Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](Cl)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.[Cl-].[NH4+].O1CCC[CH2:23]1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH3:23])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: C1CCOC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(-c2cc3ccccc3c(C)n2)cc1
Yield: 100 %

Procedure:
3-(4-Methoxyphenyl)-1-chloroisoquinoline (3.25 g) was dissolved in tetrahydrofuran (30 ml), followed by the addition of 3.0M ethylmagnesium bromide diethyl ether solution (12 ml) and NiCl2(dppp) (50 mg) at 0° C. After the mixture was reacted overnight at room temperature, the resulting reaction solution was poured into an aqueous solution of saturated ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried and evaporated, to give 3-(4-methoxyphenyl)-1-methylisoquinoline as an oil (3.3 g, yield; 100%).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[C:1]([NH:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NNC(=O)c2ccccc2)cc1

Procedure:
1-Benzoyl-2-(4-nitrophenyl)hydrazine (14.3 g, 0.056 mole) and 10% palladium/charcoal (catalytic amount) were suspended in ethanol (300 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a tan crystalline powder. Yield 11.5 g (90%), m.p. 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[N:13]1([C:19]([S:21][CH3:22])=[S:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:16]1[CH2:17][CH2:18][N:13]([C:19]([S:21][CH3:22])=[S:20])[CH2:14][CH2:15]1
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1ccc(CCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=S)SC)CC2)cc1OC
Yield: 14.9 %

Procedure:
In a nitrogen atmosphere, 5.615 g (30.08 mmol.) of 3,4-dimethoxybenzyl chloride, 5.57 g (30.08 mmol., purity 95%) of methyl 1-piperazinecarbodithioate, 3.19 g (30.08 mmol.) of anhydrous sodium carbonate and 50 ml of ethanol were mixed and refluxed under heating for 5.5 hours. The solvent was distilled off under reduced pressure. To the residue were added 20 ml of dichloromethane and 20 ml of water. The organic solvent portion was taken out and washed with 30 ml of 1-N hydrochloric acid. To the organic portion was added 1-N aqueous sodium hydroxide solution. The organic solvent portion was again taken out and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To the residue was added 20 ml of ethanol. Precipitated crystals were collected by filtration and washed with ethanol to give 1.465 g of methyl 4-(3,4-dimethoxybenzyl)-1-piperazinecarbodithioate, yield 14.9%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([N:11]([CH2:15][CH2:16][CH3:17])[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[CH2:13][CH3:14]
Reactant: CCCN(CCC)C1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1

Procedure:
Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-dipropylamine (Intermediate 121, 150.0 mg, 0.50 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound was isolated by chromatography (0-3% EtOAc-hexanes).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[CH:28]=[N:27][N:26]=1.[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[CH:28]=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:53]([NH:52][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:54])=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CN)s1
Reactant: O=C=Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNC(=O)Nc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazole di-p-toluenesulfonate (5.0 g) was dissolved in dimethylformamide (20 ml). Phenyl isocyanate (0.87 ml) and triethylamine (3.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 2.47 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethyl)-N'-phenylurea.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazole-2-one was treated with ethyl 3-bromo-propionate and potassium carbonate in butanone to give after work-up the title compound. m.p. 111°-112° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[Se](=O)=[O:20]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH:18]=[O:20])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: COCCCOc1cc(F)cc2ccc(C)nc12
Solvent: C1COCCO1
Solvent: O
Product: COCCCOc1cc(F)cc2ccc(C=O)nc12
Yield: 87.3 %

Procedure:
To a solution of 6-fluoro-8-(3-methoxypropoxy)-2-methylquinoline (0.22 g, 0.87 mmol) in dioxane (20 mL) and water (0.2 mL) was added selenium dioxide (0.12 g, 1.0 mmol) and the resultant mixture was heated at reflux for 5 hours. The cooled reaction mixture was filtered through a plug of Celite®, washing the solids with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.20 g, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:26])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.0 g, 16.3 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.7 g, 17.5 mmole). After 10 min, methyliodide (11.57 g, 81.5 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (5.17 g, 99%) as a white solid: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:12])[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCCOS(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of methanesulphonyl chloride (23.7 ml) in dry dichloromethane (25 ml.) was added dropwise to a solution of hex-5-yn-1-ol (Lancaster Synthesis, 25 g) and triethylamine (47.3 ml) in dichloromethane (300 ml), stirred under a nitrogen atmosphere at -70°. The resulting mixture was allowed to warm to room temperature over 16 hours. The mixture was then washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. Hex-5-ynyl methanesulphonate was obtained as an oil (43.6 g) and was used without purification.
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.C[OH:31].O>C(Cl)Cl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH:16]=[CH:15][C:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[OH:31]
Reactant: O=C(C=Cc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Reactant: CO
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1O)c1ccccc1Cl

