Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]C)=[O:17])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].[OH-].[K+]>O.CO>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:13][CH2:12][C:11]([C:16]([OH:18])=[O:17])([CH2:14][CH2:15]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)OC)(CC1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Temperature: 60 °C

Procedure:
Ester 10-3 (880 mg, 3 mmol) was dissolved in 10% water/methanol solution (100 mL) and treated with 1 g of potassium hydroxide. The reaction was heated at 60° C. for 1 h then at 45° C. overnight. The mixture was concentrated in vacuo then acidified to pH 2 with 1M HCl and extracted with three portions of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to give 4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]octane-1-carboxylic acid (10-4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16](C=O)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.OO.S(=O)(=O)(O)[OH:29].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(C=O)ccc12
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Step 2 A solution of crude 4-(2-fluorophenyl)-7-formyl-9H-carbazole-1-carboxamide (25.2 mg, 0.076 mmol) in methanol (2 mL) at 0° C. was treated with 30% aqueous hydrogen peroxide (0.039 mL, 0.379 mmol) and sulfuric acid (0.020 mL, 0.379 mmol). After 1.5 h, additional hydrogen peroxide (0.100 mL) and sulfuric acid (0.050 mL) were added and the mixture was stirred at rt overnight. After 16 h, 1 M aqueous sodium hydroxide (2 mL) was added and the mixture was stirred for 1 h. The pH was adjusted to ca. 4 and the organic solvent was removed under vacuum. The aqueous residue was diluted with water and the precipitate was collected by filtration, washed with water and dried. The residue was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide as tan solid after lypholization (5.1 mg, 21%). 1H NMR (400 MHz, methanol-d4) δ 7.81 (1H, d, J=7.70 Hz), 7.45-7.64 (2H, m), 7.21-7.42 (2H, m), 7.03 (1H, d, J=7.92 Hz), 6.90-6.99 (2H, m), 6.45 (1H, dd, J=8.58, 2.20 Hz). Mass spectrum m/z 321.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:11][N:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10][O:11][C:12]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1onc(-c2ccc(OC)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(OC)cc2)c1CBr

Procedure:
Ethyl 3-(4-methoxyphenyl)-4-methylisoxazole-5-carboxylate (12.4 g, 47.5 mmol), NBS (10.1 g, 57.0 mmol), and benzoyl peroxide (1.15 g, 4.75 mmol) were added to 250 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The reaction mixture was filtered and the filtrate was removed in vacuo to give a brown solid, which was used in the next reaction without purification. MS: (+) m/z 340.35, 342.33 (M+1, 79Br/81Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)n[nH]1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)n[nH]1
Yield: 11 %

Procedure:
This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (20 mg, yield 11%). 1H NMR (400 MHz, MeOD) δ 9.38-9.37 (d, J=1.5 Hz, 1H), 9.15 (d, J=1.5 Hz, 1H), 8.82 (m, 1H), 8.06-8.02 (m, 2H), 7.21-7.17 (t, J=8.5 Hz, 2H), 3.76 (s, 2H), 1.53 (s, 6H). MS (ESI) m/z: Calculated for C21H17F4N7O2: 475.14. found: 476.2 (M+H)+.
Reaction SMILES: O.Cl.[CH2:3]([NH:7][NH2:8])[CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1>[CH2:11]([NH:15][C:16]([N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:8])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN=C=O
Reactant: CCCCNN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCNC(=O)N(N)CCCC
Yield: 53.4 %

Procedure:
To a cooled (water bath), stirred mixture of 2.42 g n-butylhydrazine hydrochloride in 15 mL tetrahydrofuran was added 1.7 g powdered potassium hydroxide. The resulting mixture was stirred and maintained under a nitrogen atmosphere as n-butyl isocyanate (1.49 g, 0.015 moles) in 30 mL tetrahydrofuran was added dropwise. After addition, the solution was stirred overnight at ambient temperature. Work up as in Example 5 above yielded 1.5 g N,1-dibutylhydrazinecarboxamide b.p. 135°-6° C. at 0.08 torr, m.p. 34°-36° C. This structure was confirmed by NMR analysis.
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.P([N:46]=[N+:47]=[N-:48])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([C@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:47]=[N-:48]
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@@H]2O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (1S)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.0 g) and diphenyl phosphorazidate (0.65 ml) was dissolved in toluene (10 ml). The mixture was cooled to 0° C. under N2, and neat 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.45 ml) was added. The reaction mixture was stirred for 2 hours at 0° C. then at 20° C. for 16 hours. The resulting mixture was washed with water and 1N-HCl. The organic layer was concentrated in vacuo and purified by silica gel chromatography to give (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (950 mg). MS (m/z): (400 (M+ +() IR (Neat): 2100 cm-1NMR (CDCl3, δ): 1.10 (9H, s), 1.8-2.2 (4H, m), 2.6-3.1 (2H, m), 4.5-4.7 (1H, m), 6.3-6.4 (1H, m), 6.7-7.0 (2H, m), 7.1-7.8 (10H, m)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Product: O=C(O)c1ccc(-c2ccccn2)cc1

