Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C=C(O)C=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of 2-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep about 130° C. for 3 hours in nitrogen atmosphere with distilling 22 ml (0.38 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 64.8 g (yield 76.5%) of 2-ethoxalyloxyethyl methacrylate (bp 84°-125° C./0.4 mmHg).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[O:10][CH2:11][C:12]([OH:14])=[O:13])=[N+:2]=[N-:3].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:13][C:12](=[O:14])[CH2:11][O:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[N:1]=[N+:2]=[N-:3])[CH3:21]
Reactant: CCO
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OCC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CO[C@@H]1CCCC[C@H]1N=[N+]=[N-]
Temperature: 0 °C
Yield: 68 %

Procedure:
A solution of trans-2-(2'-azidocyclohexyloxy)-acetic acid (11.16 g, 56 mmoles) and concentrated sulphuric acid (0.8 ml) in anhydrous ethanol (30 ml) was heated for 3 hours at reflux temperature, then the mixture was poured into ice water (150 ml) and extracted with n-hexane (4×60 ml). The combined hexane phases were dried over MgSO4, filtered and the solvent was evaporated. The crude product was distilled in vacuo (boiling point: 129° C./0.67 mbar), yielding 8.6 g (68%) of the title compound in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[Pd].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:8]
Reactant: COCCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOC(=O)[C@@H](N)Cc1ccccc1
Yield: 91 %

Procedure:
A solution of N-(carbobenzyloxy)-L-phenylalanine 2-methoxy-ethyl ester (4.4 g, 12.3 mmol) in ethanol (75 mL) was treated with palladium on charcoal catalyst (440 mg, 10% Pd on charcoal) as a slurry in ethyl acetate (10 mL). Hydrogen gas was passed through the suspension for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide L-phenylalanine 2-methoxy-ethyl ester as a colourless oil (2.5 g, 92%). 1H-NMR; d (methanol-d4), 7.35-7.20 (5H, m), 4.27 (2H, m), 3.79 (1H, m), 3.57 (2H, m), 3.38 (3H, s), 3.10 (1H, dd), 2.90 (1H, dd) and 1.64 (2H, s).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:9]=[C:10]2[C:17](=[CH:18][CH:19]=1)[C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][NH:11]2.C(N(CC)C(C)C)(C)C.[F:29][C:30]([F:42])([F:41])[CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.[BH4-].[Na+]>CCO>[F:7][C:8]1[CH:9]=[C:10]2[C:17]([C:13]([CH2:14][CH2:15][NH:16][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH2:31][C:30]([F:29])([F:41])[F:42])[CH:34]=3)=[CH:12][NH:11]2)=[CH:18][CH:19]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c2c1
Reaction time: 1 h

Procedure:
Combine 6-fluorotryptamine oxalate (350 mg, 1.3 mmol), N,N-diisopropylethylamine (506 mg, 3.9 mmol), 3-(2,2,2-trifluoroethoxy)benzaldehyde (266 mg, 1.3 mmol), and 4 Å molecular sieves (4 g) in EtOH (30 mL) and reflux for 7 hours. Decant the liquid into a separate flask and treat with NaBH4 (148 mg, 3.9 mmol). Stir 1 hour, concentrate the mixture in vacuo to give a residue. Partition the residue between 25 mL 5 N NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25 mL dichloromethane, combine the organic layers, dry over MgSO4, and concentrate to approximately a 20 mL volume. Chromatograph on silica gel eluting with 1% MeOH in CHCl3 mixed with conc. NH4OH to give the title compound. Combine an EtOAc solution of the title compound with an EtOAc solution of one equivalent of oxalic acid to give a solid, filter, and dry under vacuum to give the oxalate salt of the title compound: ISMS 367 (M+1); Analysis for C9H19ClF4N2O: calcd: C, 55.27; H, 4.42; N, 6.14. found: C, 55.17; H, 4.38; N, 6.09.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7]>CN(C=O)C>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccccc2c1Cl

