Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26]>CO>[CH3:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C@@H:14]([OH:15])[CH2:13][C@H:12]1[OH:26]
Reactant: CC/C=C\C[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC/C=C\C[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium borohydride (70 mg.) in 5 ml. of ice-cold methanol is added dropwise with stirring to a solution of racemic PGE3 (22 mg.) in 1.5 ml. of methanol at 0° C. This mixture is stirred at 0° C. for 30 minutes, and is then stirred and allowed to warm to 25° C. during one hour. After evaporation, water (10 ml.) is added, and the mixture is acidified with one normal hydrochloric acid, saturated with sodium chloride, and extracted repeatedly with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride solution, dried, and evaporated. The residue is chromatographed on 3 g. of acid-washed silica gel (Silicar CC4), eluting with 50 ml. of ethyl acetate and then with 50 ml. of 1% methanol in ethyl acetate, collecting 10 ml. fractions. The faster moving fractions are combined and evaporated to give racemic PGF3α ; same mobility as optically active PGF3α on TLC silica gel and silver-nitrate impregnated silica gel plates with the A IX system twice; mass spectrum spectral peaks same as for optically active PGF3α. The slower moving fractions are combined and evaporated to give racemic PGF3β ; m.p. 85°-92° C.; same mobility as optically active PGF3β on TLC silica gel plates as for PGF3β ; mass spectrum spectral peaks same as for optically active PGF3β.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([O:12][C:13]1[CH:36]=[CH:35][C:16]2[C:17]3[N:21]([CH2:22][CH2:23][O:24][C:15]=2[CH:14]=1)[CH:20]=[C:19]([C:25]1[N:26]([CH2:30][C:31]([F:34])([F:33])[F:32])[N:27]=[CH:28][N:29]=1)[N:18]=3)[C:9]([NH2:11])=[O:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[OH:6][CH2:7][C@H:8]([O:12][C:13]1[CH:36]=[CH:35][C:16]2[C:17]3[N:21]([CH:20]=[C:19]([C:25]4[N:26]([CH2:30][C:31]([F:32])([F:33])[F:34])[N:27]=[CH:28][N:29]=4)[N:18]=3)[CH2:22][CH2:23][O:24][C:15]=2[CH:14]=1)[C:9]([NH2:11])=[O:10]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)[C@H](CO)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of (S)-3-(tert-butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionamide (101 mg, 0.18 mmol) in THF (5 mL) was added TBAF (0.22 mL, 1M solution in THF, 0.22 mmol) and the reaction mixture was stirred at RT for 2 hr. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL) added. A white precipitate formed which was collected by filtration and dried in vacuo to yield 513 as a white solid (45 mg, 56%). LCMS: RT=2.98 min, [M+H]+=439; 1H NMR (400 MHz, d6-DMSO) 8.23 (1H, d, J=8.7 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.50 (1H, br s), 7.30 (1H, br s), 6.77 (1H, dd, J=8.9, 2.7 Hz), 6.54 (1H, d, J=2.6 Hz), 5.86 (2H, q, J=8.9 Hz), 5.09 (1H, t, J=5.8 Hz), 4.54 (1H, t, J=4.9 Hz), 4.50-4.41 (4H, m), 3.74-3.67 (2H, m)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:17][NH:18][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(CC)n[nH]c1CC
Yield: 72.9 %

Procedure:
A mixture of 4-oxo-3-propionyl-hexanoic acid ethyl ester (15 g, 70 mmol) and hydrazine hydrate (3.5 mL, 71 mmol) in absolute ethanol (150 mL) was refluxed for 16 h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (methanol in methylene chloride) to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester as yellow oil (11 g, 51 mmol).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=O)=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:22]([C:24]1[C:25](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[O:26][C:27]([CH3:34])([C:30]([F:33])([F:32])[F:31])[C:28]=1[CH3:29])#[N:23]>C(O)C>[CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:29][C:28]2[C:27]([CH3:34])([C:30]([F:33])([F:31])[F:32])[O:26][C:25](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[C:24]=2[C:22]#[N:23])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 92.3 %

