Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[CH3:8][O:9][N:10]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC(=O)NOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(=O)N(OC)C(C)=O
Reaction time: 8 h

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with methylene chloride (22.5 mL), triethylamine (3.80 g, 2 eq) and N-methoxynonanamide (3.5 g, 1 eq). The reaction mixture is stirred and cooled in an ice bath. Acetic anhydride (2.88 g, 1.5 eq) is then added dropwise. The reaction slowly warms to room temperature overnight. The reaction mixture is diluted with methylene chloride (50 mL) and washed with 0.05 M hydrochloric acid solution 1×50 ml), saturated aqueous sodium bicarbonate solution (3×50 mL) and brine 1×50 miL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Sn](C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH3:24])=[C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Product: Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) and tetramethystannane. White solid. MS (m/e): 260.3 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:18]([O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34](OC)OC)=[CH:30][CH:29]=1)[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[O:5][CH:4]3[CH:6]([CH2:7][OH:8])[O:9][CH:1]([N:10]4[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]4=[O:12])[CH:2]3[O:3]2)=[CH:30][CH:29]=1)[CH3:19]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCOC(=O)CCCCCOc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCOc1ccc(C2OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Uridine 5 (7, 50 g, 0.21 mol) together with 4 (70 g, 0.23 mol) was dissolved in DMF (150 mL). p-Toluenesulfonic acid monohydrate (3.8 g, 20 mmol) was added, the mixture was placed on a Buechi R-134 rotavapor and agitated under reduced pressure (70 mbar) at 50° C. for 15 h. The mixture was then neutralized with triethylamine (2.8 ml, 20 mmol) and subsequently concentrated in vacuo. The resulting residue was suspended in EtOAc (400 mL), filtered and washed with 1:1 EtOAc/H2O (400 mL), H2O (2×200 mL), 1:1 H2O/Et2O (200 mL) and Et2O (2×200 mL) to give a colorless solid as a mixture of 2 diastereomers (6, 77 g, 0.16 mol, 76%). Upon recrystallisation from EtOH/EtOAc one of the diastereomers exclusively crystallized: M.p.: 176-178° C.; 1H-NMR (400 MHz, (CD3)2SO3) δ=11.38 (s, 1H), 7.82 (d, J=8.1, 1H), 7.42 (d, J8.6, 2H), 6.95 (d, J=8.6, 2H), 5.94 (s, 1H), 5.90 (s, 1H), 5.64 (d, J=8.1, 1H), 5.10 (t, J=5.2, 1H), 4.99 (m, 1H), 4.82 (m, 1H), 4.23 (m, 1H), 4.04 (q, J=7.1, 2H), 3.97 (t, J=6.3, 2H), 3.60 (m, 2H), 2.30 (t, J=7.4, 2H), 1.71 (m, 2H), 1.58 (m, 2H), 1.41 (m, 2H), 1.16 (t, J=7.1, 3H); 13C-NMR (400 MHz, (CD3)2SO) δ=172.8, 163.2, 159.7, 150.3, 142.1, 128.4 (2C), 128.0, 114.2 (2C), 106.5, 101.7, 91.3, 86.4, 84.2, 81.6, 67.4, 61.3, 59.6, 33.4, 28.3, 25.0, 24.2, 14.1; IR (film) ν=3467, 2933, 1692, 1677, 1248, 1116, 1077, 828; HRMS (MALDI-FTMS) m/z 513.1851 (513.1849 calculated for C24H30N2O9Na (M+Na)+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[C:10]3[C:7](=[CH:2][CH:3]=[CH:4][CH:9]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCCCCC
Product: Brc1ccc(-c2cccc3ccccc23)cc1

Procedure:
An Rf value of the desired substance by a silica gel thin layer chromatography (TLC) (developing solvent: hexane) was 0.38 and that of 4-bromoiodobenzene was 0.57.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([N:7]([CH2:17][CH3:18])[C:8]1[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[C:10]([F:16])[CH:9]=1)[CH3:6].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:17]([N:7]([CH2:5][CH3:6])[C:8]1[C:14]([F:15])=[CH:13][C:11]([N:12]=[C:1]=[S:2])=[C:10]([F:16])[CH:9]=1)[CH3:18]
Reactant: CCN(CC)c1cc(F)c(N)cc1F
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1cc(F)c(N=C=S)cc1F
Yield: 101.6 %

Procedure:
