Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH:19]=[C:18]2[O:37][S:39]([CH3:38])(=[O:41])=[O:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 50.6 g (98 mmols) of 7β-phenoxyacetylamino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 500 ml of methylene chloride is cooled to -20° C. and, after adding 14 ml of methanesulphonyl chloride (142 mmols), 22.3 ml (142 mmols) of triethylamine are added slowly. After a reaction period of 1 hour at -15° C. to -20° C. under nitrogen, the solution is washed with water, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, concentrated in a rotary evaporator and dried under a high vacuum. A mixture consisting of 7β-phenoxyacetylamino-3-methanesulphonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 7β-phenoxyacetylamino-3-methanesulphonyloxy-2-cephem-4-carboxylic acid diphenylmethyl ester is obtained; thin layer chromatogram (silica gel; toluene/ethyl acetate, 2:1), 3-cephem derivative Rf=0.39; 2-cephem derivative Rf=0.32.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].Br.Br[CH:14]([C:16]1[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])[CH3:15]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([NH:1][CH:14]([C:16]2[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:22][C:21]3=[O:32])[CH3:15])[CH:3]=1)#[N:6]
Reactant: COc1ccc(C#N)cc1N
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: COc1ccc(C#N)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 52.5 %

Procedure:
3-amino-4-methoxybenzonitrile (121 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-cyano-2-methoxyphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (50 mg, 51%) as a white solid. Mass Spectrum: M+H+ 477.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][C@:42]([CH3:48])([CH:45]([CH3:47])[CH3:46])[CH2:43][OH:44].CCN(C(C)C)C(C)C>C(#N)C>[OH:44][CH2:43][C@@:42]([NH:41][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:48])[CH:45]([CH3:47])[CH3:46]
Reactant: O=C(O)c1cc(OCC2CCC2)c(Cl)cn1
Reactant: CC(C)[C@@](C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@](C)(CO)NC(=O)c1cc(OCC2CCC2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-cyclobutylmethoxy-pyridine-2-carboxylic acid (60 mg, 249 μmol) in acetonitrile (2 mL) was added HATU (123 mg, 324 μmol), (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1, 32.1 mg, 274 μmol) and DIEA (217 μL, 1.25 mmol). The brownish reaction mixture was stirred for 18 h at room temperature. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) and finally chiral chromatography (ChiralPak AD, heptane/ethanol 9:1) to deliver the desired compound (27.3 mg, 43%) as colorless oil. MS (ESI, m/z): 341.1 (MH+).
Reaction SMILES: [CH:1]1([CH:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH:19]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=4)(=[O:42])=[O:41])[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2-Dicyclohexyl-N-((3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)acetamide from Example 53 (101 mg, 0.304 mmol), triethylamine (0.042 mL, 0.304 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.049 mL, 0.304 mmol) were combined in dichloromethane (2 mL). A catalytic amount of N,N-dimethylaminopyridine was added. The reaction was stirred at room temperature for 1 hour, LCMS showed product, and TLC showed no more starting material. The reaction was quenched with aqueous sodium bicarbonate and the aqueous layer was separated. The organic layers was concentrated to give a precipitate. The precipitate was washed with water and ether and dried under a stream of nitrogen to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.49 (d, J=6.3, 1H), 8.34 (s, 1H), 8.19 (d, J=7.9, 1H), 7.93 (d, J=7.8, 1H), 7.73 (t, J=7.8, 1H), 4.46-4.38 (m, 1H), 3.73 (dd, J=3.4, 9.3, 1H), 3.17 (dd, J=2.8, 9.7, 1H), 3.07 (ddd, J=6.4, 12.0, 23.6, 3H), 2.49 (dd, J=8.0, 15.9, 1H), 2.12 (t, J=7.2, 1H), 2.02-1.77 (m, 8H), 1.73 (dd, J=5.3, 9.0, 4H), 1.68-1.58 (m, 3H), 1.52 (ddd, J=3.2, 12.5, 14.7, 1H), 1.43 (ddd, J=3.1, 12.6, 15.0, 1H), 1.37-1.03 (m, 9H); MS (ESI+) m/z 541 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([F:10])([F:9])[CH:4]([OH:8])[CH2:5][CH2:6]I.[N-:13]=[N+:14]=[N-:15].[Na+].O>CS(C)=O>[N:13]([CH2:6][CH2:5][CH:4]([OH:8])[C:3]([F:10])([F:9])[C:2]([F:12])([F:11])[F:1])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: OC(CCI)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCC(O)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
A solution of 1,1,1,2,2-pentafluoro-5-iodo-3-pentanol (1.99 g, 7.48 mmol) in dimethylsulfoxide (20 ml) was treated with sodium azide (585 mg, 8.98 mmol) and the reaction was heated to 50° C. After stirring overnight, the reaction was cooled to room temperature. It was then added to water (30 ml) and extracted with diethyl ether (3×30 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous sodium sulphate. Removal of the solvents yielded an orange liquid. Purification by silica gel chromatography using 1:1 hexanes/ethyl acetate gave the title compound as an orange liquid (1.7 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:36][C:28]([C:27]3[CH:30]=[CH:31][C:24]([N:21]4[CH2:22][CH2:23][O:18][CH2:19][CH2:20]4)=[CH:25][CH:26]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)cc2)[nH]c1-c1ccc(Cl)cc1
Yield: 24.2 %

