Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:15][CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:16]([OH:18])=O)[S:9][C:8]=3[C:7]=2[CH:19]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[NH:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C=O)C.C(#N)C>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[N:29]([CH3:30])[C:16]([C:10]1[S:9][C:8]2[C:7]3[CH:19]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=1)=[O:18]
Reactant: CNc1ccccc1Cl
Reactant: N#Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CCO2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCl
Product: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-cyano-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (300 mg) in dichloromethane (10 mL) was added DMF (1 drop) and oxalyl chloride (0.165 mL) and the reaction stirred at room temperature for 30 min. The solvent was then reduced in vacuo and the residue redissolved in acetonitrile (10 mL). To this solution was added 2-chloro-N-methylaniline (0.165 mL) and potassium carbonate (308 mg) and the reaction stirred at room temperature for 16 h. The mixture was partitioned between water (40 mL) and ethyl acetate (30 mL). The organic layer was dried (Na2SO4), reduced in vacuo and purified on silica to give 120. NMR: (CDCl3): 3.08 (t, 2H, CH2, J=5.00 Hz), 3.41 (s, 3H, CH3), 4.29 (t, 2H, CH2, J=5.02 Hz), 6.92 (s, H, ArH), 7.03 (d, H, ArH, J=8.43 Hz), 7.38-7.47 (m, 4H, 4×ArH), 7.57 (m, H, ArH), 7.72 (d, H, ArH, J=1.65 Hz). MS: (ESI+) MH+ 395
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[CH:13][C:14]=1[OH:15])=O.[NH3:16]>>[OH:15][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[C:3]([NH2:16])=[O:2]
Reactant: N
Reactant: COC(=O)c1c(O)ccc2ncccc12
Product: NC(=O)c1c(O)ccc2ncccc12

Procedure:
6-Hydroxy-5-quinolinecarboxylic acid methyl ester is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent to give the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:10][S:11]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])(=[O:13])=[O:12])[C:6]([F:9])([F:8])[F:7])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:22][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[S:11]([NH:10][CH:5]([CH2:4][OH:3])[C:6]([F:8])([F:9])[F:7])(=[O:12])=[O:13]
Reactant: CCOC(=O)C(NS(=O)(=O)c1c(C)cc(C)cc1C)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)NC(CO)C(F)(F)F)c(C)c1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 1.0 g (2.8 mmol) of 3,3,3-trifluoro-2-(2,4,6-trimethylbenzenesulfonylamino)propionic acid ethyl ester in 10 mL of THF was added 255 mg (6.5 mmol) of lithium aluminum hydride. The mixture stirred for 1 hour and was then cautiously quenched with water dropwise. Magnesium sulfate was then added and the mixture was filtered through CELITE® filter aid to afford 690 mg (78%) of 2,4,6-trimethyl-N-(2,2,2-trifluoro-1-hydroxymethylethyl)benzenesulfonamide.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4]1.N1C=CC=CC=1.N1(C2C=CN=CC=2)CCCC1.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C(Cl)Cl>[CH3:1][N:2]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4]1)[C:45](=[O:48])[O:46][CH3:47]
Reactant: CNC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reactant: COC(=O)Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(C)C1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reaction time: 2 h
Yield: 26.4 %

