Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:43]([F:44])=[CH:42][C:18]3[N:19]=[C:20]([C:22]4[C:26]([NH:27][C:28]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])=[CH:25][N:24](C5CCCCO5)[N:23]=4)[NH:21][C:17]=3[CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:44][C:43]1[C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:16][C:17]2[NH:21][C:20]([C:22]3[C:26]([NH:27][C:28]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[CH:25][NH:24][N:23]=3)=[N:19][C:18]=2[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(F)c(N3CCNCC3)cc2[nH]1)N1CCCCC1
Temperature: 22 °C
Reaction time: 48 h
Yield: 74.2 %

Procedure:
0.5 mL of water is added to a solution of 380 mg of 4-{6-fluoro-2-[4-[(piperidine-1-carbonyl)amino]-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester in solution in 2 mL of trifluoroacetic acid. The reaction medium is stirred at 22° C. for 48 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-40 cartridge. The elution is carried out with pure dichloromethane and then with dichloromethane containing 5% of ammoniacal methanol. 195 mg of N-[3-(5-fluoro-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-piperidine-1-carboxamide are obtained in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.48 to 1.68 (m, 6H); 3.23 (m, 4H); 3.30 (m, 4H); 3.47 (m, 4H); 7.24 (d, J=8.0 Hz, 1H); 7.48 (d, J=11.5 Hz, 1H); 8.01 (s, 1H). ES mass spectrum: m/z=413 MH+, m/z=328 (M+H—C5H11N)+, m/z=227.9 (M+CH3CN+2H)2+/2 (base peak). Remark: the acetonitrile explaining the m/z=227.9 peak is in the mobile phase.
Reaction SMILES: [O-][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]3[C@@H:18]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][O:16][CH2:15][C:13]3=[N:14][C:4]=2[CH:3]=1.[NH4+:23].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:23][C:3]1[C:4]2[N:14]=[C:13]3[CH2:15][O:16][CH2:17][C@H:18]([C:19]([OH:22])([CH3:21])[CH3:20])[N:12]3[C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=1
Reactant: [NH4+]
Reactant: CC(C)(O)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
2-[(11R)-5-Oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (798 mg, 2.67 mmol) was dissolved in 25 mL of CH2Cl2 and treated with 5 mL of concentrated NH4OH solution. The mixture was stirred rapidly and p-toluenesulfonyl chloride (534 mg, 2.80 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was then treated with 25 mL of H2O and the layers were separated. The aqueous portion was extracted with additional CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% methanol/CHCl3) gave a light yellow foam. Crystallization from ethyl acetate gave 2-[(11R)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (220 mg) as white crystals, mp 216-217° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[O:13][CH3:14].CN(CCN(C)C)C.C([Li])(C)(C)C.[Br:28]Br>C(OCC)C>[Br:28][C:5]1[C:4]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: BrBr
Reactant: COCOc1ccc(OC)c(OC)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COCOc1ccc(OC)c(OC)c1Br
Reaction time: 1 h

Procedure:
To a stirred solution of 1,2-bis(methyloxy)-4-{[(methyloxy)methyl]oxy}benzene (4.0 g) and TMEDA (3.93 ml) in dry diethyl ether (50 ml) was added tert-butyllithium (1.7M in pentane, 23.76 ml) at −70 C. The reaction was stirred at this temperature for 1 h before adding bromine (0.15 ml). This was allowed to stir at 0 C. for 3 h. The reaction was quenched by addition of 20% aqueous sodium dithionite and extracted with ethyl acetate. The organics were washed with dilute hydrochloric acid, aqueous sodium bicarbonate, brine and dried over sodium sulphate to yield a crude product. This was purified through silica, eluting with 0-10% ethyl acetate in hexane to give the title compound, 1.4 g
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:62])=[C:25]([N:27]2[C:31](=[O:32])[N:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[S:46](=[O:56])(=[O:55])[NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:36][C:35]=3[F:57])[C:29]([CH2:58][CH2:59][CH2:60][CH3:61])=[N:28]2)[CH:26]=1.N12CCCN=C1CCCCC2>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:51]([O:50][C:48]([NH:47][S:46]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:30]2[C:29]([CH2:58][CH2:59][CH2:60][CH3:61])=[N:28][N:27]([C:25]3[CH:26]=[C:21]([NH:20][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[CH:22]=[CH:23][C:24]=3[Cl:62])[C:31]2=[O:32])=[C:35]([F:57])[CH:36]=1)(=[O:55])=[O:56])=[O:49])([CH3:52])([CH3:53])[CH3:54]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Reactant: CCOCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nn(-c2cc(NC(=O)COCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 19.8 %