In a manner similar to Step A of Example 8, the reaction of 3.0 g (0.026 mole) of thiophosgene with 2.6 g (0.013 mole) of 4-diethylamino-2,5-difluoroaniline and 7.2 g (0.052 mole) of potassium carbonate in 100 ml of chloroform and 100 ml of water yielded 3.2 g of 4-diethylamino-2,5-difluorophenyl isothiocyanate. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]1>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]([CH3:32])=[C:21]([C:33]([NH:58][CH:59]4[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[5-(Cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid from example D.c1 (3.98 g; 8.0 mmol), triethylamine (2.43 g; 24.0 mmol) and HOBt (1.08 g; 8.0 mmol) is stirred in dry dichloromethane (40 mL) for 30 min, before addition of EDC (1.84 g; 9.6 mmol). The reaction mixture is stirred for one hour at ambient temperature. After addition of tert-butyl 4-amino-piperidine-1-carboxylate hydrochloride (2.27 g; 9.6 mmol) the reaction mixture is stirred at ambient temperature until the starting material is consumed according to LC-MS and chromatographed on silica gel (ethylacetate/cyclohexane—1:1) to yield the title compound as colorless foam.
Reaction SMILES: [C:1]([C:3]([C:17]#[N:18])=[CH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)#[N:2].C(O)C.[C-:22]#[N:23].[Na+]>O.C(O)(=O)C>[C:1]([CH:3]([C:17]#[N:18])[CH:4]([C:22]#[N:23])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)#[N:2]
Reactant: COc1cc(C=C(C#N)C#N)cc(OC)c1OC
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C(C#N)C(C#N)C#N)cc(OC)c1OC

Procedure:
To a suspension of 1,1-dicyano-2-(3,4,5-trimethoxyphenyl) ethene (8.5 g, 0.035 moles) in boiling ethanol (150 ml), sodium cyanide (1.77 g, 0.0351 moles) was added dropwise from a pipette. A dark solution formed which was additioned with distilled water (500 ml) and acidified with glacial acetic acid (to pH 2) at room temperature. No precipitate formed. With stirring, water (20 ml) was added, consequently precipitating out dirty white crystals. The crystals were filtered, washed repeatedly with water (500 ml) and dried in a vacuum oven. The product was recrystallised from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24].[C:25](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:25])[C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2n(C)c1=O

Procedure:
To a mixture of ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-2-oxo-3-quinolinecarboxylate(1.81 g), potassium carbonate powder (0.7 g), and N,N-dimethylformamide (DMF) (20 ml) was dropwise added methyl iodide (0.37 g) under stirring. The mixture was stirred for 2.5 hours, diluted with water and then extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and distilled to remove the solvent. The residue was crystallized with isopropyl ether to obtain ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylate. Recrystallization from ethanol gave colorless prisms. mp 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1B(O)O.C(Cl)Cl>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[Cl:17])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: OB(O)c1ccncc1Cl
Reactant: Nc1cc(Cl)c(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(-c2ccncc2Cl)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
4-Chloro-5-iodopyridin-2-amine (8.100 g, 31.8 mmol), sodium carbonate (5.00 g, 47.7 mmol), and 3-chloropyridin-4-ylboronic acid hydrate (11.2 g, 63.7 mmol) were combined in 100 mL of 1,4-Dioxane and 25 mL of water. Nitrogen was bubbled through the solution for ˜2 min before adding trans-dichlorobis(triphenyl-phosphine)palladium (II) (2.05 g, 2.92 mmol). The solution was heated to 60° C. overnight. Additional trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.2 g, 0.285 mmol), 3-chloropyridin-4-ylboronic acid hydrate (4.00 g, 22.8 mmol), 15 mL of water (degassed) and sodium carbonate (1.75 g, 16.6 mmol) were added. The solution was heated to 100° C. for 5 hours. Additional 3-chloropyridin-4-ylboronic acid hydrate (4.00 g, 22.8 mmol) was added and the reaction continued for 2 h at 100° C. The solution was concentrated under vacuum to ⅕th the volume and extracted between DCM and water. The aqueous layer was extracted with 10% isopropanol/DCM. The combined organics were dried over MgSO4 and then concentrated under vacuum to give an orange solid. The solid was slurried with DCM and then filtered through a fitted funnel. The solids were washed with additional DCM. The combined filtrate was purified on a 80 g Combiflash column (dry loaded), eluting with 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 8% methanol/0.4% NH4OH (˜28% in water)/DCM. The fractions containing the product were concentrated under vacuum to give a yellowish solid. The solids were triturated with DCM to give 4-chloro-5-(3-chloropyridin-4-yl)pyridin-2-amine (3.93 g, 51%) as an off white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.73 (1 H, s), 8.58 (1 H, d, J=4.9 Hz), 7.87 (1 H, s), 7.44 (1 H, d, J=4.9 Hz), 6.64 (1 H, s), 6.55 (2 H, br. s.); LCMS-ESI (POS), M/Z, M+1: Found 239.9.