Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:27]=[O:28]>>[C:19]1([N:12]([C:6]2[CH:7]=[CH:8][C:9]([CH:27]=[O:28])=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A Vilsmeier's reagent was prepared by adding dropwise phosphoryl trichloride (POCl3) (46 g) to N,N-dimethylformamide (22 g) with stirring in an ice bath. Thereto there was added a solution (200 ml) of N,N,N-triphenylamine (50 g) in N,N-dimethylformamide while continuing cooling in the ice bath. The stirring was continued for about one hour, and then the bath temperature was raised to about 90° C. While maintaining that temperature, the stirring was continued further for two hours. At the conclusion of the reaction the reaction system was cooled to room temperature, and then the reaction product was poured into ice water. The thus obtained aqueous solution was neutralized with an alkali to separate out a yellow precipitate. The precipitate was filtered off, dried and then recrystallized from ethyl alcohol. Thus, p-(N,N-diphenylamino)benzaldehyde (43 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6](Br)[CH:5]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[C:7]([C:10]#[N:11])=[CH:8][CH:9]=1)=[O:13]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(C#N)c(Br)c1
Product: COC(=O)c1ccc(C#N)c(-c2ccccc2OC)c1
Yield: 74.8 %

Procedure:
By following procedures described in General procedure C (Suzuki), 3-bromo-4-cyano-benzoic acid methylester (0.205 g, 0.85 mmol) and 2-methoxy phenyl boronic acid (0.156 g, 1.02 mmol) were used to obtain the title compound (0.170 g, 62%), following SiO2 chromatography (hexanes/EtOAc=6:1). MS(ESI) m/z 268.0 (M+H)+
Reaction SMILES: [C:1]([C:4]1[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:9]([CH3:13])=[C:10]([Cl:12])[CH:11]=1)[CH:7]=[O:8])(=[O:3])[CH3:2].O.[OH:18]P([O-])(O)=O.[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O.Cl>[C:1]([C:4]1[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:9]([CH3:13])=[C:10]([Cl:12])[CH:11]=1)[C:7]([OH:18])=[O:8])(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1C=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1C(=O)O
Reaction time: 1 h
Yield: 309.3 %

Procedure:
A solution of 3-acetyl-5-chloro-2-ethoxy-6-methylbenzaldehyde (0.58 g, 2.4 mmol) and sodium phosphate monobasic monohydrate (116 mg, 0.844 mmol) in acetonitrile (11.8 mL) and water (2.5 mL) was cooled in an ice bath. 30% Hydrogen peroxide (0.98 mL, 9.6 mmol) was added followed by solid sodium chlorite (0.545 g, 4.82 mmol). The mixture was stirred for 1 h. The mixture was diluted with 1 M HCl solution, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product (0.67 g, 100%). LCMS calculated for C12H13ClO4Na (M+Na)+: m/z=279.1; Found: 279.0.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:36]=[CH:35][C:15]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:19]=3)=[O:17])=[CH:14][C:13]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[O:53][CH3:54])[CH2:43][CH2:42]2)=[CH:6][CH:5]=1)[CH3:3].CO.[OH-].[K+]>O1CCCC1>[ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:36]=[CH:35][C:15]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:19]=3)=[O:17])=[CH:14][C:13]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[O:53][CH3:54])[CH2:43][CH2:42]2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(CNc2ccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)cc2OCCCN2CCN(c3ccccc3OC)CC2)cc1
Yield: 86 %

Procedure:
Ethyl 4-{3-{4-(4-ethylphenyl)methylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride (40.8 g) was dissolved in tetrahydrofuran (200 ml), and methanol (200 ml) and potassium hydroxide (11.3 g) were added to the solution. The resultant mixture was refluxed for one hour and 30 minutes. The reaction mixture was cooled and concentrated under reduced pressure. Water (1.2 l) was added to dilute the residue, and the resultant solution was poured into 1N hydrochloric acid (400 ml), to thereby precipitate crystals. The crystals were collected by filtration. The collected crystals were washed with water, dried, and recrystallized from 95% ethanol, to thereby obtain 33.8 g of 4-{3-{4-(4-ethylphenyl)methylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][O:15][C:16]=2[N:17]=1)[CH:3]([CH3:5])[CH3:4].[ClH:25].C(OCC)(=O)C>>[ClH:25].[CH3:1][CH:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][O:15][C:16]=2[N:17]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C(C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of the compound obtained in step 1 (0.36 g) and 4N hydrogen chloride/ethyl acetate (10 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized from ethanol-diisopropyl ether to give the title compound (0.15 g, 52%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([CH3:28])[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:29]1(B(O)O)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]1([C:2]2[C:3]([O:16][CH2:17][C:18]3([CH3:28])[CH2:19][CH2:20][C:21]4([O:22][CH2:23][CH2:24][O:25]4)[CH2:26][CH2:27]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:31][CH2:30]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC2(CC1)OCCO2
