Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:11]2[CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[CH:7][CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:10]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:11]2[CH2:15][CH2:16][OH:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CCO[Si](C)(C)C(C)(C)C)c2c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CCO)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a mixture of 131 mgs (1 equivalents, 236 μmol) of Methyl-1-(2-(tert-butyldimethyl silyloxy)ethyl)-7-chloro-3-cyclohexyl-2-(4-methoxy phenyl)-1H-indole-6-carboxylate in 4 mL of THF was added under N2 a 1 M solution of tetrabutylammonium fluoride in THF (2 equivalents, 471 μL). The reaction mixture was stirred for two hours at room temperature. The solution was concentrated en vacuo, washed with water and the product extracted with ethyl acetate. Automated flash chromatography (Biotage Horizon™, gradient elution, 10 to 50% Ethyl Acetate/Hexane) gave 97.0 mgs (93%) of Methyl-7-chloro-3-cyclohexyl-1-(2-hydroxyethyl)-2-(4-methoxyphenyl)-1H-indole-6-carboxylate. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 5 mL/minute. The NMR spectra was recorded at room temperature using a Bruker DRX300 spectrometer. Chemical shifts were reported in ppm relative to the deuterated solvent used. Coupling constants were reported in hertz. Peak multiplicity was reported using the following abbreviations: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), br (broad). 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=8.42 Hz, 1H), 7.50 (d, J=8.42 Hz, 1H), 7.25 (d, J=8.78 Hz, 2H), 7.01 (d, J=8.78 Hz, 2H), 4.50 (t, J=6.22 Hz, 2H) 3.94 (s, 3H), 3.89 (s, 3H), 3.76 (t, J=6.22 Hz, 2H), 2.55 (m, 1H), 1.71 (m, 6H) 1.38 (m, 1H) 1.23 (m, 3H). MS m/z 442.15 (M+H), Rf 2.20 min., 96.4% purity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([O:12][CH2:15][CH2:16][CH2:17][OH:18])[CH:5]=1
Reactant: CCc1ccc(C(=O)OC)cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1ccc(C(=O)OC)cc1OCCCO

Procedure:
To a solution of 4-ethyl-3-hydroxy-benzoic acid methyl ester (3.21 g, 17.81 mmol) in acetonitrile (35 mL) are added 3-bromo-1-propanol (1.85 mL, 21.37 mmol) and K2CO3 (3.69 g, 26.7 mmol). The solution is refluxed for 4 h, then poured into water and extracted three times with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to give the title product. TLC, Rf (c-hexane/AcOEt 8:2)=0.15, MS (LC-MS): 239.2 [M+H]+, tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, flow: 1.5 ml/min): 5.10 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]=2[CH:32]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]3[CH:21]=[CH:22][C:23]4[C:28](=[O:29])[O:27][C:26]([CH3:30])([CH3:31])[O:25][C:24]=4[CH:32]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Product: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-[(4-methoxyphenyl)-ethynyl]benzaldehyde (intermediate which may be obtained according to methods disclosed in EP03103780.7) and 7-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one as a brown powder (%). 1H NMR (CDCl3) δ 7.70 (d, J=8.7 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.9 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 6.30 (m, 1H), 6.01 (s, 1H), 4.37 (s, 2H), 3.81 (s, 3H), 1.67 (s, 6H). M+ (ESI): 414.1, M− (ESI): 412.1. HPLC, Rt: 4.90 min (purity: 92.8%).
