Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[CH3:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23].BrCCC1CC1.Br[CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:18]2[C:19]3[C:15](=[CH:14][C:13]([CH3:12])=[CH:21][CH:20]=3)[C:16](=[O:23])[C:17]2=[O:22])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: Cc1ccc2c(c1)C(=O)C(=O)N2C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 5-methylisatin, and (2-bromoethyl)cyclopropane with 1,1′-(bromomethylene)dibenzene, the title compound was obtained (74%) as a bright orange solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.26 (m, 11H), 7.09 (d, 1H), 6.95 (s, 1H), 6.37 (d, 1H), 2.24 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].C(O)(C)(C)C.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>O1CCCC1>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][CH3:14])=[O:12])=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(F)cc1)C(C)=O
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a suspension of potassium tert-butoxide (10.6 g, 95.0 mmol) in tetrahydrofuran (100 mL) were added methyl acetoacetate (10.0 g, 86.0 mmol) and tert-butanol (0.83 mL, 8.6 mmol) at room temperature. The resulting solution was stirred for 1 h, and then 4-fluorobenzylbromide (11.2 mL, 90 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, and then partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×), the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Column chromatography of the residue on silica (5-20% ethyl acetate in hexanes) gave methyl 2-(4-fluorobenzyl)-3-oxobutanoate (14.5 g, 75% yield) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:25])([F:24])[F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:24])([F:23])[F:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(-c4nnn[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 120 °C

Procedure:
A vial equipped with a stir bar was charged with 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.3, Step 1) (67 mg, 0.133 mmol), sodium azide (87 mg, 1.332 mmol), and ammonium chloride (72.0 mg, 1.345 mmol). DMF (1.3 mL) was added, and the mixture was degassed with N2. The vial was then sealed and heated at 120° C. for 16 hours. The reaction was then cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by mass triggered reverse phase HPLC (C-18), eluting with acetonitrile/water containing 0.1% TFA afforded 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine (TFA salt). MS ESI calc'd. for C25H27ClF3N9 [M+H]+ 546. found 546. 1H NMR (600 MHz, CD3OD) δ 8.86 (d, J=1.5, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H), 8.26 (s, 1H), 5.36-5.27 (m, 1H), 3.92 (dd, J=9.0, 14.7 Hz, 1H), 3.87-3.79 (m, 1H), 3.73-3.66 (m, 1H), 3.61 (dd, J=5.5, 14.7 Hz, 1H), 2.48-2.36 (m, 1H), 2.21-2.10 (m, 2H), 2.08-1.98 (m, 1H), 1.45 (dd, J=1.4, 11.7 Hz, 2H), 1.23-1.13 (m, 1H), 1.13-1.04 (m, 1H), 1.02-0.94 (m, 1H), 0.72 (d, J=6.6 Hz, 3H), 0.71-0.56 (m, 3H), 0.57-0.46 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[N:9][CH:8]=1)=[O:6])[CH3:3].[CH2:20](O)CC>>[CH2:2]([O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[N:9][CH:8]=1)=[O:6])[CH2:3][CH3:20]
Reactant: CCOC(=O)c1cncc2[nH]c3ccccc3c12
Reactant: CCCO
Agent: Cl
Product: CCCOC(=O)c1cncc2[nH]c3ccccc3c12

Procedure:
The compound is produced by transesterification of the β-carboline-4-carboxylic acid-ethyl ester-hydrochloride with n-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:14])[CH3:13].[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1.Cl>C(O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:12](=[O:14])[CH3:13])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C1=CCCCC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Temperature: -20 °C

