Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]1.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]([F:26])[CH2:22][CH2:21]2)[C:17]2[CH:27]=[CH:28][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:30][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:21][CH2:22][CH:23]([F:26])[CH2:24][CH2:25]2)[C:17]2[CH:27]=[CH:28][C:29]([S:31]([N:3]3[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]3)(=[O:32])=[O:33])=[CH:30][C:16]=2[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1cc[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCC(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (0.19 g, 60%, 4.8 mmol) was added to a solution of 1H-pyrrole-3-carbaldehyde (0.13 g, 1.4 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature, stirred for 1 h and cooled to 0° C. 2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.37 g, 0.96 mmol) was added to the reaction mixture and stirred for 1 h. The reaction mixture was quenched with saturated NaHCO3 solution (30 mL) and the solvent was concentrated. Water (50 mL) was added to the residue and the product was extracted with DCM (workup). The solvent was concentrated and the product was purified by MPLC on silica gel using 50-80% EtOAc/heptane to provide the title compound as white solid. Yield: 0.25 g (57%); MS (ESI) (M+H)+=445.9.
Reaction SMILES: S[C:2]1[N:3]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:24])=O.O.C(=O)(O)[O-].[Na+]>ClCCCl.CN1CCCC1=O>[Cl:24][C:2]1[N:3]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=1
Reactant: Cn1c(S)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCCl
Product: Cn1c(Cl)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
2-Mercapto-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (2.76 g, 9.33 mmol) in 1,2-dichloroethane (20 ml) and N-methylpyrrolidone (2 ml) was added to a solution of phosphorus oxychloride (3.83 g, 25.0 mmol) and N-methylpyrrolidone (5.22 g, 52.7 mmol) at 50° C. and the mixture was stirred for 20 minutes. The solution was poured into warm water, and sodium bicarbonate (10.2 g, 121 mmol) was added to the solution and the mixture was stirred until no gas was generated. The resulting solution was partitioned between water and dichloromethane, and the organic layer was washed with water and brine and passed through Celite. The solvent was removed under reduced pressure, and the residue was purified with silica gel column chromatography (eluent; hexane/ethyl acetate=2/1 to 1/1) to afford 2-chloro-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (2.08 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[C:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[N:31][CH:32]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[N:31][CH:32]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3)ncc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3)ncc2C(F)(F)F)CC1
Reaction time: 16 h

Procedure:
A suspension of tert-butyl 4-(5-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A10) (134 mg, 0.216 mmol), 10% Pd/C (100 mg) and Et3N (1.0 mL) in DMF (10 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL) and filtered through Celite. The filtrate was evaporated in vacuo and the resulting residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A11 as a colourless oil (117 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=2.6 Hz, 1H), 8.57 (s, 1H), 8.15 (dd, J=8.5, 2.7 Hz, 1H), 7.45 (s, 1H), 7.34-7.27 (m, 3H), 7.24-7.15 (m, 2H), 4.26 (s, 2H), 3.60 (s, 3H), 3.22-3.07 (m, 4H), 2.92-2.76 (m, 3H), 1.92 (d, J=11.4 Hz, 2H), 1.79-1.65 (m, 4H), 1.48 (s, 9H), 1.22-1.18 (m, 2H). LCMS-A: rt 5.971 min; m/z 626 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.S(Cl)(Cl)=O.[O:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1.N1C=CC=CC=1>ClCCl>[O:31]1[CH:35]=[CH:34][C:33]([NH:36][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:16][N:15]=[CH:14]4)[CH:4]=2)=[N:32]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 25 °C

