Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(CC)CC.S([O-])([O-])(=O)=O.C1C2C(COC([N:28]3[CH2:33][CH2:32][CH:31]([C:34]4[O:38][N:37]=[C:36]([C@@H:39]5[CH2:45][CH2:44][C@@H:43]6[CH2:46][N:40]5[C:41](=[O:52])[N:42]6[O:47][S:48]([OH:51])(=[O:50])=[O:49])[N:35]=4)[CH2:30][CH2:29]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[S:48]([OH:51])([O:47][N:42]1[C:41](=[O:52])[N:40]2[CH2:46][C@H:43]1[CH2:44][CH2:45][C@H:39]2[C:36]1[N:35]=[C:34]([CH:31]2[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]2)[O:38][N:37]=1)(=[O:49])=[O:50]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2nc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)O)no2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCNCC
Product: O=C1N2C[C@@H](CC[C@H]2c2noc(C3CCNCC3)n2)N1OS(=O)(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.1 %

Procedure:
Et2NH (0.5 mL, 5.0 mmol)) was added to a solution of tetrabutylammonium (9H-fluoren-9-yl)methyl 4-(3-((2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate sulfate (84 mg, 0.1 mmol) in dry DCM (10 mL. The mixture was stirred at rt for 12 hrs and the solvents were evaporated under vacuum. The residue was purified by prep-HPLC to afford (2S,5R)-7-oxo-2-(5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-1,6-diaza-bicyclo[3.2.1]octan-6-yl hydrogen sulfate (9.0 mg). ESI-MS (EI+, m/z): 374.15 [M+H]+. 1H NMR (300 MHz, D2O) δ 4.61 (d, J=6.0 Hz, 1H), 4.12 (br s, 1H), 3.50-3.33 (m, 3H), 3.15-3.05 (m, 3H), 2.91 (d, J=12.2 Hz, 1H), 2.35-1.72 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([Cl:13])=[C:10]([Cl:12])[Cl:11].[Br:14]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:14])=[CH:4][C:3]=1[C:9]([Cl:13])=[C:10]([Cl:11])[Cl:12]
Reactant: Cc1ccc(Cl)c(C(Cl)=C(Cl)Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1cc(CBr)ccc1Cl
Yield: 99.4 %

Procedure:
A solution of 4-chloro-3-(trichlorovinyl)toluene (13.77 g) and dibenzoyl peroxide (1.0 g) in 500 ml of benzene was heated at reflux. N-Bromosuccinimide (11.6 g) was added in portions and the resulting mixture stirred at reflux for 1.5 hours (negative KI test). The reaction mixture was concentrated under reduced pressure. The residue was partially dissolved in 300 ml of petroleum ether and the insoluble succinimide removed by filtration. The filtrate was concentrated to give 17.9 g of the benzyl bromide.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl[C:9](Cl)([O:11][C:12](=[O:18])[O:13][C:14](Cl)(Cl)Cl)Cl.C(Cl)Cl.CO>C(Cl)Cl>[NH2:3][CH2:6][CH2:7][CH:9]1[CH2:14][O:13][C:12](=[O:18])[O:11]1
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: NCCC1COC(=O)O1

Procedure:
To a solution of the diol (9 g, 37.66 mmol) in CH2Cl2 (200 mL) was added triethylamine (15.2 g, 151 mmol) at −20˜30° C. under N2. After several minutes, triphosgene (5.5 g, 18.83 mmol) was added to the mixture dropwise at this temperature and stirred at −20˜30° C. for half an hour. Then the mixture was stirred at room temperature for 15 h. TLC (CH2Cl2/MeOH=10:1) showed the starting material was almost consumed. To the mixture was added water and extracted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.CCCCCC.C(OCC)C>[C:29]1([CH2:35][C:36]([NH:38][C:39](=[O:40])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([CH2:22][N:23]5[CH2:26][CH2:25][CH2:24]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (31 mg) in N,N-dimethylformamide (1 ml) was added a solution of 0.25 M 2-phenylacetyl isocyanate in hexane (0.982 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (1.5 ml) and hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (28.0 mg, 63.1%) as white powder.
Reaction SMILES: C([O:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1([NH:17][C:18](=[O:37])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])C1C=CC=CC=1>C(O)C.[Pd].[H][H]>[OH:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1([NH:17][C:18](=[O:37])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)[CH:20]=1)[C:14]([OH:16])=[O:15]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)CCCC2OCc2ccccc2)cc1OCCc1cccc(C)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)NC2(C(=O)O)CCCC2O)cc1OCCc1cccc(C)c1

