Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.O[CH2:36][CH2:37][CH2:38][N:39]1[C:44](=[O:45])[CH2:43][O:42][CH2:41][C:40]1=[O:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2([O:4][CH3:3])[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:36][CH2:37][CH2:38][N:39]4[C:44](=[O:45])[CH2:43][O:42][CH2:41][C:40]4=[O:46])=[CH:26][CH:27]=3)[N:22]=[CH:21][NH:20]2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C1COCC(=O)N1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(Nc2ccc(Cl)cc2F)NC=Nc2cc(OCCCN3C(=O)COCC3=O)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 18.2 %

Procedure:
Diethyl azodicarboxylate (567 μl, 3.6 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (383 mg, 1.2 mmol), (prepared as described for the starting material in Example 2), 4-(3-hydroxypropyl)-3,5-dioxomorpholine (291 mg, 1.68 mmol) and triphenylphosphine (944 mg, 3.6 mmol) in methylene chloride (10 ml) under nitrogen. The mixture was stirred at ambient temperature for 6 hours and the insolubles were removed by filtration. The filtrate was purified by pouring it directly on to a column of silica and eluting with methylene chloride/acetonitrile/methanol (60/34/6 followed by 60/24/16 and 60/16/24). The semi-purified product was repurified by column chromatography eluting with methylene chloride/acetonitrile/methanol (5/4/1). The purified product was dissolved in methylene chloride/methanol, 2M ethereal hydrogen chloride (1 ml) was added and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-(3,5-dioxomorpholino)propoxy)4methoxyquinazoline hydrochloride (56 mg, 10%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 60.0 g of 2-phenylcyclohexanone in 400 ml of ethanol is stirred and treated with 160 ml of 15% aqueous sodium hydroxide and 53.0 g of benzaldehyde. The resulting solution is stirred at room temperature and the product begins to separate from solution as an oil after 30 minutes. The mixture is seeded with crystalline material and allowed to stand overnight at room temperature. The resulting slurry is poured onto 1.5 liters of ice-water, allowed to stand at room temperature for 2 hours, filtered and washed with cold water. This material weights 81.2 g, melting point 75°-78° C. After crystallization from 200 ml of isopropanol, the product weighs 62.1 g; melting point 85°-87° C. A small sample, recrystallized from ethanol, melts at 86°-88° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CC(C)=O>[Br-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][S+:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CBr)c1ccccc1
Reactant: C1CCSC1
Solvent: CC(C)=O
Product: O=C(C[S+]1CCCC1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
150 Parts of 2-bromoacetophenone was dissolved in 375 parts of acetone, and 66.5 parts of tetrahydrothiophene was added dropwise thereto. After the mixture was stirred at room temperature for 24 hours, white solid obtained was filtered, washed with acetone and then dried to obtain 207.9 parts of 1-(2-oxo-2-phenylethyl)tetrahydrothiophenium bromide in the form of white crystals.
Reaction SMILES: [Si]([C:8]1[N:9]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[C:10]([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[OH:14])=[CH:11][N:12]=1)(C(C)(C)C)(C)C.CC(O)=O.O>C1COCC1.O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:13]([OH:14])[C:10]2[N:9]([S:23]([N:26]([CH3:27])[CH3:28])(=[O:24])=[O:25])[CH:8]=[N:12][CH:11]=2)=[CH:20][CH:19]=1)#[N:22]
Reactant: CN(C)S(=O)(=O)n1c(C(O)c2ccc(C#N)cc2)cnc1[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cncc1C(O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The compound obtained in Step C (4 g, 9.5 mmol) is brought to solution in 40 ml of THF. A mixture of AcOH/H2O (7:3) (40 ml) is then added, and the whole is stirred at room temperature for 2 hours. The reaction mixture is then hydrolysed in a mixture of ice and H2O, extracted with AcOEt and washed with a saturated NaHCO3 solution, and then with a saturated NaCl solution, dried over MgSO4 and concentrated to dryness. The residual solid is then triturated in heptane, and the title product is obtained in the form of white crystals, 2.57 g, in a yield of 89%. IR: 3200 2700 ν(OH); 2230 ν(CN); 1390 and 1152 ν cm−1 (NSO2). NMR (CDCl3): 7.9, s, (1H); 7.75 and 7.55 2d, (4H); 6.55 s (1H); 6.15 d (1H); 3.25d(1H,OH); 3.0,s,(6H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34]([NH:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]([CH3:42])[C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CNCc1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N(C)Cc2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and N-benzyl-N-methylamine the title compound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=442.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].[C:9]1([C:15](Br)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C(C)=CC=CC=1C.ClC1C=CC=CC=1>O>[Cl:1][CH2:2][CH2:3][CH:4]([O:8][C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:5][CH2:6][CH3:7]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(O)CCCl
Solvent: Cc1cccc(C)n1
Solvent: Clc1ccccc1
Solvent: O
Product: CCCC(CCCl)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred solution of 27.3 g. (0.20 moles) of 1-chloro-3-hexanol, 77.6 g. (0.24 moles) of triphenylmethyl bromide, 30,0 g. (0.28 moles of 2,6-lutidine, and 200 ml. of chlorobenzene is heated at 95° C. for 1 hour. The cooled mixture is treated with water, and the organic phase is washed successively with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. Column chromatography of the residue on Florisil affords the subject compound as an oil, ν max. 1600, 1030, and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH:42]([N:45]([CH:49]([CH3:51])[CH3:50])[CH2:46][CH2:47][NH2:48])([CH3:44])[CH3:43]>C(Cl)(Cl)Cl.O>[CH:42]([N:45]([CH:49]([CH3:51])[CH3:50])[CH2:46][CH2:47][NH:48][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:40])([CH3:44])[CH3:43]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN(C(C)C)C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (74 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15](O)=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1.O=S(Cl)[Cl:21]>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([Cl:21])=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Yield: 95.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.557 mmol), SOCl2 (330 mg, 2.78 mmol) and one drop of DMF in toluene (30 mL) was refluxed for 2 h. The mixture was concentrated under vacuum to afford crude 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carbonyl chloride (200 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.F[C:16](F)(F)[C:17](OC(=O)C(F)(F)F)=[O:18]>>[CH3:14][C:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:17](=[O:18])[CH3:16])=[CH:7][CH:6]=2)[N:9]=1
Reactant: CC1=NN(c2ccc(N)cc2)C(=O)C1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)Nc1ccc(N2N=C(C)CC2=O)cc1
Yield: 65 %