Procedure:
Phosphorous oxychloride (84.3 g, 0.55 mol) was added to a stirred suspension of 3-nitroquinolin-4-ol (95.0 g, 0.50 mol) in DMF (500 mL), and an exotherm was observed. After the addition was complete, the solution was heated on a steam bath for 15 minutes. The solution was poured over ice to precipitate 4-chloro-3-nitroquinoline. The 4-chloro-3-nitroquinoline was isolated by filtration, washed with water, and pressed dry. The 4-chloro-3-nitroquinoline was dissolved in dichloromethane (1 L) and the solution was dried over magnesium sulfate and filtered. 2-(2-Aminoethoxy)ethanol (60.7 g, 0.6 mol) and triethylamine (104 mL, 0.75 mol) were added to the filtrate. The resulting solution was heated at reflux for 30 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in dilute aqueous hydrochloric acid and filtered. Ammonium hydroxide was added to the filtrate and a yellow solid formed. The solid was isolated by filtration, washed with water, and dried to provide 104.5 g of 2-{2-[(3-nitroquinolin-4-yl)aniino]ethoxy}ethanol as a yellow solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH2:33]([C:37]1[CH:38]=[CH:39][C:40]([C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:44])=[N:41][CH:42]=1)[CH2:34][CH2:35][CH3:36]>>[CH2:33]([C:37]1[CH:38]=[CH:39][C:40]([C:43]([NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)=[O:44])=[N:41][CH:42]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)nc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)nc1
Yield: 80.6 %

Procedure:
The compound of example 649 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 648.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:16]([NH2:18])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH2:16][CH3:17])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: CCN
Solvent: ClCCl
Product: CCNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 97.8 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and ethylamine (2.0 mL, 2.0 M in THF, 4.00 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-ethyl-2-(trifluoromethyl)benzenesulfonamide (0.50 g, 98%) was provided after purification. MS (ESI) m/z 332. HPLC purity 100.0% at 210-370 nm, 9.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:16][O:15][C:13]([CH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:12]1[S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (2RS,5SR)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate (2.27 g, 10.2 mmol) and triethylamine (2.13 ml, 15.3 mmol) in dichloromethane (60 ml) was added at 0° C. toluene-4-sulfonyl chloride (2.32 g, 12.2 mmol). The mixture was stirred at RT for 16 h, evaporated, dissolved in water (50 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried (MgSO4) and evaporated. The crude product was purified by crystallization from diethyl ether/hexane to give the title compound, off-white solid, m.p. 91° C. and MS: m/e=378.3 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=O)[C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:17])=O>>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:17])[C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)c(CC)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nc(C)c(CC)c(Cl)n1

Procedure:
The pyrimidinone from Example 1 2-butyl-5-ethyl-6-methylpyrimidin-4(3H)-one is converted to the title compound upon treatment with phosphoryl chloride as described by Gabriel and Colman (Ber. 1899, 32, 2921) and by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6]([CH:13]=[O:14])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[C:1]([C:3]1[C:7]([S:8][C:9]([F:11])([F:10])[F:12])=[C:6]([CH:13]([OH:14])[C:28]([F:30])([F:29])[F:27])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:24])([F:25])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C(O)C(F)(F)F)c1SC(F)(F)F
Temperature: 0 °C
Reaction time: 21 h
Yield: 46.6 %

Procedure:
The product of Example 3 (2.0 g, 0.0046 mol) was dissolved in anhydrous tetrahydrofuran (10 mL). Trifluoromethyltrimethylsilane (0.8 mL, 0.0055 mol) was added and the reaction cooled to 0° C. Tetrabutylammoniumfluoride (TBAF, 50 μL, cat.) was added. After intervals of 20 minutes, 1.5 hours, and 18 hours, aliquots of TBAF (50 μL) were added at 0° C. followed by warming to room temperature. After 21 hours, more trifluoromethyltrimethylsilane (0.8 mL, 0.0055 mol) was added and the reaction stirred for 5 days. This was poured into 10% hydrochloric acid (100 mL) and washed with diethyl ether (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to an oil. This was purified by silica gel chromatography using an ethyl acetate in hexanes gradient to provide the title compound (1.08 g) as a white solid, m.p. about 106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[C:22]([C:27](O)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:22]3[C:21]([C:20]([F:31])([F:19])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncccc1C(F)(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncccc3C(F)(F)F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=433.2 [M+H]+.
Reaction SMILES: CN(C)C=O.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:25]N1C(=O)CCC1=O>O>[Br:25][C:22]1[CH:21]=[CH:20][C:19]([N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
Into 500 ml of dry dimethylformamide, 50 g (200 mmole) of triphenylamine was dissolved. To the obtained solution, a solution prepared by dissolving 36 g (200 mmole) of N-bromosuccinimide into 100 ml of dry dimethylformamide was added and the obtained solution was stirred at the room temperature for 6 hours. After the reaction was completed, 1 liter of water was added to the reaction mixture and the formed precipitates were separated by filtration. The obtained light yellow solid was washed with water, dried at a reduced pressure and recrystallized from hexane and 38 g (the yield: 59%) of white needle crystals of the subject compound was obtained.
Reaction SMILES: C(OC(NC(=NC(OCC1C=CC=CC=1)=O)SC)=O)C1C=CC=CC=1.O.Br.Br.N1C2=NC=CC([NH:38][C:39](=[O:52])[C:40]3[CH:45]=[CH:44][C:43]([C@H](N)C)=[CH:42][C:41]=3[N+:49]([O-:51])=[O:50])=C2C=N1.C(N(CC)CC)C>CO>[N+:49]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:39]([NH2:38])=[O:52])([O-:51])=[O:50]
Reactant: C[C@@H](N)c1ccc(C(=O)Nc2ccnc3[nH]ncc23)c([N+](=O)[O-])c1
Agent: Br
Agent: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 7.5 h

Procedure:
N,N'-dibenzyloxycarbonyl-S-methylisothiourea (215 mg) was added to a mixture of (R)-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-aminoethyl)-2-nitrobenzamide dihydrobromide monohydrate (224 mg), triethylamine (0.25 ml) and methanol (5 ml) at room temperature, and the mixture was stirred at room temperature for 14 hours and at 40° C. for 7.5 hours. After the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 166 mg of (R)-N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-(1-(2',3'-dibenzyloxycarbonyl)guanidinoethyl))-2-nitrobenzamide as a pale-yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH3:20][Mg]Br.C(OCC)C>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]([OH:9])[CH3:20])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (0.793 g, 2.95 mmole) in THF (30 mL) at 0° C., is added a solution of methyl magnesium bromide in diethyl ether (3.0M, 2.0 mL, 0.60 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 30 minutes. The reaction is quenched with NH4Cl(aq) (10 mL), partitioned between ethyl acetate (50 mL) and water (50 mL). Extracted the aqueous layer with ethyl acetate (2×50 mL). The combined organic is washed with brine (3×100 mL), dried over Na2SO4, filtered and concentrated to provide the titled compound as a white solid. The crude product is used for the next step without further purification. Mass [EI+] 286 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1([CH3:34])[CH2:9][S:8][CH:7]2[N:4]([C:5](=[O:20])[CH:6]2[NH:10]C(=O)CC2C=CC=CC=2)[CH:3]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22].P(Cl)(Cl)(Cl)(Cl)Cl.CN(C)C1C=CC=CC=1.CO>ClCCl>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:21]([CH:3]2[C:2]([Cl:1])([CH3:34])[CH2:9][S:8][CH:7]3[N:4]2[C:5](=[O:20])[CH:6]3[NH2:10])=[O:22])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: CC1(Cl)CSC2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC1(Cl)CSC2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice cold solution of 3-chloro-3-methyl-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid, p-nitrobenzyl ester (5.04 g, 10 mmoles) in 100 ml of dichloromethane, are added in rapid succession phosphorus pentachloride (3.1 g, 15 mmoles) and N,N-dimethylaniline (1.8 g, 15 mmoles). The mixture is stirred at 0°C. for 15 minutes and at 25°C. for 3 hours, then 30 ml. of absolute methyl alcohol is added and the solution is further stirred for 1 hour. The solvent is flash evaporated. To the residue are added 25 ml. of ethyl acetate and 30 ml. of water and the mixture is stirred thoroughly. The crystalline solid thus obtained is filtered and air dried to give 2.75 g (65.2 per cent yield) of product, which decomposes above 160°C. NMR (DMSO-D6) ppm (δ), 1.74 (s, 3,3-CH3), 3.38 (ABq, δ 0.45 ppm, J 9 cps, 2--CH2), 4.92 (s, 1, 4H), 5.0 (d, 1, 6H), 5.34 (d, 1, 7H), 5.51 (s, 2, CO2CH2 ), 8.05 (ABq, δ 0.525 ppm, J 5 cps, p-NO2 --C6H4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.[ClH:14]>CCO.[Pd]>[ClH:14].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(N)cc1C(=O)O