Procedure:
Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate (200 g), 4-morpholinobenzaldehyde (244.4 g) and ammonium acetate (603 g) were refluxed under heating for 15 hr in acetic acid, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (2 L), and the solution was neutralized with a saturated aqueous hydrogencarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after drying, the solvent was evaporated under reduced pressure and crude crystals were obtained from ethyl acetate. The crude crystals were subjected to silica gel column chromatography to give the objective ethyl 5-(4-chlorophenyl)-2-(4-morpholinophenyl)imidazole-4-carboxylate (78 g), melting point 215° C.
Reaction SMILES: N[C:2](N)=[S:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])CBr.[OH-].[Na+].Cl>C(O)C.C(OCC)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:2][SH:3])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: NC(N)=S
Reactant: COc1ccc(CBr)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CS)cc1Cl
Temperature: 80 °C
Yield: 83 %

Procedure:
Thiourea (3.04 g, 0.04 mol) was added to a solution of 3-chloro-4-methoxybenzyl bromide (4.0 g, 0.02 mol) in ethanol (200 ml) and refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residue was subsequently dissolved in aqueous sodium hydroxide solution (30 g, 0.75 mol in 300 ml water) and heated at 80° C. for one hour. The reaction mixture was cooled with an ice bath and acidified by addition of concentrated hydrochloric acid. The product was isolated by extraction three times into diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, to give the subtitle compound as a colourless oil in 83% yield (3.0 g).
Reaction SMILES: BrCBr.[C:4](Br)(=O)C.[CH3:8]/[C:9](=[CH:12]\[CH2:13][CH:14]1[CH2:18][CH:17]=[C:16]([CH3:19])C1(C)C)/[CH2:10][OH:11].[CH3:22][C:23](OC)([CH3:25])[CH3:24]>C(OCC)C.Cl[Ti](Cl)(Cl)Cl.[Zn]>[CH3:8][C:9]1([CH2:10][OH:11])[CH2:12][CH:13]1[CH2:14][CH:18]1[CH2:17][CH:16]2[C:25]([CH3:4])([CH2:19]2)[C:23]1([CH3:22])[CH3:24]
Reactant: CC1=CCC(C/C=C(\C)CO)C1(C)C
Reactant: CC(=O)Br
Reactant: COC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: BrCBr
Product: CC1(CO)CC1CC1CC2CC2(C)C1(C)C
Reaction time: 7 h
Yield: 55 %