Procedure:
A mixture of 12 μL (13.2 mg, 0.127 mmol) of ethoxyacetic acid, 20.6 mg (0.127 mmol) of 1,1'-carbonyldiimidazole (CDI), and 1 mL of dry THF was stirred at 60° C. for 4 hours. To this solution was then added 40 mg (0.0635 mmol) of 2-(5-amino2-chlorophenyl)-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) dissolved in THF, followed by 19 μL (19.3 mg, 0.127 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred overnight at 60° C., the reaction mixture was diluted with 5% citric acid (aqueous) and extracted 2× with ethyl acetate. The combined organic fractions were washed twice with water, then with brine, and dried over Na2SO4. The filtered solution was concentrated, and the residue was flash chromatographed on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2), yielding 9 mg (20%) of the title compound as a white, glassy solid, mp 100°-102° C.; satisfactory purity by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 622 (M+Li)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[OH:11].[OH-].[K+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:11][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[OH:13]
Reactant: Oc1ccccc1O
Reactant: Cc1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1COc1ccccc1O

Procedure:
For the synthesis of I, 10.0 g of a-bromo-o-xylene were added to 5.95 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 3.3 g dissolved in 50 ml of ethanol, was added dropwise over 30 min with stirring. The solution was then refluxed under nitrogen for 2 hours. The solution was filtered to remove KBr. The solution was cooled over night and filtered to remove di-substituted product. Ethanol was removed by rotary evaporation, and the oil was dissolved in 50 ml of chloroform. The pH was adjusted to neutrality with HCl and extracted three times with equal volumes of water, to remove unreacted catechol and salts. Chloroform was removed by rotary evaporation and the oil was vacuum-distilled at 8 mm Hg. Approximately 4 g of compound I were collected in the distillate that came over at 180° C. The structure was confirmed by NMR and mass spectrum data.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:21]C(OC(C)(C)C)=O)[S:9][C:10]=1[CH:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:21])[S:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(NC(=O)OC(C)(C)C)sc1C(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nc(N)sc1Cc1ccccc1OC
Yield: 65.5 %

Procedure:
A mixture of 2-tert-butoxycarbonylamino-5-[hydroxy-(2-methoxy-phenyl)-methyl]-thiazole-4-carboxylic acid ethyl ester (12 g, 29 mmol), triethylsilane (52 g, 45 mmol), and trifluoroacetic acid (100. g, 89.6 mmol) was stirred for 15 hours in dichloromethane (150 mL). The mixture was evaporated to dryness and then diluted with water. The precipitated solid was filtered and washed with water, diethyl ether, and petroleum ether to give the pure target molecule as a trifluoroacetic acid salt (7.6 g, 19 mmol, 64%). ESI-MS m/z calc. 292.09. found; 292.25 (M+1)+ 1H NMR (CDCl3) δ 7.7 (br, 2H), 7.24 (t, 1H), 7.17 (d, 1H), 6.99 (d, 1H), 6.88 (t, 1H), 4.22-4.25 (m, 4H), 3.78 (s, 3H), 1.26 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH:16]2[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C1COC(=O)N1)C1C=CC=CC=1>>[CH3:22][O:19][C:18]([CH:16]1[CH2:17][CH:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([Cl:21])[CH:11]=1)=[O:20]
Reactant: O=C(O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: O=C1NC(Cc2ccccc2)CO1
Product: COC(=O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Yield: 60 %