Reaction SMILES: C(OC(C1NC=C(C(OCC)=O)C=1C)=O)C.OC(C)(C)C(OC)=O.[C:25]([O:29][C:30](=[O:51])[C:31]([CH3:50])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)[CH3:32])(C)(C)C>>[CH3:25][O:29][C:30](=[O:51])[C:31]([CH3:32])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)[CH3:50]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)c1c[nH]c(C(=O)OCC)c1C
Agent: COC(=O)C(C)(C)O
Product: COC(=O)C(C)(C)Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
Compound 433A (5.63 g, 98%) was prepared from 1A (4.00 g, 17.3 mmol) and methyl 2-hydroxyisobutyrate (5.00 ml, 43.3 mmol) by a route analogous to that used for the preparation of compound 388B. It is a faintly yellow solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.CO.[ClH:31].CCOCC>>[ClH:31].[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(OCc1ccc(OC(F)(F)F)cc1)N1CCNCC1

Procedure:
A solution of 174 mg (0.49 mmol) piperazine-1,4-dicarboxylic acid tert-butyl ester 4-trifluoromethoxy-benzyl ester in 4.9 ml 1.5M HCl/Et2O and 0.98 ml abs. MeOH was stirred at rt for 3 h. Evaporation of the reaction mixture provided 189 mg as colourless powder. 1H-NMR (d6-DMSO): 3.10 m, 4H and 3.62 m, 4H; 5.13 2, 2H; 7.40 d, 2H and 7.53 d, 2H, AB-system; 9.2 br, 2H. MS (ISP): 305.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:20].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][O:10][CH3:20])[CH:5]=[CH:4][CH:3]=1
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(c1cccc(Br)n1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(6-Bromopyridin-2-yl)-2-morpholin-4-ylethanol (Example 141, Step 1) (1 g, 3.48 mmol) was taken up in THF (7 mL) and cooled to 0° C. Sodium hydride (0.153 g, 3.83 mmol) was added and the suspension stirred at 0° C. for 5 minutes. A solution of iodomethane (0.240 mL, 3.83 mmol) in THF (3 mL) was added and the reaction mixture stirred at 0° C. for 30 minutes. Saturated NH4Cl was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (40-100% EtOAc-hexanes) gave the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)=[C:6]([CH:22]=1)[CH2:7][NH:8][C:9]([C@@H:11]([NH:14]C(=O)OC(C)(C)C)[CH2:12][CH3:13])=[O:10].Cl.CO.Cl.O1CCOCC1>CCOC(C)=O.O1CCOCC1>[NH2:14][C@@H:11]([CH2:12][CH3:13])[C:9]([NH:8][CH2:7][C:6]1[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:23]1[CH:27]=[N:26][N:25]=[N:24]1)=[O:10]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl (1S)-1-({[5-chloro-2-(1H-tetraazol-1-yl)benzyl]amino}carbonyl)propylcarbamate (237 mg, 0.60 mmol) in EtOAc (3.5 mL) at rt was added 4 M HCl in dioxane (0.6 mL, excess). After 30 min, a small amount of MeOH was added to keep product in solution. After 3 h, another 0.6 mL of 4 M HCl/dioxane was added and continued to stir overnight at rt. Solvent was removed in vacuo to give the title compound as a foamy yellow solid. LCMS (M+H): 295.0. 1H NMR (400 MHz, CD3OD): δ 9.58 (s, 1 H), 8.79 (m, 1 H), 7.68 (d, J=2.4 Hz, 1 H), 7.58 (dd, J=2.0 Hz, 8.4 Hz, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 4.30–4.29 (m, 2 H), 3.79 (app t, J=6.2 Hz, 1 H), 1.87–1.80 (m, 2 H), 0.97 (t, J=7.6 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([CH:34]=2)[C:23]([NH:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[O:24])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:35][CH3:36]
Reactant: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3cc(F)ccn23)n1
Temperature: 175 °C
Yield: 40 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)-2-(methyloxy)benzamide (Example 197, step A) (137 mg, 0.27 mmol) and 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (Example 214, step E) (80 mg, 0.25 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (120 μL, 0.47 mmol). The mixture was stirred and heated on a microwave at 175° C. for 40 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum, and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (83 mg, 0.10 mmol, 42%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.80 (s, 1H), 9.41-9.51 (m, 1H), 8.51 (s, 1H), 8.25 (d, J=5.3 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.79 (dd, J=8.6, 1.8 Hz, 1H), 7.61 (dd, J=9.5, 2.6 Hz, 1H), 7.48 (s, 1H), 7.36-7.46 (m, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.16-7.25 (m, 2H), 6.98-7.06 (m, 1H), 6.78 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 3.14-3.22 (m, 2H), 3.03-3.12 (m, 2H), 2.98 (s, 3H), 2.58-2.69 (m, 2H), 2.15 (s, 3H), 1.77-1.85 (m, 2H), 1.66-1.77 (m, 2H), 1.45-1.56 (m, 1H), 1.28-1.42 (m, 2H). MS (ESI): 799 [M+H]+.
