Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>CO.O>[OH:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)OCCc1oc(C)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccccc2)c(CCO)o1
Reaction time: 0.5 h

Procedure:
2N Sodium hydroxide (40 ml) was added to a solution of 5-(2-acetoxyethyl)-2-methyl-4-phenyloxazole (16.6 g) in methanol (40 ml) and the mixture was stirred for 30 minutes, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue wwas purified by silica gel chromatography (silica gel: 190 g, eluent: isopropyl ether) to give an oil of 5-(2-hydroxyethyl)-2-methyl-4-phenyloxazole, yield 11.7 g (84.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39](O)=[O:40])[N:34]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:35]3[CH:36]=[CH:37][C:33]([C:32]([F:42])([F:31])[F:43])=[N:34]3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Reactant: O=C(O)Cn1ccc(C(F)(F)F)n1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cn3ccc(C(F)(F)F)n3)ccn2)c2cnccc21

Procedure:
Prepared according to the method described for Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and [3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Preparation 74). The residue was purified using alumina eluting with 2% MeOH in DCM to afford the title compound.
Reaction SMILES: [Na].[S:2](=[C:5]([CH2:13][CH3:14])[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=[O:4])=[O:3].[CH3:15]I>>[CH3:15][N:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][C:5](=[S:2](=[O:4])=[O:3])[CH2:13][CH3:14])[CH2:12]1
Reactant: CI
Reactant: CCC(Cc1cnccn1)=S(=O)=O
Agent: [Na]
Product: CCC(CC1=NC=CN(C)C1)=S(=O)=O

Procedure:
3.2 g of 2-(2-sulfonylbutyl)pyrazine (900) was added to a solution of 10 ml methyl iodide/25 ml methanol and the mixture refluxed for 4 days. It was then concentrated and purified by gel permeation chromatography (Biogel P-2/water). Freeze-drying gave 2.9 g of an amorphous solid (1000) which was crystallized from ethyl acetate/propanol, m.p. 224°-5° (dec.). UV H2O max: 283 (3.88).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCCC2)c1
Temperature: 60 °C
Yield: 65.3 %

Procedure:
A mixture of 5-nitroindazole (4.0 g, 24 mmol) and potassium carbonate (10 g 74 mmol) in DMF (60 mL) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-piperidine hydrochloride (6.8 g 37 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (4.3 g, 64% yield). 1H NMR (300 MHz, DMSO-d6) ppm 1.34 (m, 6H), 2.36 (m, 4H), 2.72 (t, J=6.44, 2H), 4.58 (t, J=6.44, 2H), 7.90 (m, 1H), 8.21 (m, 1H), 8.40 (m, 1H), 8.82 (m, 1H); MS (DCI/NH3) m/z 275 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:23])[C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[CH3:18][N:19]([CH3:23])[C:20]([NH:22][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)=[O:21]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CN(C)C(N)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Temperature: 95 °C
Yield: 51.2 %

Procedure:
A mixture of Example A1 (1 g, 3.97 mmol) in dioxane (20 mL) was sparged with Ar, treated with N,N-dimethyl urea (0.700 g, 7.95 mmol) and Cs2CO3 (1.942 g, 5.96 mmol), sparged with Ar, treated with dppf [1,1′-bis(diphenylphosphino)ferrocene] (12.38 g, 22.33 mmol) and Pd2(dba)3 (0.182 g, 0.199 mmol), sparged once again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration through silica gel. The filtrate was concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM) to afford 1,1-dimethyl-3-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (616 mg, 51%). MS (ESI) m/z: 304.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][C:31]([C:14]2[CH:13]=[N:12][C:7]3[NH:8][CH2:9][C:10](=[O:11])[N:5]([CH2:4][C:3]4[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:2]=4[Cl:1])[C:6]=3[CH:15]=2)=[CH:30][CH:29]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1c(F)ccc(F)c1Cl
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)C(=O)CN3)cc1
Temperature: 130 °C
Yield: 19 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (280 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A, with the modification that the mixture was heated to 130° C. in a microwave oven for 5 minutes. The title compound was obtained as a white solid after silica gel chromatography (19% yield). M.p. 180-182° C., LCMS: m/z=458.37 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.34 (t, J=7.1 Hz, 3H), 4.08 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 5.39 (s, 2H), 7.18 (bs, 1H), 7.29-7.33 (m, 1H), 7.39-7.47 (m, 1H), 7.42 (s, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.97 (s, 1H).
Reaction SMILES: [NH2:1][C:2](=O)[C@H:3]([NH:5][C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:4]>C1COCC1>[NH2:1][CH2:2][C@H:3]([NH:5][C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:4]
Reactant: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Solvent: C1CCOC1
Product: C[C@H](CN)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a solution of the product from example 25 step a) (6.9 g) in THF (100 ml) was added borane-methylsulfide complex (4.4 ml) and the mixture heated under reflux for 2 hours. The mixture was carefully quenched by the addition of methanol (100 ml), evaporated to dryness and the residue taken up into methanol (100 ml) and acidified to pH 1-2 with concentrated hydrochloric acid. Heated under reflux for 30 mins then evaporated to dryness. The residue was triturated with ether to give a solid, which was collected by filtration, dissolved in water and the free base precipitated by the addition of aqueous sodium bicarbonate solution to give the subtitle compound (3.1 g).
Reaction SMILES: [NH2:1]C1C=C(C(=O)C)C=CC=1F.N([O-])=O.[Na+].S(=O)(O)[O-].[Na+].Cl[S:22]([C:25]1[CH:26]=[C:27]([C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][C:30]=1[F:31])(=[O:24])=[O:23].N>Cl.O.C(O)(=O)C>[F:31][C:30]1[CH:29]=[CH:28][C:27]([C:32](=[O:34])[CH3:33])=[CH:26][C:25]=1[S:22](=[O:24])(=[O:23])[NH2:1]
Reactant: CC(=O)c1ccc(F)c(N)c1
Reactant: CC(=O)c1ccc(F)c(S(=O)(=O)Cl)c1
Agent: Cl
Agent: N
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1

