Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[N:14][NH:13][C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31].N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[N:14][N:13]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Reactant: O=c1cc(CSc2ccc(Cl)cc2)cn[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-n2ncc(CSc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C

Procedure:
To a mixture of 5-((4-chlorophenylthio)methyl)pyridazin-3(2H)-one Part D (60 mg, 0.24 mmol), copper(II) acetate (95 mg, 0.48 mmol), and 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (114 mg, 0.48 mmol) in CH2Cl2 (20 mL) stirring at RT open to air was added pyridine (1.92 mL, 23.74 mmol) in portions over 4 hours. The mixture was poured into 3.0 N aqueous HCl (100 mL) and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated. The crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product). This material was further purified by preparative HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient). The clean fractions were lyophilized using MeCN/H2O (1:1, 10 mL) to obtain the title compound 5-((4-chlorophenylthio)methyl)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridazin-3(2H)-one E-1 (57 mg, 53% yield) as white solid. LC/MS 447 (M+H)+, tR 0.95 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ ppm 7.85 (1H, d, J=2.26 Hz), 7.30 (4H, s), 7.09-7.14 (2H, m), 6.96 (1H, d, J=9.29 Hz), 6.68-6.72 (1H, m), 3.87 (7H, t, J=5.40 Hz), 1.35 (6H, s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:16][CH:15]=1)=[O:13])(=[O:4])=[O:3]
Reactant: Nc1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (0.553 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5-carboxylic acid 3-amino-benzylamide (Example 115, 0.526 mmol) and triethylamine (1.05 mmol) in DCM (20 mL) at 0° C. The mixture is stirred at room temperature for an hour. The reaction mixture is quenched with 5% HCl and extracted with DCM (20 mL). The organic layer is separated, washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to afford 2-(phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide (200 mg) as a solid. MS: 383 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.41 (s, 3H), 4.76-4.72 (m, 2H), 7.00 (bs, N—H), 7.05-7.23 (m, 2H), 7.27-7.60 (m, 5H), 8.40-8.53 (m, 2H), 9.16 (s, 2H).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8])[CH3:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:15]Cl>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:15][CH:6]([C:7](=[O:8])[CH3:9])[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(Cl)cc(Cl)c1)C(C)=O
Yield: 55.3 %

Procedure:
Sodium metal (1.01 g, 44 mmol) was added to ethanol (100 ml) and stirred until all the metal had dissolved. Ethylacetoacetate (15.6 g, 111 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 10 minutes. 3,5-dichlorobenzyl chloride (7.24 g, 40 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the solution was concentrated under reduced pressure. The orange oil was purified by flash chromatography on silica gel eluting with pentane followed by pentane:ethyl acetate (30:1, by volume) to afford the title compound as a colourless oil (6.4 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[CH:3]=1>C(N)C(C)C>[CH3:10][CH:11]([CH3:2])[CH2:6][NH:5][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[CH:3]=1
Reactant: Clc1cc2nnnn2c2cnccc12
Solvent: CC(C)CN
Product: CC(C)CNc1cc2nnnn2c2cnccc12

