Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[C:33](=[O:34])[C:32](I)=[C:31]([O:36][CH3:37])[C:30](=[O:38])[NH:29][C:28]=2[CH:39]=1.[C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:45]([O:44][C:40](=[O:43])/[CH:41]=[CH:42]/[C:32]1[C:33](=[O:34])[C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:39][C:28]=2[NH:29][C:30](=[O:38])[C:31]=1[O:36][CH3:37])([CH3:48])([CH3:47])[CH3:46]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
A solution of tris(dibenzylidenacetone)dipalladium (O) (0.0163 g) in toluene (39 mL) was treated with tri-orthotolylphosphine (0.0815 g). The solution was stirred under argon at room temperature for 15 minutes and then it was treated with 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.22 g) followed by tert-butyl acrylate (7.30 mL, 6.45 g). The mixture was then treated with triethylamine (0.47 mL, 0.34 g) and it was heated to 105° C. for 35 minutes. The mixture was cooled and concentrated to a dark solid. The solid was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×20 cm long) using 25% ethyl acetate in hexane to give a light yellow solid (0.932 g). A portion of the solid (0.294 g) was dissolved in warm ethyl acetate (5 mL) and then it was concentrated to 3 mL volume. Hexane (1 mL) was added to the solution and crystals formed. The solid was filtered off, washed with cold ethyl acetate, washed with hexane, and dried to give a white solid (0.21 g); mp 213.2°-213.8° C. (dec); 1H NMR (CDCl3) 7.67 (d,1, J=16), 6.61 (d,1, J=16) for trans olefin protons; MS: m/z=308 (base peak), 364 (M+1). Analysis for C18H18ClNO5 : Calculated: C, 59.43; H, 4.99; N, 3.85; Found: C, 59.22; H, 4.92; N, 3.79.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1)=[CH2:2].Br[CH2:13][CH2:14]Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+].O>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CC#N)cc1
Reactant: ClCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(C2(C#N)CC2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of (4-vinylphenyl)acetonitrile (2.1 g, 0.015 mol), 1-bromo-2-chloro-ethane (1.4 mL, 0.016 mol) and benzyltriethylammonium chloride (0.2 g, 0.0008 mol) in aqueous sodium hydroxide solution (20m, 6 mL) was stirred at 70° C. for 1 h. The reaction mixture was cooled, diluted with water and extracted with ethyl ether. The combined ether layers were washed with water and brine, dried and concentrated to afford the product.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@:9](C(=O)C1C=CC=CC=1)([C@:11](C(=O)C1C=CC=CC=1)([CH2:13][OH:14])[OH:12])[OH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C[O-].[Na+].[Cl-].[NH4+]>CO>[C:1]([O:5][C:6]([CH2:8][C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](O)[C@@H](O)CO
Temperature: 25 °C
Yield: 91.9 %

Procedure:
0.61 kg (1.53 mol) of 1-t-butoxy-2-deoxy-3,4-dibenzoyl-L-ribose was dissolved in 6.02 liters of methanol for 30 minutes, and 0.041 kg of 25 w % sodium methoxide methanol solution was added thereto. The mixture solution was stirred at room temperature at room temperature. After completion of the reaction, 0.013 kg of ammonium chloride was added to the reaction solution, which was then stirred for 2 hours, and 0.038 kg of celite was added thereto. Next, the solution was stirred for 30 minutes, and then concentrated. To the concentrated residue, 2.531 liters of ethyl acetate was added at 35-45° C., and the solution was stirred at the same temperature for 2-3 hours. The stirred solution was filtered using 0.038 kg of celite, and was washed with 0.422 liters of ethyl acetate, and then completely concentrated, thus obtaining 0.29 kg (100% yield) of 1-t-butoxy-2-deoxy-L-ribose.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]=1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:27]([O:26][C:24](=[O:25])[NH:23][C:9]1[CH:10]=[C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([C:42]([F:43])([F:44])[F:45])(=[O:40])=[O:41])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=S(=O)(c1ccccc1Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(=O)(=O)C(F)(F)F)cc1NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 74.8 %

Procedure:
A mixture of [2-tert-butoxycarbonylamino-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester (0.213 g, 0.490 mmol), 1-chloro-2-trifluoromethanesulfonyl-benzene (0.100 g, 0.409 mmol), sodium carbonate (0.260 g, 2.45 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.027 g, 0.0409 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a yellow solid (0.158 g, 75%).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][CH2:26][CH2:27][CH:28]=[O:29]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH2:26][S:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([F:30])([F:17])[F:31])[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: O=CCCSc1ccccc1C(F)(F)F
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CCSc1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 93.7 %

