Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([C:24]([F:27])([F:26])[F:25])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34]>CN1CCCC1=O>[CH:29]1([CH2:28][N:3]2[C:2]([N:39]3[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]3)=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:17]2[C:18]([C:24]([F:26])([F:27])[F:25])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[N:7][C:8]=3[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)c(C(F)(F)F)n1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4C(F)(F)F)nc3n2CC2CC2)CC1
Temperature: 150 °C
Reaction time: 7 h
Yield: 48.3 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine (75 mg, 0.16 mmol) and N-methanesulfonylpiperazine (135 mg, 0.8 mmol) and the resulting mixture was stirred at 150° C. for 7 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column; NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (45 mg, 47%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: Br[Mg]CCCCCCCCc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
To 8-phenyloctylmagnesium bromide (from 24.25 mmoles of 8-phenyloctyl bromide and 21.27 mmoles of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmoles) [A. I. Meyers et al., J. Org. Chem., 43, 1372 (1978)] in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmoles) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmoles). The reaction mixture was allowed to stir for 30 minutes and was then quenched with 5 percent sodium hydroxide (50 ml). The reaction mixture was extracted with diethyl ether (2×50 ml) and the extract was washed with brine (50 ml) and dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate afforded an oil which was dissolved in acetone (50 ml), and 3N hydrochloric acid (10 ml) was added. The mixture was flushed with argon and stirred for 16 hours at ambient temperature. The volatiles were removed under vacuum and the residue partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous phase was extracted with more diethyl ether (50 ml). The combined organic phase was washed with brine (50 ml) and dried over anhydrous magnesium sulfate. Evaporation of the organic phase yielded an oil which was purified by flash chromatography over silica gel with 2 percent ethyl acetate in hexane as eluant to afford the desired product as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14](F)[CH:13]=[C:12]([F:17])[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:18][NH:19][CH3:20].C(O)C>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[C:12]([F:17])[CH:13]=[C:14]([N:19]([CH3:20])[CH3:18])[N:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N1CCN(c2nc(F)cc(F)n2)CC1
Solvent: CCO
Product: CC(=O)N1CCN(c2nc(F)cc(N(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-4-(4,6-difluoropyrimidin-2-yl)piperazine (1.9 g) was dissolved in 12% dimethylamine-ethanol solution (30 ml) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (2.1 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([N+]([O-])=O)[CH:11]=1.O>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:11]=1
Reactant: CC(C)=NO
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(ON=C(C)C)c1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
In 20 ml of DMF was dissolved acetone oxime (0.74 g), followed by sodium hydride (0.30 g). After this mixture had stirred for 30 minutes, 4-methoxy-2-nitro-benzonitrile (1.50 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of 4-methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile, m.p. 78°-79° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CC(C)=O>[CH:18]([O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:10])[CH3:1])([CH3:20])[CH3:19]
Reactant: CN(C)c1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cccc(N(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(dimethylamino)phenol (2.0 g, 14.60 mmol) in acetone (40.0 mL) were added K2CO3 (20.2 g, 146.0 mmol) and 2-iodopropane (2.20 mL, 21.90 mmol), and the reaction was refluxed for 18 h, then cooled to room temperature, and filtered through Celite. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography using ethyl acetate (20%) and hexanes (80%) as eluent to produce Compound 135 as yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:26]=[CH:25][C:12]([CH2:13]OC3C=CC=CC=3C(OC)=O)=[CH:11][CH:10]=2)[O:3]1.[OH:28][C:29]1[C:34](=[O:35])[CH:33]=[CH:32][N:31]([CH3:36])[C:30]=1[CH3:37].BrCC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:36][N:31]1[CH:32]=[CH:33][C:34](=[O:35])[C:29]([O:28][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:27])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]3)=[CH:26][CH:25]=2)=[C:30]1[CH3:37]
Reactant: COC(=O)c1ccccc1OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1c(O)c(=O)ccn1C
Agent: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(OCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)ccn1C
Yield: 50 %

