Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCC#N)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
4-Methoxyphenol (263.0 g) was dissolved in acrylonitrile (224.8 g), and Triton B (18 mL) was added dropwise to the solution at room temperature, followed by stirring at 80° C. for 48 hours. The reaction mixture was cooled to room temperature under gentle stirring, and the mixture was further stirred for 12 hours. Subsequently, the mixture was left to stand at 6° C., to thereby allow precipitation of white prisms. After removal of the mother liquor through decantation, cold toluene (300 mL) was added, and crystals were collected through filtration. The thus-collected crude crystals were dried under reduced pressure at room temperature for 3 hours (crude crystals: 232.6 g). The crude crystals were dissolved in ethyl acetate (250 mL) at 50° C., and n-heptane (250 mL) was added slowly to the resultant solution under stirring. The crude crystals were recrystallized under gentle stirring for 12 hours. After removal of the mother liquor through decantation, n-heptane (300 mL) was added, and crystals were collected through filtration. The thus-collected crystals were washed with n-heptane (400 mL), and the crystals were dried under reduced pressure at room temperature (first crop of crystals: white prisms (154.5 g)). Since the mother liquor still produced crystals, they were collected as secondary crystals which were pale yellow prisms (second crop of crystals: pale yellow prisms (56.1 g)). Subsequently, all the filtrates and the n-heptane wash liquid were collected, and the combined mixture was concentrated under reduced pressure. Toluene (500 mL) was added to the residue, and the mixture was washed sequentially with 1N aqueous sodium hydroxide solution (100 mL×3), water (500 mL), 1N aqueous hydrochloric acid solution (100 mL×3), water (500 mL), and saturated brine (300 mL), followed by drying over sodium sulfate anhydrate for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) at 50° C., and n-heptane (150 mL) was slowly added to the resultant solution under stirring. The liquid was gently stirred for 12 hours for recrystallization. After removal of the mother liquor through decantation, n-heptane (200 mL) was added, and crystals were collected through filtration. The thus-collected crystals were washed with n-heptane (300 mL), followed by drying under reduced pressure at room temperature (third crop of crystals: white prisms (59.0 g)). In a similar manner, pale yellow prisms were collected as quaternary crystals (fourth crop of crystals: 19.0 g). The total amount of the four crystals was 288.6 g (yield: 76.9%), with crude crystals (yellow prisms) remaining (21.8 g, 5.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)=[C:9]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic acid is boiled under reflux for 2 hours. The reactionmixture is cooled, the solvent is evaporated off and the dark-brown residueis dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 2:1 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of yellow crystals, 1H-NMR (CDCl3): δ=7.40 (s, 2H), 7.10-6.80 (m, 8H), 5.70 (br s2H), 3.83 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>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.[Cu]I.CN(C=O)C>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])([CH3:21])[CH3:20]
Reactant: NC(=O)c1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Temperature: 120 °C
Yield: 64.6 %

Procedure:
3-Iodobenzamide (I142) (1.00 g, 4.05 mmol), bis(triphenylphosphine)palladium(II) chloride (0.142 g, 5 mol %), copper(I) iodide (0.077 g, 10 mol %), DMF (4 mL) and diisopropylamine (12 mL) were loaded into a microwave tube. The mixture was degassed for ten minutes with nitrogen, then trimethylsilylacetylene (0.69 mL, 4.9 mmol) was added and the resulting mixture heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated under reduced pressure and the residue chromatographed (Biotage Isolera, 40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I143) (0.569 g, 65% yield) as a brown solid; 1H NMR (400 MHz, CDCl3) δ 7.88 (td, J=1.8, 0.5 Hz, 1H), 7.78 (ddd, J=7.8, 1.8, 1.2 Hz, 1H), 7.63-7.59 (m, 1H), 7.40 (td, J=7.8, 0.5 Hz, 1H), 6.05 (br s, 1H), 5.67 (br s, 1H), 0.26 (s, 9H). LCMS Method C: rt 5.94 min, m/z 218.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(Cl)cc1