Procedure:
15.1 Grams of methyl acetoacetate were dissolved in 20 ml of water, and 19.4 g of a 28% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 2 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.82 g of sodium acetate and 3.22 g of tetrabutylammonium bromide were added thereto and then 60.3 g of a toluene solution containing 36.9% of 3-(2-trifluoromethylphenylthio)propanal were added thereto The mixture was stirred at 45°-50° C. for 6 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 31.10 g of crude 4-hydroxy-6-(2-trifluoromethylphenylthio)-2-hexanone (purity: 83.7%, yield: 93.7%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[CH:51]=[C:52]([C:55](O)=[O:56])[S:53][CH:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:52]3[S:53][CH:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[CH:51]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CC(C)c1csc(C(=O)O)c1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 4-isopropylthiophene-2-carboxylic acid (example 74, step b) (0.07 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic layer was washed with brine (2×100 mL), dried over sodium sulphate, filtered and evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.23 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[O:25][CH2:26][C:27]([NH2:29])=O.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]2[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:29]=[C:27]2[CH2:26][O:25][C:24]2[CH:30]=[CH:31][CH:32]=[C:22]([Cl:21])[CH:23]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NC(=O)COc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(Cl)c2)c(COc2cccc(Cl)c2)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
A mixture of N-(3-chloro-4-morpholinophenyl)-3-oxobutanamide (0.48 g, 1.62 mmol), 2-(3-chlorophenoxy)acetamide (0.60 g, 3.24 mmol) and titanium tetraisopropanolate (2.4 mL) in xylene (10 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 60 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (20 mL×4). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.46 g, 64%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[CH:7]=[C:6]([CH3:12])[N:5]=2.C(N(CC)C(C)C)(C)C.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][C:33](=[O:34])[CH2:32][Cl:31])[CH:7]=[C:6]([CH3:12])[N:5]=2
Reactant: Cc1cc(C)c(-n2c(C)nc3c(N)cc(C)nc32)c(C)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-n2c(C)nc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 2,5dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridine-7-ylamine (0.8 g, 2.85 mmol), and N,N-diisopropylethylamine (0.54 mL, 3.13 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.25 mL, 3.13 mmol). Heat the solution to reflux for 5 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture wit CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:27]([N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:10][CH2:11]2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CC1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
In 40 ml of dichloromethane, are dissolved 2.3 g (0.01 mole) of 1-(3-trifluoromethylphenyl)piperazine and 1.0 g (0.01 mole) of triethylamine. To the resulting solution, while being cooled and stirred, is added dropwise a solution of 1.05 g (0.01 mole) of cyclopropanecarbonyl chloride in 10 ml of dichloromethane. The mixture is allowed to react at room temperature for 3 hours. The reaction mixture is washed successively with water, dilute hydrochloric acid and water, then dried over anhydrous sodium sulfate, and removed of the solvent by distillation to obtain oily 1-(cyclopropanecarbonyl)-4-(3-trifluoromethylphenyl)piperazine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)C1CC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C2CC2)cc1
Yield: 51 %

Procedure:
Following the procedure of Example 13, Step C, 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) was reacted with cyclopropanecarbonyl chloride. Flash chromatography of the crude product on silica gel (gradient elution with 0.3-1% MeOH in CH2Cl2) gave a 51% yield of the title compound as white crystals, mp 187°-189° C.; satisfactory purity by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 599 (M+1)+.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH3:15])[S:6]([C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7].O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:15][N:5]([CH2:4][CH:3]=[O:2])[S:6]([C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)(=[O:7])=[O:8]
Reactant: COC(CN(C)S(=O)(=O)c1cnn(C)c1)OC
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CC=O)S(=O)(=O)c1cnn(C)c1
Yield: 92 %

