Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH3:21])[CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[O:29]1[C@H:28]2[C@H:5]([OH:4])[CH2:6][C:7]3[C@:26]([CH3:30])([C@@H:27]12)[C@@H:25]1[C:10]([C@H:11]2[C@:22]([CH3:31])([CH2:23][CH2:24]1)[C@@H:14]([CH:15]([CH3:21])[CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH2:13][CH2:12]2)=[CH:9][CH:8]=3
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 85 %

Procedure:
The procedure of Example 23 was repeated except that 4.6 mg (0.0106 mmole) of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 3.5 mg of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3β-ol (yield: ca. 85%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.Cl[CH2:19][C:20](=[O:22])[CH3:21].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(C)cc23)C1
Yield: 63.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (30 g, 0.13 mole), 1-chloro-2-propanone (23.6 g, 0.25 moles), and triethylamine (27.3 g, 0.27 moles) in 550 ml of absolute ethanol is stirred at reflux for 21 hours. The reaction mixture is evaporated, and the residue is partitioned between dichloromethane (700 ml) and water (500 ml). The two-phase mixture is made basic with conc. ammonium hydroxide, the layers are separated, and the aqueous phase is extracted with fresh dichloromethane. The combined organic layers are backwashed with water, dried over sodium sulfate, and evaporated. Recrystallization of the residue from absolute ethanol yielded the product (23.5 g), mp 136°-138° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:32])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)CCCC(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.3 %

Procedure:
To 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.34 g, 1 mmol) in DCM (5.00 mL) was added 5-(methyloxy)-5-oxopentanoic acid (146.14 g, 1 mmol), HBTU (417.16 g, 1.1 mmol), and TEA (202.38 g, 2 mmol). This was stirred at room temperature for 17 h. The reaction was quenched with H2O (1 mL). The organic layer was loaded onto a Redisep silica gel cartridge (12 g) and purified by CombiFlash Chromatograph to afford the title compound (0.4499 g, 104.26%). LC-MS m/z 432 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[OH-].[Na+]>CO>[CH3:1][C@H:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CC[C@H](C)Oc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Oc1ccc(C(=O)O)cc1
Yield: 85.8 %

Procedure:
A solution of 1.0 g (4.8 mmol) of methyl 4-(2-(S)-butoxy)benzoate in 15 mL of MeOH was treated with 1 mL of 5.0 N NaOH at rt for 1 h. The solution was concentrated, acidified with 6 mL of 2 N HCl, extracted with EtOAc, dried over MgSO4 and concentrated to afford 800 mg (86%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][OH:21])[C:10]=2[CH2:9][CH:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21][S:32]([CH3:31])(=[O:34])=[O:33])[C:10]=2[CH2:9][CH:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:24]
Reactant: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 76.9 %

Procedure:
To a solution of 9-(2-hydroxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (49) (250 mg, 0.8 mmol) in dichloromethane (10 mL) was added pyridine (633 mg, 8.0 mmol, 0.6 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (367 mg, 3.2 mmol, 0.2 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×20 mL) and water (2×20 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% B, 10 g, 34 CV, 30 mL/min) then triturated with diethyl ether to afford 250 mg (80%) of methanesulfonic acid 2-(4-diethylcarbamoyl-2-methyl-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 12.9, 13.0, 15.2, 22.0, 29.7, 30.2, 36.7, 36.8, 40.8, 41.6, 42.0, 67.8, 108.6, 109.5, 118.6, 119.6, 121.2, 126.4, 136.2, 136.4, 173.7.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C(N(CC)CC)C.CS(O[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])=[O:5]
Reactant: CS(=O)(=O)OCc1ccccc1Cl
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1OCc1ccccc1Cl
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a mixture of 1.33 g (0.0049 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole, 0.54 g (0.0054 mol) of triethylamine and 30 ml of toluene was added 1.3 g (0.0059 mol) of o-chlorobenzyl methanesulfonate. Then, the reaction mixture was refluxed with stirring for 2 hours. After cooling, the reaction mixture was washed with 20 ml of water three times, and the organic layer was separated. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure and was subjected to a column chromatography (silica gel, eluent; ethyl acetate:benzene=1:9) to obtain 1.5 g of the title compound (yield: 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40].C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[CH3:18][NH:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:35]4[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[CH:34]=4)[CH:3]=3)[NH:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CNC(=O)c1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1ccc(-c2c[nH]c3ncc(-c4cc(OC)c(OC)c(OC)c4)cc23)cc1
Yield: 46.5 %

