/C (80 mg) under H2 (20-30 psi) for 5 h, then filtered. To the filtrate was added CDI (2.4 g, 14.8 mmol). The mixture was stirred at room temperature under N2 for 4 h, then refluxed for 14 h. The mixture was evaporated, then the residual solid was washed with CHCl3 (3×15 mL), and dried to give 407 mg (21%) of the title compound as an off-white powder, mp 225-6° C. 1H NMR (DMSO-d6): 3.747 (t, 2H, J=5.5), 4.234 (t, 2H, J=5.5), 6.52-6.54 (m, 2H), 6.792 (d, 1H, J=9), 10.399 (s, 1H), 10.521 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Product: O=C(Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2)C1CC1
Yield: 57 %

Procedure:
Prepared from rac-N2-(5-fluoro-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 11) (100 mg, 0.336 mmol) and cyclopropylcarbonyl chloride (34 ul, 0.370 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (70 mg, 57%), MS (ISP) m/e=366.1 [(M+H)+].
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([CH3:21])(=[O:20])=[O:19])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@H:30]([OH:34])[C:31](O)=[O:32])=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C@H:30]([OH:34])[C:31]([N:15]2[CH2:16][CH2:17][N:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:13][CH2:14]2)=[O:32])=[CH:27][CH:28]=1
Reactant: O=C(O)[C@@H](O)Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCNCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@@H](O)Cc2ccc(Cl)cc2)CC1
Reaction time: 18 h

Procedure:
To a 250-mL round bottomed-flask equipped with a magnetic stir bar and containing a solution of N-(cyclopropylmethyl)(methylsulfonyl)(2-piperazinyl-phenyl)amine (Step 2) (1.8 g, 5.8 mmol) and (2S)-3-(4-chlorophenyl)-2-hydroxypropanoic acid (Step 1) (1.2 g, 5.8 mmol) in CH2Cl2 (30 mL) and DMF (30 mL) at RT was added HOAT (Aldrich ) (0.87 g, 6.4 mmol) followed by EDC (Aldrich) (1.3 g, 7.0 mmol). This was stirred for 18 h and diluted with CH2Cl2 (300 mL) The mixture was washed with H2O (3×100 mL), aq. NaHCO3 (1×100 mL) and brine (1×100 mL). It was dried (Na2SO4) and concentrated onto silica gel. Purification by chromatography (40 to 55% EtOAc/hexanes) afforded (2S)-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]-phenyl}-piperazinyl)-2-hydroxypropan-1-one as a slightly yellow oil (1.8 g). Analytically pure material was obtained by reverse phase preparative scale chromatography (Column: MetaChem Polaris C18-A 5 micron, flow: 20 mL/min, gradient: 5 to 100% CH3CN (0.1% TFA)/H2O (0.1% TFA). MS (ESI, pos. ion) m/z 492 (M+1). Calc'd for C24H30ClN3O4S: 491.16.