Procedure:
A suspension of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine (20 g) in isobutylamine (100 mL) was heated at reflux for several hours. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane, washed with water, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from toluene to give a material that was a mixture by thin layer chromatography. The material was purified by flash chromatography, silica gel eluting with dichloromethane, 5-20% ethyl acetate in dichloromethane, and 10% methanol in dichloromethane. The fractions with the slower moving material were concentrated to provide N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine as a solid, m.p. 220-221° C. Analysis: Calculated for C12H14N6: %C, 59.49; %H, 5.82; %N, 34.69. Found: %C, 59.35; %H, 5.89; %N, 34.88.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CCCC(C)C2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCC(C)C2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(3-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [C:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][C:9]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:10]([N:24]2[C@H:27](SCC)[C@@H:26]([C@H:31]([OH:33])[CH3:32])[C:25]2=[O:34])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[S:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[Cl:43]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][C:9]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:10]([N:24]2[C@@H:27]([Cl:43])[C@@H:26]([C@H:31]([OH:33])[CH3:32])[C:25]2=[O:34])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[S:12])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)O)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)O)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a stirred solution of 10 g of 4-nitrobenzyl 3-(4-carboxyphenoxy)-2-(4(R)-ethylthio-3(S)- [1(R)-hydroxyethyl]azetidin-2-on-1-yl)-3-trimethylacetylthiopropenoate in 60 ml of chloroform at -60° C. was added a solution of 192 mmoles of chlorine in 17.8 ml of carbon tetrachloride. After 30 minutes, the reaction mixture was left to warm to room temperature, and the solvent was then removed in vacuo. Chromatography over silica gel using hexane-ethyl acetate-formic acid mixtures afforded 7.3 g of the title compound as a pale yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:3]=1[O:4][C@H:5]1[C@@H:9]([OH:10])[CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:6]1=[O:24].[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:3]=1[O:4][C@H:5]1[C@@H:9]([OH:10])[CH2:8][N:7]([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[C:6]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](O)[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(O[C@@H]2C(=O)N(C3CCNCC3)C[C@@H]2O)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-butyl 4-((3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (80 mg, 0.169 mmol) was dissolved in CH2Cl2 (1 mL) and 4N HCl in dioxane (1 mL) was added and stirred at ambient temperature for 6 hours. The reaction was concentrated to afford crude (3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (80 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[CH2:7]([O:9][C:10](=[O:14])[C@H:11]([CH3:13])[NH2:12])[CH3:8].[OH-].[Na+]>ClC(Cl)C>[CH2:7]([O:9][C:10](=[O:14])[C@H:11]([CH3:13])[NH:12][C:3](=[O:4])[CH2:2][Cl:1])[CH3:8]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@H](C)NC(=O)CCl
Reaction time: 3 h

Procedure:
A solution of 7.2 g (0.064 mole) of chloroacetyl chloride in 20 ml dichloroethane was added dropwise at 0°-5° C. to a rapidly stirred mixture of 10 g (0.064 mole) of the DL-alanine ethyl ester, hydrochloride prepared above and 10.2 g of 50% aqueous sodium hydroxide (0.128 mole) in 80 ml dichloroethane. The mixture was allowed to come to room temperature after addition was complete. After standing 3 hours the product was isolated by washing with 50 ml of saturated salt solution, dried over magnesium sulfate, followed by evaporation of the solvent. The product, 8.0 g was a solid having a m.p. of 43°-47° C. and was identified by nuclear magnetic resonance (NMR) and infrared (IF) spectroscopy analysis as the title compound.
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:20][C:21]([NH2:23])=[S:22]>C(Cl)Cl>[NH2:23][C:21]1[S:22][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:20]=1
Reactant: CCCCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=S
Solvent: ClCCl
Product: CCCCCc1nc(N)sc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
An equimolar mixture (18 mmol) of 2-chloro-1-(4-nitrophenyl)octan-3-one and thiourea is heated at 60° C. for 6 hours. The reaction mixture is taken up in methylene chloride and filtered. After concentration, the filtrate is washed with water which has been rendered basic, and extracted with chloroform to give 3 g of 2-amino-5-(4-nitrobenzyl)-4-pentylthiazole in the form of a brown oil, which is used as such for the next step.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.C(Cl)(=O)C(C)(C)C.C([O:21][C:22](=[O:30])[C@H:23]([CH2:25][CH2:26][C:27](=[O:29])[NH2:28])[NH2:24])(C)(C)C>>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:24][C@H:23]([C:22]([OH:30])=[O:21])[CH2:25][CH2:26][C:27](=[O:29])[NH2:28])=[O:9]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CC(C)(C)C(=O)Cl
Product: NC(=O)CC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)O

