Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:29]Br.O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:11](=[O:23])[C:10]=1[Br:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(Cn2ccc(OCc3ccccc3)cc2=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Reaction time: 2 h

Procedure:
The material prepared in Example 1 (2.1 g, 0.007 mol) and sodium acetate (738 mg, 0.009 mol) in glacial acetic acid (15 mL) were cooled to 15° C. Bromine (0.412 mL, 0.008) in glacial acetic acid (5 mL) was added dropwise. Contents were stirred 2 hours, coming to room temperature. Water (200 mL) was added and a light yellow solid was filtered. Mp 150.4-151.2° C. FABHRMS m/z 384.0599 (M+H, C20H19BrNO2 requires 384.0601). 1H NMR (CDCl3/300 MHz) δ: 7.42-7.30 (m, 5H); 7.22-7.08 (m, 5H); 6.02 (d, 1H); 5.20 (s, 2H); 5.12 (s, 2H); 2.32 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29].C(=O)([O-])[O-]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:21])=[O:22])[CH2:18][CH2:19]2)[CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C
Yield: 68.9 %

Procedure:
To a solution of 5-bromo-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (420 mg, 0.9 mmol) in dioxane (6.0 mL) and water (2.0 ml), (3-formylphenyl)boronic acid (750.0 mg, 5.0 mmol), Pd(PPh3)4 (100.0 mg, 10%) and cessium carbonate (800 mg, 1.8 mmol) were added. The reaction mixture was heated in a Smith synthesizer microwave at 160° C. for 20 min. All solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (300.0 mg, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C@@H:34]([OH:36])C)N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:3][N:2]([CH2:1][C@@H:34]([OH:36])[CH3:33])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: C[C@H](O)CNN
Product: C[C@H](O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (S)-1-Hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.42 (m, 2H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.61 (s, 1H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2H), 7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21 (dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J=13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.CO>C(Cl)Cl>[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:32])=[CH:34][CH:35]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 59 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 59% yield as an oil following radial chromatography (SiO2; gradient of 2-5% MeOH in CH2Cl2).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:7]=1
Reactant: CC(C)(C)c1nn(CCl)cc1Cl
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Cl
Yield: 30 %

Procedure:
0.98 g of 4-chloro-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.11 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of [(4-chloro-3-t-butyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (13), hereinafter) shown by below formula.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[N:24][CH:25]=3)[N:22]([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19]4)[CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[N:24][CH:25]=3)[N:22]([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19]4)[CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a solution of 6-(1′-acetyl-1′,2′,3′,6′-tetrahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (91 mg, 0.24 mmol) in 2.0 mL of MeOH is added 10% Pd/C (38 mg, 0.036 mmol). Then ammonium formate (60 mg, 0.96 mmol) is added and the mixture is stirred for 2 hrs at 80° C. The solid of the reaction mixture is filtered and the filtrate is concentrated to give the crude product. Purification by flash column chromatography affords 38 mg of 6-(1′-acetyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1.O>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH2:3])=[CH:7][CH:8]=2)=[N:15][CH:16]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Sodium hydride/60 percent oil dispersion (0.72 mg, 18 mmol) was added in portions to a slurry of tyramine (2.1 g, 15 mmol) in anh. DMF (25 mL). After 15 minutes, 2-chloro-5-(trifluoromethyl)pyridine (2.9 g, 16 mmol) was added neat and the reaction heated to 50° C. for 3 hours. After cooling, the reaction was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic portions were combined and washed with brine (50 mL) and dried (Na2SO4). Filtration and removal of solvent left a brown residue that partially solidified. This was triturated in minimal ethyl acetate and collected by filtration, leaving product as a white solid, 3.0 g, 10.6 mmol, 71 percent yield.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](Cl)=[O:10]>ClC1C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[C:8]([C:9](=[O:10])[C:6]2[CH:7]=[CH:8][C:12]([Cl:1])=[CH:13][CH:14]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: [Cl-]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cc(C)cc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 172.3 %