Procedure:
200 g (1.15 mol) of dibromomethane and 1 ml (0.013 mol) of acetyl bromide were added successively to a suspension of 85 g (1.3 mol) of zinc powder and 12 g (83 mmol) of finely ground cuprous bromide in 250 ml of anhydrous diethyl ether. The reaction mixture was stirred until its color changed from grey to black (~30 minutes). After addition of 50 g (0.26 mol) of (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-en-1-ol dissolved in 50 ml of the same solvent (Et2O), in 10 minutes (the exothermic reaction triggers a smooth reflux of ether), and 2 drops of TiCl4, stirring at room temperature was continued for further 7 hours. The reaction mixture was then diluted with 300 ml of MTBE, filtered through Celite, the filtrate washed with 200 ml of ice-cold 0.1N HCl and 3×200 ml of brine, dried (MgSO4), concentrated in vacuo and distilled rapidly (0.1 Torr) to give 39 g of a yellowish oil containing 81% of [1-methyl-2-(1,2,2-trimethyl-bicyclo[3.1.0]hex-3-yl-methyl)cyclopropyl]methanol (yield 55%). Further purification by distillation using a 15 cm Vigreux column under 0.08 Torr afforded 27.4 g (48% yield) of olfactorily pure product. GC purity >91%, b.p. 104-105° C./0.08 Torr. More product could be recovered from 4.5 g of rejected (66% pure) fractions.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[OH:14].N12CCCN=C1CCCCC2>C(O)(C)C.C(Cl)Cl>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: OCCCBr
Solvent: ClCCl
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: OCCCOc1ccc(Cl)cc1Cl
Yield: 105.9 %

Procedure:
A solution of 3-bromopropanol (53.86 g, 0.368 mol) in isopropanol is added dropwise to a mixture of 2,4-dichlorophenol (50 g, 0.307 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (70.05 g, 0.406 mol) in isopropanol at reflux. The reaction mixture is heated at reflux for 3 hours and concentrated in vacuo to obtain a residue. The residue is dissolved in methylene chloride and the organic solution is washed sequentially with 0.5N sodium hydroxide solution, 1M hydrochloric acid and brine, dried over MgSO4 and concentrated in vacuo to obtain an oil which solidifies to give the title product as a white solid (71.9 g, mp 53°-55° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:11]1[C:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH:19]=2)[NH:14][C:13](=O)[C:12]1=[O:22])([CH3:10])([CH3:9])[CH3:8].P(Cl)(OCC)(OCC)=O.[F:32][C:33]1[CH:41]=[CH:40][C:36]([CH2:37][N+:38]#[C-:39])=[CH:35][CH:34]=1>C1COCC1>[C:7]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:39]=[N:38][C:37]([C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)=[C:13]2[C:12]1=[O:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]Cc1ccc(F)cc1
Reactant: CC(C)(C)N1C(=O)C(=O)NC2CCCC=C21
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1c(=O)c2c(-c3ccc(F)cc3)ncn2c2ccccc21
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0 M in THF, 24.1 ml) is added to a mixture of 1-(tert-butyl)-tetrahydroquinoxalin-2,3-dione (XXXI, 5.00 g) and THF (54.0 ml) at -20°. The mixture is allowed to warm to 0° over 30 min. After cooling to -40°, diethyl chlorophosphate (3.53 ml) is added and the solution is allowed to warm to 20°-25° over 40 min. After cooling to -78°, a solution of 4-fluorobenzyl isocyanide (3.62 g) and THF (5.0 ml) is added. Potassium tert-butoxide (24.1 ml) is then added dropwise over several min. The mixture is stirred at -78° for 30 min and is allowed to warm slowly to 20°-25° over 2 hr. Aqueous workup (ethyl acetate, magnesium sulfate) and purification by flash chromatography eluting with ethyl acetate/hexane (1/2), pooling the appropriate fractions and concentration gives the title compound, mp 135°-137°; IR (mineral oil) 2953, 2925, 2855, 1668, 1498, 1299 and 751 cm-1 ; NMR (CDCl3) 8.31, 8.22, 7.63, 7.55, 7.05-7.35 and 1.76 δ; MS (m/z) 335, 279.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:5]([CH3:28])[C:6](=[O:27])[C:7]2[C:8]([N:26]=1)=[C:9]([O:24]C)[C:10]1[C:11](=[O:23])[N:12]([CH3:22])[C:13]([CH2:19][O:20]C)=[N:14][C:15]=1[C:16]=2[O:17]C.CO.[K+].[Br-]>C1C=CC=CC=1>[OH:2][CH2:3][C:4]1[N:5]([CH3:28])[C:6](=[O:27])[C:7]2[C:8]([N:26]=1)=[C:9]([OH:24])[C:10]1[C:11](=[O:23])[N:12]([CH3:22])[C:13]([CH2:19][OH:20])=[N:14][C:15]=1[C:16]=2[OH:17]
Reactant: COCc1nc2c(OC)c3c(=O)n(C)c(COC)nc3c(OC)c2c(=O)n1C
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Product: Cn1c(CO)nc2c(O)c3c(=O)n(C)c(CO)nc3c(O)c2c1=O
Temperature: 25 °C