Procedure:
In 5 ml of ethanol were dissolved 145 mg (0.50 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal and 140 mg (0.55 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 2 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography to give 242 mg of a dark greenish brown crystal (yield: 92.1%; mp: 169-170° C.).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Cl>C1COCC1.C(O)(C)C>[CH3:2][N:3]([CH3:4])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]
Reactant: CNC
Reactant: COC(=O)/C=C/CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)/C=C/CN(C)C
Yield: 52.2 %

Procedure:
Trithylamine (37.5 ml, 0.27 mol, 2.8 equiv) was dissolved in THF (100 ml), and dimethylamine hydrochloride (9.3 g, 0.114 mol, 1.2 equiv) was added. Methyl 4-bromocrotonate (20 g, 85% purity, 0.095 mol, 1.00 equiv) in 100 ml of THF was added drop-wise to the resulting solution at room temperature while stirring. The reaction mixture was allowed to react overnight at room temperature. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give yellow oil. The oil was dissolved in 50 ml of isopropanol, and hydrogen chloride was added until pH 2.0 was reached. The white solid was formed and filtered and dried to give 7.1 g product. MS (ESI) m/z: 563 (M+1).
Reaction SMILES: [C:1]([O:8]C)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:19][C@@H:20]2[C@@H:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:35])=[C:31]([O:33][CH3:34])[CH:32]=3)[C:23](=[O:24])[O:22][CH2:21]2)[CH:15]=[CH:16][C:17]=1[OH:18].N1C=CC=C[CH:37]=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:19][C@@H:20]2[C@@H:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:35])=[C:31]([O:33][CH3:34])[CH:32]=3)[C:23](=[O:24])[O:22][CH2:21]2)[CH:15]=[CH:16][C:17]=1[OH:18].[CH3:37][CH:3]([CH2:2][C:1]([O-:8])=[O:7])[C:4]([O-:6])=[O:5]
Reactant: c1ccncc1
Reactant: COC(=O)CCC(=O)[O-]
Agent: COc1cc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(O)c(OC)c2)ccc1O
Solvent: ClCCl
Product: CC(CC(=O)[O-])C(=O)[O-]
Temperature: 60 °C

Procedure:
Monomethyl succinate (1 g, 7.56 mmol) was stirred in a flame dried round bottomed flask. Thionyl chloride was added (30 ml, 4.5 g) dropwise and the mixture was heated to 60° C. for 3 h. Then, excess thionyl chloride was remowed under reduced pressure and the residue was analysed by NMR spectroscopy. The fully chlorinated product was dissolved in 20 ml dry CH2Cl2 and dropwise added to a solution of matairesinol (1 g) in 40 ml CH2Cl2 and 1.8 g pyridine (8 eqv.) at 0° C. The mixture was stirred and allowed to warm to room temp over night. The mixture was then extracted with 2×50 ml water and the organic phase was dried and concentrated. The residue was chromatographed on a silica column (eluent EtOAc:PE 1:1) to yield a fraction containing the product. Yield 1.1 g (purity 80%, NMR, some other components present). The product was rechromatographed with CHCl3 to yield 0.92 g (70%) of a pure fraction containing two components, totally coeluting. The mixture was analysed with LC-MS (ESI-ion trap) and the components were identified as free matairesinol and matairesinol bis methylsuccinate (product). According to NMR analyses the product contained approximately 15% free matairesinol. It seems unlikely that the components can be separated by normal column chromatography. However, pure product can probably be obtained by varying the ratio of reagents (excess of acid chloride).
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C:17]([O:19]CC)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[Na+].Cl>CO>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C:17]([OH:19])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(CC(=O)O)c2ccc(F)cc2)CCN(C)C1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
Ethyl 4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate (100 mg, 0.24 mmol) was dissolved in 10 mL of MeOH. To this solution was added 1N NaOH (5 mL). The reaction mixture was heated in an oil bath at a temperature of 50° C. overnight. The reaction mixture was cooled to RT, acidified with 1M HCl and evaporated to dryness. The residue was purified by HPLC to obtain 50 mg of product as the TFA salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[C:40]4[CH:47]=[C:46]([CH:48]=O)[NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)=[CH:34][CH:33]=2)=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[C:40]4[CH:47]=[C:46]([CH2:48][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)=[CH:36][CH:37]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(CN4CCOCC4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 0.5 ml of tetrahydrofuran, 10 μl of morpholine and 26 mg of sodium triacetoxyborohydride to the 1-(4-fluorophenyl)-3-[4-(6-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea synthesized in Example 168, the mixture was stirred overnight at room temperature. The reaction system was subjected to liquid separation and extraction with a tetrahydrofuran-ethyl acetate mixed solvent, and then dried over anhydrous sodium sulfate and concentrated to dryness to obtain 5 mg of the title compound.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)=[O:13]>>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[O:13])=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)c1ccc(OC(=O)P(=O)(OCC)OCC)cc1

