Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl[C:3]([N:22]([CH3:24])[CH3:23])=[N:4][C:5]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:7]=[CH:8][C:9]=1[C:10]#[N:11]>ClCCCl>[Cl:1][C:10]1[N:11]=[C:3]([N:22]([CH3:24])[CH3:23])[N:4]=[C:5]2[N:6]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:7]=[CH:8][C:9]=12
Reactant: CN(C)C(Cl)=Nc1c(C#N)cnn1-c1ccc(S(C)(=O)=O)cc1
Reactant: Cl
Solvent: ClCCCl
Product: CN(C)c1nc(Cl)c2cnn(-c3ccc(S(C)(=O)=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stream of dry hydrogen chloride was passed through a solution of 1-chloro-N′-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-dimethyl-formamidine (0.600 g, 1.70 mmol) in 1,2-dichloroethane (20 mL) for 1 h. The solution was stirred at rt for 3 days. The solvent was removed under reduced pressure and the crude washed several times with dichloromethane. [4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-dimethyl-amine recrystallized in dichloromethane and it was retrieved by filtration as an off-white solid (0.4 g, 67%). Exact mass calculated for C14H14ClN5O2S 351.06, found 352.20 (MH+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=CC=2F)=NOC=1C)=O)C>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2cccc(C)c2)noc1C
Agent: CCOC(=O)c1c(-c2ccccc2F)noc1C
Product: Cc1cccc(-c2noc(C)c2CO)c1
Yield: 75.7 %

Procedure:
As described for example 84d, 5-methyl-3-m-tolyl-isoxazole-4-carboxylic acid ethyl ester (5.1 g, 20.8 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (3.2 g, 77%) which was obtained as a light yellow oil. MS: m/e=262.3 [M+OAc]−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.O>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(OCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)n2)CC1
Temperature: 95 °C
Yield: 95.6 %

Procedure:
To a flask equipped with an N2 inlet adaptor, add 2-(benzyloxy)-6-chloropyridine (1.63 g, 7.42 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.3 g, 7.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (339.5 mg, 371.0 μmol), potassium phosphate (3.94 g, 18.55 mmol), tricyclohexylphosphine (208 mg, 0.742 mmol), water (4 mL) and 1,4-dioxane (40 mL). Flush with N2, then heat the mixture at 95° C. overnight under a nitrogen atmosphere. Filter and concentrate under vacuum to give a residue. Purify via silica gel flash column chromatography using a gradient of 0-30% ethyl acetate in petroleum ether to give the title compound as a white solid (2.6 g, 95.6%). MS (m/z): 367 (M+1).
Reaction SMILES: [OH:1]O.[C:3]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[CH2:16][CH:15]=[CH:14]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)=O>[C:3]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[CH2:16][C:15](=[O:1])[CH2:14]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OO
Reactant: C1=Cc2cccc(-c3ccccc3)c2C1
Solvent: O=CO
Product: O=C1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 53.2 ml of formic acid and 10.5 ml of 30% hydrogen peroxide was heated to 35° C., and 14.5 g (0.075 mole) of 7-phenyl-1H-indene was added dropwise causing the reaction mixture temperature to rise to 41° C. Upon complete addition the reaction mixture was allowed to cool to ambient temperature and was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residual semi-solid which was subjected to steam distillation in the presence of aqueous dilute sulfuric acid. The steam distillates were filtered to give 1.84 of 4-phenyl-2-indanone; m.p. 133°-136° C. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]3[CH2:14][CH:15]4[NH:19][CH:18]([C:5]=3[C:4]=2[C:3]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:16]4.[C:27]1([S:33]([O-:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>ClCCl.C1(C)C=CC=CC=1>[C:27]1([S:33]([C:2]2[CH:10]=[CH:9][C:8]3[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]4[CH2:14][CH:15]5[NH:19][CH:18]([C:5]=4[C:4]=3[C:3]=2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:16]5)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)n1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)n1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Temperature: 115 °C
Yield: 32.5 %