Procedure:
100 ml chlorobenzene and 14.7 g aluminium trichloride are added in a 250 ml three-neck flask, and then 16.8 g 3,5-dimethyl benzoyl chloride is dropped into the solution at room temperature. Maintaining the temperature at 70° C., react with stirring for 16 h. The reaction solution is acidolyzed and washed with water, and then is distilled to remove chlorobenzene, obtaining 21 g residue, the yield is 86%. The residue is recrystallized with ethanol to obtain a purified white crystal, and the melting point is 72-73° C. 1H-NMR data (solvent CDCl3): δ2.371 ppm, s, 6H; δ7.230 ppm, s, 1H; δ7.363 ppm, s, 2H; δ7.438, 7.466 ppm, d, 2H; δ7.729, 7.757 ppm, d, 2H.
Reaction SMILES: OC[CH:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH2:4]1.Cl.[CH3:21][O:22][NH2:23]>N1C=CC=CC=1>[CH3:21][O:22][N:23]=[CH:4][C:3]1[C:12]2([CH2:13][CH2:14][CH2:15]2)[O:11][C:10]2[C:9](=[C:8]([CH3:17])[C:7]([OH:18])=[C:6]([CH3:19])[CH:5]=2)[CH:16]=1
Reactant: CON
Reactant: Cc1c(C)c2c(c(C)c1O)CC(CO)C1(CCC1)O2
Agent: Cl
Solvent: c1ccncc1
Product: CON=CC1=Cc2c(cc(C)c(O)c2C)OC12CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutane]-3-carbaldehyde (421 mg, prepared as described in Example 19) in 8 mL of pyridine was added methoxyamine hydrochloride (628 mg). The reaction mixture was allowed to stir at room temperature overnight. The mixture was extracted with ethyl acetate and washed with 1N HCl. The organic solvent was evaporated in vacuo, the residue was purified by flash chromatography eluted with 10% ethyl acetate in hexane to give 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutane]-3-carbaldehyde O-methyloxime as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=7.82 (s, 1H), 6.68 (s, 1H), 6.60 (s, 1H), 4.45 (s, 1H), 3.98 (s, 3H), 2.75 (m, 2H), 2.44 (m, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 1.98 (m, 2H) ppm. 13C-NMR (75 MHz, CDCl3) δ=148.6, 146.5, 146.4, 131.2, 125.8, 125.1, 119.9, 119.6, 116.0, 80.5, 62.1, 34.2, 16.6, 13.6, 11.4 ppm. MS: (m/z)=274.0 (M+H+).
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1oc(-c2ccc(F)cn2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2ccc(F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A mixture of 2-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-5-fluoropyridine (0.4 g), ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.3 g), sodium carbonate (0.2 g) and sodium iodide (0.2 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.2 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (285 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.[CH2:38]([CH2:40][NH2:41])[OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([NH:41][CH2:40][CH2:38][OH:39])=[O:37])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Reactant: NCCO
Product: O=C(/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1)NCCO
Yield: 60 %

Procedure:
The title compound was prepared as described in Example 34. B using (2E)-3-(4-{[2-(4-fluorophenyl)-6-(phenylmethoxy)(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoic acid (0.494 g, 1.0 mmol) and ethanolamine (0.122 g, 2.0 mmol) to provide the title compound (0.322 g, 60% yield): 1H NMR (CDCl3) 8.02 (br, 1H), 7.61 (d, 1H), 7.32-7.41 (m, 7H), 7.00 (d, 2H), 6.91 (m, 2H), 6.69-6.77 (m, 5H), 6.37 (d, 1H), 6.12 (t, 1H), 5.03 (s, 2H), 4.75 (t, 1H), 3.80 (t, 2H), 3.57 (t, 2H), 3.45-3.56 (m 2H), 3.15 (dd, 1H), 2.89 (m, 2H), 2.66 (dt, 1H); ES-MS m/z 537 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:20]=1[C:21](O)=[O:22])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:9][N:8]([C:21]([C:20]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=1[O:18][CH:15]([CH3:17])[CH3:16])=[O:22])[CH2:7][CH2:6]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1cc2c(c(OC)c1)CNCC2
Product: COc1cc2c(c(OC)c1)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)CC2