Procedure:
Alternatively, 1-methyl-1H-pyrazole-4-sulfonic acid (2,2-dimethoxy-ethyl)-methyl-amide (1.0 equivalents) is suspended in toluene (5 volumes) and water (0.5 volumes) and trifluoroacetic acid is added keeping the temperature below 25° C. The resulting solution is allowed to stir for at least 8 hours below 25° C. and sampled for reaction completion. Once the reaction is deemed complete the solution is concentrated to an oil. The resulting oil is dissolved in brine (7.5 volumes) and water (2.5 volumes). Potassium carbonate is added portion wise to keep the temperature below 25° C. until a pH of 7.5 is achieved. The reaction is then washed with methylene chloride (3×10 volumes) and the combined organic layers are dried with sodium sulfate (200 wt %). The slurry is then filtered and the cake washed with methylene chloride (2×3 volumes). The resulting filtrate is held under vacuum for ≧24 hr., to concentrate the title preparation to a viscous amber oil (92% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[CH3:26])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH2:19]([O:18][C:16]([NH:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:26])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc2c(cc1C)[C@@H](NC(=O)OCc1ccccc1)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OCc1ccccc1
Yield: 94.1 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(benzyloxycarbonylamino)-6-methylthiochromane-7-carboxylic acid methyl ester (1.70 g) and potassium carbonate (1.26 g), the objective (S)-4-(benzyloxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (1.54 g) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][CH:3]=1.[CH3:10][O:11]C(N(C)C)OC.C(N(CC)CC)C.Cl.[OH-].[Na+]>ClC1C=CC=CC=1>[CH2:7]([C:5]1[NH:6][C:2]([Cl:1])=[C:3]([CH:10]=[O:11])[N:4]=1)[CH2:8][CH3:9]
Reactant: CCCc1ncc(Cl)[nH]1
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C=O)c(Cl)[nH]1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-2-propyl-1H-imidazole (1.45 g, 10 mmol), dimethoxymethyldimethylamine (1.55 g. approximately 92 percent pure, 12 mmol) and triethylamine (0.10 g, 1 mmol) in chlorobenzene (50 ml) was heated for 1 hour at 80% and 2.5 hours under reflux, cooled to room temperature and poured into 2M hydrochloric acid (100 ml). The pH was adjusted to pH 1.97 by addition of 30 percent strength sodium hydroxide solution (19 ml) and the mixture was extracted three times, each time with 50 ml of ethyl acetate. The combined organic phases were dried and concentrated on a rotavapor. The yield of the product was 1.27 g (approximately 90 percent pure according to H-NMR), 66 percent based on 5-chloro-2-propyl-1H-imidazole. Other data concerning the product was:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1C(OC(C)(C)C)=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:37]3[CH2:36][CH2:35][NH:34][C@@H:33]([CH3:32])[CH2:38]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](C)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-methylpiperazine-1-carboxylic acid, tert-butyl ester and purified by HPLC.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].C(O)C.[ClH:17]>O1CCOCC1.[Pt]=O>[ClH:17].[ClH:17].[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CS(=O)(=O)CCCC1CCNCC1

Procedure:
In a round bottom of flask was charged with 4-(3-methanesulfonyl-propyl)-pyridine (373 mg) and ethanol (5 mL). Hydrochloric acid was added (1 mL, 4N solution in dioxane) with stirring. The mixture was concentrated then the residue was taken in methanol and water. Platinum oxide (21 mg, 0.09 mmol, Aldrich) was added, and the mixture was hydrogenated at 60 psi overnight using a Parr apparatus. Upon completion, the mixture was filtered through Celite and washed thoroughly with methanol. The filtrate was concentrated to give 4-(3-methanesulfonyl-propyl)-piperidine dihydrochloride as a white solid (480.7 mg, 85% pure). The crude product was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][C:50]1([CH3:67])[C:54]2[C:55]([O:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][CH:61]=3)=[CH:56][CH:57]=[CH:58][C:53]=2[O:52][CH2:51]1>CN(C=O)C>[CH3:49][C:50]1([CH3:67])[C:54]2[C:55]([O:59][C:60]3[N:65]=[CH:64][C:63]([NH:66][C:13]([C:9]4([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12]4)=[O:15])=[CH:62][CH:61]=3)=[CH:56][CH:57]=[CH:58][C:53]=2[O:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CC1(C)COc2cccc(Oc3ccc(N)cn3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)Nc2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclobutanecarboxylic acid (Intermediate 68, 20.16 mg) in dry N,Ndimethylformamide (3 ml), DIPEA (20.44 μl, 0.117 mmol) and then HATU (35.6 mg, 0.094 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature under argon. Then 6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinamine Intermediate 59, 20 mg) was added and the reaction mixture was stirred at 60° C. under argon during 12 hours. The reaction mixture was cooled down and a prestirred (15 min) solution of HATU (1 equiv), 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclobutanecarboxylic acid (1 equiv) and DIPEA (1 equiv) in 1 mL of dry DMF was added. The reaction mixture was heated under argon an additional 12 hours at 60° C. The reaction mixture was evaporated. The residue obtained was purified on silica gel (Companion instrument) with cyclohexane/ethylacetate as eluents from 100/0 to 70/30. This afforded the title compound (14 mg)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[C:38]([F:54])[CH:37]=1)#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:44](=[O:45])[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:37][C:38]=4[F:54])=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 77.1 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (2.2 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (7.4 g) in diethylaniline (10 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (4.0 g, 75%).