Procedure:
To a mixture of the product of step A (270 mg, 0.64 mmol), sodium benzenesulfinate (211 mg, 1.29 mmol), di-palladium-tris(dibenzylideneacetone) (59 mg, 0.06 mmol), cesium carbonate (314 mg, 0.96 mmol) and xantphos (74 mg, 0.12 mmol) under an argon atmosphere was added anhydrous toluene (4 mL). The mixture was heated at 115° C. overnight, cooled to ambient temperature, diluted with dichloromethane and filtered through celite bed. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-5-isopropyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (100 mg, 38%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.18 (s, 1H), 7.94-7.97 (m, 2H), 7.62 (d, J=8.7 Hz, 1H), 7.43-7.52 (m, 4H), 5.24 (br s, 1H), 4.69 (br s, 1H), 4.46-4.61 (m, 1H), 3.46 (br s, 1H), 2.54 (d, J=15.9 Hz, 1H), 2.25-2.35 (m, 1H), 2.12-2.23 (m, 1H), 1.95 (t, J=9.9 Hz, 1H), 1.56-1.63 (m, 1H), 1.54 (d, J=6.9 Hz, 3H), 1.50 (d, J=6.9 Hz, 3H), 1.33 (s, 9H).
Reaction SMILES: [CH2:1]([C:8]1([NH:14][CH:15]=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCCC.CCOC(C)=O>[O:11]1[CH2:12][CH2:13][C:8]2([CH2:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:15]=[N:14]2)[CH2:9][CH2:10]1
Reactant: O=CNC1(Cc2ccccc2)CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C1=NC2(CCOCC2)Cc2ccccc21

Procedure:
Formamide 19 (1.00 g, 4.57 mmol) from the previous experiment is cyclized according to general procedure C to give the imine 21 as a yellow oil after FC (1:1 hexane/EtOAc, then EtOAc). The yield is 0.38 g (41%). 1H NMR (CDCl3) 8.35(s,1), 7.45-7.30(m,3), 7.16(d,1,J=7.0), 4.05-3.95(m,2), 3.80-3.70(m,2), 2.75(s,2), 1.80-1.60(m,4); 13C NMR (CDCl3) 158.21, 134.50, 131.33, 128.25, 128.05, 127.18, 127.13, 63.72, 53.85, 37.29, 37.13; MS(MW=201.3, EI, eE=70 eV) m/z 201(M+), 200, 186, 170, 156 (base peak), 144, 118, 115, 102, 89, 77, 63, 51, 41.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH3:20])[O:17][N:16]=3)[N:4]2[N:3]=1.[N:21]1([CH:25]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][OH:34])=[N:31][CH:32]=2)[CH3:26])[CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH:25]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][O:34][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]4=[N:12][N:13]=[C:14]([C:15]5[CH:19]=[C:18]([CH3:20])[O:17][N:16]=5)[N:4]4[N:3]=3)=[N:31][CH:32]=2)[CH3:26])[CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: CC(c1ccc(CO)nc1)N1CCC1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C(C)N5CCC5)cn4)nn23)no1

Procedure:
The reaction was carried out as described in Example 1, Step 4 using 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (100 mg, 0.35 mmol) and [5-{1-(azetidin-1-yl)ethyl}pyridin-2-yl]methanol (67 mg, 0.35 mmol) to give, after column chromatography on silica, eluting with 2.5% MeOH/CH2Cl2 containing 1% NH3 solution, the amine (121 mg, 79%) which was recrystallised from CH2Cl2/hexane.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C1COCC1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:19]1[CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCN(c3ccccn3)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OCc1cccc(N2CCN(c3ccccn3)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl]-4-(pyridin-2-yl)piperazine (240 mg) was mixed with THF (2 ml), and a 1 M hydrochloric acid (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3-[4-(pyridin-2-yl)piperazin-1-yl]phenyl}methanol (166 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[C:2]=1[C:14]([OH:16])=[O:15].C(OC(=O)C)(=O)C>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:16][C:14](=[O:15])[C:2]=12)=[O:13]
Reactant: O=C(O)c1cc2ccccc2nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3ccccc3cc21

Procedure:
Following isolation, the formula (LXXXV) quinoline-2,3-dicarboxylic acid is heated to about 70° to 95° C. with an excess of acetic anhydride to yield the formula (LXXXVI) 2,3-quinolinedicarboxylic acid anhydride. A co-solvent such as pyridine or pyridinedimethoxyethane may also be used in this reaction, but is not essential to obtain the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:14]([N:2]([CH3:1])[C:3]([NH:5][CH3:6])=[O:4])(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CNC(=O)NC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N(C)C(=O)NC
Reaction time: 8 h

