Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[C:14]1([C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A solution of glutaryl chloride (10 mmol, 1.3 mL) dissolved in anhydrous dichloromethane (20 mL) is introduced into a 100 mL two-necked round-bottomed flask under an inert atmosphere. Aluminum chloride (30 mmol, 4.00 g) is added to the mixture, which immediately turns orange-yellow. A solution of benzene (20 mmol, 1.8 mL) dissolved in anhydrous dichloromethane (10 mL) is added dropwise at room temperature. The solution becomes bright red. The mixture is then refluxed for 24 hours, and turns brown-black. The mixture is then cooled to room temperature and poured into a crystallizing basin containing 20 mL of 10% acidified water, with stirring. A black solid forms, and is filtered off on a Büchner funnel. The yellow organic phase is then extracted with ethyl acetate, dried over MgSO4, filtered, concentrated on a rotary evaporator and recrystallized from 20 mL of methanol. The product obtained is a white solid in a mass of 680 mg. The reaction yield is 27%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:13]1[N:18]=[C:17]([C:19]2[C:20]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:21][N:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=23)[CH:16]=[CH:15][N:14]=1)(=O)=O>O>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][N:22]3[N:21]=2)=[CH:33][CH:34]=1
Reactant: NCCN1CCCC1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)n1
Solvent: O
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NCCN3CCCC3)n2)cc1

Procedure:
2-Pyrrolidin-1-ylethylamine (0.04 mL) and 4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl methyl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a beige solid (0.012 g); 1H NMR (CDCl3) δ 8.83(1H, s), 8.51(1H, d), 8.11(1H, d), 7.63(2H, dd), 7.43 (1H, dd), 7.15(2H, dd), 6.33(1H, d), 5.75(1H, bs), 3.58(2H, dt), 2.76(2H, t), 2.58(2H, bt), 1.81(2H, bm); m/z 471 (M+1)+.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:32][C:31]2[S:30][C:29]3[N:28]=[CH:27][NH:26][C:25](=O)[C:24]=3[C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O>[C:13]([O:17][C:18]([N:20]1[CH2:32][C:31]2[S:30][C:29]3[N:28]=[CH:27][N:26]=[C:25]([Cl:3])[C:24]=3[C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 60 °C
Yield: 25 %

Procedure:
To a of mixture of POCl3 (30 mL) and triethylamine (50 mL) at 0° C. was added 4-oxo-3,5,6,8-tetrahydro-4H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (10.0 g). The reaction mixture was heated at 60° C. for 3 h. Water was then added, followed by sodium bicarbonate to neutralize the reaction mixture. The resulting mixture was extracted with dichloromethane. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (10:1) to give the title compound (3.1 g, 25%). 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 4.69 (s, 2H), 3.74 (t, 2H, J=5.6 Hz), 3.14-3.18 (brs, 2H), 1.46 (s, 9H). LC-MS (ESI) m/z 326.0 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH3:16])[NH:11]1.[CH2:17](O)C>>[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH3:16])[N:11]1[CH2:17][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CCBr
Reactant: CC1CCCC(C)N1
Reactant: CCO
Product: CCOC(=O)CCCN1C(C)CCCC1C

Procedure:
A mixture of ethyl 3-bromo-propionate(25.8g), 2,6-dimethyl-piperidine (30 g) and ethanol (40 cc) is heated for 2 hours under reflux. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in 5N sodium hydroxide solution (30 cc) and then extracted with methylene chloride (3×50 cc). The organic phase is dried over magnesium sulphate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Ethyl 4-(2,6-dimethyl-1-piperidyl)butyrate(29 g) is thus obtained as an oil which can be employed in the subsequent synthesis without purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([O:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:6]=1
Reactant: Oc1ccccc1
Reactant: Brc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Brc1nnc(Oc2ccccc2)s1
Temperature: 25 °C

Procedure:
A solution of 2,5-dibromo-1,3,4-thiadiazole (1.00 g, 4.10 mmol; prepared as described in Yasuda, T.; Imase, T.; Sasaki, S.; Yamamoto, T. Macromolecules 2005, 38, 1500) and phenol (188 mg, 2.00 mmol; Aldrich) in anhydrous tetrahydrofuran (4 mL) was treated with cesium carbonate (2.0 g, 6.0 mmol) and heated to reflux for 5 hours. The mixture was cooled to room temperature, diluted with chloroform, filtered through Celite, and the residue was purified by flash chromatography (Analogix 40×120 mm 80 g silica gel column, chloroform) to afford the title compound: 1H NMR (300 MHz, chloroform-D) δ ppm 7.28-7.35 (m, 3H), 7.41-7.49 (m, 2H). MS (+ESI) m/z=257/259 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:40][Zn+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15]([CH3:40])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Zn+]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 51.3 %

