Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Br)CBr
Reactant: CC(C)(CNc1ccccc1Cl)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(CN(C(=O)CBr)c1ccccc1Cl)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
1.52 ml of bromoacetyl bromide (17.5 mmol) was added to a solution of 3.49 g of [2-(2-chlorophenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (1h) (11.7 mmol) in N,N-dimethylacetamide (58 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 4.68 g of the title compound (yield: 95%).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])=[O:6])[CH3:3].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]Cl>C(O)C>[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])=[C:15]([O:20][CH3:21])[CH:14]=2)[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])=[O:6])[CH3:3]
Reactant: CN(C)CCCCl
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(O)c(OC)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(OCCCN(C)C)c(OC)c1

Procedure:
A solution of 2.3 g of sodium in 100 ml of ethanol is added to a warm solution of 37.5 g of 2,6-dimethyl-4-(3-methoxy-4-hydroxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (melting point 172°C) in 300 ml of ethanol. The mixture is heated at reflux and 15 g of 3-dimethylaminopropyl chloride are added dropwise. After refluxing for several hours, the mixture is filtered hot, the residue being washed with alcohol, and the filtrate is evaporated in vacuo to yield yellow crystals of melting point 62°C after recrystallization from ligroin-petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:45]=[C:44]([F:46])[C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[C:23]4[O:24][CH2:25][CH:26]([OH:43])[CH2:27][N:28]([C:29]([O:31][CH2:32][CH2:33][O:34][C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=5[CH3:42])=[O:30])[C:22]=4[CH:21]=[CH:20][CH:19]=3)[CH:15]=[N:14]2)=[C:10]([Cl:47])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([C:8]1[CH:45]=[C:44]([F:46])[C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[C:23]4[O:24][CH2:25][C:26](=[O:43])[CH2:27][N:28]([C:29]([O:31][CH2:32][CH2:33][O:34][C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=5[CH3:42])=[O:30])[C:22]=4[CH:21]=[CH:20][CH:19]=3)[CH:15]=[N:14]2)=[C:10]([Cl:47])[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(Cl)cccc1OCCOC(=O)N1CC(O)COc2c(-c3cnn(Cc4c(F)cc(C(=O)OC(C)(C)C)cc4Cl)c3)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)cccc1OCCOC(=O)N1CC(=O)COc2c(-c3cnn(Cc4c(F)cc(C(=O)OC(C)(C)C)cc4Cl)c3)cccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.5 %

Procedure:
To a solution of 2-(3-chloro-2-methylphenoxy)ethyl 9-(1-(4-(tert-butoxycarbonyl)-2-chloro-6-fluorobenzyl)-1H-pyrazol-4-yl)-3-hydroxy-3,4-dihydrobenzo[b][1,4]oxazepine-5(2H)-carboxylate (59 mg, 0.086 mmol) in DCM (5.0 mL) was added Dess-Martin periodinane (109 mg, 0.258 mmol). The reaction was stirred at room temperature for 2 d. The mixture was diluted with a solution of saturated sodium bicarbonate (15 mL) and extracted with DCM (20 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (58 mg, 92% yield) as white form. LCMS, [M+H]+=684.3. 1H NMR (400 MHz, CDCl3) δ 7.89-7.86 (m, 1H), 7.83 (d, J=6.8 Hz, 2H), 7.66 (dd, J=9.5, 1.5 Hz, 1H), 7.42 (dd, J=7.7, 1.5 Hz, 1H), 7.18 (br. s., 1H), 7.10-6.95 (m, 3H), 6.68 (d, J=7.3 Hz, 1H), 5.54 (d, J=1.5 Hz, 2H), 4.54 (s, 4H), 4.49 (s, 2H), 4.16 (br. s., 2H), 2.21 (br. s., 3H), 1.59 (s, 9H).