Procedure:
The synthesis of B12 was accomplished following the procedure outlined for B1 using 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (80 mg, 0.54 mmol), 4-bromomethylphenyl boronic acid pinacol ester (180 mg, 0.59 mmol), and K2CO3(223 mg, 1.6 mmol) in 8 mL of acetonitrile affording B12 in 50% yield (0.09 g, 0.26 mmol). 1HNMR (400 MHz, CDCl3) δ=7.70 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.27 (d, J=7.6 Hz, 1H), 5.18 (s, 2H), 3.44 (s, 3H), 2.02 (s, 3H), 1.29 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=173.55, 146.13, 141.63, 140.83, 139.19, 134.91, 128.46, 117.21, 84.05, 73.00, 41.80, 24.97, 13.15. ESI-MS(+): m/z 356.20 [M+H]+, 378.10 [M+Na]+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ncccn2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 418.38 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:24]=[CH:23][C:16]2[O:17][C@H:18]([CH2:21][OH:22])[CH2:19][O:20][C:15]=2[CH:14]=1.Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+]>CC(=CC)C.O.C(O)(C)(C)C.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:26])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:24]=[CH:23][C:16]2[O:17][C@H:18]([CH2:21][OH:22])[CH2:19][O:20][C:15]=2[CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc4c(c3)OC[C@@H](CO)O4)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc4c(c3)OC[C@@H](CO)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
A mixture of 6-chloro-5-[(2R)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1H-indole-3-carbaldehyde (1.0 g, 2.9 mmol), sodium chlorite (5.28 g, 58.3 mmol), sodium dihydrogen phosphate (9.06 g, 58.1 mmol) in 2-methyl-2-butene (10 mL), water (10 mL), t-butanol (10 mL) and acetonitrile (10 mL) was stirred overnight at room temperature. The mixture was quenched with saturated aqueous sodium bisulfite. Water (50 mL) and methylene chloride (50 mL) was added. The aqueous layer was extracted with methylene chloride (50 mL×3). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give residue which was purified by reverse phase HPLC to give the title compound (105 mg, 14.3% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:17]1[C:22]([NH:23][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Oc2ncccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1cccnc1Oc1cccc(CCNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 54.3 %

Procedure:
A mixture of tert-butyl[2-[3-(3-amino-2-pyridyloxy)phenyl]ethyl]carbamate (3.3 g, 10 mmols), ethyl 4-bromobutyrate (2.8 ml, 20 mmols), potassium carbonate (1.4 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[3-[2-(tert-butoxycarbonylamino)ethyl]phenoxy]-3-pyridyl]aminobutyrate (2.41 g, 54.4%).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:15][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Yield: 51.5 %

Procedure:
Analogous to the procedure described for Example 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (2 g, 14 mmol) was reacted with 3-chlorobenzylmagnesium chloride (0.25M in Et2O, 62 mL, 15.5 mmol) over 2 h. Purification by medium pressure chromatography eluting with a solvent gradient (2:1 hexanes:EtOAc to EtOAc to 5% MeOH in CH2Cl2) provided 5-[4-(3-chloro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (1.9142 g). 1H NMR (CDCl3) δ7.27 (m, 2H), 7.19 (m, 1H), 7.08 (m, 1H), 6.27 (br, 1H), 3.68 (s, 2H), 3.60 (m, 1H), 2.52 (t, 2H), 2.29 (m, 2H), 2.21 (m, 1H), 1.88-1.60 (m, 3H); MS 266.2 (M+1), 264.2 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:2][NH:1][C:30](=[O:31])[O:32][CH2:33][CH3:34])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of 500 mg (1.64 mmol) of the compound from Example 101A and 321 μl (2.30 mmol) of triethylamine in 15 ml of dichloromethane was cooled to 0° C. and admixed with 189 μl (1.97 mmol) of ethyl chloroformate. The ice bath was removed and the mixture was stirred for a further 1 h. The volatile constituents were removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. The product fractions were combined and freed from the solvents on a rotary evaporator. The residue was dried in an HV. This gave 527 mg (85% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[CH:8]=[O:9].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[CH2:8][OH:9]
Reactant: Cn1cnc(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cnc(CO)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a 0° C. solution of 5-chloro-1-methyl-1H-imidazole-4-carbaldehyde (475 mg, 3.3 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (190 mg, 5.0 mmol). The reaction mixture was stirred at room temperature for 4 hours. Water (25 mL) was added. The mixture was evaporated. The resultant residue was treated with EtOAc (20 mL). The mixture was extracted with water (5 mL). The organic extract was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (5-chloro-1-methyl-1H-imidazol-4-yl)methanol (397 mg, 82% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>CC(C)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2nc3ccc(O)cc3n2Cc2ccccc2)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3n2Cc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A stirred solution of 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) and 4-fluoro-benzenesulfonyl chloride (190 mg) in acetone (8 ml) was treated with triethylamine (258 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (157 mg) as a yellow solid. Mass spectrum: 534 [M+H]+, retention time: 3.7 minutes.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:13]=[N:14][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:17]=2[C:18]#[N:19])=[CH:7][C:6]=1[S:24]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH3:38])([CH3:37])[CH2:29][CH2:28]1)(=[O:26])=[O:25]>C1COCC1.Cl>[Cl:11][C:9]1[C:8]([C:12]2[CH:13]=[N:14][C:15]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:17]=2[C:18]#[N:19])=[CH:7][C:6]([S:24]([N:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:38])([CH3:37])[CH2:29][CH2:28]2)(=[O:25])=[O:26])=[C:5]([CH2:4][C:3]([OH:39])=[O:2])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N1CCC(C)(C)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2CC(=O)O)c2ccccc21