Procedure:
4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N-methyl-benzamide (Intermediate CE, 100 mg, 0.206 mmol), 3,4,5-trimethoxyphenylboronic acid (53 mg, 0.248 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9 mg, 0.012 mmol) were combined in CH3CN (2 ml) and 1 M Na2CO3 (2 ml) and reacted in a microwave reactor for 20 min at 150° C. Water was added, the aqueous phase was extracted with DCM and the organic phase was dried and evaporated. Purification by silica gel chromatography using 0-8% MeOH:DCM yielded 40 mg (47%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 12.09 (s, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.43 (q, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.94 (d, J=4.0, 2H), 7.91 (d, J=4.0 Hz, 2H), 7.00 (s, 2H), 3.89 (s, 6H), 3.70 (s, 3H), 2.80, (d, J=4.5 Hz, 3H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[NH2-].[Li+].[CH3:24][CH:25]([CH3:29])[C:26](=[O:28])[CH3:27]>C1COCC1>[CH3:24][CH:25]([CH3:29])[C@:26]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][N:16]=1)([OH:28])[CH3:27]
Reactant: CC(=O)C(C)C
Reactant: c1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@](C)(O)c1cnccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (282.2 g, 337.2 mL, 1.998 mol) in dry THF (1.400 L) was cooled to −35° C. under nitrogen. nBuLi (2.5M in hexanes) (799.2 mL of 2.5 M, 1.998 mol) was added over 30 minutes, keeping the internal temperature between −25 and −35° C. The mixture was allowed to warm to 0° (+/−1°) and stirred for 10 minutes. The mixture was then cooled to −78° C. and held at this temperature for 20 minutes. A solution of pyrazine (80 g, 998.9 mmol) in dry THF (200.0 mL) was then cannulated into the lithium amide mixture, keeping the internal temperature below −70° C. The deep red mixture was stirred for 20 minutes, then 3-methylbutan-2-one (430.1 g, 534.3 mL, 4.994 mol) (cooled in a −78° C. bath) was added as rapidly as possible, keeping the internal temperature below −60°. The mixture was then stirred at −78° C. (+/−5° C.) for 2 hrs. Lc/Ms after this time showed no pyrazine remaining. The reaction was quenched at −78° C. by slow addition of 2M HCl (2 L). Ethyl acetate (800 mL) was then added. The mixture was allowed to warm to ambient and the organic phase separated. The mixture was very dark but the phases were easily separated. The aqueous phase was extracted with ethyl acetate (2×500 ml). The combined organics were washed with sat NaHCO3 (800 ml), then water (1 L) then brine (500 ml). The mixture was then concentrated. The residue was dissolved in petrol (1.2 L). Some solid was present. MgSO4 was added and the mixture dried, filtered and concentrated. The crude was a dark red oil (260 g). The crude was purified on silica gel, eluting with 0-50% ethyl acetate/petrol). The title compound was obtained as a pale yellow oil (103.2 g, 62%); 1H NMR (CDCl3) 0.74 (3H, d), 1.01 (3H, d), 2.07 (1H, m), 4.19 (1H, s), 8.52 (2H, s), 8.73 (1H, s); MS ES(+) 167.35 (M+1).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[F:13][C:14]([F:40])([C:20]1[N:25]=[C:24]([O:26]C(OC(C)(C)C)=O)[CH:23]=[C:22]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:21]=1)[C:15](OCC)=[O:16].P([O-])(O)(O)=O.[K+]>C1(C)C=CC=CC=1.O>[F:40][C:14]([F:13])([C:20]1[NH:25][C:24](=[O:26])[CH:23]=[C:22]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:21]=1)[C:15]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([F:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)c1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Agent: O=P([O-])(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(F)cc1)C(F)(F)c1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 40 °C