Procedure:
4.9 g of 3'-amino-4'-fluoroacetophenone were diazotized in 25 ml of concentrated hydrochloric acid at 0° to 5° C with a solution of 2.3 g of NaNO2 in 5 ml of water and treated with a solution, prepared from 2.7 g of sodium bisulfite in 5 ml of water and 25 ml of concentrated hydrochloric acid and the oily 3'-chlorosulfonyl-4'-fluoroacetophenone was reacted with 20 ml of liquid ammonia to give the 4'-fluoro-3'-sulfamoylacetophenone, melting point: 135° C from glacial acetic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:13]([CH3:14])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1cnc(Cl)cn1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
5-chloropyrazine-2-carbonyl chloride (2.13 gram, 12.05 mmol) and dimethylamine HCl salt (1.06 gram, 12.7 mmol) were suspended in dichloromethane (50 mL) with stirring. Triethylamine (5.04 mL, 36.2 mmol) in dichloromethane (25 mL) was added dropwise at 0° C. to the reaction mixture. The combined solution was warmed up to ambient temperature and stirred for 4 hours. The compound was diluted with dichloromethane, washed with 1N HCl, water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient of 30 to 80% ethyl acetate in heptane) to provide desired 5-chloro-N,N-dimethylpyrazine-2-carboxamide (SM-1: 2.24 g, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.74 (d, J=1.37 Hz, 1H) 8.53 (d, J=1.37 Hz, 1H) 3.15 (s, 3H) 3.12 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccc(OC)c(OC)c2)c1

Procedure:
3,4-Dimethoxyphenylboronic acid (215 mg) and ethyl 2-chioroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.CN(C)[CH:16]=[O:17].Cl.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH:16]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=Cc1cccc(-c2ccccn2)n1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of 7.05 g (30 mmol) of 6-bromo-2,2'-bipyridine in 50 ml of diethyl ether is added to a solution of 19.4 ml (31 mmol) of 1.6M butyllithium-in-hexane solution in 100 ml of diethyl ether at -80° C. under a nitrogen atmosphere. After the addition is complete, stirring is carried out for a further 30 minutes at this temperature, after which a solution of 4.39 g (60 mmol) of dimethylformamide in 30 ml of diethyl ether is added at from -80° to -90° C. After further stirring at this temperature for 1.5 hours, hydrolysis is carried out with 150 ml of quarter-concentrated hydrochloric acid at from -60° to -50° C. The reaction mixture is then neutralized at room temperature by adding solid sodium bicarbonate, the phases are separated and the aqueous phase is extracted once again with 50 ml of diethyl ether. The organic phases are combined and are dried over sodium sulfate and finally the solvent is distilled off under reduced pressure. The title compound is obtained as a reddish brown oil which crystallizes on standing.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C1C(N)=CC=[C:13]([OH:18])[CH:12]=1>>[C:13]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:10])=[CH:2][CH:1]=1)(=[O:18])[CH3:12]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CC(=O)Nc1ccc(O)cc1