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]3[NH:28][N:29]=[CH:30][C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:53]([O:57][C:58]([N:60]([CH:73]([CH3:75])[CH3:74])[CH2:61][C@H:62]([C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[C:63](O)=[O:64])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:72][C:69]1[CH:70]=[CH:71][C:66]([C@H:62]([C:63](=[O:64])[N:15]2[CH2:14][CH2:13][N:12]([C:18]3[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][N:21]=[C:20]4[NH:28][N:29]=[CH:30][C:19]=34)[CH2:17][CH2:16]2)[CH2:61][N:60]([CH:73]([CH3:74])[CH3:75])[C:58](=[O:59])[O:57][C:53]([CH3:55])([CH3:54])[CH3:56])=[CH:67][CH:68]=1
Reactant: FC(F)(F)c1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(C(F)(F)F)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIEA (0.0607 mL, 0.349 mmol) was added to a solution of 4-(piperazin-1-yl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.030 g, 0.0872 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0336 g, 0.105 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0298 g, 0.0872 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 2 hours. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1) and an aqueous LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.027 g, 54%). MS APCI (+) m/z 495.3 detected.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[S:20])[CH:12]=[CH:13]C2C=CC=CC=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1(C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(Cl)(Cl)=O>CN(C=O)C.C(N(CC)CC)C>[C:1]1([S:7]([N:10]=[C:11]([S:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=[CH:13][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(NC(=S)C=Cc1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(N=C(C=CSc1ccccc1)Sc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
N-phenylsulfonyl-3-phenylthioacrylamide (0.50 g) was suspended to toluene (10 ml), then thionyl chloride (0.20 ml), triethylamine (0.40 ml) and one drop of DMF were added thereto at room temperature. The mixture was stirred on the 60° C. oil bath for three hours. Then it was cooled and filtered off the insoluble matter. The filtrate was concentrated under reduced pressure. The residue was dissolved to DMF (8 ml). DMF (2 ml) solution of sodium salt of thiophenol (0.30 g) was added thereto under ice-cooling, and it was stirred at room temperature for 1.5 hours. Ethyl acetate (80 ml) was added to the reaction mixture, and it was successively washed with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered off an inorganic salt, concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl N-phenylsulfonyl-3-(phenylthio)thioacrylimidate (0.14 g) as light yellow oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CC1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (67 mg, 79%), MS (ISP) m/z=455.5 [(M+H)+], mp 191° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (75 mg, 0.19 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc(Br)cc2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cc(Br)cc2ccccc12
Temperature: 0 °C

Procedure:
To a solution of 5.10 g (19.2 mmol) of the above methyl 3-bromo-1-naphthoate in 20 mL of anhydrous tetrahydrofuran at −78° C. under an atmosphere of nitrogen was added 48 mL (48 mmol) of a 1.0 M solution of diisobutylaluminum hydride in toluene. The resulting solution was allowed to gradually warm to 0° C. over 90 min and quenched with a saturated aqueous solution of potassium sodium tartrate (25 mL). The resulting suspension was vigorously stirred with gradual warming to ambient temperature over 2 h and the layers separated. The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid which was used without further purification LC/MS 237.0 (M+1) and 239.0 (M+3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH:11](Br)[CH2:12]CC)[CH:5]=1.C(C([O:24][CH2:25][C:26]([NH2:28])=[S:27])=O)(C)(C)C>CCO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:28]=[C:26]([CH2:25][OH:24])[S:27][C:11]=2[CH3:12])[CH:5]=1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: CCCC(Br)C(=O)c1cccc(C(=O)OC)c1