Procedure:
A solution of 4-methyl-3-(1-morpholinophthalazin-6-yl)benzoic acid (Example 8, 160 mg, 0.45 mmol) in thionyl chloride (1.0 mL, 1.37 mmol) was stirred at RT for 1 h. Excess SOCl2 was removed under reduced pressure and the residue was treated with 1 mL of toluene and concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 mL), and isoxazol-3-amine (58 mg, 0.69 mmol) followed by pyridine (72 mg, 0.92 mmol) was added. After the resulting mixture was refluxed for 1 h, cooled to RT, diluted with dichloromethane, and washed with 1 N NaOH. The dichloromethane layer was dried, concentrated, and purified on an ISCO 12 g column (eluted with 5-15% MeOH in ethyl acetate) to provide N-(isoxazol-3-yl)-4-methyl-3-(1-morpholinophthalazin-6-yl)benzamide as an amorphous off-white solid. Found MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C(Br)C.[CH2:23]1[CH2:27]OC[CH2:24]1>C1CCCCC1>[O:11]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1([CH2:27][CH:23]=[CH2:24])[CH2:15][CH:14]=[CH2:13]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCc2ccccc2C1
Reactant: C1CCOC1
Agent: [Li+]
Solvent: CCBr
Solvent: C1CCCCC1
Product: C=CCC1(CC=C)C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7.3 g (50 mmol) 2-tetralone in 75 ml THF in a three-neck round-bottomed flask, equipped with a gas inlet and septum, was added 36.7 mL LDA (55 mmol, 1.5M in cyclohexane, at -30° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. over a thirty-minute period and 5.6 mL (65 mmol) ethyl bromide was added. TLC analysis was used to monitor the reaction. After stirring for 24 hours at room temperature, the reaction mixture was quenched with 10% sodium bisulfate to pH2-3. After removal of THF under reduced pressure, the mixture was extracted with ethyl acetate (2×1 L) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by liquid chromatography on 800 g of silica gel 60 (230-400 m), eluting with 1 L hexane, followed by 5 L of 5% ethyl acetate/hexane, and collecting 40 mL fractions. Fractions 41-64 gave 4.2 g (37%) of pure and 1,2,3,4-tetrahydro-2-oxo-1,1-di-(2-propenyl)naphthalene as a colorless oil and fractions 65-82 gave 3.1 g (33%) of pure 1,2,3,4-tetrahydro-2-oxo-1-(2-propenyl)-naphthalene as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:27])(CC=C)[CH:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C[N+]1([O-])CC[O:36]CC1.[O:40]1C[CH2:43][CH2:42][CH2:41]1>CO.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:43][CH:42]([OH:36])[CH2:41][OH:40])[C:21]([OH:27])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C1CCOC1
Reactant: C=CCC1(O)C=CC(c2csc(-c3ccc(OCC)c(OCC)c3)n2)=CC1C(=O)OC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CC(O)CO)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-4-allylphenyl)thiazole in 20 ml of methanol and 20 ml of tetrahydrofuran were added 0.5 ml of osmium tetroxide (a 4% aqueous solution) and 1.22 g of 4-methylmorpholine N-oxide. The mixture was stirred at room temperature for 4 hours. The solvent was removed by distillation. The residue was mixed with 50 ml of dichloromethane and 25 ml of water for phase separation. The organic layer was washed with 25 ml of a saturated aqueous sodium chloride solution and dried. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol =199/1) to obtain 860 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl]thiazole.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]([NH2:7])[CH3:6].N1C=CC=CC=1.[Cl:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19]>C1COCC1>[Cl:14][CH2:15][CH2:16][NH:17][C:18]([NH:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH3:2])=[O:19]
Reactant: COC[C@@H](C)N
Reactant: O=C=NCCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC[C@H](C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of (R)-1-methoxypropan-2-amine hydrochloride (500 mg, 3.98 mmol) and pyridine (315 mg, 3.98 mmol) in THF (15 mL) was treated drop-wise with 2-chloroethylisocyanate (420 mg, 3.98 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, partitioned between EtOAc and brine and the organic layer dried over Na2SO4 and concentrated to dryness to afford (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (393 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 6.08 (s, 1 H), 5.93 (d, J=8.1 Hz, 1 H), 3.71 (m, 1 H), 3.56-3.51 (m, 3 H), 3.30-3.23 (m, 3 H), 3.22 (s, 3 H), 0.98 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[CH2:19][I:20])([O-:15])=[O:14].C1C(Cl)=CC=C(Cl)C=1>>[I-:20].[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[CH2:19][N+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH3:12])([CH3:11])[C:2]=1[CH3:1])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(CI)cc([N+](=O)[O-])c1
Reactant: CC1=Nc2ccccc2C1(C)C
Solvent: Clc1ccc(Cl)cc1
Product: CC1=[N+](Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c2ccccc2C1(C)C
Product: [I-]
Temperature: 90 °C
Yield: 55.9 %

Procedure:
To 2,3,3-trimethylindolenine (1.64 g) was added 3,5-dinitrobenzyl iodide (3.71 g) and dichlorobenzene (15 ml). After heating to 90° C. for 6 hours the mixture was allowed to cool and the resultant precipitate removed by filtration. The solid was washed with dichlorobenzene (2×10 ml) and ether (2×50 ml). The material was dried in a vacuum oven to give the product as a yellow solid (2.69 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C1COCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19](=[O:20])[NH:5][C:4]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=3[O:2][CH3:1])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 87.5 %

