Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](OC(=O)C)(=[O:30])C>C(O)=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][CH:28]=[O:30])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Solvent: O=CO
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC=O)c3Cl)cccn2c1Br
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a suspension of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg) in formic acid (1 ml) was added acetic anhydride (65 mg), and the mixture was stirred for 1.5 hours. Acetic anhydride (40 mg) was added thereto, and the mixture was stirred for 3 hours. The mixture was concentrated in vacuo, and a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride:methanol=5:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(formylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (102 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)COc1ccc(CCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(CCCOS(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
A solution of methyl [4-(3-hydroxypropyl)phenoxy]acetate (4.5 g, 20.5 mmol) in dichloromethane (50 ml) was treated at 0° C. with triethylamine (4.36 g, 43.1 mmol) followed by methanesulfonyl chloride (3.99 g, 34.8 mmol) added dropwise over 5 min. After 30 min at 0° C., the reaction mixture was diluted with dichloromethane, washed with 1N hydrochloric acid, water and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 8:18) gave 5.51 g (89%) of the title material as a white solid: mp 49-51° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:14]=[C:15]([C:18]([F:20])([F:21])[F:19])[CH:16]=[CH:17][C:12]=1[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(C(F)(F)F)ccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 29.6 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 0.50 g, 3.4 mmol), 2-fluoro-5-(trifluoromethyl)phenylboronic acid (Aldrich; 561 mg, 3.4 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2-fluoro-5-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (310 mg, 31%) as a colorless oil that solidified.
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:32]2[CH:37]=[CH:36][C:35]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH3:30])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[C:44]([C@@H:41]1[CH2:42][CH2:43][C@H:38]([C:35]2[CH:34]=[CH:33][C:32]([C@H:14]([C:15](=[O:31])[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[CH3:30])=[CH:21][CH:22]=3)[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:48])=[O:5])=[CH:8][CH:9]=3)=[CH:37][CH:36]=2)[CH2:39][CH2:40]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1cc(Cl)ccc1-c1ccc(NC(=O)[C@H](Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)[C@H](Cc2ccc(C(=O)O)cc2)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 431 mg of 4-[(R)-2-[4-(4-(cis)-tert-Butyl-cyclohexyl)-phenyl]-2-(4′-chlor-2′-methyl-biphenyl-4-ylcarbamoyl)-ethyl]-benzoic acid tert-butyl ester in dichloromethane (10 mL) was treated with trifluoroacetic acid (2 mL) and concentrated aqueous hydrochloric acid (1 mL). The resulting mixture was stirred for 16 h at room temperature. The organic phase was separated, washed with water and dried over magnesium sulfate. Concentration left a residue that was used without further purification.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:3]=1.[C:25]1([O:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[C:34]([CH3:47])[CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:47][C:34]1[CH:33]=[C:32]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:37]=[CH:36][C:35]=1[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccccc2)ccc1-c1cn([C@H]2CC[C@H](N3CCN(C)CC3)CC2)c2ncnc(N)c12
Temperature: 80 °C

Procedure:
A mixture of trans-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.347 g, 0.000788 mol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl phenyl ether (0.27 g, 0.000867 mol), tetrakis(triphenyl-phosphine)palladium(0) (0.054 g, 0.000047 mmol), and sodium carbonate (0.209 g, 0.00197 mol) in N,N-dimethylformamide (15 mL) and water (10 mL) was heated at 80° C. under an atmosphere of nitrogen for 16 hours. The mixture was allowed to cool to ambient temperature and the solvent removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine/dichloromethane (5:95) followed by methanol/triethylamine/ dichloromethane (3:5:92) as mobile phase to yield trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.376 g, 0.000757 mol). Trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.376 g, 0.000757 mol) was dissolved in refluxing ethanol (10 mL) and a preheated solution of maleic acid (0.264 g, 0.00227 mol) in ethanol (5 mL) was added. The mixture was refluxed for 15 minutes, cooled to ambient temperature and the precipitate collected by filtration, washed with cool ethanol and dried to give trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate (0.153 g, 0.000181 mol): 1H NMR (DMSO-d6, 400 MHz) 8.22 (s, 1H), 7.42 (m, 3H), 7.25 (d, 1H), 7.17 (t, 1H), 7.09 (d, 2H), 7.02 (s, 1H), 6.89 (d, 1H), 6.16 (s, 6H), 4.58 (m, 1H), 3.3 (br, 9H), 2.68 (s, 3H), 2.22 (s, 3H), 2.01 (br, 6H), 1.57 (br, 2H) RP-HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 23 min with 0.1 M ammonium acetate, 1 mL/min) Rt 7.30 min. MS: MH+497.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Product: Cc1ccc(-c2cc(C(F)(F)F)n3ncc(C#N)c3n2)cc1
Yield: 50 %