Procedure:
To a mixture of chlorobenzene (1500 g, 13.3 moles) and aluminum chloride (1080 g, 8.1 moles), a mixture of acetyl chloride (473 g, 6.0 moles) and cyclohexene (555 g, 6.8 moles) was dropwise added in about 3 hours while maintaining the temperature at a level of not higher than -20° C. After the dropwise addition, the reaction system was brought to room temperature. After the termination of the generation of hydrogen chloride gas, the reaction mixture was poured into 5 l of 1:1 hydrochloric acid. After separating the organic layer, the aqueous layer was extracted with diethyl ether, and the organic layers thereby obtained were put together and then dried. The solvent was distilled off by an evaporator. The remaining oily substance was distilled under reduced pressure, whereby 1131 g of a fraction having a boiling point of from 120° to 130° C./0.1 mmHg was obtained. To this fraction, 2 l of a 1:1 mixture of methanol and ethanol was added, and the mixture was cooled in a dry ice/methanol bath to obtain crude crystals. The crude crystals were recrystallized from 500 ml of methanol, whereby 165 g of trans-4-(p-chlorophenyl)-1-acetyl-cyclohexane was obtained. The yield was 12%, and the melting point was 74.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Cl)cc2)cc1
Yield: 61.5 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (8 g, 26 mmol) and sodium bicarbonate (4.36 g, 52 mmol) in isopropanol (240 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating the reaction mixture at 75°-80° C. for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (16.2 g) was chromatographed (silica gel, hexane/ethyl acetate, 55/45) to give pure 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (6.7 g, 62%) as a white solid: Anal. Calc'd. for C17H14N2SO3ClF3 : C, 48.75, H, 3.37, N, 6.69. Found: C, 48.56, H, 3.22, N, 6.51.
Reaction SMILES: [NH2:1][N+:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Br:10])[C:3]=1[NH2:11].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH2:25]([O:27][C:28]([C:30]1([CH:33]=O)[CH2:32][CH2:31]1)=[O:29])[CH3:26].[OH-].[K+]>O1CCOCC1.CO>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[N:11]=[C:3]3[C:4]([Br:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[N:2]3[N:1]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(C=O)CC1
Reactant: COc1ccc(Br)c(N)[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C1(c2nc3c(Br)ccc(OC)n3n2)CC1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
1.0 g (2.6 mmol) of crude 2,4,6-Trimethyl-benzenesulfonate 1,2-diamino-3-bromo-6-methoxy-pyridinium (see preparation of compound 311) was dissolved in dioxane (8.5 mL), under argon, and treated with 1-formyl-cyclopropanecarboxylic acid ethyl ester (0.56 g, 3.9 mmol) and heated to 90° C. for 22 hours. The brown solution was cooled to rt and treated with 1N KOH in MeOH (2.6 mL) and left at rt for 6 hours. The solvent was evaporated in vacuo and a NaCl solution was added to the product as well as aq. NaHCO3. The product was extracted with DCM (×3) and the combined organic phases was dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using DCM:EtOAc 96:4->85:15 as eluent. The title compound was obtained as a colourless solid (0.22 g).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[O:28][C:24]=2[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[O:28][C:24]=2[CH:23]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2cc3ccc(Cl)cc3o2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccc(Cl)cc4o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in 1,4-dioxane (1 mL) was added 2-(6-chloro-1-benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, crude), and K3PO4 (140 mg, 0.66 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) under nitrogen atmosphere. After stirring 1 h at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(6-chloro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (60 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[C-]#N.[K+].C[N:18]([CH3:21])C=O.I[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:10]([C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([C:21]#[N:18])=[C:2]([Br:1])[C:3]=1[O:13][CH2:23][CH3:24])(=[O:12])[CH3:11]
Reactant: CCI
Reactant: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1Br
Temperature: 85 °C
Yield: 50.7 %