Reaction SMILES: [N+:1](=[C:3]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[NH:17]([CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:22]1)[C:18](N)=[O:19].ClC(Cl)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[CH2:7]([O:6][C:4]([C:3]1[NH:1][C:18](=[O:19])[N:17]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])[CH2:22]2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccccc1
Reactant: NC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c(=O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A flask containing a mixture of ethyl 2-diazo-3-oxo-3-phenylpropanoate (16C) (2.80 g, 12.84 mmol), 16B (4.45 g, 16.05 mmol) from previous step, and 128 mL of 1:1 toluene:dichloroethane was heated at 80° C. for about 10 minutes. A suspension of rhodium octanoate dimer (0.20 g, 0.26 mmol) in 25 mL toluene was added dropwise to the reaction mixture via an addition funnel. The reaction was held at 80° C. for an additional hour after the addition was completed. After the disappearance of 16C, the reaction was cooled to RT. Approximately 8 mL of TFA was then added and the reaction was allowed to stir overnight at RT. The reaction mixture was concentrated to a green oil then purified by flash chromatography on silica gel using 5% methanol/DCM to afford benzyl 3-(4-(ethoxycarbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate (16D) as a tan solid (2.50 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.07 Hz, 3H) 1.07-1.18 (m, 2H) 1.24 (br. s., 1H) 1.62-1.78 (m, 2H) 2.36-2.43 (m, 1H) 2.59-2.68 (m, 1H) 3.46-3.58 (m, 2H) 3.96 (q, J=6.91 Hz, 2H) 4.99 (s, 1H) 7.26-7.51 (m, 11H) 10.97 (s, 1H) ESI-MS: m/z 450.1 (M+H)+.
Reaction SMILES: O.Cl.[CH2:3]([N:10]1[CH2:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:13][C:12](=[O:23])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[Na]>C(O)C>[CH2:3]([N:10]1[CH2:11][CH:12]([OH:23])[CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(C2=CC(=O)CN(Cc3ccccc3)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C2=CC(O)CN(Cc3ccccc3)C2)cc1
Yield: 88.5 %

Procedure:
A solution of 1-benzyl-1,6-dihydro-5-(p-tolyl)-3-[2H]-pyridone hydrochloride hydrate (4.7 g) in ethanol (100 ml) was treated with sodium bicarbonate (1.2 g), followed by sodium borohydridge (1 g). After 1 hour the solvents were removed under reduced pressure and the residue partitioned between water (50 ml) and ether (200 ml). The ether layer was dried and the solvent removed under reduced pressure to give the title compound as an oil (3.5 g).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8]([Cl:11])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.OP([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CN(C=O)C>[Cl:11][C:8]1[C:9]2[S:10][C:2]([C:16]3[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=3)=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ncnc2cc(Br)sc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc3ncnc(Cl)c3s2)cn1
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-chloro-thieno[3,2-d]pyrimidine (4.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (4.4 mmol), Pd2(dba)3 (0.8 mmol), Ph3As (0.8 mmol) and K2HPO4(8.0 mmol) in a DMF (40 mL) and water (10 mL) are stirred at room temperature until the reaction was complete. The reaction is partitioned between EtOAc and water, washed with brine, dried, concentrated and purified by flash column chromatography on silica gel to give 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)-thieno[3,2-d]pyrimidine (compound 58.4).