Procedure:
14 Mar. 2011 To a round bottomed flask was added N-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine (0.0999 g, 0.277 mmol), pyridine (0.045 ml, 0.554 mmol), and 4-(pyrrolidin-1-yl)pyridine (0.041 g, 0.277 mmol) to stir at RT in DCM (0.924 ml). Methyl carbonochloridate (0.027 ml, 0.416 mmol) was added and allowed to stir for 2 h. Solvent was evaporated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage 50 g SNAP HP-silica column, eluting with a gradient of 1% to 4% MeOH in CH2Cl2, to provide methyl methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (0.0307 g, 0.073 mmol, 26.5% yield).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:17]([NH:24][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCCCCCN
Product: CCCCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 90° C. and MS: m/e=309 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and heptylamine.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:17][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[C:27]2[C:23]=1[CH2:24][CH2:25][C@H:26]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: Cc1cc(-c2cnn(C)c(=O)c2)cc(C)c1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnn(C)c(=O)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-iodo-3,5-dimethylphenyl)-2-methylpyridazin-3(2H)-one and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 14): tR=1.18 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[CH:14]=[C:13]([C:16]3[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:34]>C(O)(C(F)(F)F)=O>[CH3:24][O:23][C:17]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]3[C:9]4[N:25]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[N:26]=[CH:27][C:8]=4[C:7](=[O:34])[NH:6][C:15]=3[CH:14]=2)=[C:21]([CH3:22])[CH:20]=[CH:19][N:18]=1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)ccnc4OC)cc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCOCC3)c12
Temperature: 65 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg) obtained in Preparation Example 1(5) was dissolved in 1,4-dioxane (4 mL). 3-bromo-2-methoxy-4-methylpyridine obtained in Preparation Example 37 (2) (55.6 mg), Pd(PPh3)4 (10.6 mg), cesium carbonate (179 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for three hours. The reaction mixture was returned to room temperature and then partitioned by adding ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg). The 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg) was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80% to 100%) to give the title compound (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[N+](=[CH2:28])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([O:18][CH3:28])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[CH:25]=1
Reactant: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: COC(=O)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To this solution of 7-chloro-2-[(1-carboxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine under nitrogen, is added with stirring, 50 ml. (0.015 mole) of an ethereal 0.3 molar solution of diazomethane. After 10 minutes the solution is evaporated giving 7-chloro-2-[[1-(methoxycarbonyl)ethylidene]-hydrazino]-5-phenyl-3H-1,4-benzodiazepine is obtained.
Reaction SMILES: C=CC=C.[C:5]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=O)[CH:7]=[CH:6]1>>[CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: C=CC=C
Product: c1ccc2ccccc2c1

Procedure:
The present invention relates to a process for purifying crude anthraquinone (hereinafter referred to as "AQ") obtained by the oxidation, by molecular oxygen in the presence of a basic compound, of an adduct obtained by the Diels-Alder (hereinafter referred to as "DA") reaction of butadiene (hereinafter referred to as "BD") with 1,4-naphthoquinone (hereinafter referred to as "NQ") obtained by a catalytic vapor phase oxidation reaction of naphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:22]1[CH2:24][CH2:23]1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.ClC1C=CC(C(C2CC2)C2C3C(=C(CS(C)=[O:44])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:22]1[CH2:24][CH2:23]1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:44])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3Cl)C3CC3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3Cl)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 65 mg (0.18 mmol) of the compound from Example 229 in analogy to the synthesis of the compound from Example 235. 68 mg (100% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=[O:14])([O-:3])=[O:2].O=S(Cl)Cl.Cl.[CH3:21]O>>[CH3:21][O:14][C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:15]
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-nitro-1H-indazole-3-carboxylic acid 17AP (10.74 g, 51.88 mmol) in MeOH (145 ml) at 0° C. was added SOCl2 (35 ml) dropwise. After stirring for 10 min at 0° C., the reaction mixture was refluxed overnight. HCl gas was evolved (Condenser was equipped with empty balloon to trap HCl). It was then cooled to room temperature, solid was collected by filtration and washed with MeOH to give desired 5-nitro-1H-indazole-3-carboxylic acid methyl ester 18AP (7 g, 61%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[O:13]1[CH2:19][CH:18](O)[CH2:17][O:16][CH2:15][CH2:14]1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:16]1[CH2:17][CH:18]([N:32]([N:23]2[C:22](=[O:21])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:31])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:19][O:13][CH2:14][CH2:15]1
Reactant: OC1COCCOC1
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C1COCCOC1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 92.1 %