Procedure:
Yield: 1.5 g of N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)phenyl)acetamide (65% of theory), oil obtained analogously from 2-(4-aminophenyl)-5-methyl-2,4-dihydro-3-pyrazolone and trifluoroacetic anhydride is N-(4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)trifluoroacetamide from 2-(3-aminophenyl)-5-methyl-2,4-dihydro-3-pyrazolone and trifluoroacetic anhydride is N-(3-(4,5-dihydro-3-methy-5-oxo-1H-pyrazol-1-yl)-phenyl)trifluoroacetamide from 2-(3-aminophenyl)-5-methyl-2,4-dihydro-3-pyrazolone and acetic anhydride is N-(3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-phenyl)acetamide from 5-methyl-2-(4-aminophenyl)-2,4-dihydro-3-pyrazolone (prepared in analogy to Example 10) and acetic anhydride is N-(4-(4,5-dihydro-3-methyl-5-oxo-5H-pyrazol-1-yl)-phenyl)acetamide and by reaction with 2-ethylaniline N-(4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)phenyl)acetamide, m.p.: 230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (161 mg, 0.5 mmol) and 3-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (133 mg, 56%). MS (ISP) 477.1 [(M+H)+]; mp 218–220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5](Cl)=[CH:4][N:3]=1.[OH-].[NH4+:10].O.[NH2:12]N>O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([NH:10][NH2:12])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Clc1cnc(Cl)cn1
Reactant: NN
Agent: [OH-]
Solvent: O
Product: NNc1cnc(Cl)cn1
Yield: 82.5 %