Procedure:
Diastereomer 1 and diastereomer 2 of the compound of example 66 were separately dissolved in ethanol and hydrogenated with palladium 10% on charcoal at room temperature with 1 bar hydrogen pressure until completion of the reaction. After filtration, the solutions were evaporated to dryness and the residues purified by RP HPLC (water/ACN gradient) to yield the two diastereomers of the title compound separately.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.[NH4+]>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([C:2]2[N:3]=[N:4][C:5]3[C:6]4[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=4[CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1cc2c(nn1)-c1ccccc1CC2
Agent: Cl
Agent: [NH4+]
Product: c1ccc(N2CCN(c3cc4c(nn3)-c3ccccc3CC4)CC2)nc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A mixture of comprising about 0.01 mol of 3-chloro-5,6-dihydrobenzo[h]cinnoline, about 0.05 mol of 1-(pyridin-2-yl)piperazine and about 0.01 mol of ammonium hydrochloride was prepared in about 15 ml of 1-BuOH. The mixture was stirred at 130° C. for 48 h, and then the solvent was removed under reduced pressure. The remaining residue was then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4. Removal of solvent followed by recrystallization from 95% ethanol yielded light yellow crystals, yield 81.1%; HPLC: 96.4% purity; HRMS calculated 343.1791, found 343.1787; 1H NMR (CDCl3): 5 8.452 (d, J=7.5, 1H), 8.232 (s, 1H), 7.211-7.534 (m, 4H), 6.794 (s, 1H), 6.678-6.731 (m, 2H), 3.862 (d, J=4.0, 4H), 3.745 (d, J=4.0, 4H), 2.918 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][OH:22])[C:9]2=[O:23])[CH:7]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[N+:44]([C:41]1[CH:40]=[CH:39][C:38]([O:37][C:35](=[O:36])[O:22][CH2:21][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])([F:24])[C:9]2=[O:23])=[CH:43][CH:42]=1)([O-:46])=[O:45]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(COC(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL round bottom flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-hydroxymethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-IV) (0.397 g, 1.02 mmol) was added 5 mL anhydrous dichloromethane, triethylamine (0.204 g, 2.04 mmol), and 4-nitrophenyl chloroformate (0.246 g, 1.22 mmol). The reaction was allowed to stir overnight at room temperature, affording carbonic acid 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-ylmethyl ester 4-nitro-phenyl ester (VIII), after which 2-aminoethanol (0.186 g, 3.05 mmol) was added and the reaction was allowed to stir for an additional 24 hours. The solvent was removed in vacuo, and the crude residue was purified by column chromatography (silica gel; 1:1 Hex:EtOAc to 4:1 EtOAc:Hex) producing 0.250 g (51%) of the title compound. 1H NMR (CDCl3 400 MHz): δ=7.78 (s,1H), 7.51 (s, 1H), 7.33 (d, 2H, J=7 Hz), 7.22 (d, 1H, J=7 Hz), 6.74 (d, 1H, J=7 Hz), 5.88 (d, 1H, J=12 Hz), 5.83 (d, 1H, J=12 Hz), 3.75 (m, 2H), 3.50 (s, 3H), 3.39 (m, 2H, J=7 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:32])=[C:17]([C@@:19]2([CH3:31])[N:27]=[C:26]([NH2:28])[C:22]3([CH2:25][CH2:24][CH2:23]3)[S:21](=[O:30])(=[O:29])[CH2:20]2)[CH:18]=1>>[NH2:28][C:26]1[C:22]2([CH2:25][CH2:24][CH2:23]2)[S:21](=[O:29])(=[O:30])[CH2:20][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:32])([CH3:31])[N:27]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Yield: 39419.6 %

Procedure:
Prepared from 5-cyanopicolinic acid (33.1 mg, 224 μmol, Eq: 1.2) and (R)-7-(5-amino-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (58 mg, 186 mmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (39 mg, 88.3 mmol, 47.4% yield) as a light yellow foam. MS (ISP): m/z=442.4 [(M+H)+].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][N:8]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:7]1)=[O:5])C.C1NCC2C1CC1C(C#N)=CSC=12>>[C:18]1([CH:16]([N:8]2[CH2:9][CH:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(C(C)c2ccccc2)CC1c1cccs1
Agent: N#Cc1csc2c1CC1CNCC21
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2cccs2)C1