Procedure:
4-Chlorophenyl acetate is prepared by acylation of 4-chlorophenol with acetic anhydride using Schotten Baumann conditions.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76.6 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (113d) (0.73 g, 2.8 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.61 g, 2.98 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.89 g of the title compound as a colorless solid (77%).
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH2:6][CH2:7]Cl)=[O:4].C(OC)(=O)[CH2:12][OH:13].C([O:19]CC)C>>[OH:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH2:6][C:7]([O:13][CH3:12])=[O:19])=[O:4]
Reactant: CCOCC
Reactant: CC(C)(O)C(=O)OCCCl
Reactant: COC(=O)CO
Product: COC(=O)COC(=O)C(C)(C)O

Procedure:
2-Chloroethyl 2-hydroxy-2-methylpropionate, prepared as described in Step 1 of Example 3a, (5.22 g, 31.3 mmol) and methyl glycolate (2.83 g, 31.4 mmol) in 125 mL of ethyl ether containing 0.125% tert-butylbenzene was added to 9.0 g Lipase P30 and the reaction mixture was agitated on an orbital shaker for 4d. The enzyme powder was removed by filtration, the solvent was removed, and a portion of the resulting residue was purified by flash chromatography (ethyl acetate:hexane, 20/80) to give the title compound as an oil: 1H NMR δ 1.51 (s, 6H), δ 3.14 (s, 1H), δ 3.78 (s, 3 H), δ 4.71 (s, 2H); 13C NMR 27.0, 52.1, 61.1, 72.1, 167.6, 176.4 ppm.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8]>ClC(Cl)(Cl)Cl>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: CON=C(C(=O)OC)c1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(C(=O)OC)c1ccccc1CBr
Yield: 45.7 %

Procedure:
21.4 g (0.133 mol) of bromine are added to a stirred solution of 27.5 g (0.133 mol) of methyl 2-methylphenylglyoxylate O-methyloxime in 400 ml of tetrachloromethane. The mixture is then refluxed while irradiating with a 300 W Hg vapor lamp for four hours. It is then concentrated, the residue is taken up in ethyl acetate/water, and the organic phase is washed with H2O, dried with sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel with cyclohexane/ethyl acetate (9/1). 17.4 g (46%) of the abovementioned compound are obtained as an oil.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][S:5](=[O:19])(=[O:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].[OH-].[Na+].Cl.CCOCC.CCCCCC>O1CCOCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][S:5]([CH2:4][C:3]([OH:20])=[O:2])(=[O:19])=[O:18])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1
Reactant: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
2.2 g (6.98 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-acetic acid methyl ester is dissolved in 20 ml of dioxane, and the solution is mixed with 10 ml (20 mmol) of 2N sodium hydroxide solution. A slight warming occurs and the saponification is complete after 10 minutes. The solution is neutralized with 2N hydrochloric acid with pH control and gently evaporated to dryness in a vacuum. The residue is extracted with 30 ml ethyl acetate, the solution is shaken out once with 10 ml of water, the organic phase is dried on magnesium sulfate, filtered and evaporated to dryness. 1.96 g (6.51 mmol)=93.2% of the theoretical yield is obtained. Melting point 120-121° C. (ether/hexane).
Reaction SMILES: [Cl:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([C:21]2[CH:22]=[C:23]3[C:28]4=[C:29]([CH2:31][CH2:32][N:27]4[C:26](=[O:33])[CH2:25][CH2:24]3)[CH:30]=2)=[O:20])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[ClH:1].[CH:2]1([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28]5=[C:29]([CH2:31][CH2:32][N:27]5[C:26](=[O:33])[CH2:25][CH2:24]4)[CH:30]=3)=[O:20])[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reactant: ClC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cl
Product: O=C(CCC1CCN(C2CCc3ccccc32)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reaction time: 12 h
Yield: 27.4 %

