Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[C:5]([C:12]([OH:14])=[O:13])[CH:4]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:10][C:9]([C:7]1[CH:8]=[N:3][CH:4]=[C:5]([CH:6]=1)[C:12]([OH:14])=[O:13])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cncc(C(=O)O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cncc(C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a suspension of 60% sodium hydride (527 mg) in dimethylformamide (20 mL) was added 3,5-pyridinedicarboxylic acid (2.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. To the mixture was added (bromomethyl)benzene (2.05 g) and the mixture was stirred at 60° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with ethyl acetate to give 5-[(benzyloxy)carbonyl]nicotinic acid as a pale yellow powder (722 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:44][C:45]([C:46]#[N:47])([CH3:49])[CH3:48])=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(N)C#N
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)NC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 2-amino-2-methylpropionitrile (22 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H19ClN6O2, 351.13. found 351.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[O:16])[CH:5]3[CH2:14][CH2:13][C:12](=O)[N:6]3[CH2:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH2:17].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:26]O>C(O)C.O>[Cl:1][C:2]1[C:3]2[C:4](=[O:16])[CH:5]3[CH2:14][CH2:13][C:12](=[N:26][OH:17])[N:6]3[CH2:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O
Reactant: NO
Reactant: O=C1c2c(Cl)cccc2CN2C(=O)CCC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2c(Cl)cccc2CN2C(=NO)CCC12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 1.00 g of 9-chloro-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 95% ethanol (10 ml) was treated with a premixed solution prepared from 1.17 g of sodium acetate trihydrate in water (5 ml) and 0.60 g of hydroxylamine hydrochloride in water (5 ml). The suspension was heated to reflux and after 15 minutes a solution formed. After 1 hour of reflux, a precipitate began to form. Heating was continued for another 1.5 hours, after which time the mixture was allowed to cool to ambient temperature. The precipitate was isolated by vacuum filtration and dried under vacuum at 40° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].Cl.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[OH:28]>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][NH:18][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[C:21]([OH:28])[CH:22]=1)#[N:25]
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Reactant: N#Cc1ccc(CN)c(O)c1
Agent: Cl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-hydroxy-benzonitrile hydrochloride according to general procedure B to give (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Colorless solid. MS 457.1 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1ccc(NC(=O)c2cc3cccc(OC)c3o2)cc1

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and p-anisidine to give N-(4-methoxyphenyl)-7-methoxybenzofuran-2-carboxamide (Compound 399a). Successively, it was formylated to give N-(4-methoxyphenyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 399b), then compound 399b was reacted with cyclobutylamine to give compound 399 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:17])[NH:9]2)[C:5]([OH:18])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:25])[CH:23]=O)[CH3:20].S(O)(C)(=O)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:23]([C:22]([O:21][CH2:19][CH3:20])=[O:25])[N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH2:16][CH:8]3[C:6]=2[N:7]=1
Reactant: CCOC(=O)C=O
Reactant: Oc1ccc(Cl)nc1C1Cc2c(F)cccc2N1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1Oc2ccc(Cl)nc2C2Cc3c(F)cccc3N12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8.53 g, 32.31 mmol) and Glyoxylic acid ethyl ester (6.59 g, 64.59 mmol) in THF (80 mL), MsOH (0.31 g, 3.23 mmol) was added. The mixture was stirred at 50° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=10:1) to provide ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (10.2 g, yield: 90.3%). 1H-NMR (CDCl3, 400 MHz) δ 7.04˜7.13 (m, 3H), 6.63 (d, J=8.0 Hz, 1H), 6.55 (t, J=8.4 Hz, 1H), 6.03 (s, 1H), 5.09 (d, J=8.8 Hz, 1H), 4.22˜4.34 (m, 2H), 3.73 (d, J=16.4 Hz, 1H), 3.44˜3.51 (m, 1H), 1.29 (d, J=7.2 Hz, 3H). MS (M+H)+: 349.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.I[CH3:18]>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:18])=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1c[nH]c2cc(Cl)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CC(=O)O)c2ccc(Cl)cc21
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.19 g of 60% suspension in oil) was suspended in dry THF (10 ml). 6-Chloroindole-3-acetic acid (SR058)(100 mg, 0.48 mmol) in THF (5 ml) was added dropwise and the mixture then stirred for 10 minutes. Iodomethane (0.34 g, 2.4 mmol) was then added, and the mixture stirred overnight. Excess sodium hydride was carefully destroyed by dropwise addition of water, and then the mixture was acidified (1M HCl) and extracted with ethyl acetate (3×50 ml), the organic layers dried over MgSO4, and the solvent evaporated to give a brown powder, yield 75 mg, 70%, m.p. 130-132° C. dec.; m/z 225, 223 (M+), 180, 178 (M+-CO2H); δH/ppm 7.46-6.92 (4H, m, Ar—H), 3.77 (3H, s, N—Me), 3.70 (2H, s, ArCH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][NH:50][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:24])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(C4=NCCN4)cc3)co2)c(C)c1
Temperature: 25 °C