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)OCCO2
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a solution of tert-butyl 5-chloro-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)benzoate (3.09 g, 7.45 mmol), cyclopropylboronic acid (0.96 g, 11.17 mmol), potassium phosphate (7.12 g, 33.53 mmol) and tricyclohexylphosphine tetrafluoroborate (0.28 g, 0.75 mmol) in toluene (50 mL) and water (2.5 mL). The resulting suspension was sparged with Argon for 15 minutes before the addition of palladium acetate (0.083 g, 0.37 mmol). The reaction mixture was heated at 100° C. for 18 hours and then cooled to ambient temperature; filtered through a pad of diatomaceous earth and rinsed with ethyl acetate. The filtrate was diluted with additional water (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was filtered through a plug of silica gel (100% ethyl acetate) to afford the title compound (2.59 g, 83%) as a colorless oil: MS (ES+) m/z 365.2 (M−55).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].C1CCN2C(=NCCC2)CC1.CS(O)(=O)=O>C(O)C.O>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:19]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(S)nc(-c2ccncn2)cc1=O
Temperature: 0 °C
Yield: 77.9 %

Procedure:
A solution of ethyl 3-oxo-3-(4-pyrimidyl)propionate (34.1 g, 176 mmol), N-methyl thiourea (47.5 g, 527 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (26.3 ml, 176 mmol) in ethanol (340 ml) was refluxed for 2 hours and the solution of methanesulfonic acid (16.9 g, 176 mmol) in water (70 ml) was added after cooling by ice-water. The precipitate was washed with water, filtered and dried to give the title compound (30.2 g, 78%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:31][C:25]4[N:26]=[CH:27][NH:28][C:29](=[O:30])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[O:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:31][C:25]4[N:26]=[CH:27][NH:28][C:29](=[O:30])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Cl)nc34)cc12
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Oc5ccccc5)nc34)cc12
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
NaH (60% in mineral oil; 0.063 g, 1.576 mmol) was suspended in 1 mL DMF and phenol (0.148 g, 1.576 mmol) was added. After 10 min, 6-(2-chloroquinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one hydrochloride (Example 19b; 0.075 g, 0.225 mmol) was added, and the reaction was sealed and heated at 70° C. for 2 h, then at 90° C. for 1 h. The reaction was treated with TFA (0.121 ml, 1.576 mmol) and 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 20-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo to give 6-(2-phenoxyquinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.022 g, 0.062 mmol, 28% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (1H, br. s), 11.64 (1H, br. s), 8.50 (1H, d, J=8.8 Hz), 8.22 (1H, dd, J=7.5, 1.5 Hz), 7.90 (1H, dd, J=8.0, 1.4 Hz), 7.81 (1H, d, J=3.7 Hz), 7.49-7.58 (3H, m), 7.30-7.42 (4H, m), 7.13 (1H, d, J=2.3 Hz). m/z (ESI, +ve) 355.0 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[S:15])=[O:7].[C:23](=O)([O-])[O-:24].[Na+].[Na+].[BH4-].[Na+].Cl>COCCOC.C(OCC)(=O)C.O>[O:24]1[CH:23]=[CH:5][CH:4]=[C:3]1[C:2]([CH:6]([OH:7])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[S:15])=[O:1]
Reactant: O=C(CCCCCC(C(O)=S)c1ccccc1)c1ccco1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(c1ccco1)C(O)CCCCCC(C(O)=S)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 3.61 g of 7-(2-furoyl)-2-phenylthioheptanoic acid in 15 ml of DME is added 25 ml of water and 5.45 ml of 1.0 M aqueous sodium carbonate. The resulting solution is treated furing 1 min. with 0.41 g of sodium borohydride in small portions. The mixture is stirred at ambient temperature for 3.5 hours, diluted with ethyl acetate, cooled to 0°, and treated with 4 M hydrochloric acid. The ethyl acetate layer is washed with water and brine, dried over MgSO4, and concentrated to give an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:18])=[N:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:7]=1[CH3:8].NN>CO>[Cl:2][C:3]1[C:4]([CH3:18])=[N:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[C:7]=1[CH3:8]
