Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:19](=[O:20])[C:18]1[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=1[C:16]([NH:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]1)=[O:25]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(NC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), ethyl 4-amino-1-piperidinecarboxylate (0.620 g, 3.60 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from ether to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)3,4,5,6-tetrahydrophthalamide as white crystals (0.732 g, 50.9% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][N:12]=[C:13]=[S:14]>C(O)(=O)C>[CH3:11][NH:12][C:13](=[S:14])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CN=C=S
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CC(=O)O
Product: CNC(=S)Nc1cccc(C(=O)O)c1
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A mixture of 279.6 9 of 3-amino-benzoic acid, 164.1 g of methyl isothiocyanate and 1000 g of 100% acetic acid is heated to 80-85° C. The temperature rises to 95-100° C. in the course of 20 minutes without further heating, and a clear solution from which the product slowly crystallizes out forms. The suspension is kept at 90-100° C. for 2 hours, subsequently cooled to 15-20° C. and filtered with suction and the material on the suction filter is washed with acetic acid. 404 g of the title compound result, purity: 99.5%, melting point: 190-91° C., decomposition. Yield: 95.7% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:16]1([NH:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:21]([CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:22]2[CH:23]=[C:24]([F:30])[C:25]([F:29])=[C:26]([F:28])[CH:27]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Fc1cc(NC2CCCC2)cc(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN(c1cc(F)c(F)c(F)c1)C1CCCC1)C(=O)OCC
Temperature: 130 °C
Reaction time: 4 h

Procedure:
3.2 ml of diethyl(ethoxymethylene)malonate was added to 3.3 g of N-cyclopentyl-3,4,5-trifluoroaniline, followed by stirring at 130° C. for 4 hours. By purifying by silica gel column chromatography, 2.2 g of diethyl {[cyclopentyl(3,4,5-trifluorophenyl)amino]methylene}malonate was obtained.
Reaction SMILES: C([NH:8][OH:9])(OC(C)(C)C)=O.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.Cl>C1COCC1.C(OCC)C>[NH2:8][O:9][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CON)cc1
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol) in dry THF (60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7 mmol) was then added and the suspension stirred. A catalytic amount of KI was then added to the reaction prior to the cautious addition of 4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was then allowed to stir overnight before removal of solvent in vacuo. The residue was taken up with diethyl ether (100 ml) and HCl gas bubbled in for 20 minutes, causing the start of precipitation of the product. The flask was stoppered and left to stand overnight. The product was then filtered off as a off-white wax (39–52% yield according to varying batches).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:21][CH2:22][OH:23])[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[OH:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH3:25].[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:28].[Na+]>CO.C(O)(=O)C.C(=O)([O-])O.[Na+].O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH:11]([OH:12])[C:9]1[N:8]([CH2:21][CH2:22][OH:23])[C:7]2[C:2]([N:1]([CH2:24][CH3:25])[CH2:27][CH3:28])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCO)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCO)c12
Yield: 99.1 %

Procedure:
To a solution of 2-{7-amino-2-[(2,4-dichlorophenyl) (hydroxy)methyl]-1H-benzimidazol-1-yl}ethanol (7.58 g, 21.5 mmol) in methanol (220 mL) and acetic acid (11 mL) was added acetoaldehyde (8.04 mL, 129 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (27.3 g, 129 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 2 h, the mixture was diluted with aqueous sodium hydrogen carbonate and water, and extracted with ethyl acetate. The combined organic layer was washed with 1N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford a crude solid, which was washed with diisopropylether to give the title compound as a colorless solid (8.70 g, 21.3 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11](C#N)=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:16].[OH-].[Na+].Cl.[C:25](=[O:28])([O-])[OH:26].[Na+]>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:25]([OH:26])=[O:28])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:16]
Reactant: O=C([O-])O
Reactant: Cc1nc2ccc(C#N)nc2n1Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)nc2n1Cc1ccc(Cl)cc1Cl
Reaction time: 12 h

