Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]1([C:19](=[O:20])[C:18]#[C:17][C:14]2[CH:13]=[CH:12][N:11]=[CH:16][CH:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(C#Cc1ccncc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(C#Cc1ccncc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 32.6 %

Procedure:
Place oxalyl chloride (0.5 mL of a 2 M solution in methylene chloride, 1 mmol) under argon atmosphere and cool with a dry ice/acetone bath. Add dimethylsulfoxide (0.14 mL, 2 mmol) and stir for 10 minutes at -70° C. Add α-[(4-pyridinyl)ethynyl]-benzenemethanol (0.18 g, 0.86 mmol) in methylene chloride (1 mL). Stir for 20 minutes at -78° C. Add triethylamine (0.56 mL, 4 mmol), remove the cooling bath and stir for 45 minutes. Pour onto silica gel and elute with 60% ethyl acetate/hexane. Evaporate the solvent in vacuo and recrystallize (hexane/chloroform) to yield 58.1 mg of the title compound; mp 74°-75° C.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[Mn:13]([Cl:16])([Cl:15])=[O:14]>CCCCCC.C1COCC1>[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][Mn:13]([Cl:16])([Cl:15])=[O:14])=[CH:8][CH:7]=1
Reactant: O=[Mn](Cl)Cl
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=[Mn](Cl)(Cl)Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, butyl lithium in hexane (8.35 ml, 1.6 M solution) was added to a solution of 4-picoline (1.23 g) in THF (25 ml) at -30° C. slowly over 20 mins. The solution was then stirred at room temperature for 1 hr and anhydrous manganous chloride (1.51 g) added at 0° C. The suspension was stirred for ca. 3/4 hr at room temperature.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH:3]1[C:18]1[N:22]2[C:23]3[CH:29]=[CH:28][N:27](S(C4C=CC(C)=CC=4)(=O)=O)[C:24]=3[N:25]=[CH:26][C:21]2=[N:20][CH:19]=1.[OH-].[Na+]>O1CCOCC1>[CH:29]1[C:23]2[N:22]3[C:18]([CH:3]4[CH:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[O:9])[CH2:4]4)=[CH:19][N:20]=[C:21]3[CH:26]=[N:25][C:24]=2[NH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CN(C(=O)OCc5ccccc5)CCC4C)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1CCN(C(=O)OCc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Temperature: 90 °C
Yield: 83.1 %

Procedure:
To a solution of benzyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate (0.93 g, 1.7 mmol) in 1,4-dioxane (20 mL) was added aqueous NaOH (2 N, 1.0 mL), and the resulting mixture was heated at about 90° C. for about 80 min. The solvents were removed under reduced pressure and the residue was treated with saturated aqueous NH4Cl (26 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated to yield the crude product as a brown amorphous solid. The material was purified by silica gel chromatography eluting with a gradient of 5-100% MeOH/DCM to give benzyl 3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidine-1-carboxylate (0.55 g, 83%) as a yellow solid: LC/MS (Table 2, Method a) Rt=1.94 min; MS m/z: 390 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH3:22])=[C:13]([Cl:23])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH2:35]Cl)=[CH:31][CH:30]=1)(=[O:27])=[O:26].C(N(CC)CC)C.N>CO.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:35][CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:29]([NH:28][S:25]([CH3:24])(=[O:26])=[O:27])=[CH:38][CH:37]=2)[CH3:22])=[C:13]([Cl:23])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(OCCCl)cc1
Reactant: CNCCCNc1c(Cl)cnn(COCc2ccccc2)c1=O
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCCNc1c(Cl)cnn(COCc2ccccc2)c1=O)CCOc1ccc(NS(C)(=O)=O)cc1
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A mixture of 3.2 g (9.5 mmoles) of 2-benzyloxymethyl-5-chloro-4-[3-(N-methylamino)-propylamino]-3(2H)-pyridazinone, 3.56 g (14.25 mmoles) of 4-[(methylsulfonyl)-amino]-phenoxyethyl chloride and 2 ml (14.25 mmoles) of triethylamine is melted at a temperature of 80° C. for 16 hours. Then it is subjected to column chromatography using first ethyl acetate, then a 9:1:0.5 mixture of ethyl acetate--methanol--cc. ammonia. Thus 1.8 g (69%) of the aimed compound are obtained. Rf =0.7.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C>C1COCC1>[C:13]1([C@H:11]([O:10][C:8](=[O:9])[NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:35])[CH2:32][CH2:33]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.1 g, 0.2 mmol), methanesulfonamide (0.08 g, 0.8 mmol), and N,N′-carbonyldiimidazole (0.15 g, 0.6 mmol) were combined in THF (4 mL). Diisopropylethylamine (0.5 mL) was added, and the reaction was stirred at 65° C. overnight. The mixture was acidified and extracted with CH2Cl2. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH2:18]([N:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 71 °C
Yield: 65.6 %