Procedure:
This example shows the stepwise reduction of p-nitrophenol and acetylation of p-aminophenol to produce the N-acetyl-p-aminophenol according to this invention: 90 grams of p-nitrophenol was added to 243 ml of water containing 1.25 grams charcoal and 0.31 grams catalyst (50% catalyst 50% water) of 5% palladium-on-charcoal. The system was heated to 95°-98° C. and hydrogen pressure of 70 psig. After 1 hour hydrogenation, the batch was cooled to 48° C. (pH 5.8) and 35 grams acetic anhydride was added. The reduction was continued at 95°-98° C. and 70 psig until hydrogen uptake ceased. The batch was cooled to 40° C. (pH 5.0) and 35 grams of acetic anhydride was added with heating to 95° C. The batch was filtered to recover catalyst. The N-acetyl-p-aminophenol was crystallized to yield a white crystalline product. Quality of the APAP was good giving only a slight pink caustic test and the product yield was 81.2 %.
Reaction SMILES: [C:1]1([C:7]([NH:9][NH2:10])=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:14])[CH:12]=O>C(O)C>[C:1]1([C:7]2[S:8][CH:12]([C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=S)c1ccccc1
Reactant: O=CC(=O)OCc1ccccc1
Solvent: CCO
Product: O=C(OCc1ccccc1)C1NN=C(c2ccccc2)S1

Procedure:
A solution of benzenecarbothioic acid hydrazide (2g) and benzyl glyoxylate (2.6g) in ethanol (5ml) was stirred at room temperature for 18 hours under nitrogen. The solvent was removed by evaporation and the residue was flash chromatographed to yield the sub-title product (3.5g) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14]CC)=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:18][CH3:19].[OH-].[Na+].C(O)C.O>C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(OC)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1F
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of ethyl 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (2.2 g, 8.30 mmol) and 13.2 mL of 1 N sodium hydroxide and 40 mL of ethanol is heated at reflux for 3 hours then cooled to room temperature. Water is added and the mixture is acidified with acetic acid. The resultant solid is collected by filtration washing with water to provide 1.90 g of 7-fluoro-6-methoxy-4-oxo-1,4,-dihydro-3-quinolinecarboxylic acid as a white solid, mp 265-267° C.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].C([Li])CCC.CCCCCC.Cl.[C:26](=O)([O-])[O-:27].[K+].[K+]>O1CCCC1.CN(C)C=O>[CH:26]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[O:27]
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1ccncc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
2,2-Dimethyl-N-pyridin-4-yl-propionamide (5.60 g) was dissolved in tetrahydrofuran (70 ml) to prepare a solution which was cooled to −78° C. A 1.57 M n-butyllithium/n-hexane solution (62 ml) was gradually added dropwise thereto, and the mixture was stirred at −78° C. for 15 min. The reaction solution was stirred at 0° C. for 4 hr and was then again cooled to −78° C. A solution of N,N-dimethylformamide (6.69 g) in tetrahydrofuran (7 ml) was gradually added dropwise thereto. The temperature was raised to room temperature. The reaction solution was then poured into a mixture of ice (10 g) with 6 N hydrochloric acid (30 ml), and the mixture was stirred for 15 min. The aqueous layer was neutralized with potassium carbonate powder and was extracted with diethyl ether. The diethyl ether layer was then washed with water and saturated brine and was dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give N-(3-formyl-pyridin-4-yl)-2,2-dimethyl-propionamide (3.35 g, yield 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C@H:9]([CH:10]=O)[C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]1=[O:20].[C:27]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:29])[NH2:28]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C@@H:9](/[CH:10]=[CH:30]/[C:27](=[O:29])[NH2:28])[C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:7]1=[O:20]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2C=O)c(OC)c1
Reactant: NC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2/C=C/C(N)=O)c(OC)c1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
4.0 g (11 mmol) of t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-formyl-2-oxo-3-azetidinecarbamate are dissolved in 300 ml of methylene chloride and the solution obtained is treated dropwise with a solution of 3.9 g (12 mmol) of carbamoylmethylene-triphenylphosphorane in 100 ml of methylene chloride. After 1 hour, the mixture is filtered and the crystals obtained are washed with methylene chloride. There are obtained 3.6 g (81%) of t-butyl(3R,4S)-1-(2,4-dimethoxybenzyl)-4-[(E)-2-carbamoylvinyl]-2-oxo-3-azetidinecarbamate of melting point 270° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1
Reactant: OCC1CCNCC1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCC1CCN(c2nc3ccccc3s2)CC1

Procedure:
30 g of 4-hydroxymethylpiperidine, 44 g of 2-chlorobenzothiazole and 72 g of potassium carbonate are reacted in 600 ml of acetonitrile under reflux overnight. After filtration and evaporation of the solvent, the residue is taken up in 200 ml of ethyl acetate and extracted with 1 N hydrochloric acid. The aqueous phase is made alkaline with caustic soda and extracted with dichloromethane. The expected product is obtained by drying and evaporation.
Reaction SMILES: Br.[NH:2]=[C:3]1[N:7]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[S:4]1.[BH4-].[Na+].O.[ClH:24].C(O)C>C(O)C>[ClH:24].[NH:2]=[C:3]1[N:7]([CH2:8][CH:9]([OH:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[S:4]1
Reactant: N=c1sc2ccccc2n1CC(=O)c1ccccc1
Agent: Br
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: N=c1sc2ccccc2n1CC(O)c1ccccc1
Reaction time: 1 h