Procedure:
DEAD (2.2 M in toluen, 1.55 mL) was added dropwise to a solution of 1,4-dioxepan-6-ol (265 mg), t-butyl (1,3-dioxoisoindolin-2-yl)carbamate (560 mg) obtained in preparation example 14-(1) and triphenylphosphine (840 mg) in THF (10 mL) under ice-cooling over 3 minutes. The reaction mixture was stirred at 0° C. for 6 minutes, and further stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure. After toluene (2.5 mL) was added to the resulting residue, the precipitated solid was removed by filtration. The filtrate was purified by silica gel column chromatography (ethyl acetate/n-heptane, 20%) to give the title compound (713 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24](OC(C)=O)=[O:25].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a suspension of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4-(4H)-one (90 mg, 0.30 mmol) in CH2Cl2 (10 mL) was added Ac2O (0.30 mL, 3.2 mmol) and Et3N (0.60 mL, 4.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, diluted with EtOAc (40 mL), washed with water, 2N NaOH water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography to afford the title compound as a white solid (70 mg, 0.21 mmol, 70%), mp: 177°-180° C. 1H NMR (CDCl3) 8.34 (s, 1H), 7.57 (s, 4H), 7.27 (s, 1H), 6.83 (s, 1H), 6.64 (s, 1H), 6.03 (s, 2H), 3.45 (s, 2H), 2.22 (s, 3H). Anal. calcd. for C18H15N3O4.(1/2)H2O: C, 62.42; H, 4.66; N, 12.13. Found: C, 62.60; H, 4.62; N, 11.57.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:15]([O:14][C:12]([CH2:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)COc1cc(O)cc(CO)c1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1cc(CO)cc(OCC(=O)OCC)c1

Procedure:
The subtitle compound was prepared from the product of step (i) (1.6 g) and ethyl 4-bromobutyrate (1.38 g) by the method of example 21 step (ii). Purified by chromatography eluting with 30% ethyl acetate in toluene. Yield 0.43 g.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:20][CH:21](Br)[CH3:22]>CN(C=O)C>[Br:20][CH2:21][CH2:22][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: CC(Br)Br
Reactant: COc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(OCCBr)ccc2c1
Temperature: 55 °C
Yield: 30.1 %

Procedure:
To a solution of 6-methoxynaphthalen-2-ol (1.07 g, 6.14 mmol) in DMF (4 mL) were added cesium carbonate (3.11 g, 9.55 mmol) and dibromoethane (2.5 mL, 29 mmol). The mixture was stirred and heated at 55° C. for 48 h. The reaction mixture was cooled, filtered, diluted with EtOAc, and washed with brine (2×30 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified using radial chromatography (2:98 to 25:75 EtOAc:Hex) to give the title compound as a white solid (0.52 g, 30%): 1H NMR (400 MHz, CDCl3) δ 3.61 (t, J=6.1 Hz, 2H), 3.82 (s, 3H), 4.30 (t, J=6.4 Hz, 2H), 7.01-7.08 (m, 4H), 7.56 (dd, J=12.0, 9.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)[N:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:21][CH:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:26]([CH2:29][Cl:30])[CH2:27][S:28][C@H:23]12>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([O:33][CH:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:32])=[C:26]([CH2:29][Cl:30])[CH2:27][S:28][C@H:23]23)=[O:10])[N:3]=1
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid (III-1), (2.1 g, 10 mmole) in dry CH2Cl2 (50 ml) was added PCl5 (2.09 g, 10 mmole) at -30° C., and the mixture was stirred for 20 minutes at -15° to -20° C. To the above acid chloride solution was added a solution of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (II) (4.5 g, 10 mmole) in CH2Cl2 (50 ml) containing N,O-bis-(trimethylsilyl)acetamide (10 g, 50 mmole) at -30° C. After stirring at -10° C. for 1 hour, the mixture was concentrated to remove the CH2Cl2 and diluted with ethyl acetate (200 ml). The mixture was washed with 10% aqueous NaHCO3 (2×40 ml), H2O (2×20 ml) and brine (10 ml), successively, and dried over MgSO4. The solvent was evaporated in vacuo and the resulting oily residue (10 g) was dissolved in CHCl3 (20 ml) and chromatographed on a silica gel (Wako gel C-200, 100 g containing 10 ml of 1/1.5M pH 7 phosphate buffer) using 1-3% CH3OH--CHCl3. Fractions containing the title compound were evaporated to give 5.7 g (95%) of IV-1 as a yellow amorphous powder. M.p. >140° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.CC1C2[O:18][CH:17]=[CH:16]C=2C=CC=1.C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[C:7]([S:8][C:17](=[O:18])[CH3:16])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(C)c(S)n1
Reactant: Cc1cccc2ccoc12
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Sc1nc(C)cnc1C