Procedure:
To a solution of 740 mg (2.12 mmol) of 1-4 in 15 mL of CH2Cl2 at −78° C. was added dropwise 2.75 mL (2.75 mmol) of a 1M solution of BBr3 in CH2Cl2. After stirring for 30 min at that temperature, 1 mL of MeOH was added, and the mixture was dumped into water, extracted twice with 50 mL of CH2Cl2, washed again with water, and dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel with a gradient of 2 to 70% EtOAc in hexanes over 30 min to provide 1-5 as a beige solid. Data for 1-5: 1HNMR (500 MHz, CDCl3) δ 7.5-7.3 (m, 5H), 7.25 (m, 1H), 7.2-7.0 (m, 3H), 6.9 (m, 1H), 5.1 (bs, 1H) ppm.
Reaction SMILES: C(OC([N:8]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([Cl:42])[CH:40]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:11]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[C:9]1=[O:43])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:42][C:39]1[CH:40]=[C:41]2[NH:8][C:9](=[O:43])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[C:36]2=[CH:37][CH:38]=1
Reactant: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)C1c1ccccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C1c1ccccc1C
Yield: 68 %

Procedure:
In a manner similar to the method described in example 24d, racemic 2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.37 g, 0.59 mmol) prepared in example 29a was reacted with trifluoroacetic acid (20 mL) in dichlormethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.21 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24])C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:26])[NH:7][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a solution of N-(5-methoxy-2-nitrophenyl)-N-t-butoxycarbonylcarbamic acid t-butyl ester (10.6 g) in toluene (5 ml) and methanol (30 ml) was added 24% sodium methoxide in methanol (3.1 ml) and the mixture was stirred at 25° C. for 3 hours. At the end of this time the reaction mixture was cooled to 0° C. and the precipitated crystals were filtered to give the title compound (5.8 g, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:32])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[N:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[C:3]([OH:32])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[N:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of methyl 6-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)picolinate (0.185 g, 0.37 mmol), 1 N NaOH (2 mL), THF (2 mL) and MeOH (2 mL) was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and 1 N HCl. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the filtrate solution was concentrated to give the desired product (0.18 g, 99%) as a colorless oil. 1H NMR (CDCl3) δ 8.12 (d, J=8.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.58 (d, J=4.0 Hz, 1H), 7.55 (d, J=4.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.06-7.03 (m, 2H), 6.93 (t, J=8.0 Hz, 2H), 4.64 (s, 2H), 4.40 (s, 2H). MS (ESI): 485.0 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][C:10]([CH3:14])=[CH:11]2)[N:6]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26].ClCCl>N1C=CC=CC=1>[CH2:25]([O:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:17][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][C:10]([CH3:14])=[CH:11]2)[N:6]=1)(=[O:4])=[O:3])[CH3:26]
Reactant: CCOc1ccncc1N
Reactant: COc1nc(C)cc2nc(S(=O)(=O)Cl)nn12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccncc1NS(=O)(=O)c1nc2cc(C)nc(OC)n2n1

Procedure:
2-Chlorosulfonyl-5-methoxy-7-methyl[1,2,4]triazolo[1,5-c]pyrimidine (1.5 g, 5.7 mmol) was added to a solution of 0.8 g (5.7 mmol) of 3-amino-4-ethoxypyridine in 30 mL of dry pyridine in portions over 10 minutes with stirring. After 16 hours the reaction mixture was poured into 400 mL of dichloromethane. The resulting mixture was washed with 150 mL of water, dried over magnesium smlfate, and filtered. The liltrate was combined with 5 g of silica gel and the mixture was concentrated by evaporation under reduced pressure. The resulting silica plug was placed onto a 200 g silica gel column and eluted with dichloromethane containing increasing amount of ethanol. The product fractions were combined and concentrated by evaporation under reduced pressure and the solid obtained was dried to obtain 0.75 g (36 percent of theory) of the title compound as a white solid melting at 184°-186° C.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.[C:9]([O:12][C@@H:13]1[N:16]([S:17]([OH:20])(=[O:19])=[O:18])[C:15](=[O:21])[C@H:14]1[NH2:22])(=[O:11])[CH3:10].[Na+:23].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C1COCC1.O>[C:9]([O:12][C@@H:13]1[N:16]([S:17]([O-:20])(=[O:19])=[O:18])[C:15](=[O:21])[C@H:14]1[NH:22][C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:11])[CH3:10].[Na+:23]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Reaction time: 1.5 h

