Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7](CC#N)=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]>C1COCC1.O.[Pd](Cl)Cl>[Cl:5][C:6]1[C:7]([CH2:2][C:1]([NH2:4])=[O:3])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]
Reactant: CC(N)=O
Reactant: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cccc2cc(Cl)c(CC(N)=O)cc12
Reaction time: 18 h

Procedure:
Palladium(II)-chloride (4.3 mg, 0.024 mmol, 0.1 equiv) and acetamide (60 mg, 1.0 mmol, 4.2 equiv) were added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile in THF (0.75 ml) and water (0.25 ml). After 18 hours at room temperature, the reaction mixture was adsorbed on silica gel, concentrated to dryness, and purified via two flash columns. Since purification on silica gel failed to remove unreacted acetamide, the resulting mixture was used directly in the next step. MS (ES+): 277 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C:2]2[CH:13]=[CH:12][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=3[CH:3]=2)=[CH:23][CH:22]=1
Reactant: O=C1CCCCc2ccc(O)cc21
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc3c(c2)C(=O)CCCC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
To 3-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) dissolved in DMF (10 ml) were added potassium carbonate (2.76 g, 20.0 mmol) and 4-methylbenzyl bromide (2.04 g, 11.0 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with water (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 40 g, ethyl acetate/hexane=1/30). The objective fractions were concentrated under reduced pressure to obtain 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.74 g, 9.77 mmol, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[CH:29]1([C:32]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:16]=4)=[CH:6][N:5]3[CH:28]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)ccc2F)n(C)n1
Yield: 61.4 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (730 mg, 1.92 mmol) in N,N-dimethylacetamide (7 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (262 μL, 2.88 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-ethanol to give the title compound (529 mg, 61%) as a white solid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:11][CH2:12][C:13]1[C:14]([F:43])=[C:15]([F:42])[C:16]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([I:40])=[CH:36][C:35]=2[F:41])=[C:17]([CH:32]=1)[C:18]([NH:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:19])(=[O:10])[CH:8]=C>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:24][CH2:23][CH2:22][O:21][NH:20][C:18](=[O:19])[C:17]1[CH:32]=[C:13]([CH2:12][NH:11][C:7](=[O:10])[CH:8]=[O:2])[C:14]([F:43])=[C:15]([F:42])[C:16]=1[NH:33][C:34]1[CH:39]=[CH:38][C:37]([I:40])=[CH:36][C:35]=1[F:41])([CH3:31])([CH3:29])[CH3:30]
Reactant: C=CC(=O)NCc1cc(C(=O)NOCCO[Si](C)(C)C(C)(C)C)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(CNC(=O)C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 3 h

Procedure:
Aqueous osmium tetroxide (4%, 0.1 mL) and sodium metaperiodate (12 mg, 0.056 mmol) were added to a solution of 5-(acryloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (7.3 mg, 0.011 mmol) obtained in Step B in tetrahydrofuran (4 mL) and water (1 mL). The mixture was stirred for 3 hours. After the disappearance of the starting material was confirmed by LC/MS, the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-oxo-acetylamino)-methyl]-benzamide. Subsequently, this was dissolved in methanol (2.0 mL). Sodium borohydride (3 mg, 0.079 mmol) was added to this solution at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 60% ethyl acetate/hexane as an eluent) to give N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-benzamide (4.34 mg, 60% in 2 