Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:9]([CH3:27])[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH:1]1([N:6]([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:9]([CH3:27])[CH2:8]2)[C:37](=[O:39])[CH3:38])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](NC3CCCC3)C[C@@H]2C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)C3CCCC3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution (2S,4R)-N-cyclopentyl-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (100 mg, 02.7 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (120 uL, 0.70 mmol) followed by acetyl chloride (90 uL, 1.27 mmol). The mixture was stirred at r.t. for 4 h. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford pure N-cyclopentyl-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (100 mg, 91%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:21]1[CH2:26][C@@H:25]([CH3:27])[S:24](=[O:29])(=[O:28])[C:23]2[S:30][CH:31]=[CH:32][C:22]1=2.[CH2:33]([NH:35][S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N+:45]([O-:47])=[O:46])(=[O:38])=[O:37])[CH3:34]>>[CH2:33]([N:35]([C@H:21]1[CH2:26][C@H:25]([CH3:27])[S:24](=[O:29])(=[O:28])[C:23]2[S:30][CH:31]=[CH:32][C:22]1=2)[S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N+:45]([O-:47])=[O:46])(=[O:37])=[O:38])[CH3:34]
Reactant: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C[C@@H]1C[C@H](O)c2ccsc2S1(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN([C@H]1C[C@H](C)S(=O)(=O)c2sccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: -30 °C
Yield: 81.8 %

Procedure:
triphenylphosphine (6.8 g); cis-4-hydroxy-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide (5 g) and N-ethyl-2-nitrobenzenesulfonamide (5.54 g) are mixed under nitrogen atmosphere. The mixture is cooled at −30° C. and diisopropyl azadicarboxylate (4.8 mL) is added. It is stirred until completing the transformation. It is filtered, washed and dried. The isolated raw product is column-purified to give 8.07 g of trans-4-[N-ethyl-N-(2-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:13][C@H:12]([OH:14])[C@@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:3]=1.[NH2:17][C@@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>C(O)CCC>[C@@H:18]1([NH:17][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]3[CH2:13][C@H:12]([OH:14])[C@@H:11]([CH2:15][OH:16])[CH2:10]3)[CH:3]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O
Solvent: CCCCO
Product: OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Temperature: 200 °C
Yield: 73.5 %

Procedure:
A mixture of (1S,2R,4R)-4-[(6-chloropyrimidin-4-yl)amino]-2-(hydroxymethyl)cyclopentanol (500. mg, 2.05 mmol), 1-butanol (4.00 mL) and (S)-(+)-1-aminoindan (0.806 mL, 6.16 mmol) was heated to 200° C. for 90 min in a sealed tube using MWI. The mixture was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 5 to 25% MeOH in DCM to afford the title compound as an amorphous solid (513 mg, 73%). LC/MS: Rt=1.20 min, ES+ 341 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].S(OC)(O[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:34])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]

Procedure:
3-(4-chloro-3-ethoxycarbonylamino-6-fluoro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.96 g) was stirred with dimethyl sulfate (0.72 ml) and potassium carbonate (0.33 g) in N,N-dimethylformamide (10 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated to give the title compound (1.1 g, oil).
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([OH:34])[CH2:31][C:32]#[CH:33]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:33]#[C:32][CH2:31][CH:30]([OH:34])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: C#CCC(O)c1ccccn1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3ccccn3)oc21

Procedure:
Analogous to the procedures described in Example 88, 2-bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 79) is treated with 1-(pyridin-2-yl)but-3-yn-1-ol (Preparation 76) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(Br)C(=O)OCC
Reactant: CCCC(=O)c1ccc(O)cc1
Product: CCCCCCCCC(Oc1ccc(C(=O)CCC)cc1)C(=O)OCC
Yield: 85 %