Procedure:
From 21.6 g (0.13 mole) of triethylphosphite and 22.8 g (0.10 mole) of 4-ethoxycarbonylphenyl chloroformate. (120° C., 2 hours). Yield 26.1 g (88%). Bp0.01 190°-2° C. nD25 1.4890.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=2)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32]C1C=CC(O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:31][OH:32])=[CH:25][CH:24]=2)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(Cl)nc1Oc1ccc(CO)cc1

Procedure:
The title compound was prepared in a same manner to Compound 1e in Example 1. Using an adaptation of the method described in Procedures A-C, substituting 4-hydroxymethyl-phenol for 4-methoxyphenol in Procedure A, the title Compound 18a was obtained. MS: m/z 435.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11](=[O:38])[NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]([F:36])([F:35])[CH:22]([O:24][C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[F:23])=[C:15]([Cl:37])[CH:14]=2)[C:6](=[O:7])[N:5]([CH3:39])[C:3]1=[O:4].[CH2:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41]>C(#N)C>[CH2:40]([NH+:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41].[CH3:39][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:38])[NH:12][C:13]2[CH:14]=[C:15]([Cl:37])[C:16]([O:20][C:21]([F:36])([F:35])[CH:22]([O:24][C:25]([F:33])([F:34])[C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])[F:23])=[C:17]([Cl:19])[CH:18]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: CCN(CC)CC
Agent: CN1C(=O)C(C(=O)Nc2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)c(Cl)c2)C(=O)N(C)C1=O
Solvent: CC#N
Product: CC[NH+](CC)CC

Procedure:
2.25 g (3.34 mmol) of 1,3-dimethyl-5-(3,5-dichloro-(4-(2-(1,1,2,2,3,3,3-heptafluoropropoxy)-1,1,2-trifluoroethoxy))-phenylcarbamoyl)-barbituric acid in 30 ml of acetonitrile were stirred with 0.38 g (3.7 mmol) of triethylamine at room temperature for 2 hours. The solution was concentrated and the residue was dried at 50° C. under an oil pump vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:1][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C(=O)O)cc(N)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 179.6 %

Procedure:
To a stirred mixture of 2-amino-6-methylisonicotinic acid (150 mg, 0.99 mmol) and pyridine (310 mg, 3.9 mmol) in N,N-dimethylformamide (2.0 mL) is added pivaloyl chloride (240 mg, 2.0 mmol) at room temperature. The mixture is stirred overnight at room temperature, and diluted with saturated aqueous citric acid (10 mL). Whole is extracted with ethyl acetate/toluene (2:1, 10 mL×3). Combined organic layers are washed with water, brine, dried over sodium sulfate. The organic solvent is removed under reduced pressure to give 420 mg (quantitative yield) of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31].O>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH2:30][CH3:31])[CH:20]=2)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:23])[CH:3]=1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (354 mg) in N,N-dimethylacetamide (4.7 ml) were added powdered potassium carbonate (131 mg) and ethyl iodide (141 mg). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (324 mg) as a light yellow oil. MS (m/e)=438.2 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][C:2]2[CH:7]=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[N:11]=[C:10]([CH3:20])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:24]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(-c2ccnc(Cl)c2)n(-c2cccc(F)c2)n1
Solvent: O
Product: Cc1cc(-c2ccnc(NCc3cccnc3)c2)n(-c2cccc(F)c2)n1
Temperature: 190 °C
Yield: 60 %