Procedure:
Prepared in analogy to example 1.1 from 6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (CA [88207-92-5]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[N:6]=[C:7]([CH2:14][CH2:15][CH3:16])[N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[OH-:19].[K+]>CCO>[CH2:14]([C:7]1[N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[C:5]([C:3]([OH:4])=[O:19])[N:6]=1)[CH2:15][CH3:16]
Reactant: [OH-]
Reactant: CCCc1nc(C(=O)C(F)(F)F)c2ccccn12
Agent: [K+]
Solvent: CCO
Product: CCCc1nc(C(=O)O)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.2 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(3-propyl-imidazo[1,5-a]pyridin-1-yl)-ethanone (379 mg, 1.48 mmol) in EtOH (10 mL) was added KOH (830 mg, 14.8 mmol). The mixture was stirred at ambient temperature for 15 h. After this time the mixture was concentrated, diluted with water (10 mL) and acidified to pH 3 with 2N HCl. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the title compound (170 mg, 56%). 1H NMR (DMSO-d6) δ 12.1 (1H), 8.38 (1H), 7.99 (1H), 7.18 (1H), 6.90 (1H), 2.99 (2H), 1.79 (2H), 0.98 (3H); m/z (M+H)=205.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1ccccc1-c1ccc2ncnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccccc1-c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
Preparation D6, Step 3. A suspension of 6-(2-methoxyphenyl)quinazolin-4-ol (250 mg, 0.99 mmol) in POCl3 (10 mL) was heated at reflux for 1 h, during which time a clear solution was observed. The mixture was cooled to room temperature, concentrated in-vacuo, then concentrated from methylene chloride (3×100 mL) to remove any remaining POCl3. The residue was partitioned between ethyl acetate (25 mL) and saturated NaHCO3 (30 mL), and the mixture was stirred until gas evolution ceased (10 min). The layers were separated, the organic phase was washed with saturated NaHCO3, water, and brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 1:3 ethyl acetate/heptane, to yield 217 mg of 4-chloro-6-(2-methoxyphenyl)quinazoline as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.03 (s, 1H), 8.36 (s, 1H), 8.19 (d, J=7.15 Hz, 1H), 8.10 (d, J=8.80 Hz, 1H), 7.42 (m, 2H), 7.10 (t, J=7.42 Hz, 1H), 7.04 (d, J=8.25 Hz, 1H), 3.86 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[NH2:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[C:21]([F:27])[C:20]=1[SH:28]>>[F:25][C:24]1[C:19]2[N:18]=[C:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])=[CH:7][CH:8]=3)[S:28][C:20]=2[C:21]([F:27])=[CH:22][C:23]=1[F:26]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: CCOC(=O)Cc1ccc(CC(=O)O)cc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(Cc2nc3c(F)c(F)cc(F)c3s2)cc1
Yield: 35.2 %

Procedure:
The procedure of Example 16-i) was repeated using 1,4-phenylene diacetic acid monoethyl ester (510 mg, 2.1 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (2.0 g, 11.7 mmol) to obtain ethyl 4-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]phenylacetate (270 mg, 35%) as a colorless powder.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)([OH:3])=O.[NH4+].O[N:31]1C(=O)CCC1=O>>[NH2:31][C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CC/C(Nc1ccc(CC(=O)O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21
Agent: [NH4+]
Product: CC/C(Nc1ccc(CC(N)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone and N-hydroxy-succinimide-ammonium salt
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:16][C:17](=[O:19])N)([C:14]#[CH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=[O:23])C>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:16][C:17](=[O:19])[O:23][C:14]2=[CH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: C#CC1(OC(N)=O)CCN(Cc2ccccc2)CC1
Agent: Br
Product: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Yield: 59.3 %

Procedure:
5.16 g of 1-benzyl-4-carbamoyloxy-4-ethynylpiperidine are stirred in 30 ml of 30% by weight solution of hydrogen bromide in acetic acid at room temperature for 6 hours. After evaporating the solvent under reduced pressure and adding 50 ml of water to the residue the base is liberated by sodium hydrogen carbonate. The solid product obtained is filtered, washed to bromide-free with water, dried and recrystallized from n-hexane to give the title compound in 59.3% yield the physical characteristics of which are in agreement with those given in Example 1.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CCC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CCC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 41.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.45 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CS(O[CH2:6][C:7]#[CH:8])(=O)=O.[Cl:9][C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[C:18]=2[Cl:28])=[C:12]([F:29])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)C)=O>[Cl:9][C:10]1[C:15]([O:16][CH2:8][C:7]#[CH:6])=[CH:14][C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[C:18]=2[Cl:28])=[C:12]([F:29])[CH:11]=1
Reactant: C#CCOS(C)(=O)=O
Reactant: Cn1c(Cl)c(-c2cc(O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C#CCOc1cc(-c2c(Cl)c(C(F)(F)F)n(C)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 39.9 %

Procedure:
2-propinyl methanesulfonate (0.35 g; 2.6 mmoles) is added to a mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl) -2,4-dichloro-1-methyl-5-trifluoromethyl pyrrole (0.9 g; 2.5 mmoles) and potassium carbonate (0.33 g; 2.39 mmoles) in methylisobutylketone (10 ml). The mixture is heated to 80° C. for 3 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated in a rotavapor. The raw product obtained (1.0 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 90:10. 0.40 g of solid white product are obtained.