Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH3:11][O:12]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: c1ccc(CC2CC2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of (cyclopropylmethyl)benzene (1.32 g) and dichloromethyl methyl ether (1.25 ml) in dichloromethane (20 ml) was added 1.0M solution of titanium(IV) chloride in dichloromethane (15 ml) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 10 minutes, then poured into ice water. The organic layer was separated and washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (9:1) to give 4-(cyclopropylmethyl)benzaldehyde (580 mg) as an oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(C)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(m-tolyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([O:11]C)=O.[NH2:13][C:14]1[NH:18][N:17]=[C:16]([CH3:19])[CH:15]=1>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[C:9](=[O:11])[N:18]3[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]3[NH:13][C:2]=2[CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: Cc1cc(N)[nH]n1
Solvent: CCCCO
Product: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1

Procedure:
205 g. of 4,6-dichloropyridine-3-carboxylic acid, methyl ester and 194 g. of 5-amino-3-methylpyrazole are refluxed together in 500 ml. of butyl alcohol with stirring for 24 hours. After this time, 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is filtered off, washed with water and recrystallized from dimethylformamide, yield: 195 g. (83%); m.p. >300°.
Reaction SMILES: [C:1]([O-])(=O)C.[NH4+].C[N:7]([CH3:19])[CH:8]=[CH:9][C:10]1[NH:15][C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:1][C:19]1[N:7]=[CH:8][CH:9]=[C:10]2[C:11]=1[CH:12]=[C:13]([C:17]#[N:18])[C:14](=[O:16])[NH:15]2
Reactant: CC(=O)[O-]
Reactant: CN(C)C=Cc1ccc(C#N)c(=O)[nH]1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nccc2[nH]c(=O)c(C#N)cc12
Temperature: 5 °C

Procedure:
The above preparation was also carried out using ammonium acetate in place of formamidine acetate as follows: A mixture containing 1.305 kg of 1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile, 9 liters of dimethylformamide and 915 g of ammonium acetate was refluxed for five hours The reaction suspension was cooled to 5° C. for three hours and the precipitated product was collected, washed twice with cold 60/40 by volume of dimethylformamide/water, twice with cold ethanol, once with ether and dried to yield 826 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile, m.p. 75°-277° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH2:14]1[CH:19]2[CH2:20][C:21]3([CH:24]=O)[CH2:23][CH:17]([CH2:18]2)[CH2:16][CH:15]1[CH2:22]3>>[C:21]12([CH:24]3[NH:1][C:2]4[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=4[S:10](=[O:12])(=[O:11])[NH:13]3)[CH2:20][CH:19]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:23]1)[CH2:22]2
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Product: O=S1(=O)NC(C23CC4CC(CC(C4)C2)C3)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using 1-adamantylcarboxaldehyde). M.p. 270–273° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](=[S:6])[NH2:5].[Cl:8][CH2:9][C:10]([CH2:12]Cl)=O.C(=O)(O)[O-].[Na+].S(Cl)(Cl)=O>ClCCCl>[ClH:8].[Cl:8][CH2:9][C:10]1[N:5]=[C:4]([CH2:3][N:2]([CH3:7])[CH3:1])[S:6][CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: CN(C)CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1nc(CCl)cs1
Product: Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 136 %

Procedure:
2-(Dimethylamino)ethanethioamide (0.382 g, 3.24 mmol), 1,3-dichloroacetone (0.453 g, 3.56 mmol) and sodium bicarbonate (0.301 g, 3.56 mmol) was stirred in 1,2-dichloroethane (4 mL) at room temperature for 24 h. The reaction mixture was filtered and the filter cake was washed with 1,2-dichloroethane. The filtrate was added dropwise to a cooled (ice bath) solution of thionyl chloride (0.260 mL, 3.56 mmol) in 1,2-dichloroethane (2 mL). The solution was stirred at 70° C. for 0.5 h and then cooled to room temperature. The brown mixture was filtered and washed with 1,2-dichloroethane to afford N-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride as a brown solid (0.550 g, 2.42 mmol, 75% yield). 1H NMR (400 MHz; D2O): 2.79 (s, 6H); 4.52 (s, 2H); 4.61 (s, 2H); 7.60 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:30]([CH:28]3[CH2:29][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]3)=[O:31])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)C3CN(C(=O)OC(C)(C)C)C3)ccc12
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-1H-indazol-6-amine (500 mg, 1.96 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), triethylamine (0.5 mL), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (470 mg, 2.34 mmol, 1.19 equiv), HATU (2.235 g, 5.88 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 15° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5˜1:3) to yield tert-butyl 3-((3-(methylthio)-1-phenyl-1H-indazol-6-yl)carbamoyl)azetidine-1-carboxylate as a white solid. MS: 439 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.Cl[CH:18](OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: Clc1ccccc1CNCCc1cccs1
Solvent: CN(C)C=O
Product: CCOC(=O)C1c2ccsc2CCN1Cc1ccccc1Cl
Product: Cl