Procedure:
The mixture (85 mg) of 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid and 4-benzyloxazolidin-2-on obtained in Step A was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (54 mg, two-step yield 60%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[O:7][C:8]1[CH:9]=[C:10]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.Cl>C1COCC1.O>[CH:3]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[O:7][C:8]1[CH:9]=[C:10]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:2]
Reactant: COC(OC)c1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of N-[3-(3-dimethoxymethyl-4-nitrophenoxy)-phenyl]-benzenesulfonamide (0.0083 mol) in THF (12 mL) was stirred at room temperature, then 12N HCl (6 mL) and water (6 mL) were added and the reaction mixture was stirred for 48 hours at room temperature. The mixture was stirred in H2O and extracted with diisopropyl ether. The organic layer was separated, washed with a 10% NaHCO3 solution, separated again, dried, filtered, and the solvent was evaporated. The obtained residue was stirred in diisopropyl ether, and then the desired product was filtered off and dried to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]1=[O:15].[N+:20]([CH3:23])([O-:22])=[O:21]>O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])([CH2:23][N+:20]([O-:22])=[O:21])[C:6]1=[O:15]
Reactant: O=C1C(=O)N(Cc2ccccc2Cl)c2ccccc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1N(Cc2ccccc2Cl)c2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 9 h

Procedure:
1-(2-chlorobenzyl)indoline-2,3-dione (0.135 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 9 hours. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](OC(C)(C)C)=O)[CH2:8]1.ClC1[N:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:25]=1[C:26]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:27]>>[Cl:46][C:43]1[CH:44]=[N:45][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:7]([CH2:6][O:5][C:4]3[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[C:25]([CH:42]=1)[C:26]([NH:28][C:29]1([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)[CH2:31][CH2:30]1)=[O:27]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2cccc(F)c2)C1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC(COc4cccc(F)c4)C3)CC2)cc1
Yield: 112 %

Procedure:
The title compound (D203) (97 mg) was prepared according to the experimental procedure described in Description 160 starting from tert-butyl 3-((3-fluorophenoxy)methyl)piperidine-1-carboxylate (D45) (100 mg, 0.323 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (59 mg, 0.161 mmol).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:11])[C:8](=[O:10])[CH3:9].[Br:13]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:13][CH2:9][C:8](=[O:10])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])=[O:11]
Reactant: BrBr
Reactant: CC(=O)C(=O)c1ccccc1C
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1C(=O)C(=O)CBr
Temperature: 70 °C
Yield: 97.6 %

Procedure:
A mixture of 3 g (18.49 mmol) 1-o-Tolyl-propane-1,2-dione and 1.05 ml (20.34 mmol) bromine in 30 ml CHCl3 and 0.53 ml acetic acid was heated to 70° C. for 16 h. The mixture was evaporated under reduced pressure to yield 4.35 g (98%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([NH2:14])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][NH2:14]
Reactant: NC(=O)CCc1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCc1cc2ccccc2[nH]1
Yield: 92.9 %