Procedure:
1-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (2.0 g, 7.5 mmol) was combined with potassium cyanide (0.58 g, 9.0 mmol) in N,N-dimethylformamide (16 mL, 210 mmol) and heated to 85° C. in an oil bath. After heating for 18 hours, the reaction was allowed to cool to room temperature and iodoethane (0.90 mL, 11 mmol) and potassium carbonate (2.1 g, 15 mmol) were added. The reaction was heated to 65° C. and monitored by LC/MS. After heating for 3 hours the reaction was complete and allowed to cool to room temperature, then taken up in ethyl acetate and washed with water, brine, and dried over magnesium sulfate. The resultant solution was concentrated to give the crude product as a dark oil. The product was purified by flash column chromatography on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (1.15 gm, 50%) as a solid residue, LCMS calculated for C1iH9BrClNO2(M+H)+: m/z=301.9, 303.9; found: (no ionization)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C=O)C>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(C=O)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Mix 4-hydroxybenzaldehyde (1.23 g, 10.1 mmol), imidazole (1.37 g, 20.2 mmol), and triisopropylsilyl chloride (2.60 mL, 12.1 mmol) in DMF (10 mL) and stir at room temperature for 2 hours. Quench the reaction with saturated aqueous NH4Cl (50 mL) and extract with EtOAc (3×100 mL). Wash the organic layers with H2O and brine (50 mL each). Combine the organic layers, dry over MgSO4, concentrate and purify by flash chromatography, eluting with 2.5% Et2O/hexanes to afford 4-triisopropylsilyloxybenzaldehyde (2.78 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:26]([OH:29])[OH:27])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 30 (15.00 g, 0.047 mol) in anhydrous THF (150 ml), n-butyllithium (20 ml, 2.5M in hexane, 0.050 mol), trimethyl borate (9.79 g, 0.094 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: C([C:3]([CH2:8][OH:9])([CH2:6]O)CC)O.[CH2:10]([O:14][CH2:15][CH:16]1O[CH2:17]1)[CH:11]1[O:13][CH2:12]1.OC1[CH:25]=[CH:24][C:23]([C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)([CH3:28])[CH3:27])=CC=1>>[CH3:28][C:26]([C:23]1[CH:17]=[CH:16][C:15]([O:14][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:6][CH:3]2[O:9][CH2:8]2)=[CH:33][CH:34]=1)[CH3:27]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCC(CO)(CO)CO
Reactant: C(OCC1CO1)C1CO1
Product: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1

Procedure:
Trimethylolpropane (TMP) used in the epoxy hardeners is a cheap, non-toxic, low melting point crystalline solid which is incompatible with diglycidylether of bisphenol A (DGEBA). TMP is presently used as a hardener for flexible polyurethanes. Clear solutions with DGEBA may be obtained by heating the mixture above the melting point of TMP, but the mixture becomes milky on cooling to room temperature and gross phase separation occurs on standing. TMP is unreactive with epoxy absent a suitable catalyst.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH3:36][NH:37][CH2:38][CH2:39][CH3:40].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[N:37]([CH3:36])[CH2:38][CH2:39][CH3:40]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCNC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (56 mg) was dissolved in chloroform (4 ml) and triethylamine (0.3 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, N-methylpropylamine (26 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional one hr. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol. The solvent was removed by distillation, and the resultant crystal was washed with hexane to give 42 mg (yield 58%) of the title compound.
Reaction SMILES: COC(=O)C1C=CC(NC(=O)C2C=CC(O)=C(N)C=2)=CC=1F.[CH2:23]([O:25][C:26](=[O:47])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][NH:41][C:40]=3[CH:45]=2)=[O:35])=[CH:29][C:28]=1[F:46])[CH3:24].[F:48][C:49]([F:61])([F:60])[C:50]1[CH:51]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1>>[CH2:23]([O:25][C:26](=[O:47])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][N:41]([S:56]([C:52]4[CH:53]=[CH:54][CH:55]=[C:50]([C:49]([F:48])([F:60])[F:61])[CH:51]=4)(=[O:58])=[O:57])[C:40]=3[CH:45]=2)=[O:35])=[CH:29][C:28]=1[F:46])[CH3:24]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1F
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: COC(=O)c1ccc(NC(=O)c2ccc(O)c(N)c2)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCO3)cc1F