Procedure:
1-[4-Hydroxyphenyl]-1-butanone (328 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Butyrylphenoxy]decanoate (616 mg, 85%) as a clear, colourless oil. 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.64 (dd, J=5.7, 6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.85-1.99 (m, 2H), 1.65-1.75 (m, 2H), 1.39-1.44 (m, 2H), 1.22-1.34 (m, 10H), 1.20 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.04, 171.39, 161.80, 130.98, 130.48 (2C), 114.74 (2C), 76.68, 61.55, 40.37, 32.85, 32.01, 29.53, 29.37 (2C), 25.33, 22.84, 18.11, 14.34, 14.29, 14.10. The resulting ester (616 mg, 1.70 mmol) was saponified with lithium hydroxide (203 mg, 8.5 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Butyrylphenoxy]decanoic Acid (166 mg, 29%). 1H NMR (400 MHz, CDCl3): δ 10.06 (br s, 1H), 7.91 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.70 (dd, J=5.9, 6.4 Hz, 1H), 2.87 (t, J=7.3 Hz, 2H), 1.96-2.02 (m, 2H), 1.68-1.77 (m, 2H), 1.44-1.59 (m, 2H), 1.24-1.37 (m, 10H), 0.97 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.95, 176.56, 161.74, 131.03, 130.73 (2C), 114.82 (2C), 76.16, 40.47, 32.79, 32.03, 29.53, 29.39, 29.37, 25.38, 22.86, 18.26, 14.31, 14.12. The acid (166 mg, 0.5 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Butyrylphenoxy]decanoate (149 mg, 85%) as a white solid. mp 262-278° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 4.70 (dd, J=6.1, 6.5 Hz, 1H), 2.90 (t, J=7.3 Hz, 2H), 1.88-1.93 (m, 2H), 1.67 (tq, J=7.4, 7.4 Hz, 2H), 1.41-1.57 (m, 2H), 1.20-1.35 (m, 10H), 0.95 (t, J=7.4 Hz, 3H), 0.83 (t, J=6.9 Hz, 3H); 13C NMR (101 MHz, CD3OD): δ201.82, 178.07, 163.36, 130.53 (2C), 129.54, 114.83 (2C), 79.46, 39.99, 33.11, 31.80, 29.40, 29.27, 29.15, 25.72, 22.54, 18.30, 14.46, 14.15; LRMS (ESI): m/z 713 (M2H+), 669 (2M-2Na++3H+), 335 (M-Na++2H+); HPLC: 3 min.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:18])[C:10]([CH2:15][C:16]#[N:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[OH-:19].[Na+]>C(O)C.O>[CH2:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:18])[C:10]([CH2:15][C:16](=[O:19])[NH2:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)N1CCCc2c1cc(C)c(CC#N)c2C
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCN1CCCc2c1cc(C)c(CC(N)=O)c2C
Temperature: 40 °C
Reaction time: 10 h
Yield: 32.6 %

