Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([N:26]([CH:28]([C:41]1[CH:46]=[CH:45][N:44]=[C:43]([F:47])[CH:42]=1)[CH:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[CH3:27])=O)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N:50](CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24]1[N:26]([CH3:27])[C:28]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([F:47])[CH:42]=2)=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)[N:50]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C(=O)CCNC(=O)OCc1ccccc1)C(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1c(CCNC(=O)OCc2ccccc2)nc(-c2cccc(C(F)(F)F)c2)c1-c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
Oxalyl chloride (0.34 mL, 3.9 mmol) was added to a solution of dimethyl sulfoxide (0.41 mL, 5.8 mmol) in methylene chloride (10 mL) at −78° C. After 20 min. at −78° C., 3-(benzyloxycarbonyl-amino)-N-[1-(2-fluoro-pyridin4-yl)-2-hydroxy-2-(3-trifluoromethyl-phenyl)ethyl]-N-methyl-propionamide (1.0 g, 1.9 mmol) in methylene chloride (10 mL) was added and the reaction solution was stirred at −78° C. for 2 hrs. Triethylamine (1.3 mL, 9.6 mmol) was added and the cooling bath was removed. The solution was diluted with ethyl acetate (150 mL), washed with aqueous ammonium chloride (75 mL) and brine (75 mL), dried (sodium sulfate), and concentrated. Some non-polar impurities were removed by passing the residue through silica gel, eluting with 50% ethyl acetate in hexane. The ketone was then transferred to a flask containing anhydrous ammonium trifluoroacetate (4 g) using a minimum amount of ether-methylene chloride. The mixture was placed under vacuum to remove the solvent, and then placed in a preheated oil bath (150° C.). Once all solid had melted and efficient stirring was achieved (approx. 10 min.) the formation of the imidazole was found to be complete. The heating bath was removed and the solids were partitioned between ethyl acetate and water (150/50 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated. The product was purified by filtration through silica gel (imidazole is the least polar component) using ethyl acetate to yield 735 mg of a foam.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>C(N(CC)CC)C>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 4.17 g. (0.01 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide is treated with 2 ml. of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol. of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C@H:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:21][OH:22]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.5 g, 7.73 mmol) in EtOH (25 ml) at 0° C. was added triethylamine (1.6 ml, 11.6 mmol) and a solution of (2R)-2amino-2-(4-fluorophenyl)ethanol (prepared according to a procedure in J. Med. Chem. 1999, 42, 4981-5001, 1.2 g, 7.73 mmol). The reaction mixture was stirred at 0° C. for 3 hours. The solvent was removed and the residue was dissolved in EtOAc and was washed with water. The organic layer was concentrated. Flash chromatography on silica gel (20-50% EtOAc in hexanes) gave the title compound as a solid (703 mg, 29%). NMR (CDCl3) 4.00 (m, 2H), 5.50 (m, 1H), 7.07 (m, 2H), 7.38 (m, 2H), 9.04 (s, 1H), 9.10 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[C:5]([O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H][H]>O1CCOCC1.[Ni]>[NH2:22][C:4]1[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:20][CH:21]=2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2N)cc1
Yield: 95.9 %

Procedure:
190.8 g (0.541 mole) of methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate are dissolved in 1.9 l of dioxan. 40 g of Raney nickel catalyst are added and hydrogenation is effected with hydrogen at 20°-25° C. The catalyst is then removed by filtration, the solvent is distilled off and the still warm oily residue is crystallised by stirring it in hexane. The crystalline precipitate is isolated by filtration and dried, affording 167.4 g (96% of theory) of methyl 2-[4-(3-amino-5-chloropyridin-2-yloxy)phenoxy]propionate with a melting point of 92°-94° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][N:13]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:12]1=[O:28].[O:29]=[C:30]1[N:39]([CH:40]2[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]2)[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1>ClCCCl>[CH:25]1([CH2:24][N:13]2[CH2:14][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17][C@@H:11]([NH:10][C:46]([N:43]3[CH2:44][CH2:45][CH:40]([N:39]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:29])[CH2:41][CH2:42]3)=[O:47])[C:12]2=[O:28])[CH2:27][CH2:26]1
Reactant: N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
Diisopropylethylamine (0.16 mL, 0.90 mmol) was added to a solution of (3R,6S)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one (116 mg, 0.45 mmol) and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride (132 mg, 0.45 mmol) in 1,2-dichloroethane (10 mL) and the mixture heated to reflux. After 1 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→5% methanol/dichloromethane) gave the title compound (32 mg). MS 516 (M+1).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:3]2[N:4]([CH:15]=[N:2][N:1]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ncccc1-c1ccccn1
Product: c1ccc(-c2cccn3cnnc23)nc1