Procedure:
The product from step b), diastereomer 1 (5.8 g, 0.019 mol) was treated by the method outlined in Example 34, step c) to afford the subtitle compound that was used in the next step without further purification. MS calculated for C17H19NO2S +H: 302, observed: 302.
Reaction SMILES: [CH3:1][N:2]([CH2:27][C:28]([OH:30])=O)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[N:13]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[O:11])=[CH:5][N:4]=1.[CH3:31][NH2:32]>>[CH3:1][N:2]([CH2:27][C:28](=[O:30])[NH:32][CH3:31])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[N:13]=[C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:15][C:16]=2[C:17]([F:18])([F:20])[F:19])=[O:11])=[CH:7][CH:8]=1
Reactant: CN(CC(=O)O)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Reactant: CN
Product: CNC(=O)CN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-methylcarbamoylmethyl-amino)-pyridin-3-yl]-amide was prepared from (methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-acetic acid and methyl amine. LCMS calcd for C20H18F3N5O3 (m/e) 433, obsd 434 (M+H).
Reaction SMILES: [O:1]1[C@@H:25]2[C@:2]31[C@H:11]([C@H:12]1[C@:23]([CH3:26])([CH2:24]2)[C@@:15]([O:27][C:28](=[O:30])[CH3:29])([C:16](=[O:22])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1)[CH2:10][CH:9]=[C:8]1[C@:3]3([CH3:35])[CH2:4][CH2:5][C:6]([O:31]C(=O)C)=[CH:7]1.Cl([F:40])(=O)(=O)=O>O1CCOCC1.O.N1C=CC=CC=1>[O:1]1[C@@H:25]2[C@:2]31[C@H:11]([C@H:12]1[C@:23]([CH3:26])([CH2:24]2)[C@@:15]([O:27][C:28](=[O:30])[CH3:29])([C:16](=[O:22])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1)[CH2:10][C@H:9]([F:40])[C:8]1[C@:3]3([CH3:35])[CH2:4][CH2:5][C:6](=[O:31])[CH:7]=1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CC=C4C=C(OC(C)=O)CC[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: -10 °C
Yield: 96.2 %

Procedure:
17,5 g of 9β,11β-epoxy-3,17,21-triacetoxy-pregna 3,5-diene-20-one, prepared as described in Example I were dissolved in a mixture of 200 ml dioxane, 90 ml water, 10 ml pyridine, with the temperature being maintained at -10° C. Next a total quantity of approximately 4 g perchlorylfluoride was introduced at this temperature over a period of 4 hours. The further procedure was as described in Example IX; 16 g 9β,11β-epoxy-6α-fluoro-17α,21-diacetoxy-4-pregnen-3,20-dione were obtained.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([NH2:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1)#[N:2].[CH2:24]([SH:28])[CH2:25][CH2:26][CH3:27]>COCCOCCOC>[NH2:19][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=2)[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([C:1]([S:28][CH2:24][CH2:25][CH2:26][CH3:27])=[NH:2])[CH2:4][CH2:5]2)[N:18]=1
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Reactant: CCCCS
Solvent: COCCOCCOC
Product: CCCCSC(=N)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 6.3 g. (0.02 mole) of 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline in 75 ml. of diethyleneglycol dimethyl ether is added dropwise over 15 minutes a solution of 1.8 g. (0.02 mole) n-butyl mercaptan in 25 ml. of the same solvent. The resulting mixture is stirred at 20°-25° C. for 2 hours, then the solvent is removed in vacuo. The residue is triturated with ethyl ether, filtered and dried to obtain the title compound.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(B([CH2:14][CH3:15])CC)C.Br[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH:20]=[O:21]>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:23]1[CH:22]=[C:19]([CH:18]=[C:17]([CH2:14][CH3:15])[CH:24]=1)[CH:20]=[O:21]
Reactant: O=Cc1cc(Cl)cc(Br)c1
Reactant: CCB(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(Cl)cc(C=O)c1
Yield: 42.9 %

