Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=1)=O.C(OP([CH2:56][C:57]#[N:58])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=2)=[CH:56][C:57]#[N:58])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2cccc([N+](=O)[O-])c2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-3′nitrobenzophenone (1.44 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 3% hexane/methylene chloride) to afford 1.12 g (72%) of a mixture of the E and Z isomers as a yellow solid: mp 117.5-120° C.; 1H NMR (CDCl3) δ8.40-8.17 (m, 4 H), 7.90-7.55 (m, 4 H), 7.08-6.89 (m, 6 H), 5.84 (s, 1 H), 5.71 (s, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H); 13CNMR (CDCl3) δ160.2, 160.1, 151.7, 151.1, 149.2, 148.3, 148.2, 141.0, 138.8, 135.4, 134.4, 129.9, 129.7, 129.7, 128.1, 124.8, 124.6, 124.4, 123.3, 123.1, 122.3, 117.4, 117.3, 112.3, 111.0, 110.4, 95.7, 94.8, 56.0, 55.9; Anal. Calcd for C17H14N2O4. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.57; H, 4.64; N, 8.92.
Reaction SMILES: [Cl-:1].[NH4+].O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][S:16]([NH:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=[O:18])=[O:17])=[CH:9][CH:8]=1)([O-])=O>[Zn].C(O)C>[ClH:1].[ClH:1].[NH2:4][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][S:16]([NH:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=[O:18])=[O:17])=[CH:9][CH:8]=1
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccc(NCCS(=O)(=O)NCC2CCCO2)cc1
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cl
Product: Nc1ccc(NCCS(=O)(=O)NCC2CCCO2)cc1
Yield: 104.5 %

Procedure:
A mixture of zinc powder (3.8 g), ammonium chloride (0.22 g), water (0.75 mL), and 96% ethanol (10 mL) was refluxed in a boiling water bath. The derivative 2-[(4-nitrophenyl)amino]-N-(tetrahydrofuran-2-ylmethyl)ethanesulfonamide (10) (2.52 g, 7.6 mmol) was added in portions and heating was continued until the reaction medium decolorized. The resulting mixture was filtered while boiling and the filtrate was recovered onto 12 mL of ethanol and 1.5 mL of concentrated hydrochloric acid. Acetone was added to precipitate the hydrochloride formed (1.8 g). The product was filtered off and recrystallized from 15 mL of ethanol to give 0.8 g of dihydrochlorided product with the following elemental analyses:
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][CH2:4][CH2:5][Si:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>>[Cl:2][CH2:3][CH2:4][CH2:5][Si:6]([O:13][CH2:14][CH3:15])([O:7][CH2:8][CH3:9])[O:10][CH2:11][CH3:12].[NH2:1][CH2:3][CH2:4][CH2:5][Si:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: N
Agent: CCO[Si](CCCCl)(OCC)OCC
Product: CCO[Si](CCCN)(OCC)OCC
Reaction time: 1 h

Procedure:
Into a ten-liter steel autoclave with stirrer, 3400 g (200 moles) of liquid ammonia was poured, and the reactor was sealed. Then the ammonia was heated to 75° C., causing a pressure of 36 bars to be established. After this temperature was reached, γ-chloropropyltriethoxysilane was fed in, with stirring at 183 rpm, for a period of one hour, in the amount of 2.67 moles; then stirring was continued for 8 hours at 75° C. Then the pressure was let off and the ammonia was removed. After the removal of ammonium chloride by filtration, the remaining raw product was purified by vacuum distillation. From the 642 grams of γ-chloropropyltriethoxysilane, 486 g of γ-aminopropyltriethoxysilane was obtained (82.4% of the theoretical yield) plus 98.3 g of byproducts (secondary and tertiary amines).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:14]([O:21][CH3:22])(=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1>ClCCl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:15]([C:14]([O:21][CH3:22])=[O:20])[C:16]([O:18][CH3:19])=[O:17])[CH:10]([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(c1ccc(F)c(F)c1)C(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C(=O)OC)=C(c1ccc(F)c(F)c1)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Titanium tetrachloride (11.4 mL, 104.1 mmol) in dichloromethane (28 mL) was added dropwise to a flask containing tetrahydrofuran (205 mL) under a nitrogen atmosphere, cooled in icebath. Then 1-(3,4-difluorophenyl)-2,2-difluoro-ethanone (10 g, 52 mmol) and dimethyl malonate (5.93 mL, 52 mmol) were added both at once. The resulting mixture was stirred under nitrogen atmosphere for 60 minutes while cooling was continued. Then, pyridine (16.8 mL, 208 mmol) in tetrahydrofuran (37 mL) was added to the mixture and this was allowed to warm to room temperature and stirred overnight. Next, distilled water (40 mL) and diethylether (40 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted with diethylether (2×40 mL). The combined organics were washed with brine (60 mL), NaHCO3 (60 mL) (aq/sat) and again with brine (60 mL). The organic layer was dried on MgSO4, filtered and concentrated under reduced pressure yielding dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (15.6 g) as a clear oil. Dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (5 g) was dissolved in 1,4-dioxane (25 mL) and treated with 3,5-difluoropyridine-2-carboximidamide (3.1 g, 19.6 mmol). The resulting mixture was stirred at 40° C. overnight. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate-heptane 0:100 to 50:50) yielding methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate (5.45 g) as a yellow solid which was used as such. Methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate was treated with phosphorus oxychloride (10 mL, 107.6 mmol) and the mixture was stirred at reflux for 2 hours.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][CH2:23][Cl:24])[CH3:21]>C1C=CC=CC=1>[Cl-:24].[CH2:20]([O:22][CH2:23][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:21]
Reactant: CCOCCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 84 °C