steps) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5]([CH3:9])[C:4](=[O:10])[O:3]1.ClC[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C(OCC)(=O)C.CC(C)=O>[CH3:11][C:2]1([CH3:1])[O:3][C:4](=[O:10])[CH:5]([CH2:9][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=2)[C:6](=[O:8])[O:7]1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CC1C(=O)OC(C)(C)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=Cc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a 500 mL 3-necked round bottomed flask equipped with a stir bar, thermowell, and a condenser connected to a nitrogen line was added 10.0 g (0.0632 mole) of 2,2,5-trimethyl-1,3-dioxane-4,6-dione, 10.6 g (0.0632 mol) of p-(chloromethyl)styrene, 35 g (0.2528 mol) of potassium carbonate and 200 mL of acetone. Approximately 1 g of phenothiazine was added as a stabilizer. The mixture was refluxed with stirring overnight at which time it was allowed to cool, diluted with 200 mL of ethyl acetate and filtered through a bed of Celite. The filtrate was washed with water and brine and dried overnight over anhydrous sodium sulfate. The suspension was filtered and the filtrate evaporated on a rotary evaporator to a light brown oil which spontaneously crystallized. The crystals were collected and washed with 35-65 petroleum ether to yield 3.5 g of 2,2-dimethyl-5-(4-vinylbenzyl)-1,3-dioxane-4,6-dione as shown by formula (III).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:6].C([Li])CCC.[S:22](Cl)([Cl:25])(=[O:24])=[O:23]>C1COCC1>[C:10]([O:9][C:7]([N:5]([CH3:6])[C:4]1[CH:14]=[CH:15][CH:16]=[C:2]([S:22]([Cl:25])(=[O:24])=[O:23])[CH:3]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cccc(S(=O)(=O)Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-N-tert-butoxycarbonyl-N-methylaniline (0.358 g, 1.2 mmol) was dissolved in freshly distilled THF (5 ml) under a N2 atmosphere. The solution was chilled to −78° C. and n-butyl lithium (0.750 ml, 2.0 M solution in cyclohexane, 1.5 mmol) was added. After 15 minutes, sulfuryl chloride (0.121 ml, 1.5 mmol) was added and the reaction was allowed to warm to room temperature and stirring was continued overnight. THF was removed by evaporation and the resulting residue was diluted in EtOAc. Organic phase was washed with H2O and brine before being dried with MgSO4. The solvent was removed in vacuo. Purification by flash chromatography (1:19/EtOAc/Hex gradient to 1:9 and then to 1:4). Recovered 0.089 g (23%) of the product as a colorless oil. Rf=0.14 (1:9 EtOAc/Hex). 1H NMR (CDCl3) 7.96 (1H,s), 7.80 (1H,d), 7.68 (1H,d), 7.57 (1H,t), 3.33 (3H,s), 1.50 (9H,s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:18][C:22]([CH3:28])([CH3:27])[C:23](=[O:24])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CC(C)(Br)C(=O)C#N
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-{3-bromo4(methylthio)phenyl}-2-phenyl-ethan-1-one (1.54 g) in 50 ml THF, was added 232 mg of 60% oil dispersion of sodium hydride. The mixture was stirred for 1 hour at 0° C., which was followed by dropwise addition of 1.1 ml α-bromoisobutyryl cyanide diluted in 20 ml THF. The reaction mixture was then slowly warmed to room temperature and was stirred overnight. The solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=6:1) to yield 1.1 g of 5-{3-bromo-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.47 (s, 3H), 6.99 (d, J=8.7 Hz, 1H), 7.32 (m, 5H), 7.48 (dd, J=8.7, 2.1 Hz, 1H), 7.88 (d, J=1.8 Hz, 1H).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered potassium hydroxide (144.4 g) was added carefully to a mechanically stirred mixture of 6-fluoroindole (49.23 g, 0.364 mol) and piperidine monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml) The mixture was then heated under reflux under nitrogen for 18 h and then more potassium hydroxide (40 g) was added and the reaction mixture heated under reflux for a further 4 h. The reaction mixture was allowed to cool to room temperature and poured onto ice-water (3000 ml) and stirred for 1 h and the precipitated solid isolated by filtration and dried at 50C in vacuo to give a solid.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[Na].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].C(S(O)(=O)=O)=C>O.O1CCOCC1>[C:9]([NH:13][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(=O)(O)CCBr