Procedure:
1-Chloroindane (360 mg) was added to a suspension of 8-[3-(4-piperidinyl)propanoyl]1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (700 mg), potassium carbonate (700 mg) and potassium iodide (catalytic amount) in acetonitrile (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (15 ml) and ethyl acetate (20 ml) were added to the residue, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as colorless crystals (285 mg) having a melting point of 111 to 113° C. The free base compound (270 mg) was treated with a hydrogen 20 chloride-ethanol solution to give, the title compound (270 mg) as pale yellow amorphous powders.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:5](=[O:6])[CH2:4][CH:3]1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:11])[C:5](=[O:6])[CH2:4][CH:3]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C1CC(=O)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(=O)CC1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of methyl 2,2-dimethyl-3-oxocyclobutanecarboxylate (1.0 equiv.) in MeOH (1.1 M) was added aqueous solution of sodium hydroxide (4.48 N, 2.0 equiv.), and the resulting mixture was stirred at 50° C. for 2 h. The starting material was consumed as monitored by thin layer chromatography, eluting with 20% ethyl acetate in petroleum ether. After removal of the volatile solvent, aqueous solution of hydrochloride (2 N, 1.4 equiv.) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the product (88% yield) as a white solid, which was used for the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 12.4 (br, 1H), 3.31-3.23 (m, 1H), 3.17-3.08 (m, 1H), 2.97-2.91 (m, 1H), 1.22 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1C=CC=CC=1>[CH2:1]([N:4]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CCCNCCC
Solvent: c1ccccc1
Product: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Yield: 87 %

Procedure:
Di-n-propylamine (15.2 g) and diethyl bromomalonate (17.9) were dissolved in dry benzene (90 ml), and the mixture was heated under reflux for 7 hours with stirring. The reaction mixture was worked up in the same way as in Example 2, (1). The resulting residue was chromatographed on a silica gel column using benzene/ethyl acetate (20:1) as an eluent to give 16.9 g (yield 87%) of diethyl di-n-propylaminomalonate.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].[I:21]Cl.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: ClI
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reaction time: 42 h
Yield: 93.4 %

Procedure:
To a solution of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (6.50 g) in mL glacial Acetic acid was added a solution of 9.205 g ICl (iodine monochloride) in 8 mL of acetic acid, with addition carried out at a rate such that the temperature of the resulting mixture did not exceed 24 degrees C. Water (11.0 mL) was added and the resultant mixture was stirred at 25 degrees C. for 42 hours. Excess ICl was decomposed by the addition of aqueous solution of sodium bisulfite (3.5 mL) at a rate such that the temperature of the reaction mixture did not exceed 20 degrees C. Water (40 mL) was added, and the precipitate was collected by filtration and air-dried to give 8.86 g of crude 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. A suspension of the crude product in 90 mL water was made basic by addition of 50% NaOH, and the resulting solution was extracted into warm EtOAc. The combined organic layers were filtered and EtOAc was replaced by isopropanol via distillation. To the hot isopropanol solution was added 3.4 mL of 6N HCl and the resultant mixture was cooled slowly to 15 degrees C. Crystals of the resulting HCl salt were isolated by filtration, rinsed with isopropanol, and dried under vacuum at 70 degrees C. to give 6.08 g (58.8%) of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine hydrochloride salt, m.p.=262.0-263.0° C., MS (M+H)=401.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.O>O1CCCC1.[Br-].[Na+].C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 105.7 %

