Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)=O)([O-:3])=[O:2].C([SiH](CC)CC)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC[N+](=O)[O-])cc1
Temperature: -5 °C
Yield: 200.6 %

Procedure:
3-nitro-1-(4-octylphenyl)propan-1-one (20 g) and dichloromethane (100 mL) are charged into a round bottom flask at 25-30° C. and stirred. The mixture is cooled to −10° C. to 0° C. and triethylsilane (19.9 g) is added. A solution of titanium tetrachloride (19.57 g) in dichloromethane (100 mL) is added over a period of 15 minutes and the obtained reaction mixture is maintained at −10 to 0° C. for 5 hours. Water (200 mL) precooled to 0-10° C. is slowly added to the reaction mixture over a period of 20 minutes and the temperature is allowed to raise to 25-30° C. The reaction mixture is stirred for about 1 hour, organic layer is separated, washed with 5% sodium bicarbonate solution (100 mL), followed by 20% brine solution (100 mL), the organic layer is concentrated under vacuum at 45° C. to obtain 38.2 g of crude 1-(3-nitropropyl)-4-octylbenzene. Toluene (200 mL) and crude 1-(3-nitropropyl)-4-octylbenzene (38.2 g) are charged into the round bottom flask at 25-30° C. and stirred. Potassium carbonate (18.96 g) and paraformaldehyde (7.21 g) are charged and the reaction mixture is stirred at the same temperature for about 6 hours. The reaction mixture is filtered and washed with toluene (40 mL). The obtained filtrate, water (200 mL) and ethyl acetate (60 mL) are charged into a round bottom flask and stirred for 2 hours. The organic layer is separated, washed with 5% hydrochloric acid solution (100 mL), 5% sodium bicarbonate solution (100 mL) and followed by 5% brine solution (100 mL). The resultant organic layer is concentrated under vacuum at below 45° C. n-Hexane (100 mL) is added to the obtained compound and stirred. The obtained mixture is cooled to 0 to 5° C., maintained at the same temperature for about 60 minutes, filtered and washed with n-hexane (20 mL). The obtained wet compound and toluene (80 mL) are charged into a round bottom flask, heated to 40-45° C. and maintained at the same temperature for about 15 minutes. The reaction mixture is cooled to 0-5° C., maintained for about 45 minutes, filtered and washed the product with toluene (40 mL) precooled to 0-5° C. and the product obtained is dried under vacuum at 25-30° C. to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[N:13][C:12]=1Cl)[CH3:8].[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[N:13][C:12]=1[O:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][C:29]([F:28])([F:38])[F:39])=[CH:32][CH:33]=1)[CH3:8]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
Potassium carbonate (60 mg, 0.43 mmol) was added to a stirred and cooled (0° C.) solution of 2-chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester 0.13 g (0.43 mmol) in 10 ml DMF and stirred for 10 min at the same temperature. This was followed by the addition of 76.5 mg (0.43 mmol) of 4-trifluoromethoxy phenol, dissolved in 2 ml of DMF, over a period of 10 min. After the addition was completed, the contents were allowed to stir at RT. This was followed by heating for 3 h at 80° C. The reaction mixture was concentrated under reduced pressure, poured into ice-cold water and dissolved in 50 ml of ethyl acetate. Organic layer was then washed with brine solution followed by water and the crude product was purified by column chromatography using hexane:ethyl acetate (8:2) to afford 0.18 g of the required product. Percentage purity: LCMS−ve mode): 20.12%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ncc(-c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccccc3)cn2)CC1

Procedure:
A mixture of 2-chloro-5-phenyl-pyrimidine (1.2 g, 6.29 mmol, 1.0 equiv; commercially available from Acme Bioscience Inc., USA), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.52 g, 12.59 mmol, 2.0 equiv; commercially available) and triethylamine (1.75 mL, 1.27 g, 12.59 mmol, 2.0 equiv) in anhydrous acetonitrile (5 mL) was heated by microwave irradiation to 150° C. for 30 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.06 g (48%) of the title compound. MS (ISP): 355.5 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[I-:28].[Na+]>CC(C)=O>[I:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9]
Reactant: [I-]
Reactant: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Yield: 96.7 %

Procedure:
A mixture of 0.86 g of α-(5-chloropentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile, 3.2 g of sodium iodide, and 10 mL of acetone is heated to reflux overnight, protected from light. The volatiles are removed in yacuo and 30 mL of diethyl ether is added to the residue. The insolubles are collected and the volatiles removed in vacuo. The residue is purified via column chromatography using hexane/ethyl acetate (2:1) to afford 1.02 g of the desired product as a clear oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[S:7][CH:8]=2)[CH2:3][CH2:2]1.[C:18]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[CH2:19]1>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22]([OH:24])=[O:23])[CH:14]=[CH:15][CH:16]=3)[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CC3)cs2)c1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CC3)cs2)c1
Yield: 88.7 %