Procedure:
PdCl2(dppf)(37 mg, 0.046 mmol), potassium phosphate (1.93 g, 9.11 mmol) and triethylborane (1M in hexane, 0.45 g, 4.56 mmol) were added to a solution of 3-bromo-5-chloro-benzaldehyde (1.0 g, 4.56 mmol) in THF (20 mL) at ambient temperature and the mixture was refluxed for 12 h. The reaction mixture was brought to ambient temperature, diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 2% EtOAc in petroleum ether to afford the title compound (330 mg, 41%) as a pale yellow liquid: 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.75 (d, J=1.6 Hz 1H), 7.73 (s, 1H), 7.65 (s, 1H), 2.74-2.68 (m, 2H), 1.23 (t, J=7.6 Hz, 3H); ESIMS m/z 168.0 ([M]+); IR (thin film) 3071, 1699, 692 cm−1.
Reaction SMILES: C[NH:2][C:3]([CH3:9])=[CH:4][C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:23][N:2]=[C:3]([CH3:9])[C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CNC(C)=CC(=O)OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1c(C)noc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
Methyl 3-oxobutanoate (29.4 g) was dissolved in methanol (30.0 ml), and a 40%-methylamine-methanol solution (32.0 ml) was added dropwise at room temperature. The mixture was stirred for 1 hour. After the completion of the reaction, the reaction solution as such was concentrated, and then dried using a vacuum pump. Thus, methyl 3-(methylamino)-2-butenoate (31.8 g, yield 97%) was obtained. Subsequently, methyl 3-(methylamino)-2-butenoate (5.38 g) was dissolved in tetrahydrofuran (100 ml), and pyridine (5.0 ml) was added dropwise at room temperature. Under ice cooling, p-chloromethyl benzoyl chloride (8.0 g) was added dropwise and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, distilled water was added, and the product was extracted by liquid separation using ether and then washed with saturated aqueous solution of sodium chloride. The product was dried over sodium sulfate to concentrate and the residue was dried using a vacuum pump. Subsequently, the residue was dissolved in acetic acid (30.0 ml). Hydroxylamine hydrochloride (2.8 g) was added at room temperature, and the mixture was heated under reflux for 1 hour and 30 minutes. After the completion of the reaction, saturated aqueous solution of sodium hydrogencarbonate was added to neutralize the reaction system, and the product was extracted by liquid separation using ether. The resultant organic layer was washed with saturated solution of sodium chloride and dried over sodium sulfate to concentrate. The residue was purified through a column using a hexane-acetone elution system. Thus, methyl 5-[4-(chloromethyl)phenyl]-3-methyl-4-isoxazole carboxylate (5.42 g, yield 49.0%) was obtained.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40].C(OCC)(=O)C>O1CCCC1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C=CS(C)(=O)=O
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCN1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea (0.05 g, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and methylvinylsulfone (0.016 g, 0.15 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at ambient temperature for 16 h. Ethyl acetate (10 mL) was added to the reaction mixture and everything subsequently washed with water. The organic phase was dried over sodium sulfate, filtered and the filtrate evaporated. The residue was subjected to column chromatography (basic silica gel, ethyl acetate) to yield the title compound (0.026 g, 41%) as an off-white solid; MS: m/e=508.8 (M+H+).
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.ClCl.S(Cl)(Cl)(=O)=[O:15]>ClC1C=CC=CC=1>[S:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5](=[O:15])[NH:6]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ccccc1C=NO
Agent: ClCl
Solvent: Clc1ccccc1
Product: O=c1[nH]sc2ccccc12
Yield: 91.1 %

Procedure:
From the monochlorobenzene layer obtained by the same procedures as in Example 1, 2-(methylthio)benzaldehyde oxime was isolated in the same manner as in Example 2. 39.7 g of the oxime isolated was dissolved in 150 g of monochlorobenzene. Then, the oxime was cyclized in the same manner as in Example 1 except that chlorine was changed to 35.3 g (0.26 mol) of sulfuryl chloride. As a result, 32.7 g of 1,2-benzisothiazol-3-one was obtained. The yield against 2-(methylthio)benzaldehyde oxime was 91%.
Reaction SMILES: [BH4-].[Na+].[O:3]=[S:4]1(=[O:36])[CH2:8][CH2:7][C@H:6](/[CH:9]=[CH:10]/[C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]1[CH2:24][CH2:25][CH2:26][C:27]1[S:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:28]=1>CO>[OH:23][CH:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)/[CH:10]=[CH:9]/[C@H:6]1[CH2:7][CH2:8][S:4](=[O:3])(=[O:36])[N:5]1[CH2:24][CH2:25][CH2:26][C:27]1[S:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(CCCN2[C@@H](/C=C/C(=O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CCCN2[C@@H](/C=C/C(O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 8.9 %

Procedure:
Sodium tetrahydridoborate (22 mg, 0.58 mmol) was added to a solution of the enone 12 (268 mg, 0.52 mmol) in MeOH (3.0 mL) at 0° C. The reaction was gradually allowed to warm to room temperature and stirred an additional 5 h. The solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated aqueous ammonium chloride. The organic portion was separated then washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 3:1 EtOAc/hex) afforded 24 mg (9%) of pure alcohol 13.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][CH:10]=[C:11]1[C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Oc1ccccc1S
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Product: CCOC(=O)C(=NOC)C1=CSc2ccccc2O1
Yield: 15.5 %

Procedure:
2-Mercaptophenol (3.5 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (6.2 g.) in a similar manner to that of Example A-(i) to give ethyl 2-(1,4-benzoxathiin-2-yl)-2-methoxyiminoacetate (syn isomer, 1.2 g.), pale yellow crystals, mp. 78° to 80° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:6]=1.[CH3:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[CH:23]=O.CCOCC>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([CH:1]=[CH:23][C:16]2[N:15]([CH3:14])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=2)=[N:6][N:5]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: Cc1nnc(-c2ccccc2Cl)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nnc(-c2ccccc2Cl)s1
Yield: 53.4 %

Procedure:
21 g of 2-methyl-5-(2-chlorophenyl)-1,3,4-thiadiazole and 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 0.5 g of ZnCl2 in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride for 6 hours at reflux temperature. After cooling, ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamide. 18.5 g of product is obtained, corresponding to 53% of the theory. The compound melts at 239° C.