Procedure:
A solution of 99.66 g of triphenylphosphine and 37.82 g of chloromethyl ethyl ether in 240 ml of dry benzene was stirred and refluxed (84° C.) for 6 hours. The mixture then was chilled and filtered to give 7, as a white solid, mp 205°-206° C.
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]([CH:12]2[CH2:15][CH2:14]C2)S[C:10]=1N)=O)C.C(O[C:19]([C:21]1[N:22]=[C:23]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[S:24][C:25]=1[NH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:20])C.C1(C2SC(NC3C=NC=CC=3)=C(C(O)=O)[N:45]=2)CCC1>>[CH3:10][C:6]1[N:7]=[C:8]([NH:45][C:19]([C:21]2[N:22]=[C:23]([CH:33]3[CH2:34][CH2:35][CH2:36]3)[S:24][C:25]=2[NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:20])[CH:12]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nc(C2CCC2)sc1N
Reactant: O=C(O)c1nc(C2CCC2)sc1Nc1cccnc1
Reactant: CCOC(=O)c1nc(C2CCC2)sc1Nc1cccnc1
Product: Cc1cccc(NC(=O)c2nc(C3CCC3)sc2Nc2cccnc2)n1

Procedure:
The title compound, MS (ISP): m/e=366.0 (M+H+), was prepared as for example 153, steps A to G. Step C was performed using cyclobutanecarbonyl chloride, and yielded cyano-(cyclobutanecarbonyl-amino)-acetic acid ethyl ester, which was cyclized to 5-amino-2-cyclobutyl-thiazole-4-carboxylic acid ethyl ester in step D. This was used in step E to generate 2-cyclobutyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester, which was hydrolized to 2-cyclobutyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid in step F. Coupling as described in step G generated the title compound.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:15]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH2:18][CH3:19].Cl.N[OH:29]>O>[CH2:15]([C:20]1[CH:26]=[C:25]2[C:23](=[CH:22][CH:21]=1)[NH:24][C:2](=[O:29])[C:3]2=[O:5])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCCCCc1ccc(N)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 25 °C
Yield: 40 %

Procedure:
28.5 g Chloral hydrate (172 mmole) and 170 g sodium sulphate were dissolved in 600 ml water (solution 1). 27.8 ml 4-n-Pentylaniline (157 mmole) was dissolved with 15 ml concentrated HCl in 475 ml water (solution 2). 29.6 ml 50% Aqueous hydroxylamine was dissolved with 42 ml concentrated HCl in 80 ml water (solution 3). While stirring, solution 1 was heated to 60° C., then solution 2 followed by solution 3 were added dropwise. The temperature was raised until reflux for 15 minutes. The reaction mixture was allowed to cool down to room temperature. The solid residue was filtered off, dissolved in 500 ml ethyl acetate and washed three times with 200 ml water. After evaporation, the residue, mainly containing compound 14, was slowly added to an ice cooled beaker containing 100 ml concentrated sulphuric acid, while stirring. After all compound 14 was added, the reaction mixture was allowed to reach room temperature followed by heating at 80° C. for 15 minutes. 1000 g Ice was added and the formed solid was filtered and redissolved in 300 ml ethyl acetate. This solution was washed three times with 200 ml water and evaporated. The resulting residue was purified by flash chromatography (Acros Silicagel 0.060-0.200 mm) using isooctane/acetone 65:35, affording compound 15 as an orange solid (11.4 g, 40% yield).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][O:39][CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:32][O:33][CH2:34][CH2:35][N:36]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH2:37][CH2:38][O:39][CH3:40]
Reactant: COCCNCCOC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(CCOC)CCOC)c4)cc23)CC1
Yield: 16.8 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methyloxy)-N-[2-(methyloxy)ethyl]ethanamine (114.3 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (10.5 mg, 16%).
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>>[F:29][C:30]([F:36])([F:35])[S:31]([NH:34][C:26](=[O:27])[CH:25]=[CH:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:23][CH:22]=1)(=[O:33])=[O:32]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)C(F)(F)F

Procedure:
Prepared by coupling 2e and trifluoromethanesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (12%); 1H NMR (d6-DMSO) δ 8.93 (br s, 2H), 7.31–7.07 (m, 9H), 6.80 (d, J=8.0 Hz, 2H), 6.72 (d, J=7.3 Hz, 1H), 6.35 (d, J=15.7 Hz, 1H), 2.76 (t, J=7.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.07 (m, 2H); APcI m/z: 496 (M−H−).
Reaction SMILES: C(OCC)(OCC)OCC.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]1([N:24]=[CH:25]OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:12]1([NH:11][CH:25]=[N:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CCOC=Nc1ccccc1
Solvent: CCOC(OCC)OCC
Product: C(=Nc1ccccc1)Nc1ccccc1
Yield: 80 %

Procedure:
Thus, a mixture of triethyl orthoformate (1equ.) and aniline (2equ.) is heated at reflux for 2 hours. The ethanol evolved during the reaction is then distilled through a fractionating column. The reaction mixture is then allowed to cool, whereupon it solidifies. Recrystallisation of the solid from toluene yields N,N′-diphenyl formamidine in 80% yield.
Reaction SMILES: [Cl:1][C:2]1[N:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.COC(OC)N(C)C.[C:27]1([CH3:33])C=CC=C[CH:28]=1.Cl.[CH:35]([NH:38][NH2:39])(C)C.C(O)(=O)C>>[Cl:1][C:2]1[N:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:39]([CH:27]([CH3:33])[CH3:28])[N:38]=[CH:35][N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: Cc1ccccc1
Reactant: CC(C)NN
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 85 °C

Procedure:
A mixture of [9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine-2-carboxamide (0.520 g, 1.96 mmol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (1.305 mL, 9.824 mmol) in Toluene (28.2 mL, 265 mmol) was heated under reflux for 1 hour. LCMS: no stm, major peak m/z 320.1. After cooling, the intermediate was concentrated. A mixture of the intermediate and isopropylhydrazine hydrochloride (0.4345 g, 3.929 mmol) in Acetic acid (18 mL, 320 mmol) was heated at 85° C. for 3 hours. The mixture was cooled and filtered from an insoluble impurity. The mother liquor was concentrated in vacuum. The residue was diluted with EtOAc then washed with water and brine. The organic layer was dried Na2SO4, filtered, and concentrated to give 317 (264). MS: (ESI+)=331.0. 1H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 7.97 (d, J=24.4 Hz, 1H), 7.94 (s, 1H), 7.31-7.19 (m, 1H), 5.85 (dq, J=13.0, 6.4 Hz, 1H), 4.66 (dd, J=5.2, 2.5 Hz, 2H), 4.63-4.54 (m, 2H), 1.48 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc(OC)c1