Procedure:
0.756 ml of a solution of aluminium trichloride (2N) in toluene are added slowly to a solution of 0.136 ml of 4-fluoroaniline in 5 ml of toluene at a temperature of between 0° C. and 10° C. After stirring for 40 min at a temperature in the region of 20° C., 271 mg of ethyl difluoro[4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]acetate solubilized in 6 ml of toluene, are slowly added. After refluxing for 2 h30, the temperature returns to a temperature in the region of 20° C. and then, at 0° C., 26 ml of water and 26 ml of a molar solution of potassium dihydrogen phosphate are added and the resulting mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After silica column purification of the residue, eluent: 95/05 CH2Cl2/MeOH, the solid is taken up with 5 ml of dichloromethane, the mixture is heated at 40° C. for 5 min, and then the temperature is returned to a temperature in the region of 20° C. The insoluble material is spin-filter-dried, and washed by triturating, from 1 ml of dichloromethane, three times, and then dried in a vacuum bell jar. 28 mg of 2,2-difluoro-N-(4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+:18].[N+:19]([CH3:22])([O-:21])=[O:20]>CO>[N+:19]([CH2:22][CH:12]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[O-:13])([O-:21])=[O:20].[Na+:18]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])CC([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 457.2 %

Procedure:
To a solution of 4-phenoxybenzaldehyde (1.5 g, 7.56 mmol) in methanol (12 mL) was added dropwise sodium methoxide (1.49 M methanol solution, 0.19 mL, 0.91 mmol) under nitrogen atmosphere at room temperature. Nitromethane (530 μL, 9.84 mmol) was added dropwise to the reaction solution on an ice bath (0° C.). Sodium methoxide (1.49 M methanol solution, 1.66 mL, 8.16 mmol) was added dropwise thereto at room temperature, and the solution was stirred for 30 minutes at room temperature. The precipitated solids were filtered and dried under reduced pressure, and the solids were dried azeotropically with toluene to obtain the title compound (1.17 g, 55%).
Reaction SMILES: [F:1][C:2]([F:17])([O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(OCC)C>C1COCC1>[F:17][C:2]([F:1])([O:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[CH:3]([N:5]([O:7][CH3:8])[CH3:6])[OH:4]
Reactant: CON(C)C(=O)C(F)(F)Oc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON(C)C(O)C(F)(F)Oc1ccc(F)cc1
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenoxy)-N-methoxy-N-methylacetamide (2.03 g, 8.1 mmol) in anhydrous THF (15 ml) at 0° C., a solution of 1 M of lithium aluminum hydride in THF (4.05 ml, 4.05 mmol) was added. After stirring the solution for 3 h, 1N NaOH (2 ml) and ethyl ether (15 ml) were added. After 30 min, the reaction mixture was filtered through Celite and the cake was washed several times with ethyl ether. The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed and the crude was purified using a short plug of silica gel to give 2,2-difluoro-2-(4-fluorophenoxy)-1-(N-methoxy-N-methylamino)ethanol as an oil (1.15 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[ClH:11].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>ClC1C=CC=CC=1>[Cl:11][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Cl
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Fc1ccc(CCCl)cc1