Procedure:
A mixed anhydride from L-pyroglutamic acid 9 and pivaloyl chloride was coupled with L-glutamine t-butyl ester 10 followed by acidic workup to yield L-pyroglutamyl-L-glutamine 7 (Equation 2). This dipeptide was purified by reversed phase HPLC using a gradient system of acetonitrile/H2O.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[CH:9]=2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O)(=O)C.Cl>CO>[Cl:17][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[N:3]=[C:2]([NH:1][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=3)[NH:6][N:5]=2)[CH:15]=[C:14]([Cl:16])[C:11]=1[C:12]#[N:13]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1c(Cl)cc(Nc2n[nH]c(NCc3ccc(C(F)(F)F)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a solution of 4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-benzonitrile (60 mg, 223 μmol) in MeOH (3.5 ml) was added 4-(trifluoromethyl)benzaldehyde (46.6 mg, 268 μmol, Aldrich) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (32.2 mg, 349 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and extracted with EtOAc (3×20 ml). The combined organic solution was washed with brine, dried and concentrated in vacuo. Crystallization from DCM afforded a white solid as desired product (55 mg, 57% yield). MS +m/z: 427 (M+H)+
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C1CCCCC1)C.Cl.[CH3:25][CH:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].[Cl:31][C:32]1[S:40][C:39]2[S:38](=[O:42])(=[O:41])[NH:37][C:36](=O)[NH:35][C:34]=2[CH:33]=1>O>[Cl:31][C:32]1[S:40][C:39]2[S:38](=[O:42])(=[O:41])[N:37]=[C:36]([NH:30][CH:26]([CH3:25])[CH:27]([CH3:29])[CH3:28])[NH:35][C:34]=2[CH:33]=1
Reactant: O=C1Nc2cc(Cl)sc2S(=O)(=O)N1
Reactant: CC(C)C(C)N
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C1CCCCC1
Solvent: O
Product: CC(C)C(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 200 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
Phosphorus pentoxide (2.84 g; 20 mmol), N,N-dimethylcyclohexylamine (5 ml, 33 mmol) and 1,2-dimethylpropylamine hydrochloride (2.47 g; 20 mmol) were carefully mixed in a three necked flask equipped with mechanical stirring and condenser with drying tube. The mixture was heated on an oil bath at 200° C. until a homogeneous mass was obtained. Then 6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.2 g; 5 mmol) was added and the mixture was stirred at 240° C. for 45 min. The mixture was allowed to cool to about 100° C., 150 ml of water was added and stirring was continued at ambient temperature for approximately 1 h. The hydrolysed mixture was filtered and the dark precipitate was washed with water and dissolved in boiling ethanol, treated with charcoal, filtered and finally evaporated to dryness. Flash chromatography (ethyl acetate/silica gel) afforded 105 mg (7%) of the pure title compound; m.p. 216°-218° C.; 1H-NMR (DMSO-d6): δ 0.90 (d, 6H, CH(CH3)2), 1.08 (d, 3H, NCHCH3), 1.75 (m, 1H, CH(CH3)2), 3.65 (m, 1H, NHCH), 7.11 (br. s, 2H, 5-H+NH), 10.68 (s, 1H, NH); MS m/e: 307/309 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:42](=[O:44])[CH3:43])=[CH:21][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
The 3-(4-amino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (5.56 g, 11.3 mmol) was dissolved in 100 mL methylene chloride, and triethylamine (2.8 mL) is added. One equivalent of acetyl chloride was added and stirred at room temperature. Additional portions of acetyl chloride were added approximately every 30 min until the starting material was consumed. (A total of 1.5 equivalents of acetyl chloride was used over about 2 hours.) The solvent was removed and replaced with ethyl acetate. The organic solution was washed twice with 5% cold HCl, then once with water, once with saturated potassium carbonate, then once with brine. The solution was dried over anhydrous magnesium sulfate, filtered and the solvent removed. The product was chromatographed with 30% chloroform/ethyl acetate, to yield 5.16 g (85%) of 3-(4-acetylamino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic tert-butyl ester acid as a yellow foam. 1H NMR (CDCl3) 7.73 (1H, d, J=8.42 Hz), 7.6-7.5 (4H, m), 7.5-7.3 (3H, m), 6.9 (1H, d, J=8.6 Hz), 5.85 (1H, d, J=9.52), 5.3-5.1 (2H, m), 4.8-4.6 (1H, m), 3.56 (3H, s), 2.92 (3H, s), 2.7-2.38 (2H, m), 2.14 (3H, s), 1.40 (9H, s).
Reaction SMILES: [N:1]([CH:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C)[CH3:5])=[C:2]=[O:3].[CH2:15](C1CCC(C(O)=O)CC1)CCCC>>[N:1]([CH:4]1[CH2:5][CH2:15][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=[C:2]=[O:3]
Reactant: CCCCCCCCCC(C)N=C=O
Reactant: CCCCCC1CCC(C(=O)O)CC1
Product: CCCCCC1CCC(N=C=O)CC1