Procedure:
To a dry 100 mL round bottom flask equipped with a stirring bar under N2 was added 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (5 g, 20.5 mmol), anhydrous acetonitrile (60 mL), benzyl bromide (2.7 mL, 22.5 mmol), and triethylamine (8.5 mL, 61.5 mmol). The reaction mixture was heated at 71° C. for 45 minutes and concentrated under reduced pressure. It was then diluted with methylene chloride and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromato-graphy eluting with 8:1 petroleum either/ethyl acetate to afford 336a (4.5 g, 66%). MS: [M+H]+ 335. 1H NMR (500 MHz, CDCl3) δ 7.28 (m, 5H), 4.60 (m, 1H), 3.78 (m, 4H), 3.57 (m, 1H), 3.43 (m, 1H), 3.28 (m, 2H), 2.77 (m, 1H), 2.19 (m, 1H), 2.11 (m, 1H), 1.47 (s, 5H), 1.42 (s, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].[Cl-].[NH4+].[OH2:19].O=O>C(O)C>[CH3:16][C:2](=[CH:3][CH2:4][CH2:5][C:6]([CH3:15])=[CH:7][CH2:8][CH2:9][C:10]([CH3:11])([OH:19])[C:12]#[C:13][C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:15])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])[CH3:1]
Reactant: C#CC(C)(O)CC/C=C(\C)CCC=C(C)C
Reactant: O
Agent: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)(O)C#CC#CC(C)(O)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 5 l-capacity, 3-neck, round-bottom flask was charged with 114.7 g of dehydronerolidol, 305.9 g of ammonium chloride, 191.2 g of cuprous chloride, 765 ml of water and 765 ml of ethyl alcohol, and the mixture was agitated at room temperature for 18 hours while blowing oxygen thereinto. After completion of the reaction, none of the starting reactants were left. The reaction mixture was separated with a centrifuge, and the mother solution was extracted with benzene. Benzene and ethyl alcohol were removed from the organic layer by distillation, and the residue was dissolved in benzene and washed with water. The resulting benzene solution was dried with anhydrous calcium sulfate and the solids were removed from the dried solution by filtration. Distillation of benzene from the benzene solution gave 107.8 g of a viscous liquid of 2,6,10,15,19,23-hexamethyltetracosa-2,6,18,22-tetraene-11,13-diyne-10,15-diol.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8].Cl[CH2:21][CH:22]=[CH:23][CH3:24]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH2:21]([N:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:9]([CH:7]=[O:8])=[C:10]1[C:16]([O:18][CH3:19])=[O:17])[CH:22]=[CH:23][CH3:24]
Reactant: CC=CCCl
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=CCn1c(C)c(C)c(C=O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
2.21 g (0.0199 mole) of potassium tert-butoxide were added to a solution of 3.60 g (0.0199 mole) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 0.36 g (0.0014 mole) of 18-crown-6 in 220 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 45 minutes. 3.60 g (0.0398 mole) of 1-chloro-2-butene (a mixture of cis and trans isomers) was added to the mixture and heated under reflux for 7 hours. 1.80 g (0.0199 mole) of 1-chloro-2-butene were then added thereto and heated under reflux for 22 hours. The reaction mixture was allowed to cool to room temperature, subsequently ice-water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel using a 95:5 mixture of toluene and ethyl acetate as an eluent to give 4.50 g (0.0192 mole) of methyl 1-(2-butenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate (cis/trans =24/76) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>C(OCC)C>[C:1]1([C:7]#[C:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC#Cc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
25 g of 3-phenyl-2-propyn-1-ol and 40 g of toluene-4-sulfonic acid chloride are dissolved in 500 ml of diethyl ether and cooled to −20° C. 26.6 g of finely powdered potassium hydroxide are added in portions to that solution, over a period of 20 minutes, in such a manner that the internal temperature of the reaction mixture does not exceed −5° C. When the addition is complete, the reaction mixture is stirred for 2 hours at from 0 to 5° C. and then introduced into one litre of ice-water. Extraction is carried out twice using one litre of diethyl ether each time. The organic phases are washed once with 500 ml of saturated sodium chloride solution, combined, dried over sodium sulfate and concentrated, yielding toluene-4-sulfonic acid (3-phenyl-2-propyn-1-yl) ester in the form of a colourless resin.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:28][CH3:29])=[C:8]([C:14]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3C)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2]1.BrC1C(OC)=C(C(CS(C2C=CC=C([Cl:52])C=2)(=O)=O)=CC=1)C(OCC)=O.O1C=CC(B(O)O)=C1>>[Cl:52][C:23]1[CH:22]=[C:21]([S:18]([CH2:17][C:14]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:28][CH3:29])[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:16][CH:15]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(-c2ccoc2)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Agent: OB(O)c1ccoc1
Product: CCOC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 28, starting from ethyl 3-bromo-6-(3-chlorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 64) and furan-3-yl boronic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[C:13](=[O:18])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CN1CCNCC1=O
Agent: Cl
Product: CN1CCN(Cc2ccc(Cl)nc2)CC1=O
Yield: 84.1 %