Procedure:
To 172 mg 10.441 mmol) of 15, suspended in 50 mL of dry benzene, was added an excess of 99% BBr, (up to 10 fold excess). The resulting mixture was refluxed for 7 hours. After cooling the reaction mixture to room temperature, methanol was added to quench the reaction. The solvent was evaporated off in vacuo and the product purified by rinsing successively with water and methanol and then dried: 106.5 mg (72%) yield; dec pt >245° C. IR (KBr pellet) 3384, 1645, 1618, 1443, 1430, 1379, 1325, 1209, 1079, 965, 793 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) 11.86 (2H, s, 5- and 10-hydroxyls), 4.62 (4H, s, methylenes), 3.61 (6H, s, 3- and 8- methyls); mass spectrum (EI model m/z 334 (P+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[N:15]=[C:14]([CH3:16])[O:13][N:12]=1.C(O)(=[O:19])C.OO.[OH2:23]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([CH2:10][C:11]1[N:15]=[C:14]([CH3:16])[O:13][N:12]=1)(=[O:19])=[O:23]
Reactant: CC(=O)O
Reactant: Cc1nc(CSc2cccc(Cl)c2Cl)no1
Reactant: O
Agent: OO
Product: Cc1nc(CS(=O)(=O)c2cccc(Cl)c2Cl)no1
Yield: 38.9 %

Procedure:
3.9 g (14.2 mmol) of 3-(2,3-dichloro-phenylthiomethyl)-5-methyl-1,2,4-oxadiazole are introduced into 50 ml of glacial acetic acid and the mixture is treated with 9.8 ml of 30% strength hydrogen peroxide. The mixture is stirred at reflux temperature until the reaction is complete (approximately 2 hours). The entire batch is then introduced into 200 ml of water, and the crude product which has precipitated is separated off and recrystallised from isopropanol. 1.7 g (38.9% of theory) of 3-(2,3-dichloro-phenylsulphonylmethyl)-5-methyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][Cl:8])([O-:3])=[O:2].[O:12]1[CH:16]2[O:17][CH2:18][CH2:19][N:15]2[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[Cl-:8].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N+:15]12[CH2:19][CH2:18][O:17][CH:16]1[O:12][CH2:13][CH2:14]2)([O-:3])=[O:2]
Reactant: C1CN2CCOC2O1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccc(C[N+]23CCOC2OCC3)c1
Product: [Cl-]
Yield: 66.1 %