Procedure:
To a solution of tert-butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50.0 mg, 0.078 mmol) in THF (1 mL) in a heavy-walled sealed microwave tube (0.5-2.0 mL) under N2 was added methylzinc(II) chloride (2.0 M in THF, 0.055 mL, 0.109 mmol) and bis(tri-t-butylphosphine)palladium(0) (3.60 mg, 7.04 μmol). The reaction mixture was then heated to 70° C. for 2 h, quenched with saturated NaHCO3 and filtered by vacuum filtration through a pad of Celite®. The pad of Celite® was washed with EtOAc (2×5 mL). The filtrate was extracted with EtOAc (3×5 mL). The organic layers were combined and washed with saturated NaCl (1×10 mL), dried over MgSO4 and filtered by vacuum filtration. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound as a colorless oil (21.1 mg). LCMS m/z=528.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H), 1.56-1.66 (m, 2H), 1.68-1.79 (m, 2H), 1.81-1.92 (m, 2H), 2.04-2.15 (m, 2H), 2.23 (s, 3H), 2.26-2.36 (m, 1H), 2.41 (dd, J=15.66, 10.11 Hz, 1H), 2.78-2.90 (m, 2H), 3.31-3.44 (m, 1H), 3.65-3.74 (m, 1H), 3.90-3.98 (m, 1H), 3.99-4.12 (m, 1H), 5.09 (s, 2H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.03 (d, J=2.15 Hz, 1H), 7.09 (d, J=8.72 Hz, 1H), 7.47 (d, J=8.08 Hz, 1H), 7.60 (d, J=8.21 Hz, 1H), 7.71 (d, J=1.39 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O.[Pd]>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
The Suzuki coupling was carried out according to the method of Dyer et al. (2001) Tetrahedron Letters 42:1765-1767. Commercially available 4-(trifluoromethyl)phenylboronic acid (15 g, 78.7 mmol) and 3-bromobenzoic acid (15.1 g, 75 mmol) were suspended in i-PrOH:water (1:4, 72 mL). 10% Pd/C (1.5 g) was added followed by aqueous Na2CO3 (39 mL, 20% by wt.). The resulting mixture was heated at 70° C. for 4 hours. The precipitate was filtered and rinsed with 20% aqueous Na2CO3 solution. The filtrate was diluted with water and acidified to pH=2. The white solid was filtered and dried in vacuo to afford 2.1 (19.69 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Yield: 19 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (106 mg, 0.312 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (77 mg, 0.377 mmol), 4 N HCl in dioxane (94 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 2 hours. Let reaction cool to room temperature and evaporated off solvent. Purified with normal phase chromatography to yield a white solid (30 mg, 19%), N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide. mp 170-185° C.; LCMS: m/z=507.33 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.58 (d, 1H, J=9.6 Hz), 7.30 (m, 4H), 6.87 (dd, 1H, J=8.6, 2.3 Hz), 5.79 (m, 1H), 3.80 (m, 1H), 3.27 (m, 1H), 2.78 (m, 3H), 2.31 (m, 2H), 2.13 (m, 4H), 1.78 (m, 2H), 1.36 (m, 10H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[NH2:20][C:21]1[C:26]([C:27]([C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([F:37])[C:30]=2[F:38])=[O:28])=[CH:25][N:24]=[C:23](S(CC)(=O)=O)[N:22]=1.O>CN(C)C=O>[NH2:20][C:21]1[C:26]([C:27](=[O:28])[C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([F:37])[C:30]=2[F:38])=[CH:25][N:24]=[C:23]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]2)[N:22]=1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(C)(=O)=O)CC2)nc1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(4-amino-cyclohexyl)-methanesulfonamide, Example 122, (211 mg, 0.69 mmol) in dimethylformamide, triethylamine (40 μL, 2.87 mmol) and the compound of Example 103 (200 mg, 0.57 mmol) were added and the mixture was stirred at 90° C. for 1 hour. Then the mixture was poured into water and extracted with ethyl acetate, dried (sodium sulfate) and concentrated. The residue was chromatographed to give the product. 185 mg, 71%. MS(ES) (M+H)+=456.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccnc1Br
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromo-3-methylpyridine
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl.C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:33])[C:8]=1[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
5 g of 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-1H benzimidazole was dissolved in a mixture comprising 100 ml of dichloromethane and 25 ml of diethyl ether to obtain a solution. 2.83 g of 85% m-chloroperbenzoic acid was added to this solution in portions at -45° C. After the completion of the reaction, 2 g of triethylamine was added to the reaction mixture and the obtained mixture was heated to -10° C., followed by the addition of 50 ml of 1N sodium hydroxide. The obtained mixture was stirred at a room temperature for 30 minutes. The obtained aqueous layer was washed with 20 ml of dichloromethane twice and adjusted to pH 11 with a 2M aqueous solution of ammonium acetate. The aqueous layer was extracted with 50 ml of dichloromethane thrice. The obtained dichloromethane layer was washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate twide, dried over magnesium sulfate and distilled to remove the dichloromethane. The obtained oily product was crystallized from dichloromethane/ether to obtain 4.17 g of the title compound as a white crystal.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:14]([CH3:23])[N:13]=[N:12][C:11]=1[CH3:24].C(OCC)(=O)C>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[C:10]([N:6]3[CH:5]=[C:4]([CH3:3])[CH:8]=[N:7]3)=[C:11]([CH3:24])[N:12]=[N:13][C:14]=2[CH3:23])=[CH:21][CH:20]=1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnn(-c2c(C)nnc(C)c2-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 3 ml of DMF, and to this was added a solution of 0.16 g of 4-methylpyrazole in 3 ml of DMF, and the mixture was stirred for 0.5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.40 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.21 g of 5-(4-chlorophenyl)-3,6-dimethyl-4-(4-methyl-1-pyrazolyl)pyridazine (hereinafter, described as compound (5) of the present invention.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:28][CH2:29][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Temperature: 85 °C
Yield: 99.4 %