Procedure:
1-Acetyl-6-cyanomethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline (2.7 g) was dissolved in ethanol (30 ml), and a solution of NaOH (4.4 g) in water (10 ml) was added, which was followed by refluxing for 10 hr under nitrogen. The solvent was evaporated under reduced pressure, and the residue was extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 6-carbamoylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline was dissolved in N,N-dimethylformamide (10 ml), and octyl bromide (1.6 g), potassium carbonate (1.2 g) and potassium iodide (166 mg) were added, which was followed by stirring at 40° C. for 10 hr in nitrogen. The reaction mixture was extracted with ethyl acetate (100 ml). After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/ methanol=50/1−10/1) to give 600 mg of 1-octyl-6-carbamoylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC(=O)[NH:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41](Br)=[CH:42][CH:43]=1)(=[O:38])=[O:37])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:42][CH:43]=1)(=[O:38])=[O:37]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and [2-(5-bromo-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.51) (193 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as a yellow solid (89 mg, 32%). MS (ISN) 558.0 [(M−H)−]; mp 196° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]#[N:7].[CH2:9]([NH:11][NH2:12])[CH3:10].Cl>C(O)C>[CH2:9]([N:11]1[C:6]([NH2:7])=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[N:12]1)[CH3:10]
Reactant: COCC(=O)CC#N
Reactant: CCNN
Agent: Cl
Solvent: CCO
Product: CCn1nc(COC)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a 25 mL round bottom was added 4-(methyloxy)-3-oxobutanenitrile (500 mg, 4.42 mmol), ethyl hydrazine (655 mg, 4.42 mmol), and 2 M HCl (2.210 mL, 4.42 mmol) in ethanol (10 mL). The reaction mixture was stirred at the room temperature overnight. The reaction mixture was then evaporated and pardoned between 20 mL of ethyl acetate and 20 mL of 1 M Na2CO3. The organic layer was washed with brine, filtered and evaporated to obtain 1-ethyl-3-[(methyloxy)methyl]-1H-pyrazol-5-amine (450 mg, 2.465 mmol, 55.8% yield) as a yellow oil. The product was used in the next step without further purification. LCMS (M+H)+=156.1; 1H NMR (400 MHz, DMSO-d6) ppm 1.20 (t, J=7.20 Hz, 3 H) 3.19 (s, 3 H) 3.82 (q, J=7.33 Hz, 2 H) 4.11 (s, 2 H) 5.11 (s, 2 H) 5.22 (s, 1 H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:27](=[O:28])[CH:26]=[CH:25][C:22]1[CH:23]=[CH:24][C:19]([S:16](=[O:18])(=[O:17])[NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:20][CH:21]=1
Reactant: O=C(Cl)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.21 g, 3.01 mmol) in tetrahydrofuran (4.0 ml) a saturated NaHCO3 solution (2.6 ml) was added and the resultant mixture was stirred at ambient temperature for 25 min. To the reaction mixture a 3-(4-phenylsulfamoyl-phenyl)-acryloyl chloride (44a) (0.19 g, 0.59 mmol) solution in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, and the solvent was removed. The residue was washed with diethyl ether to give the title compound (0.074 g, 39%) as white crystals, m.p. 176-177.5° C. 1H NMR (DMSO-d6, HMDSO), δ: 6.54 (1H, d, J=16.0 Hz); 6.96-7.32 (5H, m); 7.47 (1H, d, J=16.0 Hz); 7.76 (4H, s); 9.14 (1H, br s); 10.29 (1H, br s); 10.86 (1H, s). Anal. Calcd for C15H14N2O4S, %: C, 56.59; H, 4.43; N, 8.80. Found, %: 55.82; H, 4.38; N, 9.01.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])[C:17]([CH3:31])=[C:16]([CH3:32])[N:15]=1>CN(C)C=O>[CH3:31][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:19][C:14]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:15][C:16]=1[CH3:32]
Reactant: CC(C)CN
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NCC(C)C)nc(N2CCc3ccccc3C2C)c1C
Yield: 23.6 %

Procedure:
After isobutylamine(0.26 ml, 2.58 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 133 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:5]2[CH2:6][N:7]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cc1
Yield: 59.4 %

Procedure:
A mixture of 400 mg of 9,10-dihydro-4H-thieno[2,3-c][1]benzazepine and 600 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between water and chloroform. The organic layer is dried (Na2 SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 518 mg of the desired product. M+1=439.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:8]=1.[CH:17]1([CH3:29])[CH2:22][CH2:21][CH:20]([CH:23]([CH3:25])[CH3:24])[CH:19]([C:26](Cl)=[O:27])[CH2:18]1>O1CCCC1>[CH:23]([C@@H:20]1[CH2:21][CH2:22][C@@H:17]([CH3:29])[CH2:18][C@H:19]1[C:26]([NH:16][CH:14]([CH3:15])[CH2:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)=[O:27])([CH3:25])[CH3:24]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: CC(N)Cc1cccnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(Cc1cccnc1)NC(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Yield: 72.7 %