Procedure:
A solution of 5.0 g of (E)-3-[2-[4-(cyclopropyl)-2-thiazolyl]ethenyl]benzeneamine, 3.35 g of homophthalic anhydride, and 100 ml of toluene was heated to reflux for 0.5 hr. After cooling, the solids that formed were collected by filtration and this material was triturated with ethyl ether to yield 7.4 g of (E)-2-[2-[3-[2-[4-(cyclopropyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid. Recrystallization from acetonitrile yielded 5.1 g of material; m.p. 200°-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][NH2:19])[O:8][C:7]=2[CH:20]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][NH:19][C:21](=[O:23])[CH3:22])[O:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)OC(CN)=C(c1ccccc1)O2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(CNC(C)=O)=C(c1ccccc1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.2 g (0.74 mmol) of the amine obtained in Step C is dissolved in 3 ml of anhydrous pyridine; the solution is then cooled to 0° C. After addition of 0.085 ml (0.89 mmol) of acetic anhydride, the reaction medium is stirred for 1 hour at 0° C. The solution is then diluted with dichloromethane and then acidified with a hydrochloric acid solution (1N). The aqueous phase is extracted with dichloromethane; the organic phase is then dried over magnesium sulphate. After evaporation of the solvent in vacuo, the residue obtained is purified on a silica column (eluant:AcOEt/PE:60/40) to yield the title amide in the form of a white solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[N:17]=[C:18]2[N:23]([CH:24]=1)[CH2:22][CH2:21][CH:20]([CH2:25][OH:26])[O:19]2)([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:46][C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1>C1COCC1>[I:46][C:47]1[CH:52]=[CH:51][C:50]([O:26][CH2:25][CH:20]2[O:19][C:18]3=[N:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][N:23]3[CH2:22][CH2:21]2)=[CH:49][CH:48]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=[N+]([O-])c1cn2c(n1)OC(CO)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(I)cc1)CC2
Temperature: 25 °C
Reaction time: 32 h
Yield: 85.7 %

Procedure:
Diethylazodicarboxylate (0.070 mL, 0.45 mmol) was added dropwise to a suspension of oxazine alcohol 134 (see Example 2BB above) (251 mg, 1.26 mmol), triphenylphosphine (448 mg, 1.71 mmol), and 4-iodophenol (377 mg, 1.71 mmol) in anhydrous THF (3.0 mL) at 0° C. under N2, and the resulting mixture was stirred at room temperature for 32 h. The solvent was removed and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 0-2% EtOAc/CH2Cl2 gave a crude solid, which was further chromatographed on silica gel. Elution with 0-50% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 10% MeOH/CH2Cl2 gave 7-[(4-iodophenoxy)methyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (135) (433 mg, 86%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 224-227° C.; 1H NMR [(CD3)2SO] δ 8.08 (s, 1H), 7.62 (dt, J=9.0, 2.7 Hz, 2H), 6.86 (dt, J=9.0, 2.7 Hz, 2H), 4.89 (m, 1H), 4.31 (dd, J=11.1, 3.4 Hz, 1H), 4.25 (dd, J=11.1, 5.8 Hz, 1H), 4.18 (ddd, J=12.6, 5.8, 3.0 Hz, 1H), 4.09 (ddd, J=12.5, 10.8, 5.2 Hz, 1H), 2.35-2.26 (m, 1H), 2.25-2.12 (m, 1H). Anal. (C13H12IN3O4) C, H, N.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](O)(=[O:47])[CH2:45][OH:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH:30]4[CH2:33][N:34]([C:45](=[O:46])[CH2:44][OH:47])[CH2:35][CH2:36][N:29]4[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: O=C(O)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(C3CN4CCN(C(=O)CO)CC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), triethylamine (43 μL, 0.31 mmol), and glycolic acid (8 mg, 0.10 mmol) in DMF (1 mL), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (51 mg, 0.11 mmol) was added at 0° C. The reaction was allowed to stir for 30 minutes while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous K2CO3 solution (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 20 mg (36%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35 to 7.27 (m, 5H), 7.11 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.16-5.12 (m, 1H), 4.35-3.96 (m, 3H), 3.88-3.85 (m, 1H), 3.67-3.55 (m, 1H), 3.36-3.27 (m, 1H), 3.12-3.01 (m, 1H), 2.79-2.64 (m, 2H), 2.55-2.41 (m, 3H), 2.19-2.10 (m, 2H); LC-MS [M+H]+=539, RT=2.19 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: CSc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(SC)cc32)CC1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
In accordance with the general procedure described in the foregoing Examples, 14.0 grams of 8-methylthio-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 12.2 grams of caprylyl chloride (octanoyl chloride) in a mixture of 20 milliliters of chloroform and 60 milliliters of benzene. After the reaction mixture had been allowed to stand for 4 days at room temperature, the reaction mixture was heated to a temperature of 60°C and further treated as described in the preceding Example. The recovered crude 8-methylthio-10-[4-(3-octanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was thereafter converted into the crystalline di(hydrogen maleate) as described in the foregoing Example. The salt was recovered in a yield of 13.7 grams and, after recrystallization from acetone, had a melting point of 122°-123°C. The pure base was recovered in the form of a viscous oil by treatment of the pure salt with a dilute aqueous solution of ammonium hydroxide as described in the foregoing Example.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[O:9][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(COc2ccc(C=O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Benzyl bromide (13.56 mL, 0.11 mol, 1.1 eq) was added to a solution of 3-hydroxy-4-[(4-methoxyphenyl)methoxy]benzaldehyde (26.91 g, 0.10 mL, 1 eq) and cesium carbonate (20.37 g, 0.06 mol, 0.6 eq) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred overnight and then concentrated in vacuo. The residual solution was diluted with ethyl acetate (200 mL) and washed with water (200 mL), saturated sodium chloride solution (3×200 mL), and 0.5M aqueous sodium hydroxide (3×200 mL), then dried over sodium sulfate and evaporated in vacuo. This gave a gummy solid which was recrystallized from ethyl acetate and petroleum ether to give the product as a pale brown powder (25.93 g, 71%). 1H NMR (CDCl3) δ 9.81 (s, 1H, O═C—H), 5.21 (s, 2H, CH2Ar), 5.20 (s, 2H, CH2Ar), 3.84 (s, 3H, OCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(Cl)cc3)nc21
Reaction time: 2 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (400 mg, 1.163 mmol), Ethanol (6 mL), THF (1 mL), and added sodium hydroxide (1.939 mL, 5.82 mmol) wherein the reaction time was 2 h. The final product was collected as 330 mg (90%). LCMS E-S (M+H)=315.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.8 Hz, 6H), 5.26-5.47 (m, 1H), 7.62 (d, J=8.6 Hz, 2H), 8.20 (s, 1H), 8.28 (d, J=8.6 Hz, 2H), 8.38 (s, 1H), 14.03 (s, 1H).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:4][O:2][CH3:3])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 63.6 %