Reactant: CC(C)(C)N
Agent: C=CS(=O)(=O)O
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NCCS(=O)(=O)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A solution of 2-bromoethanesulfonic acid, sodium salt (4.2 g, 20 mmol) in water (total 12 mL) was added over 6 hours to a 42° C. solution of t-butylamine (10 mL, 94 mmol) in a mixture of water (10 mL) and 1,4-dioxane (10 mL). The mixture was stirred at 42° for 18 hours. The mixture was then heated to 60° C. for 24 h. By proton NMR, 30% of elimination product (vinylsulfonic acid) was observed. The mixture was concentrated to dryness and treated with ethanol at refluxing temperature. The solid material was collected (crop 1). The mother liquor was concentrated to dryness and the solid was again treated with ethanol at refluxing temperature, and the solid material was collected (crop 2). Both crops of the solid material were dissolved in water, and the resultant aqueous solutions passed in sequence through a Dowex 50 W X 8 ion-exchange column (100 g resin). The fractions containing the title compound were collected and concentrated to dryness. The solid material obtained was recrystallized from a mixture of ethanol (20 mL) and water (2 mL). The crystals were collected by filtration, dried in a vacuum oven at 60° C. for 18 hours. Compound DU was obtained as fine white needles (860 mg, 24% yield). 1H NMR (500 MHz, D2O) δ 1.16 (s, 9H), 3.02 (t, J=6.8 Hz, 2H), 3.19 (t, J=6.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 24.8, 37.3, 47.0, 57.8. ES-MS 182 (M+1)
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10](=O)([O-])[O-].[K+].[K+].P(OC)(OC)(OC)=O>>[CH3:10][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COP(=O)(OC)OC
Product: COc1ccccc1C=O
Temperature: 85 °C
Yield: 188.9 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 5.0 ml (0.047 mol) of salicylaldehyde, 2.0 g (0.014 mol) of potassium carbonate, and 10.0 ml (0.085 mol) of trimethyl phosphate. The mixture was heated to 85° C. for two hours, then cooled to 50° C. and quenched with 20 ml of water. After two hours the mixture was extracted with 50 ml of methylene chloride, the extracts washed with dilute caustic and then water. The organic extracts were dried over anhydrous potassium carbonate then filtered and concentrated in vacuo to give 3.6 g (53%) of o-methoxybenzaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6].[CH:26]([C:28]1[O:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:8]([NH:7][C:5](=[O:6])[C:4]2[CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=[C:2]([C:31]3[O:32][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=3)[CH:3]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: C[C@@H](NC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(-c2ccc(C=O)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reaction time: 15 h

Procedure:
To a solution of Intermediate X (0.280 g, 0.65 mmol) and (5-formyl-2-furyl)boronic acid (0.0912 g, 0.65 mmol) in 5 mL degassed DMF was added TPPTS (0.111 g, 0.20 mmol) Pd(OAc)2 (0.015 g, 0.07 mmol) and diisopropylamine (0.066 g, 0.65 mmol). After 15 h at rt, the reaction was diluted with satd. aqueous NaHCO3 and EtOAc, and the layers were separated. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by normal phase chromatography (50->100% EtOAc/hexanes) afforded the desired coupled adduct. 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.09 (m, 1H), 7.95 (m, 1H), 7.84 (m, 1H), 7.41-7.34 (m, 3H), 7.08 (m, 2H), 6.99 (d, J=5.9 Hz, 1H), 6.54 (d, J=7.5 Hz, 1H), 5.31 (m, 1H), 3.40 (s, 3H), 2.89 (s, 3H), 1.65 (d, J=7.0 Hz, 3H). LCMS [M+H]+=445.