Reaction SMILES: [CH2:1]([O:5]C(Cl)=O)[CH:2](C)C.C(O)(=O)C.C(N(CC)CC)C.[NH2:20][C@H:21]([CH3:39])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH3:38])[C:27]1=[O:28]>ClCCl>[C:1]([NH:20][C@H:21]([CH3:39])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH3:38])[C:27]1=[O:28])(=[O:5])[CH3:2]
Reactant: C[C@@H](N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
Isobutylchloroformate (341 mg, 2.5 mmol) was added slowly to a solution of acetic acid (146 mg, 2.5 mmol) and triethylamine (252.75 mg, 2.5 mmol) in dichloromethane (20 ml) at −15° C. After warming to room temperature over 15 minutes, a solution of (R)-1-(5-aminohexyl)-3,7-dimethylxanthine (prepared as described for CT11558) (558 mg, 2 mmol) in dichloromethane (10 ml) was added. After stirring al room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 13% methanol-ethyl acetate to provide (R)-1-(5-acetamidohexyl)-3,7-dimethylxanthine (CT12538) (380 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[F:22][C:23]([F:33])([F:34])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(OC(F)(F)F)c2)cc1
Temperature: 100 °C
Yield: 65.9 %

Procedure:
A mixture of methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (50 mg, 0.17 mmol) and 3-(trifluoromethoxy)benzaldehyde (0.025 ml, 0.20 mmol), NaBH(OAc)3 (109 mg, 0.52 mmol) and catalytic CH3COOH in DCM (12 ml) was heated at 100° C. (2 cycles of 5 min each) under microwave irradiation. The resulting mixture was purified by SPE-Si (2 g) eluting with a mixture DCM/AcOEt from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D25) (52 mg).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:31].[NH2:32][N:33](C)[C:34](=O)OC(C)(C)C>>[ClH:31].[ClH:31].[CH3:34][N:33]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:32]1
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (72 g, 160 mmol) was added hydrochloric acid (610 mL of 4.0 M, 2.5 mol). The reaction mixture was allowed to stir at 25° C. for 2 hours. Solvent was removed under vacuum, and the obtained solid was azeotroped with EtOH (3×700 mL). The resulting beige-white solid was dissolved in EtOH (685 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate (29 mL, 200 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (200 mL of 4.0 M, 800 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly cool to 25° C., and solids were collected by vacuum filtration. The filter cake was rinsed with a 10% solution of EtOH in hexane (2×500 mL). The solid was placed in a vacuum oven overnight (20 mm Hg/45° C.). 1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (42 g, 78%) was obtained as an off-white solid. ESI-MS m/z calc. 255.3. found 256.3 (M+1)+; Retention time: 1.30 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.82-7.76 (m, 1H), 7.61 (s, 1H), 7.40-7.34 (s, 1H), 7.22-7.14 (m, 2H), 4.19 (s, 3H), 3.52-3.42 (m, 2H), 3.41-3.33 (m, 2H), 2.39-2.07 (m, 4H).
Reaction SMILES: Br.[CH:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)([CH3:4])[CH3:3].[NH2:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:23](=[O:25])[CH3:24].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:23]([C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[NH:14][C:11]([C:9]1[N:10]=[C:6]([NH:5][CH:2]([CH3:3])[CH3:4])[S:7][CH:8]=1)=[O:13])(=[O:25])[CH3:24]
Reactant: COc1ccc(C(C)=O)c(N)c1
Reactant: CC(C)Nc1nc(C(=O)O)cs1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A mixture of compound 69 (4.4 g, 16.5 mmol) and the aniline derivative 66 (2.75 g, 16.5 mmol) in pyridine (140 mL) was cooled to −30° C. (upon cooling, the clear solution became partially a suspension). POCl3 (3.3 mL, 35 mmol) was added slowly over a 5 min period. The mixture was stirred at −30° C. for 1 h, and was then allowed to assume rt. After stirring at rt for 1.5 h the reaction mixture was poured over ice, and the pH was adjusted to about 9-10 using solid and saturated NaHCO3. The crude product was extracted into CH2Cl2 (3×) and the combined organic phases were dried (MgSO4) and evaporated. The crude dark-beige solid was purified by flash column chromatography (hexane/EtOAc 55:45) to give compound 70 (5.6 g, 76%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:20]1([CH2:19][O:18][C:17]2[C:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCCc1ncccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(CNCCCCCCOCCCc2ncccc2OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
2-[3-[(6-Bromohexyl)oxy]propyl]-3-(phenylmethoxy)pyridine (1.0 g) was added to benzylamine (3 ml) at 120° under nitrogen. After stirring for 2 h, the solution was cooled and added to water (10 ml) and 2N hydrochloric acid (10 ml). The aqueous mixture was basified with sodium carbonate and then extracted with ethyl acetate (3×50 ml). The ethyl acetate was evaporated and the excess benzylamine was removed by distillation at reduced pressure to leave the title compound as a red oil (810 mg), t.l.c. (ethyl acetate/triethylamine 99:1) Rf 0.13.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH:14]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:14]2[C:15]([CH3:18])([CH3:17])[CH2:16][N:12]([CH2:11][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)[C:13]2=[O:32])=[CH:21][C:22]=1[C:28]([F:31])([F:30])[F:29])#[N:27]