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO.O>[C:14]1([N:20]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.1 %

Procedure:
To 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (230 mg, 1.3 mmol) in EtOH (5 mL, 200 proof) was added H2O (3.7 mL), 1NaOH(aq) (1.3 mL), and phenylhydrazine hydrochloride (188 mg, 1.3 mmol) and the mixture heated at 90° C. overnight. After cooling to room temperature, the mixture was diluted with H2O, extracted with EtOAc, the org layer concentrated in vacuo, and purified by column chromatography (5-25% EtOAc/hexanes) to give 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (150 mg, 0.56 mmol, 43%). LC-MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[C:6]([CH3:20])[N:5]=[C:4]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[N:3]=1.[CH3:29][C@@H:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:21]=1[C:4]1[N:5]=[C:6]([CH3:20])[C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[C:2]([N:34]2[CH2:33][CH2:32][NH:31][C@H:30]([CH3:29])[CH2:35]2)[N:3]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN[C@H](C)C1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidine (0.1 mmol in 0.5 mL DMA), (R)-2-methyl-piperazine (40 mg) and sodium carbonate (85 mg) is heated at 100° C. with agitation for 18 h. The reaction mixture is allowed to cool and partitioned between EtOAc (6 mL) and water (2 mL). The organic layer is separated, washed with water (2 mL×2), brine (2 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a colorless oil. Purification by chromatography on silica gel (2% MeOH/DCM/0.1% Ammonium hydroxide) provides the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.06-7.26 (m, 4H), 6.79-6.82 (m, 2H), 4.97 (dd, 2H), 3.89-3.96 (m, 2H), 2.87-3.05 (m, 5H), 2.62-2.69 (m, 1H), 2.56 (s, 3H), 2.23 (s, 3H), 2.16 (s, 6H), 1.27 (d, J=6.8 Hz, 6H), 0.93 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:16]1[CH:20]=[CH:19][S:18][C:17]=1[CH:21]=[O:22])=[CH:6][NH:7]2.[BH4-].[Na+].ClCCl>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:16]1[CH:20]=[CH:19][S:18][C:17]=1[CH2:21][OH:22])=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccsc3C=O)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccsc3CO)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
3-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl) thiophene-2-carbaldehyde (120 mg, 0.39 mmol) was suspended in ethanol (5 ml), and sodium borohydride (19.24 mg) was added to the suspension. The resulting mixture was stirred at room temperature for 1 hour. Dichloromethane was added to the reaction mixture, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 110 mg of powdery white 5-fluoro-3-(2-hydroxymethylthiophen-3-yl)-8-propoxy-1H-quinolin-4-one (yield: 82%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:33]4[C:28](=[CH:29][C:30]([N+:34]([O-])=O)=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:10]=1.[H][H]>CO.[Pd]>[NH2:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])[CH2:23][CH2:22]3)=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(N3CCN(C(=O)Nc4ccc(F)cc4)CC3)ccnc2c1

Procedure:
A suspension of 4-[4-(4-fluorophenylaminocarbonyl)piperazin-1-yl]-7-nitroquinoline trifluoroacetate (130 mg) and 10% Pd/C (20 mg) in MeOH is stirred in a hydrogen atmosphere for 30 min. The reaction mixture is filtered and concentrated giving the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][NH:23][CH:24]2[CH3:29]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][CH:27]=[CH:28][C:19]=4[C:15]4[O:14][CH:18]=[CH:17][CH:16]=4)[CH:24]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3ccco3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3ccco3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CO
Product: O=C(OC(=O)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
Three hundred grams of parahydroxybenzoic acid and one thousand and five hundred grams of 10% aqueous methanol solution were put into a 2 L flask, and heated to 80° C. to give a 10% aqueous methanol solution containing parahydroxybenzoic acid. The solution was cooled to 60° C. at a rate of 0.5° C./min, and filtered by using a centrifuge at 60° C. As a result, 184.0 g of crystalline parahydroxybenzoic acid anhydride was obtained. The water content measured by Karl Fischer's method was 4.5%. The resulting crystalline product was dried with airflow at 70° C., and 174.9 g of crystalline parahydroxybenzoic acid anhydride was obtained.