Procedure:
e. 2,5-Dimethyl-3-acetylthio-pyrazine was prepared by acetylating 2,5-dimethyl-3-mercapto-pyrazine [compound (2) a.] with acetic anhydride in an alkaline medium according to the method described in Houben-Weyl, 4th ed., vol. 9, 753 (1955). The product has a m.p. of 36°-42° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:12])([F:13])[F:14])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1C(F)(F)F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 12 h
Yield: 96.5 %

Procedure:
Dissolve 5-chloro-2-(trifluoromethyl)benzoic acid (10 g, 0.044 mol) in MeOH (150 mL). Add thionyl chloride (50 g, 0.421 mol) slowly. Heat the resulting mixture to 70° C., and stir for 12 hours. Concentrate the mixture under reduced pressure. Pour the residue into water (100 mL), and extract the aqueous with EtOAc (2×200 mL). Dry the combined organics over sodium sulfate, and concentrate under reduced pressure to give the title compound (11.5 g, 96.5%) as an oil. 1H NMR (300 MHz, CDCl3,) δ 7.78 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.57 (dd, J=2.1, 8.7 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: Br[C:2]1C=NC(N2C3C(=CC=C(C(OC)=O)C=3)C(SC)=C2)=NC=1.[NH2:23][C:24](=[O:57])[CH2:25][N:26]([CH3:56])[C:27]([C:29]1[CH:37]=[C:36]2[C:32]([C:33]([S:53]([CH3:55])=[O:54])=[CH:34][N:35]2[C:38]2[N:43]=[CH:42][C:41]([C:44]3[CH:49]=[C:48](OC)[CH:47]=[CH:46][C:45]=3[F:52])=[CH:40][N:39]=2)=[CH:31][CH:30]=1)=[O:28].C1C=C(Cl)C=C(C(OO)=O)C=1.Cl.CNCC(OC)=O.FC1C=CC(C)=CC=1C1C=NC(N2C3C(=CC=C(C(N(CC(OC)=O)C)=O)C=3)C(S(C)=O)=C2)=NC=1>>[NH2:23][C:24](=[O:57])[CH2:25][N:26]([CH3:56])[C:27]([C:29]1[CH:37]=[C:36]2[C:32]([C:33]([S:53]([CH3:55])=[O:54])=[CH:34][N:35]2[C:38]2[N:43]=[CH:42][C:41]([C:44]3[CH:49]=[C:48]([CH3:2])[CH:47]=[CH:46][C:45]=3[F:52])=[CH:40][N:39]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: COc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Agent: CNCC(=O)OC
Agent: COC(=O)CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1
Agent: Cl
Product: Cc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1

Procedure:
Methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate and 2-fluoro-5-methylyphenylboronic acid were submitted to a Suzuki reaction as described under 279b). The resulting coupling product was oxidized (m-CPBA) to the corresponding sulfoxide, transformed into its carboxylic acid (LiOH/THF/water) and then reacted with methyl 2-(methylamino)acetate hydrochloride (TBTU). Ester hydrolysis of the product methyl 2-(1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-methyl-3-(methylsulfinyl)-1H-indole-6-carboxamido)acetate, and subsequent reaction with HOBt ammonium salt provided the target compound as white solid. Yield: 0.13 g