Procedure:
To a suspension of 3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (113 mg) in ethanol (0.6 ml) was added a 30% aqueous sodium hydroxide solution (0.3 ml), and the mixture was refluxed under heating for 12 hr. After 12 hr, a 30% aqueous sodium hydroxide solution (0.5 ml) was added and the mixture was refluxed under heating 3 hr. The reaction mixture was cooled, adjusted to pH 1 with 6N hydrochloric acid, stirred for 1 hr and adjusted to pH 4 with a saturated aqueous sodium hydrogencarbonate solution. The precipitated crystals were collected by filtration to give the objective compound (144 mg) as colorless crystals.
Reaction SMILES: [O-:1]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>>[C:3]1([C:9]([OH:1])([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: [O-]O
Reactant: CC(C)c1ccccc1
Product: CC(C)(O)c1ccccc1

Procedure:
Cumene hydroperoxide solution was pumped into the T-mixer with a flow of 0.250 ml/min. Hydrogen gas was fed into the T-mixer with a flow of 0.600 ml/min (1 bar). The T-mixer produced a taylor flow regime (liquid slugs). The product coming out of the reactor was collected. Samples were analysed with GC and HPLC. A conversion of 73% with >99% selectivity was obtained towards 2-phenyl-2-propanol.
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C[Si](Cl)(C)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH3:35]>N1C=CC=CC=1.O>[N:35]#[N:9].[C:25]1([CH2:31][C:32]([C@@:1]2([N:9]3[C:19]4[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=4[N:11]=[CH:10]3)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Product: N#N
Product: Nc1nc2c(ncn2[C@@]2(C(=O)Cc3ccccc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
2'-Deoxyguanosine (1)(32.5 g, 120 mmoles) was dried three times by co-evaporation with dried pyridine and suspended in 700 ml of dry pyridine. To this suspension at 0° C. trimethylsilyl chloride (80 ml, 600 mmoles) was added and the mixture stirred at 0° C. for 1 hour. Phenylacetyl chloride (80 ml, 600 mmoles) was added dropwise and the solution stirred for 15 hours. The reaction mixture was then cooled in an ice bath and 150 ml of cold water was added. After 30 minutes, 150 ml of 29% aqueous ammonia was added and the mixture stirred for 30 minutes. The solution was then evaporated to near dryness and the residue dissolved in 700 ml water and 700 ml methylene chloride. The product crystallized out of the aqueous solution upon extraction with CH2Cl2 was filtered off, washed with CH2Cl2 (3×70 ml) and ether (3×70 ml) and air dried to yield 27 g (56%) of N2 -(phenylacetyl)-2'-deoxyguanosine (2a), as confirmed by spectroscopic and elemental analysis.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][C:4]=1[Cl:9].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[S:7][C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[C:4]([Cl:9])[N:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1nc(Cl)c(CBr)s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2sc(Cl)nc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 5-(bromomethyl)-2,4-dichloro-1,3-thiazole, 6-methyl-2-sulfanylpyrimidin-4-ol (500 mg, 3.5 mmol), and triethylamine (2.5 mL, 18.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (778 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.46 (s, 2H), 6.09 (s (br), 1H); M+ 310.
Reaction SMILES: O1C=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[O:16]1C=CC(C(O)=O)=[CH:17]1>>[O:16]1[CH:4]=[CH:3][C:2]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])=[CH:17]1
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Reactant: O=C(O)c1ccoc1
Product: O=C1CCCCCN1C(=O)c1ccoc1

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example X) using 3-furoic acid in place of 2-furoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1)#[N:2].[ClH:12].Cl.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[OH2:11].[ClH:32].[ClH:12].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[O:11])[CH2:24][CH2:23]2)=[CH:27][CH:28]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Product: O
Yield: 153.9 %