Procedure:
Seal tube containing 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperidin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (product of step-iii of example 82) (125 mg, 0.194 mmol), (S)-2-methyloxirane (23 mg, 0.389 mmol), DIPEA (100 mg, 0.778 mmol) and ethanol were heated at 85° C. for 3 hours and distilled the solvent on rotavapor to get 128 mg (99% yield) of the titled compound. MS: m/z=664.4 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[OH:20])([CH3:10])[CH3:9]>C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[C:4]([O:20][C:12]1[C:13]([CH:17]([CH3:18])[CH3:19])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OC(=O)CCC(=O)O
Reaction time: 16 h
Yield: 80.2 %

Procedure:
Succinic anhydride (14 g, 140 mmol) and dimethylaminopyridine (0.02 g, 0.16 mmol) were added to a solution of 2,6-diisopropylphenol (20.8 ml, 112 mmol) in triethylamine (50 ml) under nitrogen. After 16 hr at room temperature, solvents were removed under vacuum. The residue was dissolved in water and added to an iced solution of dilute hydrochloric acid. The precipitated product was filtered and recrystallized from ethanol-water to yield 25.0 g (80.2% yield) of 2,6-diisopropylphenyl hydrogen succinate (propofol hemisuccinate), mp 101-102° C.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[C:8]([CH:9]=[CH2:1])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cccnc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccnc1Br
Temperature: 0 °C

Procedure:
See Spivey, A. C.; Shukla, L.; Hayler, J. F. Org. Lett. 2007, 9, 891-894. Butyllithium (22.75 mL, 59.1 mmol) was added to the THF (450 mL) suspension of methyltriphenylphosphonium bromide (21.13 g, 59.1 mmol) at 0° C. The solution turned to orange and the reaction was lift to room temperature for 30 min before cooled it back to 0° C. 2-bromonicotinaldehyde (10 g, 53.8 mmol) in 50 mL THF was added through canula to the reaction solution. The precipitate was formed and the reaction was lift to room temperature. The color of the reaction turned to green, gray. After a while, the color of the reaction became orange again. The reaction was stirred at room temperature over weekend. The solvent was removed mostly via vacuum and the crude was partitioned between water and diethyl ether. The organic layer was separated and the aqueous layer was extract twice with diethyl ether. The diethyl ether layer was combined, dried (Na2SO4), filtered and concentrated. The product was obtained by flash column eluted with ethyl acetate in hexane (10%) as yellow oil (8.78 g, 89%). MS(ESI)[M+H+]=184.04; 1H NMR δ ppm (400 MHz, CHLOROFORM-d) 8.21-8.29 (m, 1 H) 7.78 (dd, J=7.68, 1.89 Hz, 1 H) 7.20-7.28 (m, 1 H) 6.96 (dd, J=17.37, 11.08 Hz, 1 H) 5.72 (d, J=17.37 Hz, 1 H) 5.46 (d, J=11.08 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+]>C(O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(O)cn2)cc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(-c2ccc(OCCCC)cn2)cc1

Procedure:
2.8g of the resulting 2-(p-pentylphenyl)-5-hydroxypyridine, 2g of 1-bromobutane and 0.8g of potassium hydroxide placed in 60ml of ethanol were heated under reflux for 4 hours. The potassium bromide precipitated during the reaction was removed by filtration. The ethanol was removed by distillation. The residue was extracted with diethylether and the ether layer was washed with water several times and then the ether was removed by distillation. The residue was distilled under reduced pressure. The collected fraction having a boiling point of 185° to 187° C./2mmHg was recrystallized from methanol to yield 1.7g of 2-(p-pentylphenyl)-5-butyloxypyridine.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[OH:27])[O:23][CH2:22][CH2:21][CH2:20]4)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][C:26]=4[O:27][CH2:35]3)[O:23][CH2:22][CH2:21][CH2:20]5)[C:9]2=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (70%) as an off-white solid: mp 208-211° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.41-7.29 (m, 10H), 7.16 (dd, J=6.6, 1.8 Hz, 1H), 7.08 (s, 1H), 7.05-6.94 (m, 2H), 6.52 (d, J=7.8 Hz, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.11 (dd, J=5.1, 5.1 Hz, 2H), 2.56 (t, J=6.3 Hz, 2H), 1.94-1.86 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.1, 160.1, 156.3, 141.8, 137.9, 137.5, 132.9, 128.75, 128.73, 128.53, 128.52, 128.2, 128.00, 127.96, 132.9, 132.8, 123.2, 121.3, 115.2, 112.3, 98.9, 80.3, 66.6, 58.8, 57.5, 24.8, 22.3; MS (ES+) m/z 460.1 (M+1).