Procedure:
Reaction of 1-(4-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 4-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (151 mg, 50%). MS (ISP) 303.1 [(M+H)+]; mp 121° C.
Reaction SMILES: [CH3:1][C:2]([NH:6][CH2:7][C@@H:8]1[CH2:13][N:12]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]1[C:22]1[CH:27]=[CH:26][C:25]([C@@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)([CH3:5])[CH2:3][OH:4].CC(NC[C@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC([C@](O)(C)C(F)(F)F)=CC=1)(C)CO.CC(NC[C@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC([C@@](O)(C)C(F)(F)F)=CC=1)(C)CO.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH3:5][C:2]([NH:6][CH2:7][C@@H:8]1[CH2:13][N:12]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:16])[CH2:11][CH2:10][N:9]1[C:22]1[CH:27]=[CH:26][C:25]([C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CC(C)(CO)NC[C@@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: CC(C)(CO)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1
Agent: CC(C)(CO)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CC(C)(CO)NC[C@@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1

Procedure:
2-methyl-2-((((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol; 2-methyl-2-((((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol; 2-methyl-2-((((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)-1-propanol. 1H NMR (400 MHz, CDCl3) δ 7.65-7.64 (m, 1H), 7.58-7.56 (m, 1H), 7.44-7.42 (d, J=8.6 Hz, 2H), 7.18-7.15 (m, 1H), 6.86-6.83 (d, J=8.6 Hz, 2H), 3.93-3.86 (m, 2H), 3.78-3.73 (m, 1H), 3.51-3.46 (m, 1H), 3.34-3.21 (m, 3H), 2.92-2.87 (m, 1H), 2.72-2.59 (m, 3H), 1.74 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H). m/z (ESI, +ve ion) 522.2 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.97 μM; GK-GKRP EC50 (LC MS/MS)=2.78 μM
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:37]([O:39][CH2:40][CH3:41])=[CH2:38])CCC>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.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([C:37]([O:39][CH2:40][CH3:41])=[CH2:38])[N:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(C(=O)OC)cc(Cl)n1
Temperature: 100 °C
Yield: 84 %

Procedure:
Add 2,6-dichloro-isonicotinic acid methyl ester, tetrakis(triphenylphosphine)palladium(0) (0.763 g, 0.66 mmol), triphenylphosphine (0.346 g, 1.32 mmol), tributyl(l-ethoxyvinyl)tin (5.0 g, 13.9 mmol) and toluene (30 mL), to a sealed flask flushed with nitrogen. Heat at 100° C. overnight and cool to room temperature. Filter the mixture through a filtering agent, concentrate and purify (silica gel chromatography eluting with 25:75 ethyl acetate:hexanes) to give the title compound (84%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]([F:17])([CH2:15][OH:16])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.CO>[ClH:1].[F:17][C:12]1([CH2:15][OH:16])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OCC1(F)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4 N solution of hydrochloric acid in 1,4-dioxane (213 μL) was added to a solution of 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (24.9 mg, 0.107 μmol) in MeOH (213 μL) at room temperature, and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to give (4-fluoro-piperidin-4-yl)-methanol hydrochloride as a brown form (19.6 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].IC.[C:25](=O)([O-])[O-].[K+].[K+]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@@H:12]1[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cn([C@@H]2CCNC2)c2ccc(I)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cn([C@@H]2CCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
To a solution of (R)-ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Intermediate 110, 282 mg, 0.68 mmol, 1 equiv.) in THF (7 mL) was added iodomethane (0.0471 mL, 0.75 mmol, 1.1 equiv.) followed by potassium carbonate (378 mg, 2.74 mmol, 4 equiv.). This was stirred at 60° C. for 1 d. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organics were concentrated to provide (R)-ethyl 6-iodo-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a light yellow solid (282 mg, >99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([CH:13]2[CH2:16][CH2:15][CH:14]2[C:17]([OH:19])=O)=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]([NH2:35])=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([CH:13]2[CH2:16][CH2:15][CH:14]2[C:17]([NH:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH2:20][CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:19])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: N#Cc1ccc(NC(=O)C2CCC2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)C3CCC3C(=O)Nc3ccc(C#N)c(Cl)c3)ccc21
Yield: 6.1 %