Procedure:
To a solution of 0.61 g of acetate of sodium (3S,4S)-4-acetoxy-3-amino-2-oxoazetidine-1-sulfonate obtained in Example 21B in 20 ml of a mixture of water and THF(1:1) is added under ice-cooling 0.61 g of phenylacetyl chloride while keeping the pH of the reaction mixture at pH 7.0-7.5 by use of sodium hydrogen carbonate. The stirring is continued for 1.5 hours at the same temperature. THF is removed by evaporation under reduced pressure. The residue is purified on an XAD-II (Rohm and Haas Co.) column chromatography to give 0.42 g of sodium (3S,4S)-4-acetoxy-3-phenylacetamido-2-oxoazetidine-1-sulfonate. The IR spectrum and NMR data of this compound are in agreement with those of the compound obtained in Example 19B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].S([O-])(O)=O.[Na+].CN(C)C(=O)C.[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH3:36])[C:33]=1[CH:34]=O>O>[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH3:36])[C:33]=1[C:34]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]=2[N:16]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: Cc1c[nH]c(C)c1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c[nH]c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
3,4-Diaminobenzophenone (1.48 g) and sodium hydrogensulfite (0.87 g) were added to N,N-dimethylacetamide (5 ml) at 130° C., and stirred for 5 minutes. 2,4-Dimethyl-3-formyl-pyrrole (1.03 g) was added and stirred at 130° C. for 8 hours. The reaction mixture was cooled to room temperature and stirred, and after addition of water to reaction mixture, precipitate was collected by filtration, and dried in vacuo to afford 2-(2,4-dimethyl-pyrrol-3-yl)-5-benzoylbenzimidazole (1.78 g, 81%) as a brown solid.
Reaction SMILES: FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH2:19][C@H:18]([NH3+:22])[C@H:17]1[NH3+:23].C(N(CC)CC)C.[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O>ClCCl>[C:36]([O:35][C:33](=[O:32])[NH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C:16]([F:24])([F:15])[C@@H:17]1[NH2:23])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: [NH3+][C@@H]1[C@@H]([NH3+])CCCC1(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCC(F)(F)[C@@H]1N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of (1S,2R)-3,3-difluorocyclohexane-1,2-diaminium bis(trifluoroacetate) (7.5 g, 19.8 mmol) in dichloromethane (100 mL) was added triethylamine (11.1 mL, 79.0 mmol) followed by BOC2O (5.52 mL, 23.8 mmol). The reaction was stirred for 10 hr at ambient temperature. Concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (CDCl3, 500 MHz) 4.76 (br s, 1H); 3.39 (m, 1H); 2.71-2.64 (m, 1H); 2.2-2.1 (m, 2H); 1.7-1.59 (m, 2H); 1.56-1.51 (m, 2H); 1.45 (s, 9H); 1.29-1.21 (m, 2H). 19F NMR (CDCl3, 564 MHz) −100.4-−100.9 (d, 1F); −114.35-−114.87 (d, 1F).
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:19])=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:19].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:24]4[CH2:25][C:29]5[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27]4)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: CCN(CC)Cc1ccccc1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A stirred mixture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D25) (0.25 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.13 g) in DCM (10 ml) at rt was treated with isoindoline (0.098 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E59) as a white powder (220 mg). MS electrospray (+ion) 377 (MH+). 1H NMR δ (DMSO-d6): 10.62 (1H, s), 7.62 (2H, m), 7.40-7.25 (4H, m), 7.08 (2H, m) 4.82 (4H, m), 4.64 (1H, m), 3.81-3.58. (1H, m), 3.45-3.20 (2H, m), 2.95 (2H, m), 2.38-1.62 (10H, m).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH:13]=[CH2:14].O.[OH-].[Li+].[CH2:18]1COCC1>O>[CH:13]1([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[F:1])[C:6]([OH:8])=[O:7])[CH2:14][CH2:18]1
Reactant: C=Cc1cc(C(=O)OCC)ccc1F
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)c(C2CC2)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of compound 3 ethyl 4-fluoro-3-vinylbenzoate (Preparation 54, 87 g, 0.42 mol, 1 eq) in THF (470 mL) and water (400 mL) was added lithium hydroxide monohydrate (35.1 g, 0.84 mol, 2.0 eq). The resulting mixture was stirred at 40° C. overnight. THF was removed in vacuum, then 6N hydrogen chloride solution was added dropwise until pH=2. The mixture was extracted with ethyl acetate (3×600 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo to give title compound as a white solid (60.8 g, 0.34 mol, 81%).