Procedure:
A slurry of 5-nitro-2-methyl-benzoic acid (17.1 g, 94.4 mmol) and 10% Pd/C (500 mg) in EtOH (500 mL) was shaken under 40 psi H2 at ambient temperature for 4 hours. HCl was added and the solution filtered through a pad of celite. The filtrate was concentrated in vacuo to give the title compound (17.2 g).
Reaction SMILES: COP([CH2:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][NH:14][C:13]=2[N:12]=1)(=O)OC.[CH2:22]([O:24][C:25](=[O:38])[CH2:26][CH:27]([C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[N:35][CH:36]=1)[CH2:28][CH:29]=O)[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:38])[CH2:26][CH:27]([C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[N:35][CH:36]=1)[CH2:28][CH:29]=[CH:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][NH:14][C:13]=2[N:12]=1)[CH3:23]
Reactant: COP(=O)(CC(=O)CCc1ccc2c(n1)NCCC2)OC
Reactant: CCOC(=O)CC(CC=O)c1cnc(C)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC=CC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1
Temperature: 50 °C

Procedure:
To a mixture of 4-10 (100 mg, 0.42 mmol) and 4-6 (160 mg, 0.54 mmol) in DMF (3 mL) was added K2CO3 (87 mg, 0.63 mmol) followed by heating to 50° C. for 18 hours. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 CHCl3/EtOAc/MeOH) to give 4-11 as a clear oil.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>C1C=CC=CC=1>[C:14]([N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]2[CH:1]=[N:2][N:3]=[C:4]2[NH:5]1)(=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)Cl
Reactant: c1ccc2c(c1)NNc1nncn1-2
Solvent: c1ccccc1
Product: CCC(=O)N1Nc2nncn2-c2ccccc21
Yield: 70 %

Procedure:
A mixture of 4.0 g (0.023 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine, 2.2 g (0.023 mole) of propionyl chloride and 50 ml of benzene is refluxed under nitrogen atmosphere. The reaction mixture is cooled and the separated product is filtered off. The title compound, melting at 244° C., is obtained with a yield of 70%. The product does not show melting point depression in admixture with the compound prepared according to Example 4.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:16])[C:12](Br)([CH3:14])[CH3:13]>>[CH3:9][O:10][C:11](=[O:16])[C:12]([CH3:14])([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH3:13]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was alkylated with 2-Bromo-2-methyl-propionic acid methyl ester to provide the title compound: 1H NMR (400 MHz, CDCl3) 1.89 (s, 6H), 3.78 (s, 3H), 7.59 (d, 1H, J=1.7 Hz), 7.89 (s, 1H, J=1.7 Hz); MS 214.1 m/z (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]=4[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:15]3)=[CH:11][CH:10]=2)O1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1OS(C(F)(F)F)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[Pd](Cl)Cl.O.O1CCOCC1>[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:15]2)=[CH:27][CH:28]=1
Reactant: O=S(=O)(Oc1ccccn1)C(F)(F)F
Reactant: COC(=O)c1cccc2ccn(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)c12
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc2ccn(Cc3ccc(-c4ccccn4)cc3)c12
Temperature: 100 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
To methyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1H-indole-7-carboxylate (0.30 g), pyridin-2-yltrifluoromethanesulfonate (0.35 g), tripotassium phosphate (0.49 g), palladium(II) chloride (27 mg), and biphenyl-2-yl(dicyclohexyl)phosphine (0.11 g) were added dioxane (12 mL) and water (3.0 mL), followed by stirring at 100° C. for 4 hours. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=5/1-4/1) to obtain methyl 1-(4-pyridin-2-yl benzyl)-1H-indole-7-carboxylate (0.15 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.Cl.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 2-chloro-5-methoxyaniline hydrochloride (56 mg, 0.288 mmol) similar to Example 76 and isolated as a tan solid (41 mg, 56%). 1H NMR (CDCl3): 9.75 (d, J=1.2 Hz, 1H), 8.79 (dd, J=1.7, 2.6 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.04 (s, 1H), 6.78 (dd, J=2.9, 8.9 Hz, 1H), 3.89 (s, 3H).