Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C[O:7][C:8]1C=CC=[C:10]([CH:11]=O)[C:9]=1O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:3]([C:2]1[CH:1]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:7])=[CH2:4]
Reactant: [Li]CCCC
Reactant: COc1cccc(C=O)c1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (19.65 g, 55.00 mmol) in tetrahydrofuran (200 mL) cooled to 0° C. is added n-butyllithium (1.6 M in hexanes, 37.5 mL, 60.00 mmol) and the reaction mixture is allowed to stir at 0° C. for 30 min. The ylide is added via cannula to a solution of 3-methoxysalicylaldehyde (3.80 g, 25.00 mmol) in tetrahydrofuran (100 mL) and the reaction mixture is allowed to stir at room temperature for 3 hours. The reaction mixture is quenched by the addition of aqueous ammonium chloride (100 mL) and diluted with water (300 mL). The aqueous layer is separated and extracted with diethyl ether (3×200 mL). The combined organic extracts are washed with water (300 mL) and aqueous sodium chloride (300 mL), dried (magnesium sulfate), and filtered through a plug of silica (10 cm×5 cm). The solvent is removed in vacuo to give the 2-vinylphenol as a crude oil which is dissolved in tetrahydrofuran (200 mL). To the resulting solution is added (S)-2-hydroxy-3-buten-1-yl p-tosylate (7.27 g, 30.00 mmol), triphenylphosphine (7.87 g, 30.00 mmol), and diethyl azodicarboxylate (5.22 g, 30.00 mmol). The reaction mixture is allowed to stir at room temperature for 12 hours. The reaction mixture is quenched by the addition of water (200 mL). The aqueous layer is separated and extracted with ethyl acetate (2×250 mL). The combined organic extracts are washed with water (200 mL) and aqueous sodium chloride (300 mL), dried using magnesium sulfate, and the solvent is removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) provides 5.33 g (57% y, >97% ee) of (2R)-2-(2-methoxy-6-vinylphenoxy)-3-butenyl 4-methylbenzenesulfonate as a colorless oil. [α]D25=−8.06 (c 9.93 in chloroform, >97% ee); Rf=0.57 (silica, ethyl acetate:hexanes 3:7); Anal. Calcd. for C20H22O5S.0.2H2O: C, 63.57; H, 5.97. Found: C, 63.37; H, 5.66.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9](O)[CH2:10][CH2:11][CH3:12].O>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCP(=O)(O)CCO
Reactant: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCO
Yield: 85.8 %

Procedure:
414 g (3 mol) of the ethyl(2-hydroxyethyl)phosphinic acid obtained (produced as in Example 8) are at 85° C. dissolved in 400 ml of toluene and admixed with 888 g (12 mol) of butanol. At a reaction temperature of about 100° C., the water formed is removed by azeotropic distillation to leave 500 g (86% of theory) of butyl ethyl(2-hydroxyethyl)phosphinate purified by distillation at reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:29][NH2:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:30][CH3:29])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12
Product: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
5-Fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester (from Example 119.1) was reacted with methyl amine as described in Example 86 to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-methylaminomethyl-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][C:45]1[N:46]=[C:47]([CH:50]([NH2:52])[CH3:51])[S:48][CH:49]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:52][CH:50]([C:47]2[S:48][CH:49]=[C:45]([CH3:44])[N:46]=2)[CH3:51])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: Cc1csc(C(C)N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NC(C)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (22 mg, yield 48%).
Reaction SMILES: [K+].[C:2]1([S:8]([NH-:11])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1>CN1CCCC1=O.[OH-].[Na+]>[CH3:12][NH:13][C:14]1[N:19]=[C:18]([NH:11][S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])[CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: [NH-]S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccccc2)n1
Temperature: 150 °C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
5.38 g (0.0275 mol) of benzenesulfonamide potassium salt and 2.45 g (0.0138 mol) of 2-methylamino-4,6-dichloro-pyrimidine were suspended in 22 ml of 1-methyl-2-pyrrolidone and stirred at 150° C. for 24 hours. The solvent was removed in a high vacuum and the residue was suspended in 250 ml of water. The mixture was extracted three times with 100 ml of ethyl acetate each time and the combined organic phases were washed with 200 ml of saturated NaHCO3. The combined aqueous phases were made acid with 3N HCl and the precipitate which thereby separated was filtered off under suction. It was chromatographed on silica gel with dichloromethane/methanol 99:1→98:2. The yellowish crystals obtained after the chromatography were suspended in 70 ml of 1N NaOH, the suspension was filtered and the clear filtrate was adjusted to pH 3.5 with 1N HCl. The precipitate which thereby separated was isolated and dried. There were obtained 1.9 g (46%) of N-(2-methylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide as colorless crystals; m.p.: 186-187° C.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([C:18]1[C:19]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=1)=O>O>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:24]([CH3:28])[C:25](=[O:27])[CH:26]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)N(C)c1ncccc1C(=O)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Under ice-cooling, potassium tert-butoxide (623 mg, 5 mmol) was added to tetrahydrofuran (10 ml) solution of N-[3-(3-chlorobenzoyl)-2-pyridyl]-N-methylacetamide (1.40 g, 5 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (benzene-ethyl acetate) to give 4-(3-chlorophenyl)-1-methyl-1,8-naphthyridin-2(1H)-one (709 mg, 54%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.N>CO.ClCCl>[CH3:11][C:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][N:9]=1
Reactant: CC(=O)NCCc1ccccc1
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC1=NCCc2ccccc21
Temperature: 0 °C
Yield: 86.4 %