Procedure:
In 100 ml of ethanol was suspended 7.5 g of 2-imino-3-phenacyl-2,3-dihydrobenzothiazole hydrobromide and after cooling the suspension to 0° C. to 5° C., 1.2 g of sodium borohydride was gradually added to the suspension, and the mixture was stirred for one hour. The reaction mixture was mixed with 5 ml of water and concentrated under reduced pressure. The residue was extracted with toluene and the extract was washed with water, dried with anhydrous magnesium sulfate, and then the solvent was distilled off to provide a tacky residue. The tacky product was dissolved in ethanol and hydrochloric acid-ethanol was added to the solution to provide 6 g of 2-imino-3-(β-hydroxyphenethyl)-2,3-dihydrobenzothiazole hydrochloride. Melting point: 253°-255° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](OC(C)(C)C)=O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1CN1CCN(Cc2ccccc2)CC1
Yield: 95.8 %

Procedure:
(S)-tert-butyl 2-(4-benzylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate 1.01 g (2.71 mmol) in THF (10 ml) was added slowly to a solution of 1M lithium aluminum hydride in THF (8.2 ml) at 0° C. under argon protection. The reaction mixture was refluxed for 2 hours, cooled, quenched with water and extracted with ethyl ether 2×50 ml. The combined organic solution was washed with brine, dried over sodium sulfate and concentrated to give 0.71 g of desired product in 96% yield.
Reaction SMILES: COC([C:5]1[NH:6][C:7](=[O:21])[N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:9]=12)=O.I[Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[C:9]3[N:8]([C:7](=[O:21])[NH:6][CH:5]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1[nH]c(=O)n2cccc(-c3ccc(C)cc3)c12
Agent: C[Si](C)(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-c2cccn3c(=O)[nH]cc23)cc1
Temperature: 25 °C

Procedure:
Combine 18 g (64 mmol) of the product of Example X with 19 ml (0.13 mol) of iodotrimethylsilane in 500 ml of methylene chloride and heat to reflux for 24 hr. Cool to room temperature and pour the reaction into 1 liter of 10% potassium carbonate. Dry the methylene chloride portion over magnesium sulfate, treat with charcoal, and remove the solvent in vacuo. Crystallize from ether to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])=O.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:12]([N:14]([CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])[CH2:15][CH3:16])[CH3:13]
Reactant: CCNCC
Reactant: Cc1cc(C(=O)O)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)Cc1sc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
To a solution of 5-formyl-4-methyl-thiophene-2-carboxylic acid (6.90 g, 40.5 mmol) in THF (150 mL), diethylamine (5.93 g, 81.1 mmol) and acetic acid (10 mL) followed by sodium triacetoxyborohydride (14.32 g, 60.8 mmol) is added. The mixture becomes slightly warm. The reaction mixture is stirred at rt for 16 h before it is concentrated and separated by CC on silica gel eluting with EA containing 0-50% of methanol to give the title compound (4.95 g) containing large amount of diethylammonium salts. The material (4.94 g, 21.8 mmol) is therefore dissolved in methanol (70 mL) and treated with chloro trimethylsilane (23.7 g, 218 mmol). The mixture is stirred at 50° C. for 18 h before it is concentrated, dissolved in EA and washed with sat. aq. NaHCO3 solution. The organic extract is dried over Na2SO4, filtered, concentrated and dried to give 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid methyl ester (4.05 g) as a yellow oil; 1H NMR (CDCl3): δ 1.08 (t, J=7.0 Hz, 6H), 2.19 (s, 3H), 2.59 (q, J=7.0 Hz, 4H), 3.67 (s, 2H), 3.87 (s, 3H), 7.28 (s, 1H), 7.52 (s, 1H). This material is dissolved in 1 N aq. HCl (80 mL) and stirred at 65° C. for 214 h. The solvent is evaporated and the residue is dried under high vacuum to give the title compound (3.56 g) as a pale beige solid; LC-MS: tR=0.26 min; [M+1]+=228.20; 1H NMR (D6-DMSO): δ 1.28 (t, J=7.3 Hz, 6H), 2.31 (s, 3H), 3.12 (q, J=6.8 Hz, 4H), 4.48 (s, 2H), 7.59 (s, 1H).