Procedure:
The title compound was prepared in a similar manner as described in the preparation of 2-isocyanatoundecane (compound 81, example 17), except commercially available 4-pentylcyclohexanecarboxylic acid was used in the place of 2-methylundecanoic acid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].C(N)CN.ClCC1NC2C=CC=CC=2N=1.[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][N:34]=[C:35]=[S:36]>>[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][NH:34][C:35]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:36]
Reactant: NCCNCc1nc2ccccc2[nH]1
Reactant: CN(C)CCN=C=S
Agent: ClCc1nc2ccccc2[nH]1
Solvent: NCCN
Product: CN(C)CCNC(=S)NCCNCc1nc2ccccc2[nH]1

Procedure:
N-(2-Benzimidazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 2-chloromethylbenzimidazole by the procedure of Example 40, is reacted with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([NH:23][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCC1
Reactant: CCCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCCc1nnc2c(NC3CCCC3)nc3ccccc3n12
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.9 %

Procedure:
A reaction mixture of 4-chloro-1-propyl[1,2,4]triazolo[4,3-a]quinoxaline (1.0 g; 0.004 mole) and cyclopentanamine (1.0 g; 0.012 mole) in 15 ml of DMF was stirred at room temperature for 20 hours. The precipitated solid was filtered, washed with ethanol, and dried affording 0.98 g (82%) of N-cyclopentyl-1-propyl[1,2,4]triazolo[4,3-a]quinoxalin-4-amine having a mp of 186°-188° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20])=[C:13]([CH3:23])[CH:12]=1.[CH2:25]([O:29][C:30]1[CH:31]=[C:32]([C:40]2[NH:44][C:43](=[O:45])[C:42]3([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[N:41]=2)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:26][CH:27]=[CH2:28]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19]([N:48]2[CH2:49][CH2:50][C:42]3([N:41]=[C:40]([C:32]4[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([O:29][CH2:25][CH2:26][CH:27]=[CH2:28])[CH:31]=4)[NH:44][C:43]3=[O:45])[CH2:46][CH2:47]2)(=[O:21])=[O:20])=[C:13]([CH3:23])[CH:12]=1
Reactant: COC(=O)c1ccc(CCS(=O)(=O)Cl)c(C)c1
Reactant: C=CCCOc1cc(C2=NC3(CCNCC3)C(=O)N2)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Triethylamine (1.27 ml, 9.11 mmol) and 4-(2-chlorosulfonyl-ethyl)-3-methyl-benzoic acid methyl ester (1.01 g, 3.65 mmol) were added to a solution of 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (1.40 g, 3.83 mmol) in methylene chloride (35 ml) at 0° C. The mixture was stirred at room temperature for two hours, and then quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 4-{2-[2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid methyl ester (2.10 g). This compound was used in the next reaction without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH:11](O)[CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cccc2ncccc12
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1cccc2ncccc12
Temperature: 0 °C

Procedure:
The alcohol, 1-quinolin-5-yl-ethanol (5.0 g, 28.9 mmol) in chloroform was treated with a dropwise addition of thionyl chloride (5.26 mL, 72.1 mmol) at rt. After 1 h the mixture was cooled to 0° C. and carefully quenched with a sat. solution of NaHCO3 followed by 2M NaOH until the pH was >8. The aqueous layer was extracted with chloroform and the organic fractions were combined, dried over MgSO4, filtered, and freed of solvent. The residue was purified by chromatography on SiO2 eluting with 30% ethyl acetate:hexane. The product, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) was obtained as a clear oil, 4.22 g (76%).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([S:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])[CH2:7][CH3:8])[C:3]([OH:5])=O.[NH2:18][CH:19]1[C:34](=[O:35])[N:21]2[C:22]([C:31]([OH:33])=[O:32])=[C:23]([CH2:26][O:27][C:28](=[O:30])[NH2:29])[CH2:24][S:25][C@H:20]12>>[CH3:1][CH:2]([CH:6]([S:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])[CH2:7][CH3:8])[C:3]([NH:18][CH:19]1[C:34](=[O:35])[N:21]2[C:22]([C:31]([OH:33])=[O:32])=[C:23]([CH2:26][O:27][C:28](=[O:30])[NH2:29])[CH2:24][S:25][C@H:20]12)=[O:5]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CCC(C(C)C(=O)O)S(=O)c1ccc(O)cc1
Product: CCC(C(C)C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)S(=O)c1ccc(O)cc1

Procedure:
540 mg. of 2-methyl-3-(p-hydroxyphenylsulfinyl) pentanoic acid and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 144 mg. of 7-[2-methyl-3-(p-hydroxyphenylsulfinyl)pentanamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid were obtained.