Reactant: CCOC(=O)c1ccc(CN2CC(C)(C)C(Oc3ccc(C#N)c(C(F)(F)F)c3)C2=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CN(Cc2ccc(C(=O)O)o2)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound obtained in Example 29, 5-[3-(4-cyano-3-trifluoromethyl-phenoxy)-4,4-dimethyl-2-oxo-pyrrolidin-1-ylmethyl]-furan-2-carboxylic acid ethyl ester, (0.461 g, 1.024 mmol) was dissolved in 5 mL THF and 1.5 mL 1 M NaOH was added. The reaction was stirred at ambient temperature overnight. The reaction mixture was acidified with 1 N HCl to pH ˜3 and extracted into ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the carboxylic acid, 5-[3-(4-cyano-3-trifluoromethyl-phenoxy)-4,4-dimethyl-2-oxo-pyrrolidin-1-ylmethyl]-furan-2-carboxylic acid, as a white solid (0.417 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[CH:13]=1.[OH-:27].[K+].Cl>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C>[F:11][C:9]1[CH:10]=[C:2]([OH:27])[C:3]2[CH:4]=[N:5][N:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:14]([F:26])[CH:13]=3)[C:7]=2[CH:8]=1
Reactant: [OH-]
Reactant: Fc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Oc1cc(F)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
To a solution of 4-bromo-6-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole (D7) (670 mg, 1.61 mmol) in dioxane (20 mL) and water (20 mL) was added potassium hydroxide (362 mg, 6.46 mmol). The reaction mixture was degassed with argon and then treated with bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (41 mg, 0.097 mmol) and tris(dibenzylideneacetone)dipalladium (0) (30 mg, 0.033 mmol). After heating at 90° C. for 1 hour, the mixture was allowed to cool to room temperature and then diluted with ethyl acetate and water. The pH was adjusted to 7 by the addition of 1M hydrochloric acid. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-80% ethyl acetate in hexane to yield the title compound (D8) (473 mg).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH3:19][N:20]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1)[CH3:21]>C1(C)C=CC=CC=1>[CH:7]1[C:6]2[CH:5]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]3[CH2:22][N:20]([CH3:21])[CH3:19])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CC1CCCCN1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: CN(C)CC1CCCCN1C1c2ccccc2Oc2ccccc21

Procedure:
A solution of 3.5 g. (14.6 mmoles) of 9-acetoxyxanthene and 2.1 g. (14.8 mmoles) of 2-(dimethylaminomethyl)-piperidine in 50 ml. of toluene was refluxed for 40 hours. The mixture was then washed with sodium bicarbonate, dried and evaporated. Recrystallization of the residue from hexane afforded 1-(9-xanthenyl)-2-(dimethylaminomethyl)-piperidine, m.p. 81°-83°C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2]>C(Cl)(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ccc2ccc(CO)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)n1ccc2ccc(C=O)cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of (1-isopropyl-1H-indol-6-yl)methanol (0.18 g, 0.97 mmol) in CCl4(5 mL) was added manganese dioxide (0.13 g, 1.45 mmol). After stirring at 60° C. for 1 h, then 77° C. for 2 h, filtered reaction mixture through celite and concentrated. Partitioned crude compound between saturated sodium bicarbonate and EtOAc, washed with H2O and brine, dried with Na2SO4, and concentrated. The crude compound was chromatographed to give the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Cl:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH2:23]([O:22][C:20]([C:19]1[C:18]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[Cl:9])=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:24]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(F)cc1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 125.6 %

Procedure:
To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g), toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g), and purged with argon. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixture was stirred in an oil bath at 110° C. for 3 hr. The oil bath was removed, and water (125 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hr, and filtered through celite. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene, and the organic layers were combined. The organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (41.8 g). The obtained solid was directly used for the next reaction without further purification.