Procedure:
A mixture of 7 g 2-(4-fluoro-phenyl)-ethanol, 25 mL of chlorobenzene, 42 mL of 37% HCl, and 0.9 g of Aliquot® 336 (tricaprylylmethyl ammonium chloride) was heated to reflux for 3 days, cooled and extracted into 3×100 mL of hexane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was mainly 1-(2-chloro-ethyl)-4-fluoro-benzene:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21]Cl)[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Na+].[I-].[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][OH:31])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CCNCCO
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CSCCCl)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCSC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 94 mg (0.25 mmol) of trans-[4-(2-Chloro-ethylsulfanylmethyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in 1 ml DMA was treated with a catalytic amount of NaI and with 0.05 ml (0.5 mmol) of 2-ethylaminoethanol and stirred at RT for 16 h. The reaction mixture was stirred for 1 week, adding every day twice 0.05 ml (0.5 mmol) of 2-ethylaminoethanol. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution and dried over Na2SO4 to yield after flash column chromatography on silica gel (CH2Cl2MeOH 95:5) 40 mg (39%) of trans-(4-{2-[Ethyl-(2-hydroxy-ethyl)-amino]-ethylsulfanylmethyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 429 (MH+, 1Cl).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH3:9][O-:10].[Na+]>N1C=CC=CC=1>[O:10]([C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:7]=[CH:8][CH:1]=[CH:3][CH:4]=1
Reactant: C[O-]
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Solvent: c1ccncc1
Product: Oc1cccc(Oc2ccccc2)c1

Procedure:
To a stirred solution of 49.5 g (0.45 mol) of resorcinol in 75 ml dry pyridine under nitrogen atmosphere, 16.2 g (0.3 mol) of Sodium methoxide was added. Heating started and methanol fractionally distilled off over a period of 0.5 hr. Bromobenzene, 142 g (0.9 mole) was run in to the reaction mixture followed by 2.2 g, of Cuprous chloride. Reaction mixture heated under reflux for 3–4 hr, pyridine distilled off while the pot temperature rose to 150° C. The residue was poured into 50 ml conc. HCl in 120 ml water and stirred. Organic material extracted in 200 ml benzene followed by washing with 25 ml of 20% HCl. Organic layer extracted with 100 ml of 10% NaOH solution followed by a second extraction With 20 ml of 10% NaOH. The combined aqueous extracts were acidified with, HClconc, liberated m-phenoxy phenol was extracted into benzene (300 ml). From the organic layer benzene was removed by distillation. Crude product purified by filtration over a column of silica.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH3:34][O:35][C:36]1[C:47]2=[C:48]3[N:43]([CH2:44][CH2:45][CH2:46]2)[CH2:42][CH2:41][CH2:40][C:39]3=[CH:38][C:37]=1[CH:49]=O.O>O1CCCC1.C(OCC)(=O)C>[CH3:34][O:35][C:36]1[C:47]2=[C:48]3[N:43]([CH2:44][CH2:45][CH2:46]2)[CH2:42][CH2:41][CH2:40][C:39]3=[CH:38][C:37]=1[CH:49]=[CH:14][C:9]1[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(C=O)cc2c3c1CCCN3CCC2
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C=Cc2cccs2)cc2c3c1CCCN3CCC2
Reaction time: 1.5 h
Yield: 63.9 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 3.2 g of phenyllithium (19% solution in dibutylether) (7.23 mmol), and 2.6 g (6.58 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 1.5 g (6.49 mmol) of 8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-carboaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.29 g of an orange oily matter (yield: 63.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23]C(=O)C(F)(F)F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])[CH3:32].Cl>O1CCOCC1.CC(O)C>[NH2:23][C:19]1[CH:18]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][N:31]([CH3:30])[CH3:32])[CH:35]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: CN(C)Cc1cccc(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Temperature: 90 °C
Yield: 41 %

Procedure:
To a solution of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (3.0 g, 0.007 mols) (see Example 1, Step C) in 1,4-dioxane (60 mL) and i-PrOH (60 mL) was added 3-[(dimethylamino)methyl]aniline (1.61 g, 0.011 mol) followed by catalytic 12M HCl. After heating four days at 90° C., reaction was quenched with saturated NaHCO3 (100 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (3×200 mL), organic layers concentrated, and purified by column chromatography (0-100% 9:1:0.1 DCM:MeOH:NH4OH) to provide the product (1.25 g, 40%) as tan foam. ES-LC/MS m/z=436 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:21][CH:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[N:21][CH:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc(-c2ncc(CBr)o2)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cnc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 5-(bromomethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (Example 370C): 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59 (m, 3H), 7.04 (s, 1H), 6.65 (s, 1H), 5.42 (s, 2H), 2.62 (s, 3H); MS (ES) m/z 450 (M+1).