Procedure:
The procedure described in Example 21 was followed, using 4-cyanophenyl isocyanate (1.44 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (75 ml) and triethylamine (4.3 ml; 31 mmole). Recrystallization from methanol/ethanol provided the title compound (3.87 g; 77% yield) as colorless crystals, m.p. 236°-238° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.COCCOC.C(OCC)(=O)C.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>[CH:11]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1)=[CH2:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2cn[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C=Cc1ccc2cn[nH]c2c1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a suspension of 6-bromo-1H-indazole (600 mg, 3.05 mmol) in toluene (18 ml) and 1,2-dimethoxyethane (6 ml) were added tributyl(vinyl)tin (1.33 ml, 4.57 mmol) and PdCl2(PPh3)2 (214 mg, 0.31 mmol). The reaction was purged with argon then heated at reflux for 3 h. Additional tributyl(vinyl)tin (0.66 ml, 2.28 mmol) and PdCl2(PPh3)2 (107 mg, 0.15 mmol) were added and heating was continued for 1 h. The same reaction was performed on an additional batch of 6-bromo-1H-indazole (200 mg, 1.02 mmol) and the two crude batches were combined. The reactions were diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 5% to 50% EtOAc/heptane to isolate 350 mg (60%) of 6-vinyl-1H-indazole as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.07 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.85 (dd, J=17.4, 11.0 Hz, 1H), 5.86 (d, J=17.4 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C1CCCCC1.CCOC(C)=O>C(Cl)Cl>[CH:2]([C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:1]
Reactant: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2C[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C[C@@H]1C[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of phenylmethyl (1S,4S,6S)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D9 (0.447 g) in DCM (13 ml) was added NaHCO3 (0.575 g, 6.84 mmol) and Dess-Martin periodinane (0.798 g, 1.882 mmol) and stirred at room temperature. TLC (Cyclohexane/EtOAc 1/1,2,4-dinitrophenylidrazine) showed the absence of starting material, so a solution of saturated NaHCO3/5% Na2S2O3 (60 ml) and DCM (10 ml) were added to the reaction mixture and it was left stirring for 30 minutes. The aqueous phase was back extracted with DCM (3×10 mls) and the biphasic system was passed through a phase separator cartridge. The organic solvent was evaporated under reduced pressure to yield a yellowish oil purified via Biotage SP4 (silica gel, SNAP 25 g; Cy/EtOAc, 25 CV from 1/0 to 7/3). Collected fractions gave the title compound D10 (0.370 g). MS: (ES/+) m/z: 260 (M+1), C15H17NO3 requires 259. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.50-9.38 (m, 1 H), 7.48-7.18 (m, 5 H), 5.19-4.93 (m, 2 H), 4.31-3.83 (m, 2 H), 3.28-2.90 (m, 1 H), 2.30-2.15 (m, 1H), 1.77-1.30 (m, 1 H), 1.21-0.84 (m, 2 H), 0.56-0.75 (m, 1 H), 0.22-0.03 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[OH:17][CH2:18][CH2:19][C:20](=O)[CH3:21].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH:20]([CH3:21])[CH2:19][CH2:18][OH:17])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: CC(=O)CCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CCO)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a suspension of (1S,5R)-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Preparation 18, 100 mg) in tetrahydrofuran (1.1 mL), 4-hydroxy-2-butanone (0.66 mmol), acetic acid (0.66 mmol) and NaBH(OAc)3 (0.88 mmol) were added. The mixture was stirred at room temperature for 2 h. After addition of NaOH (1M), the solvent was eliminated under vacuo, the residue was dissolved in ethyl acetate and the organic layer was washed with H2O and dried over Na2SO4. This solution was concentrated in vacuo to give 130 mg of the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[S:8](=[O:13])(=[O:12])[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH3:21]>C(#N)C.O>[CH2:20]([N:5]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[N:10][C:9]=2[S:8](=[O:13])(=[O:12])[N:7]=[CH:6]1)[CH3:21]
Reactant: CCBr
Reactant: Cc1cnc2c(c1)NC=NS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1C=NS(=O)(=O)c2ncc(C)cc21