Procedure:
A solution of the compound obtained in Step 1 (795 mg, 2.85 mmol), 9-ethyl-9H-carbazol-3-amine (600 mg, 2.85 mmol), HATU (1085 mg, 2.85 mmol) and TEA (0.437 mL, 3.14 mmol) in DMF (5 mL) was stirred at room temperature for 14 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane), and crystallized from ethyl acetate and ethanol to give the title compound (82 mg, 0.174 mmol, 6.10%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.CC1C=CC(C)=C2C=1CCC2O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2
Reactant: Cc1ccc(C)c2c1CCC2=O
Agent: Cc1ccc(C)c2c1CCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C)c2c1C=CC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
2.9 g (0.0181 moles) of 4,7-dimethyl-1-indanone (formula XVII) obtained as described above, are slowly added to a suspension of 0.350 g (0.0692 moles) of LiAlH4 in 30 ml of ethyl ether, maintained at −30° C. in an inert atmosphere. The reaction is complete after 30 minutes. Ice and HCl 2N are cautiously added until acidification, the mixture is then extracted with ethyl ether, and the organic phase is subsequently separated and washed until neutrality. It is anhydrified on sodium sulfate and evaporated, obtaining a residue essentially consisting of 4,7-dimethyl-1-indanol. The residue is dissolved in 10 ml of THF, a pinch of p-toluenesulfonic acid is added and the mixture is brought to reflux temperature for 1 hour. Solid NaHCO3 and Na2SO4 are then added. The mixture is filtered and the solvent evaporated obtaining 2.4 g of 4,7-dimethyl-indene (XVIII) (91% yield).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])[CH:8]=1)=[O:5]>C1(C)C=CC=CC=1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:33])=[O:2])[CH:12]=[CH:11][CH:10]=2)=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCCCCCOc2cccc(NC(=O)C(=O)OC)c2)ccc(C(C)=O)c1O
Solvent: Cc1ccccc1
Product: CCCc1c(OCCCCCOc2cccc(NC(=O)C(=O)O)c2)ccc(C(C)=O)c1O

Procedure:
starting from N-[3-(5-[4-acetyl-3-hydroxy-2-n-propylphenoxy]-pentyloxy)-phenyl]-oxamic acid methyl ester there is obtained N-{3-[5-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-pentyloxy]-phenyl}-oxamic acid having a melting point of 117°-118° (toluene) and the triethanolammonium salt thereof,
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12](OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of methyl 3-(benzyloxy)-5-methoxybenzoate (8.90 g) in THF (100 mL) was added lithium aluminum hydride (1.30 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.50 g) as an oil. This compound was used for the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]=[C:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[Cl:3][CH:6]=[C:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)C(=CO)Oc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Reaction time: 12 h
Yield: 81 %

Procedure:
297.5 g (2.5 mols) of thionyl chloride were slowly stirred into a solution, warmed to 60° C., of 404.6 g (1.7 mols) of 1-hydroxy-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one in 3,000 ml of anhydrous toluene. The mixture was kept at this temperature for 12 hours and the solvent and excess thionyl chloride were then distilled off. The oil which remained was distilled in vacuo. 353.3 g (81% of theory) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one of boiling point 95°-103° C./0.3 mm Hg were obtained. ##STR51##
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:15]1([C:13]2[N:10]=[C:6]3[CH:7]=[CH:8][C:9]4[O:1][CH2:2][CH2:3][C:4]=4[N:5]3[CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccc2c(n1)CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2cn3c4c(ccc3n2)OCC4)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 15.7 %

Procedure:
To a solution of 2,3-dihydrofuro[3,2-b]pyridin-5-amine (500 mg, 3.67 mmol) in ethanol (30 mL) were added 2-bromo-1-phenylethanone (730 mg, 3.67 mmol) and sodium carbonate (467 mg, 4.40 mmol), and the mixture was stirred at 80° C. for 14 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound (136 mg, yield 16%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]2[N:22]([C:25](=[O:48])[CH:26]([NH:31][C:32](=[O:47])[CH:33]([N:35]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH3:36])[CH3:34])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([O:39][C:37](=[O:38])[N:35]([CH:33]([C:32](=[O:47])[NH:31][CH:26]([C:25]([N:22]1[CH2:23][CH2:24][CH:9]2[NH:8][CH2:12][CH:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:10]12)=[O:48])[C:27]([CH3:28])([CH3:30])[CH3:29])[CH3:34])[CH3:36])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(OCc1ccc(F)cc1)CN2C(=O)OC(C)(C)C)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2NCC(OCc3ccc(F)cc3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
A solution containing 48 (4.0 g, 5.98 mmol) in DCM (20 mL) was cooled to 0° C. and TFA (10 mL) was added. After 2.5 h, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic solution was washed successively with aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 3.3 g of 49 as a beige-colored foam which was used directly in the next reaction. Mass spectrum, m/z [569.1] (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1B(O)O.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)Cc1c(C)cc(C)cc1C

Procedure:
Ethyl 2,4,6-trimethylphenylacetate was prepared according to the general experimental method from 2,4,6-trimethylphenylboronic acid (164 mg, 1.00 mmol). After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 2,4,6-trimethylphenylacetate is obtained as a colourless liquid in a yield of 62% of theory. 1H NMR (200 MHz, CDCl3): δ=6.89 (s, 2H), 4.10-4.25 (m, 2H), 3.67 (s, 2H), 2.27-2.37 (m, 9H), 1.27 (t, J=7.1 Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3): δ=171.9, 137.4, 136.8, 129.3, 129.2, 61.1, 35.6, 21.3, 20.6, 14.7 ppm; MS (70 eV), m/z (%): 206 (23) [M+], 160, (7), 133 (100), 105 (10) 91 (11); IR (NaCl): ν=2978 (m), 2867 (w), 1732 (s), 1157 (m), 1031 (m) cm−1.