Procedure:
Into a three-necked 250 ml flask are added 25.1 g (0.1 M) N- (2-chloro-benzyl)-2-(2-thienyl)ethylamine dissolved in 30 ml dimethylformamide. Ethyl 2-chloro-2-ethoxy-acetate (18.3 g; 0.11 M) is then added over 6 minutes, and the resulting material is heated at 80° C. for 4 hours after which the desired product begins to precipitate out. After cooling of the medium, the product is filtered off and recrystallized from 3×20 ml acetone, to give 20.5 g 5-(2-chloro-benzyl)-4-ethoxy-carbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Yield: 55%).
Reaction SMILES: FC(F)(OC1C=CC(OC2C=CC(C[NH2:17])=CC=2)=CC=1)C(F)F.C(N(CC)CC)C.[Cl:30][C:31]1[C:32]([CH3:40])=[N:33][N:34]([CH3:39])[C:35]=1[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[Cl:30][C:31]1[C:32]([CH3:40])=[N:33][N:34]([CH3:39])[C:35]=1[C:36]([NH2:17])=[O:37]
Reactant: Cc1nn(C)c(C(=O)Cl)c1Cl
Reactant: NCc1ccc(Oc2ccc(OC(F)(F)C(F)F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(C(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 233.5 %

Procedure:
To a stirred mixture of 4-[4-(1,1,2,2-tetrafluoroethoxy)phenoxy]benzylamine (359 mg, 1.14 mM), triethylamine (136 mg, 1.35 mM) and toluene (20 ml) was added dropwise a solution (10 ml) of 4-chloro-1,3-dimethylpyrazole-5-carbonyl chloride (200 mg, 1.04 mM) in toluene at 0°-10° C., and the mixture was stirred for 3 h at room temperature. The mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with saturated sodium hydrogen carbonate solution, saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-{4-[1,1,2,2,-tetrafluoroethoxy)phenoxy]benzyl}-4-chloro-1,3-dimethylpyrazole-5-carboxamide (420 mg, 86%) as colorless crystals, m.p. 101.3° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[N:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:32]=[CH:31][C:19]4[N:20]=[C:21]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[S:22][C:18]=4[CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[CH2:5])C.Br[N:34]1[C:38](=[O:39])CC[C:35]1=O.CNC>CN(C=O)C>[C:25]([OH:30])(=[O:39])[CH3:26].[CH3:35][N:34]([CH3:38])[CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[N:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:32]=[CH:31][C:19]4[N:20]=[C:21]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[S:22][C:18]=4[CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: CNC
Solvent: CN(C)C=O
Product: CC(=O)O
Product: CN(C)CC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-(1-ethoxyvinyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (90 mg, 0.20 mmol) from the previous step in DMF (2 mL) at 0° C. was added N-bromosuccinimide (36 mg, 0.20 mmol), and the mixture was stirred for 15 min. To the mixture was added dimethylamine (2M in THF, 0.90 mL, 1.80 mmol) and stirring was continued at 0° C. for 5 min. The reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 2-(dimethylamino)-1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone acetate salt (5 mg, 5%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J=1.7 Hz, 1H), 8.75 (s, 1H), 8.67 (d, J=1.7 Hz, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.20-7.32 (m, 2H), 5.52 (s, 2H), 4.80 (br s, 1H), 3.78 (s, 2H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.25 (s, 6H), 2.04 (br m, 1H), 1.82-1.86 (m, 4H), 1.59-1.65 (br m, 2H), 1.10-1.60 (m, 4H); LCMS (ESI) m/z 465 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[NH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].[H][H].[ClH:26]>CO.C(O)(=O)C.C(O)(C)C.[Pt]>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17])[CH2:7][CH2:6]2
Reactant: NCC(O)c1ccccc1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: [Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc2c(c1)CCC(NCC(O)c1ccccc1)C2
Yield: 47.5 %