Solvent: CCO
Product: COC(=O)c1cccc(-c2nc(CO)sc2C)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A sample of rac-3-(2-bromo-pentanoyl)-benzoic acid methyl ester (0.60 g) and and 2-(tert.-butylcarbonyloxy)thioacetamide (0.36 g) in EtOH (4 mL) was heated at reflux for 5 h. The mixture was partitioned between AcOEt and 5% NaHCO3 solution, the organic layer was washed with brine, dried and evaporated. A solution of the residual oil and of NaOMe (0.13 g) in MeOH (10 mL) was stirred at 60° C. for 30 min. The solution was diluted with AcOEt, washed with 1N HCl and brine, dried and evaporated to give 3-(2-hydroxymethyl-5-methyl-thiazol-4-yl)-benzoic acid methyl ester (0.44 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]2[C@@H:11]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:10]3[C:9](=[O:17])[O:8]2)[CH2:4][O:3]1.[Si]([C:23]([F:26])([F:25])[F:24])(C)(C)C.[F-].C([N+](CC)(CC)CC)C>C1COCC1.O>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]2[C@@H:11]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:10]3[C:9]([C:23]([F:26])([F:25])[F:24])([OH:17])[O:8]2)[CH2:4][O:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(=O)[C@H]2O1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H]([C@H]2OC(O)(C(F)(F)F)[C@H]3OC(C)(C)O[C@@H]23)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 1000 mL three neck round bottom flask, a solution of (3aS,6R,6aS)-6-((R)-2, 2-dimethyl-1, 3-dioxolan-4-yl)-2, 2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (30 g, 116.2 mmol, 1eq) in THF (600 mL) was treated with TMSCF3 (2M in THF, 122 mL, 244 mmol, commercially available from Sigma Aldrich, India) and tetraethylammonium fluoride (TEAF, 2.48 g, 23.24 mmol, Apollo scientific, UK) at rt under a nitrogen atmosphere. The reaction mixture was stirred at rt for 30 minutes and additional TEAF (24.8 g, 232.4 mmol, Apollo scientific, UK) was added to the reaction mixture. The resulting reaction mixture was stirred at rt for 12 h under a nitrogen atmosphere. Upon completion of the reaction (TLC, 30% EtOAc-hexanes, Rf 0.6), the reaction mixture was diluted with water (1000 mL), and it was then extracted with EtOAc (500 mL×2). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure. The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution, 5-10% EtOAc-hexanes) to give (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-4-(trifluoromethyl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-ol, as a yellow semi solid mixture of two isomers (27.3 g, 71.8%): 1H NMR (400 MHz, CDCl3) δ 4.95 (m, 2H), 4.78 (d, J=8 Hz, 1H), 4.61-4.32 (m, 2H), 4.23 (dd, J=8, 4 Hz, 1H), 4.18-4.10 (m, 3H), 4.06 (dd, J=8.0, 4.0 Hz, 2H), 3.98 (m, 1H), 1.52 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H); 19F NMR (376.17 MHz, CDCl3) δ −78.24 & −82.32 ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:25][CH2:24][CH2:23][S:22]1.[CH2:26](OC=C)C.[BH4-].[Na+]>C(O)C.O.C(OCC)(=O)C>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:1][CH3:26])=[C:3]([CH:21]2[S:22][CH2:23][CH2:24][S:25]2)[C:4]([C:19]#[N:20])=[N:5]1
Reactant: C=COCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1SCCS1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CNc1c(C2SCCS2)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To the solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(1,3-dithiolan-2-yl)-1H-pyrazole-3-carbonitrile-ethoxyethylene (1:1) (0.30 g, 0.6 mmol) in ethanol (40 mL) at 5 C was added sodium borohydride (74 mg, 1.9 mmol). The resulting mixture was stirred at room temperature for five hrs and then diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with saturated sodium chloride, dried (Na2SO4), concentrated to afford a yellowish oil (0.27 g, 0.6 mmol); 19-F-NMR: −63.704.