Procedure:
A solution of 1.2 g of 6-methyl-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 75) in 15 cm3 of acetonitrile is treated with 2.5 g of potassium carbonate and 2 g of ethyl bromide. After refluxing for 16 hours, the solvent is removed under partial vacuum and the solid obtained is taken up in 15 cm3 of water. The precipitate is collected on a filter, washed with water and dried.
Reaction SMILES: [H-].[Na+].[C:3]([SH:6])(=[O:5])[CH3:4].[H][H].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([C@@H:15]2[CH2:19][C@@H:18](OS(C)(=O)=O)[CH2:17][N:16]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[N:14]=1>CN(C)C=O.O.C(OCC)(=O)C>[C:3]([S:6][C@@H:18]1[CH2:17][N:16]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[C@H:15]([C:13]2[N:14]=[C:10]([NH2:9])[S:11][CH:12]=2)[CH2:19]1)(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(N)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](c2csc(N)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (62.8% dispersion in mineral oil, 285 mg) in N,N-dimethylformamide (30 ml) was added thioacetic S-acid (0.54 ml) at 0°-5° C. under an atmosphere of nitrogen. After evolution of hydrogen ceased, the mixture was stirred at room temperature, and (2S,4R)-2-(2-aminothiazol-4-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.6 g) in N,N-dimethylformamide (20 ml) was added thereto. The mixture was stirred at 90° C. for 5 hours and poured into a mixture of ethyl acetate (100 ml) and water (100 ml). The aqueous layer was separated and extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (60 g) eluting with a mixture of acetone and dichloromethane (1:5 V/V) to give (2S,4S)-4-acetylthio-2-(2-aminothiazol-4-yl)-1 -(4-nitrobenzyloxycarbonyl)pyrrolidine (1.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1([Cl:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)C1C=CC=CC1(Cl)Cl
Yield: 101.2 %

Procedure:
To a cold (5° C.) mixture at 55.0 g (0.423 mole) of ethyl acetoacetate, 70 ml. of benzene, 18.3 ml. of 33% sodium hydroxide, and 141 ml. of water was added simultaneously with vigorous stirring 80.0 g (0.457 mole) of o-chlorobenzoyl chloride and 76 ml. of 33% sodium hydroxide in 1 hour as described in Example 4. The aqueous solution of sodium salt of ethyl o-chlorobenzoylacetoacetate was stirred with 22.5 g (0.424 mole) of ammonium chloride for 18 hours. The aqueous solution was then saturated with 25.0 g of sodium chloride. At this moment, some precipitate formed which was filtered. The analysis indicated this material was mainly the sodium salt of ethyl o-chlorobenzoylacetoacetate. The sodium salt and the aqueous filtrate were combined and acidified with dilute hydrochloric acid. The oil which separated was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give 30.0 g of oil which contained mainly ethyl o-chlorobenzoylacetoacetate. This material was stirred with a mixture of 7.2 g of ammonium chloride, 14 ml. of concentrated ammonium hydroxide and 150 ml. of water and worked up as described in Example 4 to give 16.6 g (15%) of crude ethyl o-chlorobenzoylacetate which was about 92% pure. A mixture of 15.0 g (0.065 mole) of ehtyl o-chlorobenzoylacetate, 9.5 g (0.070 mole) of sulfuryl chloride and 20 ml. of chloroform was held at reflux for 6 hours and concentrated to give 17.3 g of crude ethyl 2-chloro-o-chlorobenzoylacetate. A mixture of 17.0 g (0.065 mole) of ethyl 2-chloro-o-chlorobenzoylacetate, 4.94 g (0.065 mole) of thiourea and 65 ml. of ethanol was held at reflux for 2 hours and worked up as described in Example 4 to give 15.0 g of solid, m.p. 114°-136° C. which was recrystallized twice from ethanol to give 5.8 g (31%) of ethyl 2-amino-4-(o-chlorophenyl)-5-thiazolecarboxylate, m.p. 162°-164° C. Part (1.0 g) of this material was recrystallized from toluene to give 0.75 g of pure ethyl 2-amino-4-(o-chlorophenyl)-5-thiazolecarboxylate, m.p. 165°-166° C. A solution of 4.2 g (0.015 mole) of ethyl 2-amino-4-(o-chlorophenyl)-5-thiazolecarboxylate in 50 ml. of 85% phosphoric acid and 15 ml. of nitric acid was diazotized with 1.12 g (0.016 mole) of sodium nitrite as described in Example 4. The diazonium salt solution was poured into a solution of 1.50 g (0.015 mol) of cuprous chloride in 7.5 ml. of concentrated hydrochloric acid and 7.5 ml. of water. The reaction mixture was worked up as described in Example 4 to give 4.0 g of oil which was Kugelrohr distilled (150° C. at 0.3 mm) to give 2.0 g of oil. The material was purified to give 0.66 g (15%) of ethyl 2-chloro-4-(o-chlorophenyl)-5-thiazolecarboxylate as a colorless liquid.