Procedure:
A mixture of 2-chloro-4-[1-(3-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 47; 0.48 g, 0.0017 mol) and 3-(aminomethyl)pyridine (10 mL) was heated at 190° C. overnight (about eighteen hours). The reaction mixture was cooled, treated with copious amount of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/triethylamine, 99:1) to give 0.35 g (60% yield) of product as a yellow oil: Anal. Calc'd. for C21H18FN5: C, 70.18; H, 5.05; N, 19.49. Found: C, 69.78; H, 5.35; N, 18.87.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:15](=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].O.C(OCC)(=O)C>N1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=[O:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccccc1O
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A solution of 4-(trifluoromethyl)benzenesulphonyl chloride (2.4 g, 9.84 mmol) in pyridine (40 mL) is cooled to 0° C. Salicylaldehyde (1.44 g, 11.8 mmol) is added and stirred overnight. Water and ethyl acetate are added to the reaction and shaken. The organic layer is washed with dilute HCl (0.1 N×2), H2O, bicarbonate solution, H2O and dried with sodium sulfate. The organic layer is evaporated to dryness to give a yellow solid, which is recrystallized from ether/hexane to give 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate as a yellow powder (1.70 g, 52%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.CO.[CH2:21](Cl)Cl>CS(C)=O>[F:18][C:4]([F:17])([F:3])[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]2[CH2:21][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1
Reactant: ClCCl
Reactant: COC(=O)/C=C/c1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Reaction time: 0.05 h
Yield: 10 %

Procedure:
To a vigorously stirring mixture of NaH (31.0 mg, 1. 16 mmol) in DMSO (5 mL) at ambient temperature under an argon (g) atmosphere was added (CH3)3S(I)O (248 mg, 1. 12 mmol) in small portions over ca. 1 min. Following complete addition, the reaction was stirred for 20 min. A DMSO (1 mL) solution of 26A (200 mg, 0.870 mmol) was added dropwise over ca. 1 min. The reaction was left to stir for 5 h then quenched with H2O (25 mL) and extracted into EtOAc (3×30 mL). The combined organics were washed with H2O (1×15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (SiO2—12 g; gradient elution: 0.25% MeOH/DCM for 3 min then 0.25-4% MeOH/DCM over 14 min at 25 mL/min) to afford 22.0 mg 26B (10% yield). m/z (ES+) M+1=246.1; HPLC tR=1.09 min. 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.55-7.46 (m, 1H), 3.75 (s, 3H), 2.60 (ddd, J=9.6, 6.1, 4.1 Hz, 1H), 2.00 (ddd, J=8.6, 5.6, 4.1 Hz, 1H), 1.73 (dt, J=9.2, 5.1 Hz, 1H), 1.38 (ddd, J=8.6, 6.4, 5.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(OC(C)(C)C)=O)=[CH:22][CH:21]=1)[C:15]([C:34]([O:36][CH3:37])=[O:35])=[C:14]2[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:16]2[C:15]([C:34]([O:36][CH3:37])=[O:35])=[C:14]([C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=3)[C:13]3[C:18](=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=[CH:11][CH:12]=3)[C:17]2=[O:19])=[CH:25][CH:24]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cccc(OCc3ccccc3)c2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cccc(OCc3ccccc3)c2c(=O)n1-c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A solution of the compound obtained in Example 335 (53 mg) in chloroform (4 ml) is cooled to 0° C., and thereto is added a 4M solution of hydrogen chloride in ethyl acetate (2 ml). The mixture is stirred at 0° C. for two hours, and thereto is added a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The extract is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=1:2) to give 2-(4-aminophenyl)-8-benzyloxy-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (20 mg) as listed in Table 30.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19]>[Fe](Cl)(Cl)Cl>[C:1]1([S:7]([C:15]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([CH3:12])[CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccccc1C
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Product: Cc1ccc(S(=O)(=O)c2ccccc2)cc1C
Temperature: 110 °C

Procedure:
110 g of o-xylene, 176 g of benzenesulphonyl chloride and 0.16 g of iron(III) chloride are brought together at room temperature and the mixture is heated at 110° C. in the course of 2 hours. When the evolution of HCl has ended, the mixture is heated to 140° C. and the product is discharged onto a metal sheet. On cooling, the melt solidifies to a colourless mass. Yield: 243 g.