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (100 mg, 0.3 mmol) was dissolved in DCE (6 mL) and CDI (195 mg, 0.6 mmol) was added. The reaction was stirred at room temperature until complete as determined by LCMS. 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine (54 mg, 0.3 mmol) and DIPEA (0.63 mL, 1.8 mmol) was added and the reaction stirred for 4 days. The reaction was washed with saturated aqueous NH4Cl (6 mL) and the aqueous wash extracted with DCE (3×6 mL). The combined organic extracts were dried over MgSO4 and the solvent removed in vacuo. The resulting crude product was purified using prep method B to afford the title compound.
Reaction SMILES: [OH-:1].[K+].[I:3][C:4]1C=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:5]=1C#N.[CH:16]([OH:19])([CH3:18])C>O>[I:3][C:4]1[CH:5]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:18]=1[C:16]([OH:19])=[O:1]
Reactant: CC(C)O
Reactant: [OH-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1I
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1I

Procedure:
Potassium hydroxide (3.78 g; 0.0673 mol) was added to a stirred solution of 2-iodo-5-(trifluoromethyl)benzonitrile (EXAMPLE 2; 4 g; 0.0135 mol) in a 1:1 isopropanol:H2O solution (60 mL). The reaction was heated at reflux for 14 h and then partitioned between H2O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL) and acidified to pH 5 with 6N HCl. The aqueous layer was further extracted with EtOAc (4×50 mL) and the combined extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 2-iodo-5-(trifluoromethyl)benzoic acid as a yellow solid. LCMS=317.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.27 (d, J=1.6 Hz, 1 H), 8.25 (d, J=8.2 Hz, 1 H), 7.47 (dd, J=8.2, 1.8 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>C(O)(C)(C)C>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cc1cc(Nc2cc(-c3ccccc3)nc(Cl)n2)[nH]n1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
The above prepared (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60 mg, 0.21 mmol) is combined with 4-acetamidothiophenol (176 mg, 1.05 mmol) in tert-butanol (5 mL) and the mixture heated at reflux for 20 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue is purified by flash chromatography (SiO2, DCM/MeOH gradient) to afford [2-(4-acetamido-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (74 mg, 85%)
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 52.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), isobutyryl chloride (0.56 mL, 5.2 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (30 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-isobutyramide (0.67 g). Mp 206.5-208.0° C.;MS m/z 258 ([M+H]+); Anal. Calcd. for C15H17NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.43; H, 7.39; N, 5.50.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[C:12]([CH2:14][N:15]([C:29]3[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[C:16]([CH:18]3[C:27]4[C:22](=[C:23]([OH:28])[CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:11]=[N:10]2)=[CH:4][CH:3]=1.[Cl:38]C1C=CC=C(C(OO)=[O:46])C=1>C(Cl)(Cl)Cl>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[C:12]([CH2:14][N:15]([C:29]3[CH:30]=[N+:31]([O-:46])[C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[C:16]([CH:18]3[C:27]4[C:22](=[C:23]([OH:28])[CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(F)cc3)c2)C(=O)C2CCCc3c(O)cccc32)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(F)cc3)c2)C(=O)C2CCCc3c(O)cccc32)c[n+]1[O-]
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
To a solution of N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) in chloroform (10 mL) was added m-chloroperbenzoic acid (0.29 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was partitioned between water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropyl-1-oxidopyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.13 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH2:10][CH2:11]CC)[CH3:9])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1.BrC1C=CC([C:27](O)=[O:28])=C(S(C(C)C)(=O)=O)C=1.N1CCOCC1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:9][CH2:27][O:28][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: CCCCN(C)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Solvent: C1COCCN1
Product: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)N1CCOCC1