Procedure:
In a 25 mL round bottom flask, fitted with magnetic stirrer, 15 mL of tetrahydrofuran, 1.5 mmol (1.5 eq.) of pyridine and 1.1 mmol (1.1 eq.) of 1-(pyridin-3-yl)propan-2-amine were added. p-Menthane carboxylic acid chloride (1.0 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with MTBE and NaOH (1N in water). The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography, obtaining 220 mg of a white solid, mp 108-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5]([Cl:21])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2ccnn2)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnn2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoic acid (0.22 g, 0.94 mmol) and dichloromethane (50 mL). Add dropwise oxalyl chloride (0.14 mL, 1.6 mmol) followed by dimethylformamide (5 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH3:31])[CH:20]=1)[N:6]1[CH2:14][C:13]2[C:8](=[C:9]([N+:15]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:18]>[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH:5]([N:6]1[CH2:14][C:13]2[C:8](=[C:9]([NH2:15])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:18])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH3:31])[CH:20]=1
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC(F)F
Agent: [Pd]
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(N)c3C2=O)ccc1OC(F)F

Procedure:
3-(7-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester was prepared by the procedure of example 14 from 3-(4-difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (9.1 g, 0.02 mol) and palladium on carbon under hydrogen pressure (50 psi). The product was used in the next step without further purification.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([N+:24]([O-])=O)[CH:23]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:28]([F:30])([F:29])[F:31])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([CH:23]=3)[NH2:24])[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To an aqueous 2.5% acetic acid solution (19 ml) was added an iron powder (10-20 mesh; 1.89 g), followed by a suspension of 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylnitrobenzene (4.62 g) obtained by Reference Production Example 12 in ethanol (29 ml) at 75° C., and then the mixture was stirred at the same temperature for 15 minutes. To the mixture was further added an iron powder (1.80 g) at the same temperature, and the mixture was stirred at the same temperature for 1 hour. After cooling to room temperature, the reaction mixture was filtrated and washed with ethyl acetate. Then, the filtrate was extracted with an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylaniline (3.18 g).
Reaction SMILES: C1(O)C=CC=CC=1.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH2:19])[CH:12]=[CH:11][CH:10]=1.[CH:20]1[CH:25]=[C:24]2[C:26](O[C:29]([C:31]3=[CH:32][CH:33]=[CH:34][C:22](=[C:23]23)[CH:21]=1)=O)=[O:27]>CO>[CH:16]1[C:17]2=[C:18]3[C:13]([CH:12]=[CH:11][CH:10]=[C:9]3[N:8]=[C:29]3[C:31]4[CH:32]=[CH:33][CH:34]=[C:22]5[CH:21]=[CH:20][CH:25]=[C:24]([C:23]=45)[C:26](=[O:27])[N:19]32)=[CH:14][CH:15]=1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: Nc1cccc2cccc(N)c12
Solvent: CO
Solvent: Oc1ccccc1
Product: O=c1c2cccc3cccc(c32)c2nc3cccc4cccc(c43)n12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
250 g of phenol are melted at about 60° C. 47.4 g of 1,8-diaminonaphthalene and 59.4 g of 1,8-naphthalic acid anhydride are introduced, while passing over nitrogen, and the mixture is heated to 150° C. in the course of 1 hour and kept at this temperature for 2 hours. The reaction mixture is cooled to 80° C., 120 ml of methanol are added at a temperature of 80° to 65° C. in the course of 30 minutes, and the mixture is cooled to room temperature and filtered with suction. After the residue has been washed with 240 ml of methanol and dried at 150° C., 88.8 g of the stated dyestuff are obtained in a very good quality.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([C:23](=[O:25])[CH3:24])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][N:18]([CH3:1])[C:17]=2[CH:16]=[C:15]([C:23](=[O:25])[CH3:24])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Potassium carbonate (2.43 g, 17.6 mmol) and methyl iodide (1.3 ml, 20.9 mmol) were added to a solution of the 1-[8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (3.73 g, 16.0 mmol) in dimethylformamide (35 ml) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the mixture was washed with water (twice) and brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,60 g) and then fractionated with 2% ethyl acetate-toluene to yield the title compound (2.61 g, 66.0% yield) as bright golden yellow crystals.