Reaction SMILES: C[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([Cl:23])=[CH:11][C:12]=3[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])=[N:14][CH2:15][C:5]2=C[N:3]=1.NCC1CN=C(C2C=CC=CC=2F)C2C=C(Cl)C=CC=2N1.C(O[C:49](=[O:51])[CH3:50])(=O)C>ClCCl>[C:49]([NH:3][CH:2]1[CH2:15][N:14]=[C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[F:22])[C:12]2[CH:11]=[C:10]([Cl:23])[CH:9]=[CH:8][C:7]=2[N:6]1[CH3:5])(=[O:51])[CH3:50]
Reactant: Cc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: CC(=O)OC(C)=O
Agent: NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: ClCCl
Product: CC(=O)NC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1C

Procedure:
U.S Pat. No. 4,280,957 (hereinafter the '957 patent) describes a synthetic process for preparing midazolam, which is depicted in Scheme 2 below. This process includes reacting 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (II) with acetic anhydride in dichloromethane to produce 2-acetamido-methyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (III). The latter is heated with polyphosphoric acid at 150° C. to produce 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine of formula (IV), which is purified by column chromatography. Compound IV is then mixed with toluene and manganese dioxide and heated to reflux to afford midazolam base, which is crystallized from ether to yield a product with mp of 152-154° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[C:14]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>N1C=CC=CC=1.C1C=CC=CC=1>[C:1]([O:23][CH2:22][CH2:21][CH2:20][NH:19][C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=[CH:16][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1NCCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OCCCNc1ncccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 ml of benzoyl chloride are introduced dropwise into a solution of 77.8 g (0.04 mol) of 3-[(3-nitro-2-pyridyl)amino]propanol (M. ISRAEL, N. TIROSH, J. Med. Chem. 1973, 16, 520) in 48.5 ml of pyridine and 800 ml of benzene. The mixture is stirred for 2 h at ambient temperature and the precipitate is filtered. The filtrate is washed with 1N hydrochloric acid and then with water. Drying, filtering and evaporation are carried out. A crystallized product is obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CN.O[N:35]1[C:39]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:35][CH3:39])=[CH:24][CH:23]=3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)O)cc3)ncnc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(-c2ncnc3c2ncn3-c2cc(C(=O)NC3CC3)ccc2C)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a solution of the 4-[9-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-9H-purin-6-yl]-benzoic acid (10 mg, 0.024 mmol) and the methyl amine (3.0 mg, 0.097 mmol) in 0.5 mL of dry DMF was added 1-hydroxybenzotriazole (7.4 mg, 0.048 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.2 mg, 0.048 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 4 hours. And then 2 mL of water was added. The product was collected by filtration to give a colorless solid (8.2 mg, 80%). HPLC tR=1.99 min; MS m/z 427 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]([NH:12][CH3:13])[C@H:3]([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-].[C-:15]1(C[N+](C)(C)C)[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]>C(#N)C>[C-:15]1([CH2:13][N:12]([C@@H:2]([CH3:1])[C@H:3]([O:10][CH3:11])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:25])[CH:19]=[CH:18][CH:17]=[CH:16]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]
Reactant: C[N+](C)(C)C[c-]1cccc1
Reactant: CN[C@@H](C)[C@H](OC)c1ccccc1
Agent: [Fe+2]
Agent: [I-]
Agent: c1cc[cH-]c1
Solvent: CC#N
Product: CO[C@H](c1ccccc1)[C@H](C)N(C)C[c-]1cccc1

Procedure:
Reaction of (1R,2S)-O-methylephedrine with N-ferrocenylmethyl-N,N,N-trimethylammonium iodide (D. Lednicer and C. R. Hauser, J. Org. Chem., 40 (1960), 31) in acetonitrile gives the intermediate (−)-(1R,2S)-N-(ferrocenylmethyl)-N-methyl-1-methoxy-1-phenyl-prop-2-ylamine.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:17]=[C:18]([C:26](=O)[CH:27](Br)[CH3:28])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>>[F:14][C:15]([F:31])([F:32])[C:16]1[CH:17]=[C:18]([C:26]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][C:27]=2[CH3:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: CC(Br)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(C)s2)c(C)s1

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 105 mg 1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one in a manner similar to Example 8, step (a) to give, after preparative thin-layer chromatrography purification, methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (16.2 mg, 11%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.41 (m, 2H), 8.18 (m, 2H), 3.86 (s, 3H), 2.75 (s, 3H), 2.71 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C19H13NO2S3F6, 498.0 (M+H), found 497.6.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]Cl)=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:43][CH:42]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCCCOCc1ccc(Cl)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccc(Cl)cc2)CC1
Yield: 94.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.0 g) as starting compound, potassium carbonate (1.5 g) and 5-(4-chlorobenzyloxy)pentyl chloride (1.5 g) were reacted and treated in the same manner as in Example 168 to give 1.3 g of 4-amino-5-chloro-N-((1-(5-(4-chlorobenzyloxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][C:3]=1[CH3:10].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Br:1][C:2]1[S:6][C:5]([C:7]2[O:8][CH:15]=[C:13]([CH2:12][Cl:11])[N:9]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C(N)=O)sc1Br
Reactant: O=C(CCl)CCl
Product: Cc1cc(-c2nc(CCl)co2)sc1Br
Yield: 53 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-bromo-4-methyl-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave clolorless prisms, mp 71-72° C.