Procedure:
To a solution of 1,3-dimethylurea in toluene with an appropriate base (e.g., triethylamine) is added an equimolar amount of lauroyl chloride. This is stirred overnight, filtered and concentrated to give the above product.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:31].[OH-].[K+]>CN(C)C=O.O>[C:1]([N:4]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:31])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To a solution of 3-acetylamino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (Example 2, step 1, 900 mg, 2.34 mmol) in dimethylformamide (10 ml) was added sodium hydride (60% w/w dispersion in mineral oil, 94 mg, 2.34 mmol). The mixture was stirred for 0.5 h and then iodomethane (0.22 ml, 3.51 mmol) was added dropwise, and stirring continued for 19 h. The reaction mixture was poured into water (50 ml) and extracted with diethyl ether (100 ml×2). The extracts were washed consecutively with water (50 ml) and brine (50 ml), dried (MgSO4) and solvent removed by evaporation. The residual oil was dissolved in ethanol/water (1:1, 20 ml) and KOH (85% pellets, 264 mg, 4.0 mmol) added. After stirring for 3 h, the mixture was concentrated and the residue partitioned between water (100 ml) and diethyl ether (100 ml). The organic layer was separated and washed consecutively with water (100 ml) and brine (100 m), dried (MgSO4) and solvent removed by evaporation. The residual solids were recrystallized from dichloromethane/hexane to afford 165 mg (63%) of the title compound as a yellow powder. m.p.: 232-235° C.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]([CH3:4])[CH3:3].[Cl:35][C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=1)[O:42][C:9]1[N:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(S(C)(=O)=O)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Analogously to example 1 (i), the reaction of 60 mg of tert-butyl [4-(7-isobutyl-5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 3-chlorophenol gave 65 mg (100%) of the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:10][C:11]([CH2:14]O)=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O.O>ClCCl>[CH2:1]([S:8][C:9]1[S:10][C:11]([CH2:14][Cl:18])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(SCc2ccccc2)s1
Solvent: ClCCl
Solvent: O
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.18 g of 2-benzylsulfanyl-5-hydroxymethyl-thiazole dissolved in 5 ml of dichloromethane, 0.4 ml of thionyl chloride dissolved in 5 ml of dichloromethane are added dropwise at 0° C. to. The reaction mixture is then allowed to warm to room temperature and stirred for 0.5 hour. After the addition of 5 ml of water, the organic phase is washed twice with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent in vacuo, chromatography on silica gel (ether:hexane; 1:4) yields 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 57-61° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:36])=[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.[CH3:37][S:38](Cl)(=[O:40])=[O:39].N1C=CC=CC=1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][S:38]([CH3:37])(=[O:40])=[O:39])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 17 h
Yield: 96.5 %

Procedure:
To a suspension of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dichloromethane (18 parts) cooling at -30° C. are dropwise added methanesulfonyl chloride (6 equivalents) and then pyridine (6 equivalents). The mixture is let stand at 0° to 5° C. for 17 hours. The reaction mixture is diluted with ice-water, the organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated. The residue is crystallized from a mixtue of ethyl acetate and hexane to give 3-methanesulfonyloxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3c). Yield: 96.5%. mp. 151°-152° C. (decomposition).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:22][CH3:23])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([N:6]1[C:5]([C:3]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:4])=[C:10]([OH:11])[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7]1(=[O:21])=[O:20])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:23]
Reactant: Nc1nccs1
Reactant: CCN1C(C(=O)OC)=C(O)c2ccc3ccccc3c2S1(=O)=O
Solvent: Cc1ccccc1C
Product: CCN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O