Procedure:
An amount of 4 g of 6-methoxy-2-tetralone is reacted at 35° C. for 3 hours with 3.2 g of 2-amino-1-phenylethanol in 100 ml of methanol and 4 ml of glacial acetic acid in the presence of hydrogen and 0.3 g of platinum bioxide. After filtration and concentration, the residue is taken up with sodium hydroxide and extracted with ethyl acetate. The solution is dried over anhydrous sodium sulfate and evaporated. The black oil thus obtained is purified by flash-chromatography by utilizing a mixture of methylene chloride/methanol 9/1 as eluant. The fractions containing the product are collected and evaporated to dryness. The residue is dissolved in 20 ml of isopropyl alcohol and to the solution thus obtained there is added a saturated solution of hydrogen chloride in isopropyl alcohol. Thus, there is obtained the 2-[(6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride, designated by its code number SR 58280 A, which, after crystallization from isopropyl alcohol, melts at 174°-176° C. Yield: 47.5% of the theoretical value.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[C:7]([Cl:16])[CH:6]=1)=[O:4].[CH2:17]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[S:21])[CH3:18]>CO>[ClH:1].[CH2:23]([N:22]1[C:3]([C:5]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[C:7]([Cl:16])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:19][CH2:17][CH3:18])[CH3:24]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)cc(Cl)c1Cl
Reactant: CCNC(=S)NCC
Solvent: CO
Product: CCN=C1SCC(O)(c2cc(Cl)c(Cl)c(S(N)(=O)=O)c2)N1CC
Product: Cl

Procedure:
6 g of 2,3',4'-trichloro-5'-sulfamoyl-acetophenone and 2,6 g of 1,3-diethyl-thiourea were heated for 15 minutes to 40° C in 40 ml of methanol, the 3-ethyl-2-ethylimino-4-ol-hydrochloride was precipitated with 200 ml of diisopropyl ether and crystallized from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:26])C.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH:13]=[O:26]
Reactant: CC(=O)O
Reactant: COc1cccc2c(C#N)cccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c(C=O)cccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methoxynaphthalene-1-carbonitrile (Preparation 11) (1.1 g, 6.00 mmol) in DCM (40 mL) at −78° C. under nitrogen was added DIBAL (1.0M in toluene, 18 mL) dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 h, warmed to rt for 1 h and then cooled to 0° C. Acetic acid (1 mL) followed by water (1 mL) were added. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the organic phase was separated and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 2:8) to give the title compound: RT=3.54 min; m/z (ES+)=187.0 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([CH:15]2[CH:20]([OH:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([CH3:43])[CH:42]=1)[CH2:38]Br>>[CH3:34][C:35]1[CH:42]=[C:41]([CH2:43][O:21][CH:20]2[CH:19]3[CH2:22][CH2:23][N:16]([CH2:17][CH2:18]3)[CH:15]2[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:40]=[C:37]([CH3:38])[CH:36]=1
Reactant: OC1C2CCN(CC2)C1C(Cc1ccccc1)c1ccccc1
Reactant: Cc1cc(C)cc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: Cc1cc(C)cc(COC2C3CCN(CC3)C2C(Cc2ccccc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of alcohol (Example 1, 0.78 g, 1:1 mixture of stereoisomers) was added 0.5M-potassium hexamethyldisilazide (5.84 ml, in toluene). After 1 h, 3,5-dimethylbenzyl bromide (0.58 g) was added for 3 h. The solution was evaporated to dryness after a further 3 h, and the residue partitioned between dichloromethan and water. The organic phase was dried (MgSO4), evaporated and purified by column chromatography on silica gel eluting with petroleum ether (bp 6014 80) containing increasing amounts of ethyl acetate (50% to 100%) and then methanol/ethyl acetate (15:85) to give a single diastereomer of the title compound. This was crystallised by addition of oxalic acid (72 mg) in propan-2-ol and diethyl ether to give 3-[(3,5-dimethylphenyl)methyloxy]-2-(1,2-diphenylethyl)-1-azabicyclo[2.2.2]octane hydrogen oxalate salt isomer A mp 64°-66° C.1HNMR(DMSO,360MHz)δ 7.2-6.6 (13H,m,aryl), 4.6 (1H, d, J=16.0 Hz, OCHAHB),4.4 (1H, d, J=16.0 Hz, OCHAHB),3.5 (1H, m, OCHCH),3.3 (1H, m, NCHAHB), 2.99 (1H, dd, NCHCH)),2.8-2.60 (5H, m, NCHAHB,NCH2,PhCH2), 2.4(1H,m,PhCHCH2),2.3 (6H, s, CH3, CH3),2.25 (1H, m, bridgehead CH),1.9 (1H, m, NCH2CHAHB),1.65 (1H, m, NCH2CHAHB), 1.46-1.22 (2H, m, NCH2CH2); Found C, 71.09; H, 6.84; N, 2.51. C30H35NO.C2H2O4.0.3H2O requires C, 71.19;H,6.86;N,2.67.m/e (EI) 425(M+), (CI+)426 (M+H), (CI-=)424 (M-H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:10]([OH:16])(=[O:15])[CH2:11]C(O)=O.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[CH2:11][C:10]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccc(C=O)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(C(N)CC(=O)O)cc1