Procedure:
Following the general method as outlined in Intermediate 253, starting from 4-bromo-2-(isopropylsulfonyl)benzoic acid (Intermediate 242) and morpholine, the title compound was obtained as a pink solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:19][CH:18]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(Nc2ccc(OC(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol), 4-isopropoxy-phenylamine (84.66 mg, 0.56 mmol) by a procedure similar to example 78. 1H NMR (CDCl3): 7.84-7.72 (m, 3H), 7.70-7.66 (m, 2H)), 7.50-7.45 (m, 1H), 7.30 (brs, 1H), 6.96-6.93 (m, 2H), 4.59-4.51 (m, 1H), 2.68 (s, 3H), 1.36 (d, J=6.3 Hz, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH3:35])[C:32]([CH3:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH3:35])[C:32]([CH3:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12](Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].[O-:18][C:19]#[N:20].[K+]>C(O)C.O>[OH:18][C:19]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:20]=1
Reactant: CC(C)(C)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nc(O)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
6.3 g (0.02 mol) of 2,2-dimethylpropionyl chloride 2,4,6-trichlorophenylhydrazone was dissolved in 50 ml of ethanol. Then, a solution of 3.2 g (0.04 mol) of potassium cyanate in 30 ml of water, was dropwise added thereto under stirring at room temperature. After completion of the dropwise addition, stirring was continued at the same temperature for further 0.5 hour. The precipitated crystals were collected by filtration and washed with n-hexane to obtain 6.1 g (yield: 95.3%) of 5-hydroxy-3-(tert-butyl)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole as white powder having a melting point of from 272° to 274° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:20]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CO.CCN(CC)CC>C1COCC1>[NH2:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(N2CCOCC2)cc(C(=O)O)c1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCOCC2)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A mixture of 2-amino-6-morpholino-3-nitroisonicotinic acid (12.3 g, 45.9 mmol), HATU (19.2 g, 50.5 mmol), MeOH (14.7 g, 459 mmol) and Et3N (13.9 g, 137.7 mmol) in THF (300 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was diluted with EA (500 mL). It was then washed with brine (500 mL×3). The organic layer was then concentrated in vacuo. The residue was then purified by chromatography on silica gel eluted with MeOH/DCM=1/100 to afford the crude product as a yellow solid (4.8 g, 37%); LC/MS: MS (ES+) m/e 283 (MH+).
Reaction SMILES: C[C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH2:12](Cl)Cl.[CH:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](Cl)=[S:23])=[CH:17][CH:16]=1>O>[CH3:9][C:8]1[C:7]([CH3:12])=[CH:6][C:4]([NH:5][C:22](=[S:23])[O:21][C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[C:3]([O:10][CH3:11])[CH:2]=1
Reactant: COc1c(N)ccc(C)c1C
Reactant: ClCCl
Reactant: S=C(Cl)Oc1ccccc1
Solvent: O
Product: COc1cc(C)c(C)cc1NC(=S)Oc1ccccc1
Reaction time: 2 h
Yield: 92 %

Procedure:
To 3,4-dimethyl-2-methoxyaniline(4.50 g, 0.03 mol), methylene chloride(100 ml) was added and then phenyl chlorothionoformate(5.16 g, 0.03 mol) was added slowly. The resulting mixture was stirred for 2 hours, and thereto water(150 ml) was added. The resulting mixture was extracted with methylene chloride and purified by column chromatography to obtain the titled compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:11][N:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:45][C:46]([F:58])([F:57])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54](O)=[O:55])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:9]([CH3:18])=[N:10][N:11]=[C:12]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:54](=[O:55])[CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:46]([F:57])([F:45])[F:58])=[CH:52][CH:51]=2)=[CH:5][CH:4]=1
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc([C@H]2CCCN2C(=O)Cc2ccc(C(F)(F)F)cc2)n1Cc1ccc(Cl)cc1
Yield: 91.6 %

Procedure:
(R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole hydrochloride (50 mg, 0.8 mmol) was dissolved in dichloromethane (2 ml). HATU (75 mg, 0.19 mmol), (α,α,α-trifluoro-p-tolyl)acetic acid (37 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.078 ml, 0.45 mmol) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Residue was taken up in EtOAc (20 ml) and washed with saturated solutions of NaHCO3 and NaCl. Organics were dried (NaSO4), filtered and concentrated. Purification by HPLC (water/acetonitrile gradient, 20% to 100% acetonitrile with 0.1% TFA) afforded the desired product as a white amorphous solid (76.3 mg, 91%).
Reaction SMILES: [NH2:1][CH:2]([C@@:5]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@@H:9]2[CH2:11][C@H:6]1[CH2:7][CH:8]2[OH:12])[CH2:3][CH3:4].[H-].[Na+].[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][N:28]=[C:29]2[O:32][CH3:33])=[CH:24][C:23]=1F.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][N:28]=[C:29]2[O:32][CH3:33])=[CH:24][C:23]=1[O:12][CH:8]1[CH2:7][C@@H:6]2[CH2:11][C@H:9]1[CH2:10][C@@:5]2([CH:2]([NH2:1])[CH2:3][CH3:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2O
Reactant: COc1nccc2cc(F)c(Cl)cc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2Oc1cc2ccnc(OC)c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 9.5 %

Procedure:
200 mg (0.82 mmol) of (1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]heptan-2-ol (89) were dissolved in 5 mL anhydrous dimethylacetamide. Afterwards, 39 mg (1.63 mmol) of NaH were added, followed by the addition of 173 mg (0.82 mmol) of 7-chloro-6-fluoro-1-methoxy-isoquinoline (10). The mixture was stirred at ambient temperature for 20 h. Afterwards, 50 mL of a saturated aqueous NaHCO3-solution were added and the mixture extracted three times using 30 mL ethyl acetate each. The organic layer was dried using MgSO4 and evaporated. The residue was purified using chromatography on reversed phase (acetonitrile/water). The product-containing fractions were evaporated to half of the original volume, 10 mL of a saturated aqueous Na2CO3-solution was added and the mixture extracted three times using 20 mL of ethyl acetate each. The organic layer was dried using MgSO4, filtered and evaporated yielding 34 mg of the desired product 90. Rt=0.86 min (Method 18). Detected mass: 437.3 (M+H+)