Procedure:
8.43 g of the compound(51.6 mM) prepared in Step 1 above was added to 84.36 g of polyphosporic acid, which was reacted at 160° C. for 1.5 hours with stirring. The reaction solution was poured into ice water, neutralized with ammonia water, and extracted from ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The residue thus obtained was subjected to silica gel column chromatography using a mixed solvent of methanol:dichloromethane (1:20 (v/v)) as a developing solvent to give 6.48 g of the title compound as oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23](=[O:25])[CH3:24])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23](=[O:25])[CH3:24])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CC(=O)Oc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 95.1 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-acetoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.35 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.135 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.25 g); mp 190°-200° C.; MS: m/z=573(M+1); NMR(CD3SOCD3): 1.63 (broad,6), 2.14 (broad,3), 2.27 (s,3), 2.7 (broad,1), 3.6 (m,3), 4.22 (m,1), 4.85 (d,1, J=3.6), 7.09 (m,5), 7.95 (d,1 J=8.2). Analysis for C29H34Cl2N4O4.2.0 HCl.1.0 H2O: Calculated: C, 52.42; H, 5.76, N, 8.43; Found: C, 52.83; H, 5.58; N, 8.31.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: OCCCCCCBr
Solvent: CC#N
Product: OCCCCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 5.6 %

Procedure:
Following the general procedure outlined in Example 1, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (32.0 mg, 0.116 mmol) and 6-bromo-1-hexanol (0.03 mL, 0.248 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (3 mg, 6%). EI-MS m/z 380 (M+) Rt (1.64 min).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:26]([Cl:29])(Cl)[Cl:27].[CH3:30][C:31]1([CH3:44])[O:43][C:35]2[C:36]([CH3:42])=[N:37][CH:38]=[C:39]([CH:40]=O)[C:34]=2[CH2:33][O:32]1>CCCCCCC>[Cl:27][C:26]([Cl:29])=[CH:40][C:39]1[CH:38]=[N:37][C:36]([CH3:42])=[C:35]2[O:43][C:31]([CH3:44])([CH3:30])[O:32][CH2:33][C:34]=12
Reactant: ClC(Cl)Cl
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Product: Cc1ncc(C=C(Cl)Cl)c2c1OC(C)(C)OC2

Procedure:
To a well stirred ice-cooled mixture of 0.1 mole of triphenylphosphine and 0.1 mole of potassium t-butoxide in 250 ml. of heptane is added over thirty minutes a mixture of 0.1 mole of chloroform in 200 ml. of heptane. The resulting mixture is concentrated in vacuo at 15°-20° to a volume of about 100 ml. and a solution of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]-pyridine-5-carboxaldehyde in 250 ml. of heptane is added. The reaction mixture was heated at 40°-50° for 5 hours, then cooled, filtered, and concentrated in vacuo to give crude product. Chromatography on silica gel and elution with ether-petroleum ether (10-50%) gives pure 5-(2,2-dichlorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.
Reaction SMILES: O.Cl.[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47](Cl)(=[O:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[Zn].C(Cl)(Cl)Cl>[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47]([OH:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)O)c1
Reaction time: 0.5 h