Procedure:
To 10 ml of p-tolualdehyde, were added 180 ml of ethanol, 9.8 g of malonic acid, and 15.8 g of ammonium acetate. The mixture was refluxed for 5 hours. After cooling, the insolubles were removed by filtration. After addition of 100 ml of water, the filtrate was adjusted to pH 7.0 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration to yield 5.4 g of β-amino-β-(4-methylphenyl)propionic acid; m.p. 228°-229° C.
Reaction SMILES: C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)SC=3)=NOC(C)C)C(=O)N2C=1C(O)=O)(=O)C.C(O)=[O:53]>O>[C:32]1([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[OH:53])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: O=CO
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 4.91 g of raw product of Example 12 in 30 ml of 50% aqueous formic acid was stirred in a water bath at 60° C. and was then diluted with water and vacuum filtered. The filter was rinsed with water and the product was dried to obtain 1.39 g of triphenylcarbinol. The filtrate was evaporated to dryness and the residue was taken up in water and effloresced. The mixture was vacuum filtered and the recovered product was rinsed with water and dried to obtain 800 mg of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid. 972 mg of the product was dissolved in 4 ml of methanol and the solution was diluted with 20 ml of ether and vacuum filtered. The product was rinsed and dried to obtain 404 mg of the said acid for analysis in the syn configuration and melting at ≃200° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8](=O)[CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O=P(Cl)(Cl)[Cl:20].CCN(CC)CC>C(Cl)(Cl)Cl>[Cl:20][C:8]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[Cl:1])=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C#N)C(=O)c1scc(C)c1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=C(Cl)c1scc(C)c1Cl
Temperature: 5 °C
Yield: 66.9 %

Procedure:
To a solution of ethyl 3-(3-chloro-4-methyl-2-thienyl)-2-cyano-3-oxopropanoate (15.40 g, 56.67 mmol, 1 eq.) in 200 ml of CHCl3 was added POCl3 (86.9 g, 566 mmol, 10 eq.). Et3N (14.33 g, 141.6 mmol, 2.5 eq.) was added dropwise with stirring at 5° C., and the mixture was refluxed for 4 h. The mixture was evaporated. After evaporation, the mixture was diluted with DCM (CH2Cl2) and with ice water and was extracted with DCM (CH2Cl2) and washed with brine. The organic layers were combined and dried over MgSO4 before concentration under reduced pressure. The residue was subjected to column chromatography on silica gel to give ethyl 3-chloro-3-(3-chloro-4-methyl-2-thienyl)-2-cyanoacrylate (11 g, 66% yield) as a mixture of 2 isomers
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-])=O)[C:8]=2[N:7]=1.C(O)(=O)C>C(O)C.[Fe]>[NH2:15][C:14]1[C:8]2[N:7]=[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[NH:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCNc1nc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCNc1nc2c(N)cccc2[nH]1
Yield: 86.6 %

Procedure:
To a solution of 2-[2-(dimethylamino)ethylamino]-4-nitro-1H-benzimidazole (105 mg) in ethanol (4 ml) were added iron (reduced, 118 mg) and acetic acid (0.24 ml) at room temperature and the mixture was refluxed for 6 hours. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of chloroform and methanol (5-1) and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol-ammonia solution (28%)=160-32-1) to give 4-amino-2-[2-(dimethylamino)-ethylamino]-1H-benzimidazole (80 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16]OS(C)(=O)=O)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 66.3 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as pale brown neeldes (yield: 66.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.O.Cl.[NH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C(Cl)(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)s2)CC1

Procedure:
A solution of 5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonyl chloride (1b) (5.0 g, 14 mmol) in 100 ml chloroform and a solution of 4-piperidinone hydrochloride monohydrate (4.3 g, 28 mmol) in 21 ml of NaOH (2N) were stirred vigorously for 15 h. The reaction was quenched with HCl (2N) and the organic layer was extracted twice with HCl (2N) and twice with brine. The dried organic phase affords after evaporation of chloroform 5.8 g (99.5%) of (63c) as a colourless solid: 1H NMR (CDCl3) δ7.67 (d, J=8.7 Hz, 2H), 7.42-7.38 (m, 3H), 6.99 (d, J=3.8 Hz, 1H), 6.53 (t, J=5.3 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.37 (d, J=6.2 Hz, 4H), 2.50 (d, H=6.2 Hz, 4H).