Procedure:
Production Example 14 was repeated except that 4-carboxyphenylboronic acid and 2-bromopyridine were used, to provide the title compound as white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:5][N:4]=1.[OH-:17].[Na+]>S(=O)(=O)(O)O>[CH3:1][S:2][C:3]1[C:7]([C:8]([NH2:9])=[O:17])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:5][N:4]=1
Reactant: [OH-]
Reactant: CSc1nsc(Nc2ccncc2)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CSc1nsc(Nc2ccncc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 7 (1.0 g, 4.0 mmol) is dissolved in sulfuric acid (5 mL). The resulting solution is stirred at room temperature for 2 hours, heated to 50° C. for 3.5 hours, then at room temperature for 18 hours, then heated to 50° C. for 1 hour. The reaction was then cooled to room temperature and 1N NaOH (5 mL) was added. The resulting solids were filtered and washed with saturated aqueous sodium bicarbonate to provide 8 (1.15 g, 4.0 mmol). 1H NMR (d6 DMSO): 5 8.12 (2H, d, J=5.8 Hz), 6.78 (2H, d, J=5.8 Hz), 2.32 (3H, s); LRMS (M+): 267.0, (M−): 265.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[CH:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:2].Cl>C(Cl)Cl.CC(O)C>[ClH:34].[NH2:19][CH2:18][CH2:17][O:16][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH2:15][CH:6]([NH:5][C:4](=[O:36])[O:3][CH2:1][CH3:2])[CH:7]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)NC1CCc2ccc(OCCNC(=O)OC(C)(C)C)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 142.2 %

Procedure:
[7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamic acid ethyl ester (9.27 g, 17.3 mmol) example 1 was dissolved in CH2Cl2 (200 ml) and HCl in iPrOH (6N) was added. The reaction was stirred at RT over night after which a solid precipitates. To the reaction mixture diethyl ether was added and the precipitating HCl salt was separated by filtration to give the final product as a solid (5.85 g, 12.3 mmol, 72%).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27](=[O:29])[CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27](=[O:29])[CH3:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.78 g, 0.138 mol) in CH2Cl2 (50 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (19.80 g, 0.092 mol) and trifluoroacetic acid (1.05 mL, 0.009 mol) in CH2Cl2 (100 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2/MeOH 98:2) afforded 28.3 g (88%) of the title compound as a yellow oil. ES-MS m/e: 348.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.C(=O)=O.C([Li])(C)(C)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](F)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1>[S:29]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)F)cc1
Agent: O=C=O
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of indole (586 mg, 5.0 mmol) in 10 mL THF at −70° C. was added n-butyl lithium (3.7 mL, 5.1 mmol, 1.39 M in hexane) dropwise over 35 min keeping the temperature below −65° C. The reaction was stirred at −70° C. for 30 min, then a saturated solution of CO2 in 20 mL THF added by cannula, the dry ice bath removed and the reaction mixture bubbled with CO2 as the reaction warmed to room temperature. The reaction mixture was concentrated in vacuo then taken up in 10 mL THF and cooled to −70° C. To the solution was added tert-butyl lithium (3 mL, 5.17 mmol, 1.7 M in pentane) dropwise and stirred at −70° C. 1 h, then the reaction mixture added by cannula to a solution of p-toluenesulfonyl fluoride (1.74 g, 10 mmol) in 10 mL THF and stirred at −70° C. 2 h. The reaction was quenched with 1 mL H2O, poured into a solution of ammonium chloride (pH 5), and extracted twice with CHCl3. The combined organic extract was washed successively with a saturated solution of sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 2 to 20% ethyl acetate in hexanes to give a final yield of 199 mg (0.73 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.41 (s, 3H), 7.16-7.26 (m, 2H), 7.27-7.33 (m, 2H), 7.35 (t, J=7.3 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H), 9.31 (s, 1H). 13C NMR (500 MHz, CDCl3, δ): 21.61, 108.87, 112.39, 121.52, 122.62, 125.95, 127.08, 127.35, 130.02, 134.45, 137.16, 138.53, 144.57.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](O)C>[Pd]>[CH3:13][C:6]1[CH:7]=[CH:2][C:3]([O:11][CH3:12])=[CH:4][C:5]=1[NH2:8]
Reactant: CCO
Reactant: COc1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Product: COc1ccc(C)c(N)c1
Yield: 97 %