Procedure:
Following General Method B, 6-chloro-pyridine-3-carbaldehyde (500 mg, 3.532 mmol) and 1-methylpiperazine-2-one hydrochloride (559 mg, 3.709 mmol) gave 4-(6-chloro-pyridin-3-ylmethyl)-1-methyl-piperazin-2-one (712 mg, 84%) [following SiO2 chromatography, eluting with 0-10% MeOH/dichloromethane]. MS (ESI) m/z 240.1 (M+H)−
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:35][C:36]1[S:37][CH:38]=[C:39]([C:41](=[N:45][O:46][CH3:47])[C:42]([OH:44])=O)[N:40]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:48][C:49]([O:51][CH2:52][C:53]1[CH2:62][S:61][C@@H:56]2[C@H:57]([NH2:60])[C:58](=[O:59])[N:55]2[C:54]=1[C:63]([OH:65])=[O:64])=[O:50].C(O)(=O)C>C(Cl)Cl.C(N(CC)CC)C.C(OCC)(=O)C>[C:49]([O:51][CH2:52][C:53]1[CH2:62][S:61][C@@H:56]2[CH:57]([NH:60][C:42](=[O:44])[C:41]([C:39]3[N:40]=[C:36]([NH:35][C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:37][CH:38]=3)=[N:45][O:46][CH3:47])[C:58](=[O:59])[N:55]2[C:54]=1[C:63]([OH:65])=[O:64])(=[O:50])[CH3:48]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C

Procedure:
0.78 g of dicyclohexylcarbodiimide was added to a solution of the dry acid of Step C in 30 ml of dry methylene chloride and the mixture was stirred for an hour at room temperature and was then vacuum filtered to remove dicyclohexyl urea formed. The filtrate was cooled to -10° C. and a solution of 1.01 g of 7-amino-cephalosporanic acid in 13 ml of methylene chloride and 0.9 ml of triethylamine was added. The temperature returned to room temperature and 1 ml of acetic acid was added thereto. The mixture was vacuum filtered and the filtrate was washed with aqueous hydrochloric acid, dried and concentrated to dryness. The residue was taken up in 10 ml of dioxane and 1 ml of water and 3 ml of a saturated sodium bicarbonate aqueous solution were added thereto. The mixture was stirred and vacuum filtered and the filtrate was washed and evaporated to dryness. The residue was taken up in methylene chloride and the solution was washed with 10 ml of water and 5 ml of N hydrochloric acid. The mixture was decanted and the organic phase was washed with water, dried and effloresced with ether to obtain 1.747 g of raw product. The latter was dissolved in ethyl acetate and was crystallized by addition of ether to obtain 1.255 g of pure 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-ceph-3-eme-4-carboxylic acid in the syn configuration.
Reaction SMILES: [CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:11](C3C=CC(Cl)=CC=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.C1(C(O)(C)CNC(C2C(C(F)(F)F)=NC(Br)=C([C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=3)N=2)=O)CC1>>[CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:16])[F:17])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:11]([C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F)C1CC1
Reactant: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(Br)nc1C(F)(F)F)C1CC1
Product: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(OCC2CC2)nc1C(F)(F)F)C1CC1