Procedure:
To a mixture of 2,5-dichloropyrazine (CombiPhos, 2.00 g, 13.42 mmol), ammonium hydroxide (5.05 mL, 38.9 mmol), and water (10.0 mL) was added hydrazine hydrate (1.57 mL, 32.2 mmol). The mixture was heated at reflux for about 17 h, cooled in an ice bath for about 15 min, filtered, washed with ice cold water (3×25 mL), and dried in a vacuum oven at about 70° C. to give the title compound (1.60 g, 78%): LC/MS (Table 1, Method h) Rt=1.07 min; MS m/z: 145.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:15])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:14][C:11]1([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:24])([F:25])[F:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C)(Oc2ccccc2C(F)(F)F)CC1
Product: CC1(Oc2ccccc2C(F)(F)F)CCNCC1

Procedure:
To a stirred solution of 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.500 g, 2.32 mmol) in toluene (10 mL) was added 2-hydroxybenzotrifluoride (0.414 g, 2.56 mmol), triphenylphosphine (0.682 g, 2.555 mmol) and diethyl azocarboxylate (0.5 mL, 2.56 mmol). The resulting mixture was stirred at reflux for 18 hours. Toluene was removed in vacuo and the obtained crude product was purified by column chromatography to yield the desired product, 4-methyl-4-(2-trifluoromethyl-phenoxy)piperidine-1-carboxylic acid tert-butyl ester, in 5% yield (0.025 g). 1H NMR (300 MHz, CDCl3) δ 7.57-7.54 (m, 1H), 7.41-7.36 (m, 1H), 7.09 (d, J=7.9 Hz, 1H), 7.02-6.97 (m, 1H), 3.81-3.76 (m, 2H), 3.28 (t, J=11.9 Hz, 2H), 2.15-2.11 (m, 2H), 1.67-1.58 (m, 2H), 1.44 (s, 9H), 1.39 (s, 3H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[N:12]1([C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=2)[C:21]#[N:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:12]1([C:18]2[CH:19]=[C:20]([C:21]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:22]=3)[CH:23]=[CH:24][N:25]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: N#Cc1ccnc(N2CCOCC2)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccnc(N3CCOCC3)c2)sc2ccccc12
Yield: 24.6 %

Procedure:
Methyl thiosalicylate (0.49 g, 2.9 mmol) and 2-morpholinylisonicotinonitrile (0.38 g, 2.0 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.48 ml, 3.4 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol. The obtained crystals were recrystallized from ethyl acetate again to give the titled compound (0.16 g, 25%) as white crystals.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:43]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH2:49])[CH:44]=[CH2:45].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]([NH:49][C@@H:48]([CH2:50][CH:51]([CH3:52])[CH3:53])[C:47]([O:46][CH2:43][CH:44]=[CH2:45])=[O:54])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 20.2 %

Procedure:
Following the procedure as described in Example 24, except using suspension of (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(tert-butoxycarbonylamino)propanoic acid (500 mg, 1.172 mmol), L-leucine allyl ester p-toluenesulfonate salt (411 mg, 1.196 mmol), 1-hydroxy-7-azabenzotriazole (80 mg, 0.586 mmol), CH2Cl2 (40 mL), N-methylmorpholine (0.258 mL, 2.345 mmol), and EDC (247 ing, 1.290 mmol), 137 mg (20.16%) of the title compound is isolated as a white solid. Purification is done by BIOTAGE® Silica gel chromatography on a 90 g Thompson Single Step silica cartridge using a linear gradient from 100% Hexanes to 100% (1:1 EtOAc/Hexanes) over 12 column volumes. LC/MS (Condition A): ret. T=4.50 min, (2M+Na) 1181.97.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: COP(OC)OC
Reactant: Fc1ccccc1CBr
Product: COP(=O)(Cc1ccccc1F)OC

Procedure:
Following the procedure of Compound 11, 2-fluorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:13]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 25.3 %