Procedure:
Methoxylamine hydrochloride (0.95 g (11.4 mmol)) was suspended in pyridine (4.0 ml). To this, under cooling with ice and with stirring, 2-chlorobenzenesulfonyl chloride (2.11 g (10.0 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water (50.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.41 g (64%) of 2-chloro-N-methoxybenzenesulfonamide as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[OH:22][C:24]1([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: C1CCCC2(CCC1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2(O)CCCCCCC2)c1
Temperature: 120 °C

Procedure:
A suspension of the phenol 58 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane (0.5 g, 3.2 mmol) and Cs2CO3 (1.14 g, 3.5 mmol) in DMSO (4 mL) was heated at 120° C. for 16 h. After completion of reaction, the mixture was quenched by the addition of 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (0 to 10% 7N NH3/methanol—CH2Cl2) afforded 2-(3-(3-((1-hydroxycyclooctyl)methoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (1.057 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.10-7.36 (m, 2H), 6.40-6.80 (m, 6H), 3.69 (s, 2H), 2.10-2.45 (m, 2H), 1.30-2.0 (m, 18H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC.[NH4+].[Cl-]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:13])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(CC1CCN(CC2CC2)CC1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(CC1CCN(CC2CC2)CC1)(c1ccccc1)c1ccc(F)cc1

Procedure:
1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine (Example 429, 1.0 g, 3.6 mmol) was mixed with dry tetrahydrofuran (10 mL). A solution of phenyl magnesium bromide in ether (3.0 M, 3 mL, 9 mmol) was added with stirring. The reaction mixture was stirred for 24 h; poured onto a saturated NH4Cl solution and extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo. Trituration with ether-hexanes (1:9) and filtration afforded the title compound, a solid, which was dried in vacuo (0.9 g): mp 115°-116° C.; Anal.: Calcd for C23H28FNO: C, 77.36, H, 7.90, N, 3.92, F, 5.32; Found: C, 77.47, 77.41, H, 8.00, 7.92, N, 3.42, 3.52, F, 5.09.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: COc1cc(Nc2cccc(Nc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-(trifluoromethoxy)aniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=10%). MS ISP (m/e): 456.3 (100) [(M+H)+].
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].[NH2:9][C@@H:10]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)=[O:12]>>[CH2:30]([O:29][CH2:28][C@H:10]([NH:9][C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[CH3:2])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)=[O:12])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C)CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 53.8 %

Procedure:
Proceeding as in Example 1, but substituting 3-methylbutanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 233, (S)—N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-3-methylbutanamide (3 mg, 53.8%). MS (EI) for C27H29FN2O4. found 465.5 (MH+).