Procedure:
In analogy to example 3 (6-(4-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide) the title compound was prepared by substituting 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide with 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=O)=[CH:19][C:18]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH3:7])[CH3:2].S(Cl)(Cl)=O.[CH3:34][N:35]([CH:37]=O)[CH3:36]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([NH:6][C:8]4[CH:13]=[CH:12][C:11]([CH2:37][N:35]([CH3:34])[CH:36]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:10][CH:9]=4)=[O:28])=[CH:19][C:18]=3[CH:29]=2)=[CH:12][CH:13]=1)[CH3:7])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Solvent: O=S(Cl)Cl
Product: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In DMF (3.5 ml) was dissolved 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.17 g). To the solution was added, under ice-cooling, thionyl chloride (0.08 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25 ml). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.11 g) and triethylamine (0.31 ml) in THF (6.5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/ethanol) to give crude crystals, which were recrystallized from ethanol to give 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 4) (0.14 g) as pale yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:27][NH:28][CH3:29]>C(#N)C.ClCCl>[CH3:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1)[CH3:29]
Reactant: CNC
Reactant: ClCCCn1ncc2ccc(-c3ccsc3)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)CCCn1ncc2ccc(-c3ccsc3)cc21
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole (27.8 mg, 0.10 mmol), potassium iodide (155 mg, 1 mmol), potassium carbonate (130 mg, 1 mmol), and dimethylamine (2M in THF, 0.5 mL, 1 mmol) in acetonitrile (0.5 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (5 mL) and filtered through a small plug of alumina to remove the solids, rinsing with dichloromethane (10 mL). After removal of the solvent in vacuo, flash chromatography (silica gel, 2.5-5% 2M methanolic ammonia in dichloromethane) yielded 1-(3-(N,N-dimethylamino)propyl)-6-(3-thienyl)-1H-indazole (27.2 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[S:7](=[O:9])(=[O:8])[N:6]([CH:13]([S:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:26].[C:27](Cl)(=[O:29])[CH3:28]>C(#N)C>[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[S:7](=[O:9])(=[O:8])[N:6]([CH:13]([S:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:5]2=[O:26])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)C(=O)N(C(Sc1nnn[nH]1)c1ccccc1)S2(=O)=O
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(c1)C(=O)N(C(Sc1nnn[nH]1)c1ccccc1)S2(=O)=O
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A suspension of 0.4 g of 5-amino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin in 25 ml of acetonitrile was treated with 0.08 g (0.001 mol) of acetyl chloride, the mixture was heated under reflux for 30 minutes, treated with an additional drop of acetyl chloride and refluxing continued for another 30 minutes. Evaporation of the mixture to dryness afforded a white foam which was chromatographed on silica gel with 95:5 MDC:ethyl acetate to give 200 mg (43%) of 5-acetylamino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]=[O:18])=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]3[O:23][CH2:22][CH2:21][O:18]3)=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1OC(F)F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(-n2ncc(C#N)c2C2OCCO2)c(Cl)c1OC(F)F

Procedure:
0.6 g (2.0 mmol) 1-(4-chlor-5-difluormethoxy-1-methyl-3pyrazolyl)-5-formyl-4-pyrazol-carbonitrile is dissolved in 30 ml toluene and 0.14 g (2.2 mmol) ethylene glycol and a catalytic amount of p-toluene sulphonic acid are added. The mixture is heated for 2 hours on the water-separator, the cooled solution is washed with sodium chloride solution, and it is then dried and concentrated.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2Cl)[CH3:4].[IH:15]>O>[OH:1][CH2:2][CH:3]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[I:15])[CH3:4]
Reactant: I
Reactant: CC(CO)n1cnc2c(Cl)ncnc21
Solvent: O
Product: CC(CO)n1cnc2c(I)ncnc21
Reaction time: 0.75 h

Procedure:
9-(1-Hydroxy-2-propyl)-6-chloropurine (I, 1.5 g, 7 mmol) was added to hydroiodic acid (15 ml) at -10° with stirring for 45 min. The precipitate was filtered, neutralized with anhydrous sodium acetate at 5°, and washed with a little cold water (3 times). Recrystallization from ethanol/H2O, gave colorless crystals. Yield=0.9 g (42%) mp=193°-194° uv λmax 276 nm (H2O, pH 5.5).