Procedure:
The title compound (0.03 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-bromomethyl-benzoic acid methyl ester (0.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C22H22ClN3O2, 395.14; found, m/z 396.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.63-7.19 (m, 7H), 7.03-7.02 (m, 2H), 5.27 (s, 2H), 3.15 (s, 2H), 2.79-2.67 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:4][N:3]=1.[F:13][S:14]([O:17][CH3:18])(=[O:16])=[O:15]>>[F:13][S:14]([O-:17])(=[O:16])=[O:15].[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:4][N+:3]=1[CH3:18]
Reactant: CCOC(=O)c1snc(Cl)c1Cl
Reactant: COS(=O)(=O)F
Product: CCOC(=O)c1s[n+](C)c(Cl)c1Cl
Product: O=S(=O)([O-])F
Yield: 99 %

Procedure:
3,4-Dichloro-5-ethoxycarbonylisothiazole (6.0 g, 0.027 mol) and 4 ml of methyl fluorosulfonate were heated at 110° for 1 hr under a nitrogen atmosphere. The solid was washed with ether and benzene to yield 9.0 g (99%) of 3,4-dichloro-2-methyl-5-ethoxycarbonylisothiazolium fluorosulfonate, mp 118-123. Analysis-calcuated for C7H8Cl2FNO5S2 : Cl, 20.84; N, 4.12; S, 18.85. Found Cl, 20.56; N, 4.06; S, 18.89.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1>C1COCC1>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([C:23]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[OH:11])=[O:24])=[CH:26][CH:27]=1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)c2ccc(Cl)nc2)c(O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-Amino-3-hydroxy benzoic acid (0.490 g, 0.0032 mols) and pyridine (0.76 g, 0.0096 mols) in 50 ml dry THF is added 6-chloronicotinoyl chloride (0.56 g, 0.0032 mols) and the solution is stirred under nitrogen atmosphere at RT for 10 hrs and then refluxed for 3 hrs. The reaction mixture is rotary evaporated and the residue is slurried in water and filtered to get the amide (0.8 g) which is taken for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:30]#[CH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:31]#[C:30][CH2:29][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCN1CCCC1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCN4CCCC4)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described above for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and 1-(prop-2-ynyl)pyrrolidine were converted to I-32 (42%): HRMS Calcd. for C27H27N5O3: 470.2192, Found 470.2192.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:18](Cl)(=[O:22])[C:19](Cl)=[O:20].Cl.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C(Cl)Cl>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18](=[O:22])[C:19]([N:35]2[CH2:36][CH2:37][CH:32]([C:29]4[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=4)[CH2:33][CH2:34]2)=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2cc3ccccc3[nH]2)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1cc(C2CCNCC2)ccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2C(=O)C(=O)N2CCC(c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,5-dimethylphenyl)-1H-indole (200 mg in 2 mL dry methylene chloride) was added dropwise 0.083 mL oxalyl chloride and the mixture stirred at room temperature. After 1 hour, 213 mg 1,2,3,4,5,6-hexahydro-[4,4']bipyridinyl dihydrochloride was added followed by 1.5 mL methylene chloride and 0.567 mL triethylamine and the mixture continued stirring at room temperature. After 4 hours the reaction was diluted with ethyl acetate and washed sequentially with water, saturated aqueous ammonium chloride and brine. The organic portion was dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (methylene chloride:methanol, 96:4) to give the title compound (148 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[CH2:10][O:9][B:8]([OH:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:11]2[CH2:10][O:9][B:8]([OH:12])[C:7]=2[CH:6]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: OB1OCc2c1cccc2C(F)(F)F
Product: O=[N+]([O-])c1cc2c(c(C(F)(F)F)c1)COB2O
Temperature: -40 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To 4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXX) (1.17 g, 5.79 mmol) cooled to −40° C. was slowly added HNO3 (10 mL, 99%). The reaction mixture was stirred for 3 h at −40° C. and then slowly quenched with crushed ice. The yellow precipitate was filtered and washed with hexane to produce 6-nitro-4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXXI) as a yellow crystalline solid (950 mg, 3.83 mmol, 66% yield). ESIMS found for C8H5BF3NO4 m/z 246.4 (M−H).