Reactant: Cc1nn(-c2ccc([N+](=O)[O-])cc2)c(C)c1Cl
Agent: Cl
Agent: NN
Solvent: CO
Product: Cc1nn(-c2ccc(N)cc2)c(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.1 %

Procedure:
4-Chloro-3,5-dimethyl-1-(4-nitro-phenyl)-1H-pyrazole hydrochloride (450 mg, 1.56 mmol) is dissolved in MeOH (40 mL). To this solution is then added FeCl3.6H2O (24 mg, 0.09 mmol) and active carbon (12 mg, 1 mmol). The suspension is heated to reflux. Hydrazine (2.0 mL) is added, and reflux is continued for 3 h or until TLC detected full conversion. After conversion the mixture is cooled to room temperature, the active carbon is filtered off using celite and the MeOH under reduced pressure. The residue is purified with flash chromatography to provide the 4-(4-Chloro-3,5-dimethyl-pyrazol-1-yl)-phenylamine (360 mg, 91%). MS (ESI): 222, 224 (M+1)+1.
Reaction SMILES: [N+](C1C=C[N+]([O-])=C2NC=CC=12)([O-])=O.[N+:14]([C:17]1[C:25]2[C:20](=[N+:21]([O-])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)([O-:16])=[O:15].CS([Cl:31])(=O)=O>CN(C)C=O>[Cl:31][C:24]1[CH:23]=[CH:22][N:21]=[C:20]2[NH:19][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[C:25]=12
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1c[nH]c2c1ccc[n+]2[O-]
Agent: O=[N+]([O-])c1cc[n+]([O-])c2[nH]ccc12
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of a 2:1 mixture (589.8 mg) of 4-nitro-1H-pyrrolo-[2,3-b]pyridine 7-oxide and 3-nitro-1H-pyrrolo[2,3-b]pyridine-7-oxide in N,N-dimethylformamide (6 ml) was added dropwise methanesulfonyl chloride (0.68 ml) at 65° C. The reaction mixture was stirred at 65° C. for 2 hours. The reaction mixture was quenched with water (30 ml) under ice cooling, and neutralized (pH ˜6.5) with 20% NaOH solution. The resulting precipitates were collected by filtration, dried in vacuo at 40° C., and washed with EtOAc to give 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (172.8 mg) as a brown solid.
Reaction SMILES: C(O)CCCC.[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.CS[C:17]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[N:18]=1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35]>C(O)(C)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:17]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[N:18]=2)[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2ccccc2Cc2nccn21
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Solvent: CCCCCO
Product: CN1CCN(C2=Nc3ccccc3Cc3nccn32)CC1

Procedure:
Amyl alcohol (5100 ml) and 918.35 g (9.17 moles) of N-methylpiperazine are charged into a 12 liter 3-necked reaction flask fitted with a Dean-Stark adapter. The solution is stirred under nitrogen atmosphere and 989 ml of 10N ethanolic hydrogen chloride solution are added rapidly. The reaction mixture is heated to reflux and the distillate is collected in the Dean-Stark adapter. When the temperature of the reaction mixture reaches 131° the Dean-Stark adapter is removed and an additional 918.35 g (9.17 moles) of N-methylpiperazine followed by 1045.0 g (4.56 moles) of 5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine are added. The mixture is heated at reflux under nitrogen atmosphere for 20 hours. Amyl alcohol is then removed under reduced pressure at a water bath temperature of 80°. The viscous residual oil is dissolved in 10,000 ml of dichloromethane, washed with 3×4,000 ml of 4N sodium hydroxide and 6×4,000 ml of water. The dichloromethane solution is then extracted with 3×2,000 ml of 6N hydrochloric acid. The aqueous solution is back washed with 2×2,000 ml of dichloromethane, treated with 100 g of activated carbon and filtered. The clear filtrate is adjusted to pH 9-10 with 1,500 ml of ammonium hydroxide solution (29%). The oil which separates is extracted with 3×4,000 ml of dichloromethane, the extracts are dried over 1,000 g of sodium sulfate and the solvent removed at reduced pressure with a water bath temperatures of 60°. An oil is obtained which rapidly solidifies and after drying further (5 mm Hg/40°) yields crude product, m.p. 113°-120°. The crude product is dissolved in 8,000 ml of hot (60°-70°) isopropanol. The solution is decolorized with 200 g of activated carbon and filtered. To this solution is added a solution of 760.7 g (8.28 moles) of maleic acid in 2,500 ml of warm (30°) isopropanol and the meleate salt begins to precipitate. The suspension is stirred overnight at ambient temperature to complete crystallization and the solid is collected by filtration. The product is washed with 3×500 ml of cold isopropanol and dried (0.5 mm/50°). This is recrystallized from ethanol, the resulting product is washed first with ethanol and then with ether and then dried to give 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine monomaleate, m.p. 204°-205° (dec).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:29][CH:30]([OH:48])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:29][CH:30]([OH:48])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:2]2[C:10]3[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:34]=1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1cnc2c(Br)cccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc2c(-c3cccc(OCC(O)CN4CCc5ccccc5C4)c3)cccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
A mixture of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (200 mg, 0.611 mmol), 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (375 mg, 0.916 mmol), Pd(dppf)Cl2 (89 mg, 0.12 mmol) and Na2CO3 (130 mg, 1.22 mmol) in dioxane and H2O was stirred under N2 atmosphere at 100° C. for 3 h. The mixture was extracted with DCM and the combined organic layers dried over Na2SO4 and concentrated in vacuum to give the crude product (265 mg, Yield 82%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]CC(Cl)(Cl)Cl)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) in tetrahydrofuran (2.5 ml) were added zinc powder (0.5 g) and an aqueous ammonium chloride (0.3 g) in water (4 ml) at ambient temperature with stirring, and the stirring was continued at ambient temperature for 30 minutes. After the zinc powder was removed by filtration, the filtrate was adjusted to pH 2.3 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.11 g).
Reaction SMILES: ClC1C=C(C=C(Cl)C=1N)CN.[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([O:26]C)=[O:25])#[N:13].[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([OH:26])=[O:25])#[N:13]
Reactant: COC(=O)Cc1c[nH]c2ccc(C#N)cc12
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]cc(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
Step H (3): To a solution of methyl 2-(5-cyano-1H-indol-3-yl)acetate (18 mg, 0.08 mmol) in THF (0.8 mL) was added a solution of LiOH (9.6 mg, 0.4 mmol) in water (0.3 mL). The mixture was stirred at rt for 3 h. 50 mL of EtOAc was added, and the resulting solution was washed with 0.1 N HCl and water. The organic layer was dried over Na2SO4, and the solvents was removed to give 11 mg of the title compound 2-(5-cyano-1H-indol-3-yl)acetic acid (yield, 68.7%). MS (ESI) (M−H)+=199.15. 1H NMR (500 MHz, CD3OD) δ ppm 4.86 (s, 2 H) 7.37 (s, 1 H) 7.40 (dd, J=8.24, 1.53 Hz, 1 H) 7.50 (d, J=8.54 Hz, 1 H) 8.01 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C([N:18]=[C:19]=[S:20])(=O)C1C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:19]([NH2:18])=[S:20]
Reactant: COc1ccccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1ccccc1NC(N)=S
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To 50 ml of acetone were added 2.46 g of o-anisidine and 3.75 g of benzoyl isothiocyanate, and the mixture is stirred under reflux for 2 hours and, then, allowed to stand overnight in a refrigerator at 5° C. The resulting crystals were collected by filtration, washed with cold acetone and dried under reduced pressure. The crystals were added to 50 ml of 30% methylamine-methanol and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was washed with ethanol-ethyl acetate and dried under reduced pressure. The procedure provided 2.08 g of N-(o-methoxyphenyl)thiourea.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])[CH3:23]>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH2:22][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: CCc1ccccc1N
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1CC
Yield: 69.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (3.69 g, 9.84 mmol) and 2-ethylaniline (1.55 g, 12.8 mmol) in acetonitrile (20 ml) was refluxed for 6 h. The solution was evaporated. Chromatography (SiO2 ; CH2Cl2 : MeOH 97:3) gave 2.79 g (69%) of the desired product.