Procedure:
A mixture of 1.7 g of 2'-hydrazino-2,3'-bipyridine and 50 ml of triethyl orthoformate was heated on a steam bath for 3 hours. Standing and chilling gave crystals which were collected, washed with hexane and dried, giving 1.5 g of the desired product as cream colored crystals, mp 212°-214° C.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[N:14]=[N:15][C:11]=2[C:10]=1[Cl:22])(=O)=O.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][NH:26][C:25]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Cl:22][C:10]1[C:11]2[N:15]=[N:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:12]=2[CH:20]=[CH:21][C:9]=1[C:8]#[C:7][CH2:6][N:26]1[CH2:27][C:28](=[O:29])[N:24]([CH3:23])[C:25]1=[O:30]
Reactant: CN1C(=O)CNC1=O
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(nnn2CC2CC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1C(=O)CN(CC#Cc2ccc3c(nnn3CC3CC3)c2Cl)C1=O
Temperature: 50 °C

Procedure:
3-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]prop-2-yn-1-yl methanesulfonate (30 mg, 0.088 mmol), 3-methylimidazolidine-2,4-dione (20.15 mg, 0.177 mmol), and potassium carbonate (36.6 mg, 0.265 mmol) were combined in acetonitrile (1 ml) and heated at 50° C. for 24 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic extract was dried with sodium sulfate, filtered, concentrated in vacuo. The residue was purified by silica gel gradient chromatography (0-5% acetone/dichloromethane) to provide the titled compound: 1H NMR (500 MHz, d6-DMSO) δ 7.97 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 4.64 (d, J=7.3 Hz, 2H), 4.53 (s, 2H), 4.13 (s, 2H), 2.88 (s, 3H), 1.42-1.34 (m, 1H), 0.56 (m, 2H), 0.47 (m, 2H) ppm. LRMS m/z (M+H) 358.0 [calculated for C17H17ClN5O2: 358.8].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10]([O:14][C:15]([NH:17][C@H:18]([C:23](O)=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:11][C:10]([O:14][C:15](=[O:16])[NH:17][CH:18]([C:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:24])[CH:19]([CH3:20])[CH2:21][CH3:22])([CH3:13])[CH3:12]
Reactant: NCCc1ccccn1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCCc1ccccn1

Procedure:
The title compound is prepared by the procedure of Example 1, using 1.0 g of 2-(2-amino-ethyl)pyridine, 2.163 g of N-(tert-butoxycarbonyl)-L-isoleucine, 6.15 g of BOP, 10.52 g of Hunig's base, and 15 ml of methylene chloride to give 2.5 g of the product as a white/yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:19]1[CH:35]=[C:23]2[N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:16][O:17][C:19]1[CH:35]=[C:23]2[NH:24][CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1
Reactant: OCc1ccc(Oc2ccc(F)cc2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Product: O=c1nc(OCc2ccc(Oc3ccc(F)cc3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (3-fluoro-4-(4-fluorophenoxyl)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [C:1]([O:4][CH:5](Br)[CH3:6])(=[O:3])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:35]/[O:36][CH3:37])/[C:15]([NH:17][C@@H:18]2[C:33](=[O:34])[N:20]3[C:21]([C:30]([O-:32])=[O:31])=[C:22]([C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:35]/[O:36][CH3:37])/[C:15]([NH:17][C@@H:18]2[C:33](=[O:34])[N:20]3[C:21]([C:30]([O:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:31])=[C:22]([C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Yield: 79.8 %

Procedure:
A solution of (RS)-1-acetoxyethylbromide (267mg) in 1-methyl-2-pyrrolidinone (2ml) was added dropwise, over 1 hour, to an ice cold mixture of sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (190mg) and potassium carbonate (110mg) in 1-methyl-2-pyrrolidinone (1ml). After 15 minutes the mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4), concentrated and flash chromatographed on silica gel eluting with 50,70,80 and 90% ethyl acetate in hexane to give the title compound (172mg); vmax (CHCl3) 3019, 2929, 1786, 1683, 1520, 1376 and 1135cm-1 ; δH (CDCl3, 250MHz) 1.45-1.75 (4H,m), 1.90-2.10 (2H,m), 2.09 and 2.10 (together 3H, 2s), 2.30-2.50 (1H,m), 3.36 and 3.65 (2H, ABq, J 18.8Hz), 4.93-5.10 (2H,m), 5.90-6.05 (1H,m), 6.94 and 7.07 (together 1H,q,J 5.8Hz), 7.10 and 7.15 (together 1H, 2s) and 7.60 and 7.67 (together 1H,2d, J 7.4Hz); [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (562)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:11][C:12]([F:18])([F:17])[C:13]1([NH2:16])[CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:16][C:13]2([C:12]([F:18])([F:17])[F:11])[CH2:15][CH2:14]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: NC1(C(F)(F)F)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(F)(F)F)CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A mixture of 5-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol), 1-(trifluoromethyl)cyclopropanamine (93 mg, 0.74 mmol) (Oakwood, Cat. #: 038175), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (345 mg, 0.780 mmol) and triethylamine (310 μL, 2.2 mmol) in methylene chloride (1 mL) was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (124 mg). LCMS (M+H)+: m/z=309.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][S:7](=[O:15])(=[O:14])[C:8]3[C:9]=2[C:10]=1[CH:11]=[CH:12][CH:13]=3.[H-].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[S:7](=[O:15])(=[O:14])[C:8]3[C:9]=2[C:10]=1[CH:11]=[CH:12][CH:13]=3
Reactant: O=S1(=O)Nc2ccc(Cl)c3cccc1c23
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3c(Cl)ccc(c23)N1CCCN1CC=C(c2ccccc2)CC1
Temperature: 70 °C
Yield: 45.5 %

Procedure:
The experiment is carried out as in Example 18, starting with 5-chloronaphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g), sodium hydride (0.15 in an 80% dispersion in vaseline oil, 1-(3-chloropropyl)-4-phenyl 1,2,3,6-tetrahydropyridine (1.4 g), obtained as in Example 18, and dimethylformamide (30 cc). The reaction mixture is heated for one hour at 70° C., cooled to a temperature of about 20° C. then concentrated to dryness at 20° C. under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is redissolved in dichloromethane (100 cc) and the solution is washed with distilled water (50 cc), dried over magnesium sulphate and concentrated to dryness at 20.C under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by chromatography on a silica column with a mixture of dichloromethane and ethyl acetate (90-10 vol) as eluant, and recrystallized from boiling acetonitrile (30 cc). 5-Chloro-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1 g) is obtained, m.p. 135° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][NH:8]1)=[O:6])[CH3:3].[CH2:13](N(CC)CC)[CH3:14].C(I)C>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[CH2:13][CH3:14])=[O:6])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CN1
Agent: Cl
Solvent: CCI
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H](O)CN1CC

Procedure:
To a suspension of 12 g of (2S,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride obtained in the preceeding para. (1) in 60 ml of chloroform, were added 12.42 g of triethylamine and the combined was added with 17.22 g of ethyl iodide and heat-refluxed for 4 hours. The reaction mixture was after-treated to obtain (2S,4S)2-ethoxycarbonyl-N-ethyl-4-hydroxy pyrrolidine as an oily (product Yield 9.55 g.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)=[O:27])=[N:24][CH:25]=1>CN(C=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:20]4[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)=[O:27])=[N:24][CH:25]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: O=C(NCC1CC1)c1ccc(Cl)cn1
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Yield: 240 %

Procedure:
In a similar fashion (Route 20, GP I; except using DMF instead of DMSO as solvent), 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.20 mmol) and 5-chloro-N-(cyclopropylmethyl)pyridine-2-carboxamide (84 mg, 0.40 mmol) gave the title compound as colourless oil (25 mg, 0.48 mmol, 0.047 mmol, 23%) after purification by preparative HPLC.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:13]#[C:14][NH2:15].[Na].ClN1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11](=[N:15][C:14]#[N:13])[O-:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: N#CN
Reactant: CC(=O)Nc1ccc(N=O)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+]([O-])=NC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.8 %

Procedure:
4-(N-acetylamino)nitrosobenzene (1.64 g, 10.0 mmol) was dissolved in dimethylformamide (20 ml) and treated with monosodium cyanamide (1.0 g, 15.6 mmol). N-chlorosuccinimide (1.33 g, 10.0 mmol) was added and the mixture stirred for 24 hours at ambient temperature. The mixture was poured on ice-water (100 ml) and the precipitate filtered off to give 1.2 g 4-(N-acetylamino)phenyl ONN-azoxycyanide as a yellow powder, m.pt. 240°-242° C. (Yield: 58.8% of theoretical).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=[S:33])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][N:26]=[C:25]([CH3:30])[CH:24]=3)[CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH3:31][N:22]1[C:23]2[C:28](=[CH:27][N:26]=[C:25]([CH3:30])[CH:24]=2)[CH:29]=[C:20]([C:15]2[CH:14]=[C:13]([NH:12][C:11]3[S:33][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)[CH:18]=[CH:17][C:16]=2[CH3:19])[C:21]1=[O:32]
Reactant: Cc1cc2c(cn1)cc(-c1cc(NC(=S)NNC(=O)c3ccccc3)ccc1C)c(=O)n2C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3nnc(-c4ccccc4)s3)ccc1C)c(=O)n2C
Temperature: 130 °C

Procedure:
The mixture of crude 2-benzoyl-N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)hydrazinecarbothioamide 35 and methanesulfonic acid (2 drops) in toluene (1 mL) was heated at 130° C. overnight in a sealed vial. The reaction was evaporated to dryness and the crude residue was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-phenyl-1,3,4-thiadiazol-2-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (H1). MS m/z 440.1 (M+1).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:17]([C:25]([OH:27])=O)[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23].Cl.[NH2:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:16]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:17]([C:25]([NH:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:27])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
39.6 g of DCC are added at 0° C. to a solution of 55 g of Z-Arg-OH, 30.18 g of HCl.H-Gly-OtBu and 24.3 g of HOBt in 400 ml of dimethylformamide. The mixture is left to stir at 0° C. for 1 hour and at room temperature for 3 hours and to stand at room temperature overnight. The DC-urea is filtered off with suction and the filtrate is concentrated. The residue is subjected to countercurrent partition between ethyl acetate and saturated NaHCO3 solution (400 ml each). This results in the required substance precipitating in the first separating funnel after the 3rd stage.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH:14]1([N:20]=[N:21][C:22]2(Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>CO>[CH:22]1([N:21]=[N:20][C:14]2([S:13][C:10]3[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:12][CH:11]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: ClC1(N=NC2CCCCC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(SC2(N=NC3CCCCC3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4.96 grams (.062 moles) of 50% sodium hydroxide in 100 ml of methanol in a 250 ml erlenmeyer flask was added 10.45 grams (.063 moles) of para-(t-butyl)thiophenol and the solution stirred for 15 minutes at room temperature. The solution was cooled to 5° C. and 13.7 grams (.06 moles) of 1-cyclohexylazo-1-chlorocyclohexane (from Example 3-11) was added dropwise over 20 minutes while holding the reaction temperature at 5° to 10° C. with a cold water bath. After the addition was complete the bath was removed and the reaction stirred for an additional 60 minutes at room temperature. A 1.0 gram portion of 50% sodium hydroxide was then added to react with any excess thiophenol, the reaction mixture poured into 300 ml water and the product extracted into 100 ml of pentane. The pentane solution was separated and successively washed with 50 ml portions of water, 10% HCl, water, 5% sodium hydroxide and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid that weighed 14.0 grams (63% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-cyclohexylazo-1-[para-(t-butyl)-thiophenoxy] cyclohexane.