Procedure:
To a stirred solution of 3,5-dimethoxybenzenamine (16c, 4g, 26.1 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.3 g, 28.7 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound N-(3,5-dimethoxyphenyl)-4-nitrobenzamide (18c). To a stirred solution of amide (18c, 5g, 16.5 mmol) taken in toluene add lawessons reagent (4.6 g, 11.5 mmol) and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound N-(3,5-dimethoxyphenyl)-4-nitrobenzothioamide (19c). Treating the thioamide product (19c, 3g, 9.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,7-dimethoxy-2-(4-nitrophenyl)benzo[d]thiazole (20c) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20c. Reduction of the nitro compound (20c, 500 mg, 1.5 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21c). The compound 4-(5,7-dimethoxybenzo[d]thiazol-2-yl)benzenamine (21c, 200 mg, 0.698 mmol) on reaction with 3,4,5-trimethoxybenzaldehyde (22f, 137 mg, 1 eq) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product and immediately proceeded for the next reaction by using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 6f as a yellow solid (53%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Li][CH2:10]CCC.CI>O1CCCC1>[CH3:10][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccsc1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1sccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.32 g (41.5 mmol) of 3-thiophenecarboxylic acid in 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 57.1 ml (91.4 mmol) of 1.6 M n-BuLi in hexanes. The cloudy suspension was stirred at -78° C. under a blanket of argon for 40 minutes, and was then transfered via canulla onto a solution of 59.05 g (25.9 ml, 416 mmol) of methyl iodide dissolved in 20 ml of anhydrous tetrahydrofuran (chilled to -78° C.). The resulting clear, colorless solution was allowed to warm to room temperature and stirred for 20 hours. A white solid was formed. The reaction mixture was concentrated in vacuo, partitioned between 75 ml of sat. NH4Cl solution and 150 ml of ethyl ether, and the layers separated. The aqueous phase was washed with 100 ml of ethyl ether and layered with 100 ml of ethyl ether and acidified with 1N sulfuric acid solution until all of the yellow emulsion dissapated. All organic phases were combined, washed with brine solution, dried over MgSO4, filtered and concentrated in vacuo to yield an off-white solid. Purification by flash chromatography (silica gel, 75% ethyl acetate in hexane) yielded the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[N:3]=1)[CH:8]=[O:9]
Reactant: COc1cc(CO)cc(Cl)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C=O)cc(Cl)n1

Procedure:
To a solution of (2-chloro-6-methoxypyridin-4-yl)methanol (1.73 g, 9.97 mmole) from the protocol immediately above in CH2Cl2 (40 ML) was added PCC (2.58 g, 11.96 mmole) all at once at RT. After 60 hr the mixture was diluted with Et2O and filtered through a plug of Celite®. The filtrate was concentrated to give the titled compound as a tan-yellow solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) δ9.96 (s, 1H), 7.32 (s, 1H), 7.06 (s, 1H), 4.00 (s, 3H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C@H:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>ClCCl>[Br:8][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C@@H:10]([CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26]
Reactant: CCCCCC[C@H](C)Oc1ccc(C)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
A suspension of 6.1 g (34.4 mmol) of NBS and 4 g of silica gel in 125 ml of dry dichloromethane was stirred under argon for 30 min. Then a solution of 4.56 g (17.2 mmol) of (S)-4-(1-methylheptyloxy)-2-nitro-toluene in 150 ml of dichloromethane was added via syringe. The reaction mixture was stirred at room temperature for 72 h. The resulting suspension was filtered through a short silica gel pad and the pad was washed several times with dichloromethane. The solvent was evaporated and the crude product extracted with a mixture of hexanes/ethyl acetate [95/5]. The suspension was filtered, the solvent removed and the residue was purified by flash chromatography using hexanes as eluent, affording 4.6 g (78%) of (S)-α-Bromo-4-(1-methylheptyloxy)-2-nitrotoluene (Compound 35, Scheme VI, R1 =(S)-OCH(CH3)C6H13) as a yellow liquid; Rf [hexanes/ethyl acetate 98/2]: 0.26; 1H NMR (300 MHz, CDCl3): δ 0.86(t, 3H, J=6.7 Hz), 1.18-1.48(m, 8H), 1.30(d, 3H, J=6.1 Hz), 1.58(m 1H), 1.70(m, 1H), 4.40(m, 1H), 4.77(s, 2H), 7.06(dd, 1H, J=2.7 Hz, J=8.5 Hz), 7.40(d, 1H, J=8.5 Hz), 7.50(d, 1H, J=2.7 Hz); 13C NMR (300 MHz, CDCl3): δ 13.98, 19.36, 22.50, 25.28, 29.10, 29.25, 31.67, 36.12, 75.00, 111.93, 121.08, 124.14, 133.61, 148.69, 158.92; IR (CHCl3): 3020, 2930, 2850, 1625, 1525, 1500, 1350, 1320, 1250, 1100, 975, 850, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 345(M+ +1 1.38), 343(M+ -1 1.35), 264(37), 152(100), 112(28), 71(59), 57(93), 55(38), 43(93), 41(70).
Reaction SMILES: COC1C(C(O)=O)=C(Cl)C=CC=1Cl.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16].[CH3:24][O:25][C:26](=O)[O:27]C>C[O-].[Na+]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([CH2:14][C:26]([O:25][CH3:24])=[O:27])=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: COc1c(Cl)ccc(Cl)c1C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
Alternatively, MDBA may be prepared by the carbomethoxylation of a ketone. For example, 4-chloracetophenone reacts with excess dimethylcarbonate using sodium methoxide as a catalyst to produce methyl 4-chlorobenzoylacetate as described in U.S. Pat. No. 3,950,381. NMR data was consistent with the structure.