Procedure:
A solution of 1.716 g (10 mmol) 3-nitrobenzyl chloride and 1.152 g (10 mmol) tetrahydro-[1,3]oxazolo[2,3-b][1,3]oxazole in 20 ml of chloroform was stirred at the room temperature for 3 days. The precipitate was filtered off, washed twice with dichloromethane and dried. 1.894 g (66.1%) of white amorphous product was obtained, which can be further purified by recrystallisation from rectified ethanol.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:17][OH:18])(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(OS(C)(=O)=O)ccc1OS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step B (13.6 g, 45.9 mmol) in 100 mL of dichloromethane at 0° C. was added triethylamine (12.8 mL, 92.1 mmol), followed by dropwise addition of methanesulfonyl chloride (4.30 mL, 55.6 mmol). After 20 minutes, the solution was concentrated in vacuo, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown solid which was used without further purification.
Reaction SMILES: [C:1]1([CH:6]=[O:7])([CH:4]=[O:5])[CH2:3][CH2:2]1.O.[C:9]1(C)C=CC(S(O)(=O)=O)=C[CH:10]=1.C([O-])([O-])[O:21][CH2:22][CH3:23].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:9]([O:5][CH:4]([O:21][CH2:22][CH3:23])[C:1]1([CH:6]=[O:7])[CH2:3][CH2:2]1)[CH3:10]
Reactant: CCOC([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=CC1(C=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(OCC)C1(C=O)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In toluene (260 ml) was dissolved 1,1-cyclopropane dicarboaldehyde (30 g, 306 mmol). The resulting solution was stirred at 20° C. To the reaction mixture was added dropwise a solution of p-toluenesulfonate monohydrate (153 mg, 0.77 mml) in toluene (10 ml) and the mixture was cooled to the internal temperature of 5° C. or less. A solution of ethyl orthoformate (49.7 g, 335 mmol) in toluene (30 ml) was gradually added dropwise. After completion of the dropwise addition, the mixture was stirred continuously for 1 hour over an ice bath. At the internal temperature elevated to 25° C., stirring was conducted for further 1 hour. After completion of the reaction was confirmed, the internal temperature was adjusted to 15° C., at which 2 mol/l-NaOH (3.75 ml) was added, followed by stirring for 1 hour. Water (50 ml) was added and the mixture was separated and extracted. Toluene was then evaporated under reduced pressure, whereby a colorless oil (55.8 g, stoichiometric) was obtained. Concerning a ratio of the monoacetal compound and the diacetal compound, that of the monoacetal compound was found to be 95% or greater. The instrumental analysis data were similar to those described in Example 1.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[N:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:2].[CH2:14]=[O:15]>ClCCl>[NH3:3].[CH2:1]([N:3]1[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:5][N:6]=[C:7]1[CH2:14][OH:15])[CH3:2]
Reactant: C=O
Reactant: CCn1cnnc1-c1ccncc1
Solvent: ClCCl
Product: CCn1c(CO)nnc1-c1ccncc1
Product: N
Yield: 10 %
Yield: 85 %

Procedure:
A solution of 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine (2.55 g, 14.6 mmol) in 37% formaldehyde (˜12 mL) was stirred at 37° C. for 16 hours. Flash chromatography (10% methanolic ammonia in dichloromethane) yielded title product (2.55 g, 85%, used without further purification to remove remaining para-formaldehyde). 1H NMR (CDCl3) δ (ppm): 8.81 (d, 2H), 7.72 (d, 2H), 5.74 (t, 1H), 4.73 (d, 2H), 4.26 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[CH:12]=[C:13]3[C:20](=[O:21])[NH:19][CH2:18][C:17]([CH3:23])([CH3:22])[N:14]3[C:15]=2[CH:16]=1)=[O:7])C.Cl>CCO.O>[CH3:22][C:17]1([CH3:23])[N:14]2[C:15]3[CH:16]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[CH:10][C:11]=3[CH:12]=[C:13]2[C:20](=[O:21])[NH:19][CH2:18]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)C(C)(C)CNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A 3M aqueous solution of NaOH (0.27 mL) was added to 58 mg (0.20 mmol) of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid ethyl ester in 5 mL of EtOH. After 3 h an additional 0.27 mL of NaOH (3M) was added followed by 1 mL of H2O, and the mixture was heated to 50° C. for 3 h. The mixture was diluted with water, chilled to 0° C., and concentrated HCl was added until the pH reached 2. The resulting suspension was stirred for 1 h at 0° C. then filtered and washed with water. The filter was dried in the vacuum oven at 60° C. overnight to provide 51 mg of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:7][CH:6]=1)[CH3:2].[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Cl)=[N:21][N:20]=1.C(N(CC)CC)C.CN1C(=O)CCC1>O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:22]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([Cl:18])=[N:20][N:21]=3)[CH2:15][CH2:16]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)nc1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(N2CCN(c3nnc(Cl)c4ccccc34)CC2)nc1
Temperature: 25 °C
Yield: 49 %

Procedure:
Combine 6-piperazin-1-yl-nicotinic acid ethyl ester (1.30 g, 5.40 mmol), 1,4-dichlorophthalazine (932 mg, 4.59 mmol), triethylamine (1.78 mL, 13.50 mmol), and NMP (8 mL) and heat to 85° C. for 6 h. Cool to room temperature, dilute with H2O (50 mL) and extract organics with EtOAc (3×50 mL). Combined organic layers are dried over MgSO4 and concentrated. Resulting solid is triturated with EtOAc to give the title compound as a fine tan powder (895 mg, 49% yield).