Procedure:
To a cold (-40° C.) solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide (31.5 g; 0.16 mol) in 600 mL of dry tetrahydrofuran was added n-butyllithium in hexanes (2.5 mol; 131 mL) while the temperature was maintained at -40° C. The solution turned deep red after one equivalent was added. Sodium bromide (1.6 g) was added and the mixture was stirred for 10 min. A solution of m-chlorobenzyl-chloride (26.5 g; 0.174 mol) in 125 mL of dry tetrahydrofuran (THF) was added while the temperature was again maintained at -40° C. The reaction mixture was stirred for a further 30 min. after which water was carefully added until the color dissipated. The product was isolated by extraction into ethyl acetate which was washed with water, dried (MgSO4) and concentrated to give 53.6 g (HPLC purity 89%; yield 92%) of 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide as an oil. This oil may be used directly in the next step or crystallized from hexanes to give 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide as a white solid: m.p. 45°-46° C.; NMR (200 MHz,CDCl3)δ1.50 (s,9H), 2.96 (t,2H,J=8 Hz); 3.40 (t,2H,J=8 Hz); 7.0-7.3 (m,5H); 7.39 (dd,1H,J=8, 2 Hz); 7.98 (br s, 1H); 8.30 (dd,1H, J=4, 1 Hz); mass spectrum, m/e (rel intensity) 316M+ (19). Anal. Calcd for C18H21N2OCl: C,68.22; H,6.68; N,8.88; Cl,11.19. Found: C,68.25; H,6.59; N,8.78; Cl,11.10.
Reaction SMILES: [ClH:1].[C:2]([NH:10][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@:15]2([C:27]2[S:31][N:30]=[CH:29][CH:28]=2)[N:16]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(O)C.CC(OC)(C)C>[ClH:1].[S:31]1[C:27]([C@:15]23[CH2:17][NH:18][CH2:19][C@H:14]2[CH2:13][S:12][C:11]([NH:10][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:16]3)=[CH:28][CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccns2)C1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: O=C(NC1=N[C@@]2(c3ccns3)CNC[C@H]2CS1)c1ccccc1
Reaction time: 18 h
Yield: 98 %

Procedure:
Hydrogen chloride 6 M in 2-propanol (1.65 L, 9.9 mol) is added to tert-butyl (4aR,7aR)-2-benzamido-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (200 g, 449.9 mol) in 2-propanol (1.6 L) at 22° C. and stirred for 18 hours. The mixture is concentrated to give a white solid. The solid is diluted with MTBE (1 L), stirred at 22° C. for 1 hour, filtered and dried under vacuum to constant weight to give the title compound (170 g, 98%). ES/MS (m/e): 345.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1.O>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:18][C@H:15]1[CH2:16][CH2:17][O:13][CH2:14]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.05 mL) and methanesulfonyl chloride (1.05 mL) were added to a solution of (S)-tetrahydrofuran-3-ol (1.0 g) in toluene (10 mL), and the reaction solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, then the reaction solution was extracted with toluene and washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum to obtain (S)-tetrahydrofuran-3-yl methanesulfonate as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].N1C=CC=CC=1.C1CCCCC1>O1CCOCC1>[Cl:10][C:11]1[C:12]([C:13]([NH:1][C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[O:14])=[CH:16][CH:17]=[CH:18][N:19]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: C1COCCO1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Yield: 4.7 %

Procedure:
Using a procedure analogous to that described in Example 1a, the carboxamide was prepared from 12.8 g of 3-amino-2-chloro-4-methyl pyridine, 15.8 g of 2-chloronicotinoyl chloride, 7.1 g of pyridine, 30 ml of cyclohexane and 60 ml of dioxane. After removal of the solvent, the product was dissolved in methylene chloride, washed with water and dried (sodium sulfate). After removal of the solvent, the residue was washed with ethyl acetate to give 1.2 g of the title compound, m.p. 193°-194° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:12](#[N:14])[CH3:13]>C1COCC1.C(OCC)(=O)C.Cl>[CH:3]1([C:8](=[O:10])[CH2:13][C:12]#[N:14])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (2.75 g, 68.7 mmol) in THF (15 mL) at 70° C. was added dropwise a solution of methyl cyclopentanecarboxylate (8.00 g, 62.4 mmol) and anhydrous acetonitrile (3.91 mL, 74.9 mmol) in THF (5 mL). The mixture was stirred for 16 h at 70° C.-72° C., cooled to rt, and diluted with ethyl acetate and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the solvent provided 3-cyclopentyl-3-oxopropanenitrile, which was used without further purification.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[NH:8]([C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[C@H:9]([CH2:13][OH:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 5 g (0.023 mol) of Boc-Valine dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred 15 minutes and filtered. The filtrate is added slowly to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and stirred 1 hour at ice-bath temperature then 1 hour at room temperature. The reaction mixture is cooled to 0° C. and treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl saturated with NaHCO3, dried over anhydrous MgSO4, and evaporated to dryness. The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH.