Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:21]([CH:25]=2)[C:22]([OH:24])=O)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:21]([CH:25]=2)[C:22]([NH:40][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)=[O:24])(=[O:16])=[O:15])[CH2:12][CH2:13]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.03 ml, 0.31 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 5-[(4-methyl-1-piperazinyl)sulfonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 72; 120 mg, 0.31 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated to give crude acyl chloride. A solution of this acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (28.9 mg, 0.31 mmol) and diisopropylethylamine (0.05 ml, 0.31 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give crude product as an orange oil. The crude product was crystallized from methanol to yield the title compound as a white solid. 30 mg.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[C:35]([OH:37])=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH:27]3[C:35]([OH:37])=[O:36])=[O:24])[CH:18]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)C1Cc2ccccc2N1C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
107 mg (0.31 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 65.0 mg (0.40 mmol) 2,3-dihydro-1H-indole-2-carboxylic acid, 107.0 mg (0.33 mmol) TBTU and 100 μL (0.71 mmol) triethylamine in 10 mL DMF were stirred overnight at RT. The mixture was evaporated down i. vac. and the residue was dissolved in 5 mL DMF. The purification was carried out by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=[O:25])C.O=[O+][O-].[OH2:30]>>[C:2]([NH:3][C:4]1[C:9]([C:10](=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:30])[CH3:1]
Reactant: CCOC(=O)Cc1cccc2c(-c3ccccc3)c(C)[nH]c12
Reactant: O
Reactant: CC(=O)O
Agent: O=[O+][O-]
Product: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1NC(C)=O

Procedure:
A solution of 5 g. (0.017 mole) of ethyl α-(2-methyl-3-phenylindol-7yl)acetate and 75 ml. of acetic acid was treated with ozone for 25 minutes. After ozonation, the acetic acid solution was diluted with water and extracted with ether. The ether extracts were washed with water, 5% sodium carbonate, dried (magnesium sulfate) and concentrated. Recrystallization from isopropanol gave 2.6 g. (47%) of product which melted at 133°-134° C.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[CH:8][N:7]([S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=1)=[O:4].Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:3]([C:5]1[CH:9]=[CH:8][N:7]([S:10](=[O:14])(=[O:15])[N:11]([CH3:12])[CH3:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccn(S(=O)(=O)N(C)C)n1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccn(S(=O)(=O)N(C)C)n1
Temperature: -78 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
1-Dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methyl ester (4 g, 17.15 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.18 g, 22.29 mmol) were slurried in DCM (20 mL). The mixture was flushed with nitrogen and cooled to −78° C. Then a solution of isopropylmagnesium chloride (2M in THF) (24.01 mL, 48.02 mmol) was added dropwise. When the addition was completed the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with NH4Cl (aq. sat. solution) and the product was extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield 1-dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (3.2 g, 71% yield) as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CN1CCOCC1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(NS(C)(=O)=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a slurry of 6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (Example 11B) (14 mg, 0.035 mmol) in CH2Cl2 (2 ml) was added N-methyl morpholine (12.3 μl, 0.113 mmol) followed by MsCl (4.5 μl, 0.057 mmol). The reaction mixture was stirred overnight, 10% citric acid (3 ml) was added. The resulting mixture was extracted with CHCl3 (10 ml), the organic layer was separated and dried with Na2SO4, concentrated to give the title compound (6.9 mg, 45%). It has a retention time of 6.01 min (standard LCl method, 8 min run). MS Found: (M+H)+=434.0
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)=[CH:52][CH:51]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (388 mg, 1.83 mmol) was added to a DCE solution (2 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (330 mg, 0.92 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (186 mg, 0.92 mmol), and AcOH (0.21 mL, 3.66 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>ClC(Cl)C>[C:1]([NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccsc1N
Reactant: CCCCC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1sccc1C(=O)OC
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Valeryl chloride (1.3 g) was added to a solution of methyl 2-aminothiophene-3-carboxylate (1.6 g) [Y. Kuwada et al. Chem. Abst. 82, 156252(1975)] and triethylamine (1.2 g) in dichloroethane (20 ml) under ice-cooling. The mixture was stirred for two hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (2.3 g, 96%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1[C:39]([CH:40]=O)=[CH:38][C:37]2[O:42][C:43]([F:46])([F:45])[O:44][C:36]=2[CH:35]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:46][C:43]1([F:45])[O:44][C:36]2[CH:35]=[CH:34][C:39]([CH2:40][N:29]3[CH2:28][CH2:27][CH:26]([N:23]4[C:19]5=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]6[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=6)=[C:18]5[CH:25]=[N:24]4)[CH2:31][CH2:30]3)=[CH:38][C:37]=2[O:42]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccc4c(c3)OC(F)(F)O4)CC2)cc1