Procedure:
[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-acetic acid methyl ester 16-1 (36.4 mg, 0.06 mmol) was heated in a mixture of THF (2 mL) and 6N HCl (2 mL) for 16 hrs. The mixture was concentrated and extracted with ethyl acetate. The organic layer was separated, dried and purified by a prep. TLC plate eluting with 10% MeOH in DCM to yield 5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-acetic acid 17-1 (27.3 mg). MS: 564.0 (M+H)+; tR=8.96 min (method 2).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH:18](NC(=O)C)([NH:25][C:26](=[O:28])[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P(Cl)(Cl)(Cl)=O.O>C(Cl)Cl>[C:26]([NH:25][CH:18]([C:8]1[C:7]([OH:12])=[CH:6][C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])=[CH:11][C:9]=1[OH:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)NC(NC(C)=O)c1ccccc1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(O)c(C(NC(C)=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 26.1 %

Procedure:
A stirred solution-suspension of 11.8 g (0.05 mol) of 5-(3-methyl-2-octyl)-resorcinol (4) (65% dl-erythro and 35% dl-threo) and 10.7 g (0.052 mol) of N,N'-benzylidenebisacetamide (2) in 60 ml of methylene chloride cooled to 2° in an ice bath was treated dropwise with 4.9 ml (0.05 mol) of phosphorus oxychloride over a period of 5 to 10 minutes. The stirring was continued in the melting ice bath. A clear solution formed after 2 to 2.5 hours and precipitation of produce occurred after 3 to 3.5 hours. After being stirred at room temperature overnight, the reaction mixture was treated with water (40 ml) and more methylene chloride (70 ml). After the slight exothermic reaction was complete, the organic layer containing suspended product was separated and washed successively with water (2 × 100 ml), 5% sodium bicarbonate (100 ml), and water (100 ml). Filtration of the organic layer gave 5.00 g of colorless crystalline powder, mp 204-208°. Concentration of the filtrate and cooling gave 2.58 g, mp 196-199°, as a second crop (7.58 g = 40% yield). Concentration to dryness left 10.8 g of an amorphous glassy solid which could not be crystallized. Its pmr spectrum was similar to that of the crystalline fraction, suggesting it consisted of a mixture of stereoisomers. Recrystallization from acetonitrile of a sample of the 7.58 g to constant mp gave pure 2-(α-acetylaminobenzyl)-5-(3-methyl-2-octyl)-resorcinol (6) mp 209°-210° (probably a single stereo-isomer); ir (Nujol) 3400 (νNH or OH), 3200 (broad, ν bonded OH), and 1610 cm-1 (νC=O); pmr (DMSO-d6) δ 9.0 -9.8 (m, 2H, OH), 7.98 (d, 1H, J = 9 Hz, NH), 7.0 - 7.5 (m, 5H, C6H5), 6.64 (d, 1H, J = 9 Hz, Ar2CHNH), 6.18 (s, 2H, C6H2) and 1.92 ppm (s, 3H, CH3CO); m/e (M+) 383.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1)(=O)[CH3:8].O>O1CCCC1.C(OCC)(=O)C>[CH2:7]([NH:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:8]
Reactant: COc1ccc(CCNC(C)=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCNCCc1ccc(OC)c(OC)c1

Procedure:
To a suspension of 0.98 g of lithium aluminum hydride in 50 ml of dried tetrahydrofuran (THF), a solution of 3 g of N-acetylhomoveratrylamin in 25 ml of THF was added dropwise with stirring. After heating for 3 hours under reflux, the reaction mixture was cooled with ice and gradually added dropwise under violent stirring with a solvent mixture composed of 10 ml of water and 10 ml of THF. Insoluble matter was filtered off and the filtrate was concentrated. The residue obtained was dissolved in 50 ml of ethyl acetate, washed twice with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, N-ethyl-homoveratrylamine was obtained as oily product. The yield was 2.3 g.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]([C:37]#[N:38])=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[CH2:24]1)#[N:21].O>C(O)(=O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:24]2[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]2=[C:22]([C:20]#[N:21])[C:37]#[N:38])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: N#CC(C#N)=C1CC(=C(C#N)C#N)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CCCCN(CCCC)c1ccc(C=C2C(=C(C#N)C#N)c3ccccc3C2=C(C#N)C#N)c(OC)c1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
In 10 ml of anhydrous acetic acid were dissolved 0.8 g (3.04 mmol) of 4-(dibutylamino)-2-methoxybenzaldehyde and 0.73 g (3.01 mmol) of 1,3-bis(dicyanomethylidene)indan. The mixture was stirred with heating at 80° C. for 2 hours. The reaction mixture was poured into 200 ml of water and the precipitate was separated by filtration, washed with water, and dried. The crystal was purified by silica gel column chromatography and washed with methanol to give 1.27 g of a black crystal having a mp of 195-198° C. (yield: 86.4%).
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.[CH3:30][N:31]=[C:32]=[O:33]>ClCCl>[CH3:30][NH:31][C:32]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:33]
Reactant: CN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: CC[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a solution of 2.0 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride monoethanolate and 5.0 mL (36 mMol) triethylamine in 100 mL dichloromethane were added 0.74 mL (12.6 mMol) methyl isocyanate. The reaction mixture was stirred for 15 minutes and was then washed with 100 mL of water. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was crystallized from acetonitrile to give 1.05 gm (64%) of the title compound.