Procedure:
To a suspension of 2-methyl-5-nitroanisole F1 (1.54 g; 9.21 mmol) in absolute ethanol (15 mL) was added 10% Pd/C catalyst (249 mg). The suspension was hydrogenated under a hydrogen filled balloon at atmospheric pressure and room temperature for 6.5 h. The reaction mixture was filtered through a Millex 0.45 micron filter and evaporated to dryness to provide 4-methyl-m-anisidine F2 (1.22 g; 8.89 mmol; 97% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: COc1ccc(C(=O)Nc2cccc(C(=O)C3CCN(C)CC3)c2)cc1
Yield: 101 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-methoxybenzoyl chloride (117 mg, 0.687 mmol), 81.5 mg (>100%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1([F:18])[CH2:15][CH2:16][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12][CH2:13]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCC(F)(F)CC2)C3)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
In a 20 mL vial was placed 6′-bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-one (35 mg, 0.111 mmol), 3-cyanobenzeneboronic acid (23 mg, 0.157 mmol), PdCl2(PPh3)2 (8 mg, 0.011 mmol) and cesium carbonate (91 mg, 0.279 mmol). This solid mixture was dissolved in a Dioxane/water mixture (1.1 mL, 6:1 ratio, respectively). The reaction vial was capped and allowed to stir at 90° C. for 1 hour. At this time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (5 mL) and water (5 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane twice (3 mL/each). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4,4-difluoro-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-6′-yl)benzonitrile (30 mg, 0.089 mmol, 80% yield) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[Cl:31]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:31][C:12]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:9]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[N:10][C:11]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Yield: 43.7 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (300 mg, 0.73 mmol) was dissolved in chloroform solution (5 ml), benzoyl peroxide (0.3 mg, 0.0014 mmol) and N-chlorosuccinimide (117 mg, 0.87 mmol) was added, and refluxed under heating for 1 hour. Water was added, and extraction was done with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=4:1), and 142 mg of 5-chloro-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained (yield 46%). The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 130 are shown below.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:14][C:12]([CH3:15])([CH3:13])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
5 g (40.94 mmol) of 4-hydroxybenzaldehyde were initially charged in 50 ml of DMF. 4.45 g (40.94 mmol) of 1-chloro-2-methylpropan-2-ol and 6.08 g (57.32 mmol) of sodium carbonate were added, and the mixture was then stirred at 130° C. overnight. Saturated aqueous sodium bicarbonate solution/ethyl acetate were added to the reaction mixture. The precipitate was filtered off and discarded. The two phases were separated from one another, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5/1→1/2).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[CH2:3]([N:2]([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH2:4][CH2:5][CH3:6]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CCCCNC
Product: CCCCN(C)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from N-methylbutan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.40 (br s, 1H), 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.24 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.62 (br, 4H), 2.39 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 1.26 (m, 2H), 0.85 (t, 3H); MS (ESI): 508.1.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39](S(C)(=O)=O)[N:38]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1)[C:39]1[N:38]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH:42]=[CH:41][N:40]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(Cl)cc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 23.2 %

Procedure:
To a mixture of the ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (686 mg, 2.46 mmol) and N,N-diisopropylethylamine (285 μL, 1.64 mmol) was added 4-(4-chlorophenyl)-2-(methylsulfonyl)pyrimidine (439 mg, 1.64 mmol) and the resultant mixture heated at 100° C. for 16 h in a reactivial. The cooled reaction mixture were then treated with N,N-diisopropylethylamine (285 μL, 1.64 mmol) and heated for a further 16 h at 100° C. in the reactivial. The cooled reaction mixtures were diluted with CH2Cl2 (30 mL), washed with water (20 mL), the aqueous extracted with CH2Cl2 (30 mL), the CH2Cl2 extracts combined and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluted with 10:1 cyclohexane:EtOAc gave the title compound as a colourless gum (178 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1CN(Cc2ccccc2)CCC1O
Yield: 68.7 %

Procedure:
A solution (15 ml) of 3.98 g of 1-benzyl-3-methyl-4-piperidone in diethyl ether was added to a suspension (10 ml) of 0.78 g of aluminum lithium hydride in diethyl ether in an ice bath, and the solution was heated under ref lux for 3 hours. Water was added to the solution, and the solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of hydrogen chloride. The solution was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography, and from the fractions eluted with chloroform-methanol (19:1 v/v) was obtained 2.76 g of 1-benzyl-4-hydroxy-3-methylpiperidine, which was an oily product (yield: 69%).