Procedure:
2-methoxy-4-nitroaniline (3 g, 17.8 mmol) was dissolved in THF (60 ml) and pyridine (1.6 ml, 19.6 mmol) was added. The reaction mixture was cooled to 0° C. and Fmoc-Cl (5.07 g, 19.6 mmol) was added in small portions. The reaction was allowed to come to ambient temperature and held for 5 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by recrystallisation from CH2Cl2 and MeOH to afford the title compound (6.08 g, 88%). Data: (m/z)=391 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]([CH2:15][CH:16]=C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:20].[Na+].CCOCC>[Os](=O)(=O)(=O)=O.O>[C:10]([CH:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:18])[CH2:15][CH:16]=[O:20])([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C(=O)OCC)C(=O)c1ccc(C)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(CC=O)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Ethyl 3-(4-methylphenyl)-3-oxo-2-(allyl)propanoate (74.21 g, 301 mmol, 1.0 eq), osmium tetroxide (100 mg, cat.), sodium metaperiodate (141.8 g, 663 mmol, 2.2 eq), ether (500 mL) and water (1 L) were mixed and stirred at room temperature. After 24 hours, an additional 110 mg of OsO4 was added and after another 24 hours, 200 mg more of OsO4 was added together with sodium metaperiodate (190 g, 888 mmol, 3.0 eq). After 4 days, the layers were separated and the ether layer washed with aqueous sodium bisulfite (1×500 mL) followed by brine (1×300 mL). The ether layer was dried (MgSO4) and the solvent removed in vacuo to yield 64.99 g of a dark brown oil. This oil was flash chromatographed over silica gel in 4:1 hexane/ethyl acetate to yield 37.5 g of an amber oil. NMR (200 MHz, CDCl3 ) δ 9.79 (s, 1H); 7.93 (d, 2H, J=9 Hz); 7.27 (d, 2H, J=9Hz); 4.87 (t, 1H, J=7 Hz); 4.13 (q, 2H, J=7 Hz); 3.37-3.08 (AB multiplet, 2H); 2.40 (s, 3H); 1.14 (t, 3H, J=7 Hz). Anal. Calcd. for C14H16O4 : C, 67.73; H, 6.50. Found: C, 67.53; H, 6.54.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (71 mg, 86%), MS (ISP) m/z=329.4 [(M+H)+], mp 227.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH2:21][OH:22].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][OH:22])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: OCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCCCC1CO
Temperature: 25 °C
Yield: 28 %

Procedure:
3-(Trifluoromethyl)benzenesulfonic acid chloride (1 eq), dissolved in methylene chloride (65 ml), was added dropwise to a cooled solution (0° C.) of 2-piperidinemethanol (40 mmol, 1.1 eq) in methylene chloride (160 ml) and triethylamine (2.5 eq). When the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature until, according to thin layer chromatography control, the reaction was complete (90 min). Hydrogen chloride solution (0.5 mol/l, 75 ml) was added, the mixture was stirred for 15 min, the phases were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. Yield: 28%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=1)[C:5]#[N:6].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.Cl>C(O)C>[Cl:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([NH:1][C:2]3[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:11][CH2:12][N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:9]=3)[C:5]#[N:6])=[CH:21][CH:22]=[N:23]2)=[CH:28][CH:27]=1
Reactant: N#Cc1cc(N)cc(NCCN2CCCCC2)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Product: N#Cc1cc(NCCN2CCCCC2)cc(Nc2ccnc3cc(Cl)ccc23)c1
Yield: 15.4 %

Procedure:
3-amino-5-{[2-(piperidin-1-yl)ethyl]amino}benzonitrile (200 mg, 0.82 mmol) and 4,7-dichloroquinoline (162 mg, 1 eq) were refluxed in 15 mL of ethanol and 0.82 mL of HCl 1M for 24 h. The reaction mixture was then evaporated and the residue and was purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH//95/5/1) to yield expected compound as a yellow powder (51 mg, 15% yield). m/z (ESI) 406.3 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])=[O:10].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 216 h

Procedure:
Acetyl chloride (0.17 ml) was added to a mixture of the compound of Example 42 (0.83 g), ethyldiisopropylamine (1.05 ml) and dioxane (10 ml) at 0° C., allowed to be warmed to 25° C. and stirred for 9 days. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with 1 M hydrochloric acid and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethyl acetate/hexane, thereby giving 0.25 g of the desired compound. Melting point: 233-235° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([O:19]C)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Temperature: 75 °C
Yield: 90 %

Procedure:
Methyl N-(benzyloxycarbonyl)4-aminomethyl-2-O-benzylsalicylate (6.81 g, 16.8 mmoles) was dissolved in tetrahydrofuran (50 mL). A solution of lithium hydroxide monohydrate (0.78 g, 18.5 mmoles) in water (25 mL) was added, and the reaction mixture was stirred and heated at 75° C. for 24 hours. The solution was cooled, and 1N aqueous hydrochloric acid (50 mL) was added. The reaction mixture was extracted twice with ethyl acetate (150 mL then 50 mL). The combined ethyl acetate extracts were washed with water (75 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to 150 mL. The ethyl acetate solution was heated to boiling, and hexanes (150 mL) was added. The solution was cooled in ice, and crystals formed. The crystals were collected by filtration, washed with hexanes, and dried in vacuo to afford 5.92 g (90% yield) of N-(benzyloxy-carbonyl)-4-aminomethyl-2-O-benzylsalicylic acid (m.p. 139°14 140° C., open capillary, uncorrected).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:37][O-].[Na+]>C(Cl)Cl.CO>[CH3:37][O:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:28]([F:30])([F:31])[F:29])[C:25]([CH3:27])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COCc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 283) (213 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of example 288. Obtained as an off-white solid (101 mg, 46%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH:24][CH:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH:25]([OH:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCN1CCOc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(O)Cc1ccc(OCCN2CCOc3ccccc32)cc1
Yield: 26.5 %

Procedure:
The title compound (0.14 g, 32%) was prepared as a gummy liquid from 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.36 g, 1.42 mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.42 mmol) using conditions analogous to that described in preparation 2.