Procedure:
1-[1-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 2,2-difluoro-5-formylbenzodioxole (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.98 (m, 2H), 2.15-2.25 (m, 4H), 2.92-2.98 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.57 (s, 2H), 4.77-4.83 (m, 1H), 7.18-7.20 (m, 1H), 7.35-7.39 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=544.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[C:18]([CH2:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:24][CH2:23][C:18]2[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1CN
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 4-formylpiperidine-1-carboxylic acid tert-butyl ester (Bioorg. Med. Chem Lett. 2002, 12, 1785-1790), C-(3-methylpyridin-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave 4-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1.Cl>CO.[OH-].[Na+].CCOCC>[CH3:26][C:24]([CH3:27])([O:23][C:21]([NH:20][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:28])=[O:2])=[O:22])[CH3:25]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 77.9 %

Procedure:
A solution of 1.471 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[2-(1,1-dimethylethoxy) -2-oxoethyl]benzenepropanoic acid methyl ester in 25 mL of methanol and 5 mL of 1N sodium hydroxide solution was stirred at room temperature for 2 hours. The mixture was acidified with a slight excess of hydrochloric acid, was diluted with 100 mL of ether, and was washed with water and saturated sodium chloride solution. The residue obtained after filtration and evaporation was chromatographed over 100 g of silica gel, eluting with 40:59:0.5 ethyl acetate-hexane-acetic acid. The product containing fractions were combined evaporated, diluted with toluene and evaporated finally under high vacuum to give 1.105 g of (S)-alpha-[[(1,1-dimethylethoxy) carbonyl]amino]-4-[2-(1,1-dimethylethoxy)-2-oxoethyl]benzene-propanoic acid [a]D +21.41 (ethanol).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]=1[OH:20]>C1(C)C(C)=CC=CC=1>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[C:11]=1[O:20][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(OC)c1O
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc(OC)c1OS(=O)(=O)N=C=O
Temperature: 140 °C

Procedure:
3.4 g (0.024 mol) of chlorosulfonyl isocyanate are added dropwise to a solution of 3.6 g (0.02 mol) of methyl 3-methoxy-salicylate in 20 ml of xylene at 25° C. When the dropwise addition has ended, the temperature is slowly increased to 140° C. and the mixture is heated under reflux for 2.5 hours. It is cooled and the solvent and excess chlorosulfonyl isocyanate are removed on a rotary evaporator. The yellow oil which remains (5.4 g=1004 of theory) is used without further purification.
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=1)=[O:4])[NH2:2].[CH:17](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:11][C:9]1[N:10]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:7][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1sc(NC(=O)NN)nc1C
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Yield: 73 %

Procedure:
A solution of ethyl 2-(hydrazinecarboxamido)-4-methylthiazole-5-carboxylate (0.50 g, 2.05 mmol), trimethyl orthoformate (0.25 mL, 2.28 mmol) and p-toluenesulfonic acid monohydrate (10 mg) in methanol (10 mL) was subjected to microwave irradiation for 10 minutes at 90° C. (30 psi). The solvent was removed in vacuo and the residue was suspended in dichloromethane. The solid was collected by filtration, washed with saturated sodium bicarbonate and water, and dried to afford the title compound in 73% yield (0.38 g): 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 4.32 (q, J=6.9 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=6.9 Hz, 3H); MS (ES+) m/z 255.2 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[N+:10]([C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]([N:23]=[C:24]=[S:25])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]([N:23]=[C:24]2[S:25][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[NH:2]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: NC1(CCl)CCCC1
Reactant: O=[N+]([O-])c1ccc(N=C=S)c2c1CCCC2
Agent: Cl
Product: O=[N+]([O-])c1ccc(N=C2NC3(CCCC3)CS2)c2c1CCCC2

Procedure:
1-Amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8-tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthaline according according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method C1a to give 2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([N:28]=[C:29]=[O:30])[CH2:25][CH2:26][CH3:27].Cl>C(C(C)=O)C>[CH2:24]([NH:28][C:29]([NH:17][S:14]([C:3]1[C:4]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:16])=[O:15])=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN=C=O
Reactant: CN(C)S(=O)(=O)c1cccc(Cl)c1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1c(Cl)cccc1S(=O)(=O)N(C)C
Temperature: 25 °C

Procedure:
To 140 mL of methyl ethyl ketone was added 14.3 g of 3-chloro-N,N-dimethyl-1,2-benzenedisulfonamide, 7.2 g of potassium carbonate and 7.5 ml of n-butyl isocyanate. This mixture was heated at reflux temperature for 3 hours, cooled to room temperature, poured into 1500 mL of ice water, and acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water, and dried to afford 17.4 g of N'-butylaminocarbonyl-3-chloro-N,N-dimethyl-1,2-benzenedisulfonamide as a white powder, m.p. 107°-115° C.; NMR (CDCl3): δ0.9 (br t, 3H), 1.2-1.7 (m, 4H), 3.0 (s, 6H), 3.3-3.4 (m, 2H), 6.6 (t, 1H), 7.6-8.0 (m, 2H), 8.5 (dd, 1H), 9.0 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([OH:29])=O)[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH:42][C@H:43]1[CH2:47][CH2:46][NH:45][CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([N:45]4[CH2:46][CH2:47][C@H:43]([OH:42])[CH2:44]4)=[O:29])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CC[C@H](O)C1
Reaction time: 4 h
Yield: 37.4 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.2 mmol), (S)-3-hydroxypyrrolidine (35 mg, 0.4 mmol), HATU (152 mg, 0.4 mmol) and DMAP (73 mg, 0.6 mmol) in DMF (2 mL) was stirred for 4 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic phases were washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (50 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:15][N:16]([CH2:18]N(C)C)[CH3:17].C(Cl)(=O)C>ClCCl>[CH3:15][N:16]([CH2:18][C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH3:14])[C:2]=2[Cl:1])[NH:6][CH:5]=1)[CH3:17]
Reactant: CN(C)CN(C)C
Reactant: CCCOc1ccc2[nH]ccc2c1Cl
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCCOc1ccc2[nH]cc(CN(C)C)c2c1Cl
Yield: 78.8 %

Procedure:
Treatment of 4-chloro-5-n-propyloxyindole (5.10 g, 24.3 mmol) with bis (dimethylamino)methane (BDAM) (3.34 g, 32.7 mmol) and acetyl chloride (2.57 g, 32.7 mmol) in dichloromethane by the method described in 1 (c) gave 3-dimethylaminomethyl-4-chloro-5-n-propyloxyindole (5.11 g) as a sticky solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:57][C@@H:58]1[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]1[OH:64]>CN(C=O)C>[CH2:1]([O:5][C:6]1[C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:13][C:9]([C:10]([NH:57][C@@H:58]2[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]2[OH:64])=[O:12])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ncc(C(=O)O)cc1-c1cc(C(F)(F)F)ccc1F
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
6-Butoxy-5-(2-fluoro-5-trifluoromethyl-phenyl)-nicotinic acid (0.10 g, 0.3 mmol) was dissolved in DMF (5 mL). To the solution was added TBTU (0.10 g, 0.3 mmol), N,N-diisopropylethyl amine (0.24 mL, 1.4 mmol) and (1R,2R)-2-amino-cyclohexanol (47 mg, 0.3 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 78 mg of the title compound as a light yellow solid, mp 172-178° C., MS (ISP) 455.3 (M+H)+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:36]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35](=[O:48])[N:26]2[C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[Br-:20].[C:31]([O:30][C:28]([C:27]1[N:26]2[C:35](=[O:48])[C@@H:36]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:25]2[S:24][CH2:23][C:22]=1[CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Product: [Br-]
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A solution of triphenylphosphine (1.95 g, 2 equiv.) in ethyl acetate (6 ml) was added to a solution of t-butyl 3-bromomethyl-7β-phenoxyacetamidoceph-3-em-4-carboxylate (1.80 g, 3.72 mmole) in ethyl acetate (4 ml.). The mixture was stirred for 1 hour, and the precipitated solid was filtered off, washed with ether and dried to give the title phosphonium salt (2.42 g, 87.5%), m.p. 144° to 146°, [α]D22 +31° (C 0.95; Me2SO), λmax. (EtOH) 268 nm (ε 11,300) and 275 nm (ε 10,400), νmax. (Nujol) 3400 (NH), 1778 (azetidin-2-one), 1692 and 1520 (C0NH), 1690 (CO2R) and 1430 cm-1 (P+ -C6H5), τ (Me2SO-d6) 0.89 (1H, d, j 8 Hz; NH), 2.66 and 2.99 (2H and 3H, 2 m; C6H5O), 4.29 (1H, centres of two AB-quartets, JH-H 15 Hz, JP-H 16 Hz; C3 -CH2P+), 5.33 (2H, s; C6H5OCH2), 8.76 (9H, s; CO2C(CH3)3).