Procedure:
2-Fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=523.0 (M−H), was prepared as described for example 14, steps 1 to 8. Step 4 was performed using 4-amino-2-fluoro-benzoic acid ethyl ester, yielding 4-(4-benzyloxy-3-nitro-benzoylamino)-2-fluoro-benzoic acid ethyl ester, which was reduced to 4-(3-amino-4-hydroxy-benzoylamino)-2-fluoro-benzoic acid methyl ester in step 5 and cyclized to 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-2-fluoro-benzoic acid ethyl ester in step 6. Step 7 was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][CH:13]([S-:15])[CH3:14].[Na+].O.C(#N)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([S:15][CH:13]([CH3:14])[CH3:12])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(C)Sc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
At 0 degree, to a stirring solution of 4-Bromo-2-Floronitrobenzene (2.0 g, 9.1 mmol) in DCM was added Sodium propane-2-thiolate (2.0 g, 20 mmol) in two portions. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered through a syringe filter. The product was isolated by prep-HPLC (water/Acetonitrile) as a bright yellow solid (0.8 g, 2.9 mmol, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:32])=[O:31]>>[ClH:1].[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)(=[O:31])=[O:32]
Reactant: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CS(=O)(=O)CCc1ccc(N)cc1
Product: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(CCS(C)(=O)=O)cc5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(4-methyl-benzyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 4-(2-methanesulfonyl-ethyl)-phenylamine (50 mg, 0.25 mmol) as a white solid (104 mg, 70%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.05 (s, 1H), 7.70-7.75 (m, 3H), 7.36 (t, J=5.7 Hz, 1H), 7.20-7.29 (m, 3H), 7.07-7.14 (M, 5H), 6.82 (dd, J=8.1 and 1.5 H. 1H), 5.60 (d, J=5.7 Hz, 1H), 4.54 (d, J=5.4 Hz, 2H), 3.57 (s, 3H), 3.42 (s, 3H), 3.30-3.37 (M, 2H), 2.90-2.95 (m, 5H), 2.26 (s, 3H). MS (ESI) m/z=556 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH2:21])[CH:12]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:21][C:13]2[CH:12]=[N:11][C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A solution of 4-fluorobenzoic acid (2.57 g, 18.3 mmol), quinolin-3-ylamine (2.5 g, 17.4 mmol), O-benzotriazol-1-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (7.3 g, 19.3 mmol) and N,N-diisopropylethylamine (6.4 mL, 36.7 mmol) in acetonitrile (75 mL) was stirred at ambient temperature for ten minutes, then heated at reflux for 20 hours. The solution was cooled to 0° C., and the product crystallized. The product was collected by filtration and washed with acetonitrile, to give a colorless solid, 3.86 g (79%). MS: m/z 267 (MH+). 1H NMR(DMSO-d6): δ 7.39-7.46 (m, 2 H), 7.58-7.71 (m, 2 H), 7.97-8.01 (m, 2 H), 8.11-8.16 (m, 2 H), 8.85 (d, 1 H), 9.15 (d, 1 H) and 10.73 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:16])=[C:10]2[O:14][CH:13](O)[CH2:12][C:11]=12)=[O:5])[CH3:2].C(OC(C1C=CC(F)=C2OC(OC)CC=12)=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:16])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)c2c1CC(O)O2
Agent: CCOC(=O)c1ccc(F)c2c1CC(OC)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(F)c2occc12
Reaction time: 5 h

Procedure:
A mixture of 7-fluoro-2-hydroxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester and 7-fluoro-2-methoxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester (1.15 g, see above) in toluene (6.0 mL) is added dropwise to a solution of PTSA (0.25 mmol) in toluene (5.0 mL) which is heated to reflux. Heating is continued for 5 h, an additional portion of PTSA (0.25 mmol) is added and the mixture is again heated to reflux for 7 h. The solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: heptane to heptane/EtOAc 95/5) to give the desired product. 1H-NMR (CDCl3): δ=7.99 (dd, J=8.3 Hz, J=4.3 Hz, 1H); 7.78 (s, 1H); 7.44 (bs, 1H); 7.10 (t, J=9.3 Hz, 1H); 4.46 (q, J=7.0 Hz, 2H); 1.47 (t, J=7.0 Hz, 3H).