Procedure:
3.3 gm (0.01 mol) of 2-ethyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 1.5 gm (0.015 mol) of 2-aminothiazole were reacted in 150 ml of xylene analogous to Example 40, yielding 1.0 gm (25% of theory) or 2-ethyl-4-hydroxy-N-(2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 261°-262° C (decomp.), after recrystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH3:20]>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:19][CH3:20])=[CH:4][N:3]=1
Reactant: Nc1cc2[nH]c(=O)ccc2cn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(=O)ccc2cnc(N)cc21
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of (XII) (2.1 g, 13 mmol) in dry DMF (65 mL) was added cesium carbonate (6.4 g, 19.6 mmol), followed by ethyl iodine (1.71 mL, 21.4 mmol), and the mixture was stirred at 60° C. for 4.5 hours. The cooled mixture was filtered, and the filtrate was diluted with ethyl acetate. The solution was washed with brine, dried, and concentrated to give an orange residue that was purified by silica gel chromatography, eluting with 1:1 ethyl acetate: hexanes and then ethyl acetate. Concentration of product fractions gave 7-amino-1-ethyl-1H-[1,6]naphthyridin-2-one (XIII) (1.3 g, 53%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[CH2:4][N:5]([C@@H:13]1[C:21]2[C:16](=[C:17]([C:22](=[NH:25])[NH:23][OH:24])[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:28]([O:30][C:31]1[CH:32]=[C:33]([CH2:40][C:41](O)=O)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH3:29]>>[CH2:28]([O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH2:40][C:41]1[O:24][N:23]=[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH2:15][CH2:14][C@@H:13]3[N:5]([CH2:4][C:3]([N:2]([CH3:1])[CH3:27])=[O:26])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[N:25]=1)[CH3:29]
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Reactant: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C(=N)NO)cccc21
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@@H]4N(CC(=O)N(C)C)C(=O)OC(C)(C)C)no2)cc1OCC

Procedure:
(S)-tert-butyl (4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-(dimethylamino)-2-oxoethyl)carbamate INT-64 was prepared using General Procedure 2, analogously to INT-63, from (S)-tert-butyl (2-(dimethylamino)-2-oxoethyl)(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-62 and 2-(3,4-diethoxyphenyl)acetic acid.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH2:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C(#N)C>[C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH:9][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OOC(C)(N)CC
Reactant: CCN=C=O
Solvent: CC#N
Product: C=CC(=O)OOC(C)(CC)NC(=O)NCC
Reaction time: 24 h
Yield: 60.9 %

Procedure:
To a solution of 15.9 g of ethyl-β-amino-β-ethoxy acrylate in 30 ml of acetonitrile was added 7.1 g of ethyl isocyanate, and the resulting mixture was allowed to stand at room temperature for one day and one night. The acetonitrile was distilled away under reduced pressure. To the residue was added 100 ml of ether and the system then dried over anhydrous sodium sulfate. The ether was distilled away and the residue was distilled under reduced pressure. Thus, 14 g of ethyl-β-ethylureido-β-ethoxy acrylate of a boiling point of 127° to 130° C. was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-:36])C.[K+].O=O.C(O)(=O)C>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][C:22]2[C:21](=[O:36])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13]=2[CH:12]1[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1Cc2c([nH]c3ccccc3c2=O)C1c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
2-benzyloxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (3.63 g, 8.51 mmol) ) (prepared as in Example 10) was dissolved in dry DMF (25 mL). Potassium t-butoxide (2.40 g, 21.4 mmol) was introduced in one portion and the suspension was stirred until a clear solution was obtained. Oxygen gas was then passed through the solution via a syringe needle for 16 h. The reaction was quenched by the addition of glacial acetic acid (1.23 mL, 21.0 mmol) and poured into water (250 mL), which resulted in a precipitate that was collected by filtration. The product was purified by flash chromatography (2-10% MeOH/CHCl3) to yield the product as a red powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Nc1c(Br)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(Br)cc(Br)c1N
Temperature: 25 °C

Procedure:
3,5-Dibromo-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2,4-dibromo-6-nitroaniline (500 mg, 1.69 mmol) and SnCl2 ·2H2O (1.90 g, 8.45 mmol) dissolved in 5 mL ethyl acetate and 2 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming ) to bring the pH to 5. The thick yellow white emulsion was vacuum filtered and the filtrate extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale yellow oil which crystallized on standing to yield 400 mg (89%). 1H NMR (CDCl3) δ3.62 (br s, 4H, 2(NH2)); 6.78 (d, J=1.8, 1H, H-6); 7.01 (d, J=1.8, 1H, H-4).