Procedure:
87 ml of water and 18.2 ml (0.218 mol) of 12N-HCl were added to the solution of 87 ml of chloroform and 8.65 g (0.0121 mol) of the white solid containing 3,5-dihexadecyloxycarbonylbenzenesulfonyl chloride, and then 7.93 g of zinc was added thereto at 5° C. followed by stirring for 4 hours and 30 minutes. After the insoluble component was removed therefrom, the solution was extracted with 100 ml of chloroform, washed with saturated brine, and dried with Glauber's salt. After removing Glauber's salt, the solution was concentrated under reduced pressure, and the residue was recrystalized from hot hexane to obtain a colorless crystal of 3,5-dihexadecyloxycarbonylbenzenesulfinic acid. (Yield: 4.43g, 48% (based on sodium 3,5-dimethyloxycarbonylbenzenesulfonate), m.p.: 63°-65° C.)
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH3:11][C:12]([CH3:32])([CH3:31])[CH2:13][C:14]1[N:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][C:15]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[F:30].[H-].[Na+].Cl>C1COCC1>[Cl:10][C:6]1[C:7]([O:8][CH3:9])=[C:2]([O:21][CH2:20][C:18]2[CH:17]=[CH:16][C:15]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[F:30])=[C:14]([CH2:13][C:12]([CH3:32])([CH3:31])[CH3:11])[N:19]=2)[N:3]=[CH:4][N:5]=1
Reactant: COc1c(Cl)ncnc1Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(Cl)c3OC)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4,6-dichloro-5-methoxypyrimidine (450 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (760 mg) in THF (8.0 mL) was added 60% sodium hydride (200 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.05 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[O-]CC.[Na+].Cl.Cl.Cl[CH2:13][C:14]1[CH:19]=[C:18]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][N:15]=1.Cl>C(O)C.O>[CH3:22][N:21]([CH2:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[CH:19]=1)[CH3:23]
Reactant: NCCS
Reactant: CN(C)Cc1ccnc(CCl)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCN)c1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Cysteamine hydrochloride (3.75 g) was added to a stirred solution of sodium ethoxide (prepared from 2.83 g sodium) in ethanol (200 ml) and the mixture was cooled to less than 10°. 2-Chloromethyl-4-dimethylaminomethylpyridine dihydrochloride (7.3 g) was added portionwise and the solution was stirred for 1 hour. Water (200 ml) was added, the pH was adjusted to ca. 4 with hydrochloric acid and the volume was reduced to ca. 100 ml. The solution was extracted with chloroform, the aqueous phase was basified to pH 12 and extracted with chloroform to give 2-[4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (4.7 g) as an oil.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:16](=[O:18])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Br:1][CH2:17][C:16]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:18]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: BrBr
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (6.1 ml) in dichloromethane (50 ml) was added dropwise over 3 hours at 10°-15° C. under nitrogen to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone (31.9 g) in a mixture of methanol (60 ml) and dichloromethane (10 ml), then the mixture was stirred at ambient temperature for 2.5 hours and poured into an excess of ice-water. The aqueous layer was separated and washed with dichloromethane 3×100 ml), then the combined organic solutions were washed with saturated aqueous sodium hydrogencarbonate solution (2×100 ml) and water (100 ml), dried over calcium chloride, and the solvent removed in vacuo. The residue was distilled in vacuo, and the fraction of b.p. >174° C./1.3 mbar was collected and redistilled. Material of b.p. >182° C./2.6 mbar in this second distillation was collected and redistilled to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone as a pale yellow oil (11.8 g), b.p. 156°-162° C./0.4 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Br:17])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:19].[Li+]>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:16][C:15]1[C:14]([Br:17])=[CH:13][CH:12]=[CH:11][C:10]=1[C:9]([OH:18])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C1=O
Reactant: [OH-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1c(Br)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a stirred solution of 4-bromo-1-oxo-1,3-dihydro-isoindole-2-carboxylic acid tert butyl ester (0.206 g, 0.66 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of aq. lithium hydroxide (1M, 2 ml, 1.98 mmol) and the mixture stirred at room temperature under nitrogen for 18 hours. The mixture was diluted with diethyl ether (30 ml) and washed with 1M HCl (10 ml). The aqueous layer was extracted with diethyl ether (2×20 ml) and the combined organics dried over magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure to give the title compound (0.188 g, 86%) as a white waxy solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:23])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C:2](=[O:23])[NH:1]3)[CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: CN(C)CCc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)(C)O
Product: CN(C)CCc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of {2-[3-(1H-indol-4-yl)-phenyl]-ethyl}-dimethyl-amine (600 mg, 2.2 mmol) in t-BuOH:ethanol:acetic acid (14.5 mL:8.8 mL:10.5 mL) was added pyridinium tribromide (2.3 g, 6.6 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (9.24 mL). Water (0.32 mL) and zinc dust (2.2 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was dissolved in methanol (10 mL) and hydrogenated using 10% Pd—C for overnight. The reaction was filtered through celite and the filtrate was concentrated. The residue was purified on a silica gel column to give 4-[3-(2-dimethylamino-ethyl)-phenyl]-1,3-dihydro-indol-2-one
Reaction SMILES: [I-:1].[Na+].[NH2:3][CH:4]1[C:29](=[O:30])[N:6]2[C:7]([C:13]([O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[C:8]([CH2:11][Cl:12])[CH2:9][S:10][C@H:5]12.[C:31]1([P:37]([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)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[ClH:12].[I-:1].[CH:16]([O:15][C:13]([C:7]1[N:6]2[C:29](=[O:30])[CH:4]([NH2:3])[C@H:5]2[S:10][CH2:9][C:8]=1[CH2:11][P+:37]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:14])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cl
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Sodium iodide (1.8 g) was added to a solution of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (5.0 g) and triphenylphosphine (3.2 g) in dimethyl formamide (15 ml) under ice-cooling and stirred for 3 hours at ambient temperature. The resulting solution was added dropwise to ethyl acetate (250 ml) under vigorous stirring. The precipitate, collected by filtration, was washed with ethyl acetate to give [4-benzhydryloxycarbonyl-7-amino-3-cephem-3-ylmethyl]triphenylphosphonium iodide hydrochloride (9.6 g).