Reaction SMILES: COC1C=[C:5]([CH:9](C)[CH2:10][CH2:11][C:12](=[O:15])C=C)[CH:6]=[CH:7]C=1.C(N(CC)CCC(=O)CCC(C1C=CC=C([O:33]C)C=1)C)C>[OH-].[K+]>[CH2:6]([CH:5]1[C:9](=[O:33])[CH2:10][CH2:11][C:12]1=[O:15])[CH3:7]
Reactant: CCN(CC)CCC(=O)CCC(C)c1cccc(OC)c1
Reactant: C=CC(=O)CCC(C)c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux a mixture of 6-(m-methoxyphenyl)hept-1-en-3-one and 1-diethylamino-6-(m-methoxyphenyl)heptan-3-one (10 g, obtained by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (7 g) in 0.12% methanolic potassium hydroxide solution (40 cc) for 15 hours. Remove most of the methanol under reduced pressure and add a mixture of equal volumes of ether and benzene (50 cc). Wash the solution with 5% aqueous sodium hydroxide, water, 10% hydrochloric acid, and brine, and dry. Evaporate the solvent to leave as residue the triketone adduct 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione (14 g); infrared absorption peak at 5.80 μ.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([I:28])=[CH:23][N:22]=1>C(#N)C>[Cl:20][C:21]1[N:26]=[C:25]([NH:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:24]([I:28])=[CH:23][N:22]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: NCCCN1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(I)c(NCCCN2CCOCC2)n1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
In accordance with procedure 2, 3-morpholin-4-yl-propylamine (0.73 ml, 5 mmol) and N-ethyldiisopropylamine (1.71 ml, 10 mmol) are dissolved in 100 ml acetonitrile under argon and cooled to −35° C. The solution of 2,4-dichloro-5-iodo-pyrimidine (1.37, 5.0 mmol) in 50 ml acetonitrile is then added dropwise at −35° C. internal temperature. Stirred 1 hr further at −30 to −20° C., then slowly warmed up to RT and stirred for 3 days at RT.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[O:22][CH:23]([F:25])[F:24])=[CH:4][C:5]([F:13])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[OH-].[Li+].Cl.CN(C)CCCN=C=NCC.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>O1CCCC1.O.C(OCC)(=O)C.CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:3]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[O:22][CH:23]([F:25])[F:24])=[CH:4][C:5]([F:13])=[C:6]([CH:12]=1)[C:7]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2OC(F)F)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2OC(F)F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
To a solution of ethyl 5-chloro-4-[4-chloro-2-(difluoromethoxy)phenoxy]-2-fluorobenzoate (Preparation 131, 0.070 g, 0.000177 mol) in tetrahydrofuran (2.50 mL) and water (2.50 mL) was added lithium hydroxide (0.050 g, 0.00209 mol). The reaction mixture was stirred at room temperature under nitrogen for 4 hours. The reaction was diluted with ethyl acetate (10.0 mL) and washed with a saturated aqueous solution of brine (10.0 mL). The organic layer was separated, dried with sodium sulphate, filtered and concentrated in vacuo. The crude was taken up in dichloromethane (5.0 mL) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.051 g, 0.000266 mol), N,N-dimethylpyridin-4-amine (0.049 g, 0.000401) and methanesulfonamide (0.026 g, 0.000273 mol) were added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction was diluted in dichloromethane (10.0 mL) and washed twice with an aqueous solution of hydrochloric acid (2M, 15.0 mL). The biphasic system was passed through a separation cartridge to collect the organic layer, which was then concentrated in vacuo. The crude was purified using silica gel column chromatography eluting with 0-100% EtOAc in heptane, 4 g. The compound obtained was then triturated in tert-butyl methyl ether to yield title compound as a pale pink solid (0.020 g, 25% yield).
Reaction SMILES: [Br-].[Li+].BrCC=CCBr.[C:9]([OH:12])(=[O:11])[CH3:10].C(OC(=O)C)(=O)C.C=CC=C.O=O.[C:26]([O:29][CH2:30][CH:31](OC(=O)C)[CH:32]=[CH2:33])(=[O:28])[CH3:27].C(OCC=CCOC(=O)C)(=O)C>[O-2].[O-2].[O-2].[Cr+6]>[C:9]([O:12][C:30]([O:29][C:26](=[O:28])[CH3:27])=[CH:31][CH2:32][CH3:33])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: C=CC(COC(C)=O)OC(C)=O
Agent: [Cr+6]
Agent: BrCC=CCBr
Agent: C=CC=C
Solvent: CC(=O)OC(C)=O
Product: CCC=C(OC(C)=O)OC(C)=O
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
Another run was conducted according to the process of this invention in the same apparatus as employed in the previous runs of Examples I and II. In this run, the reactor was charged with 2.3 grams (20 mmol) of chromium trioxide (CrO3), 6.5 grams (75 mmol) of lithium bromide, 4.6 grams (22.5 mmol) of 1,4-dibromo-2-butene, 50 mol of acetic acid, 25 ml of acetic anhydride, and 10.8 grams (200 mmol) of butadiene from the vapor phase. The reactor was pressured to 30 psig with oxygen, placed in an oil bath and heated to 140° C. Again, as in the previous runs, the reactor was pressured with oxygen from time to time to about 120 psig. After about 45 minutes required to reach the reaction temperature, the reaction was conducted for 5.75 hours. At the end of the reaction period, the reactor was vented, and the reaction mixture transferred to a distilling flask. The mixture was distilled under reduced pressure to remove the acetic acid. The product fraction was analyzed by (GLC) as before and there was found 12.9 mmol of 1,2-diacetoxy-3-butene and 56.5 mmol of 1,4-diacetoxy-2-butene for a diacetoxybutene yield of 35 percent based on the butadiene charged.