Procedure:
To a solution of 3-indolyl-propionamide (5 g, 24.7 mmol) in tetrahydrofuran anhydrous (150 ml) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran; 100 ml) slowly. The reaction mixture was refluxed for 3 hours, then was quenched by adding water (4 ml), 15% sodium hydroxide (4 ml) and water (12 ml) at 0° C. The mixture was filtered through celite and concentrated under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 4.0 g (86%) of product as a white solid: mp 58-60.5° C. MS EI m/e 174 (M·+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.S(O)(O)(=O)=O.[CH3:24][N:25]([CH3:29])[C:26]([NH2:28])=[NH:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:27]=[C:26]([N:25]([CH3:29])[CH3:24])[N:28]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Agent: O=S(=O)(O)O
Product: CN(C)c1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1,1-dimethylguanidine sulfate were converted to I-22 (42%): HRMS Calcd. for C14H13ClN4O: 289.0856, Found 289.0843.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:19][CH3:20])(=[O:18])[C:8]1[CH:17]=[CH:16][CH:15]=[C:10]([C:11]([O:13]C)=O)[CH:9]=1.Cl.[C:22](#[N:24])[CH3:23]>O>[C:22]([CH2:23][C:11]([C:10]1[CH:9]=[C:8]([CH:17]=[CH:16][CH:15]=1)[C:7]([O:19][CH3:20])=[O:18])=[O:13])#[N:24]
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(C(=O)CC#N)c1
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (6.4 g) was added to a solution of dimethyl isophthalate (10.0 g) in acetonitrile (90 ml) at ambient temperature and the mixture was stirred for 1 hour at 60°-64° C. The reaction mixture was added to a solution of conc. hydrochloric acid (4.7 ml) in water (150 ml) and extracted with ethyl acetate. The extract layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(cyanoacetyl)benzoate (4.72 g).
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([S:18](Cl)(=[O:20])=[O:19])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:10]([S:18]([NH:8][C:1](=[NH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])=[O:19])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: N=C(NS(=O)(=O)C=Cc1ccccc1)c1ccccc1

Procedure:
Reaction of benzamidine and styrylsulfonyl chloride according to the above procedure provides N-(STYRYLSULFONYL)BENZAMIDINE, m.p. 192.5°-194.5° C. (corr.), crystallized from acetone.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH2:4][CH3:5])[CH3:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:22])[CH3:2]
Reactant: Nc1ccccc1N
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Solvent: CCO
Product: CCN(CC)c1ccc(C=Nc2ccccc2N)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.479 g (17.64 mmol) 4-(N,N-Diethylamino)-salicylaldehyde are added at 5° C. in portions to a solution of 1.927 g (17.64 mmol) 1,2-phenylenediamine in 18 ml ethanol, the temperature being kept below 10° C. The resultant dark red suspension is stirred for 8 hours at room temperature and concentrated to dryness in vacuo. The crude product (6.34 g) is resolved by column chromatography (n-hexane/ethyl acetate 65:35). Yield: 1.27 g (26%), golden yellow crystalls.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[N:37]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]3[N:33]=[CH:34][CH:35]=[CH:36][N:37]=3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Yield: 58.2 %

Procedure:
This compound was prepared according to the general methods described in Example 1 using 2,2'-dithiobisbenzoyl chloride (3.0 g, 8.7 mmol) in 30 mL dichloromethane and 4-amino-N-(2-pyrimidinyl) benzenesulfonamide (5.3 g, 21.7 mmol) in 100 mL pyridine. The crude product was recrystallized from a mixture of dimethylformamide, ethanol, and water to yield 3.9 g of the title compound, mp 280° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7](=[N:9][OH:10])[NH2:8].[C:15]([O-])(=O)[CH3:16].[Na+].C(OC(=O)C)(=O)C>COCCOCCOC>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7]1[N:8]=[C:15]([CH3:16])[O:10][N:9]=1
Reactant: CC(=O)[O-]
Reactant: Cc1c(Cl)cccc1OCC(N)=NO
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: COCCOCCOC
Product: Cc1nc(COc2cccc(Cl)c2C)no1
Yield: 56.6 %

Procedure:
7.0 g (32.6 mmol) of 3-chloro-2-methyl-phenoxy-acetamide oxime and 14.0 g (142.8 mmol) of sodium acetate are introduced into 80 ml of diglyme and the mixture is treated with 8.6 g (84.2 mmol) of acetic anhydride. The reaction mixture is stirred at reflux temperature until the reaction is complete (approximately 2 hours). The entire batch is subsequently concentrated, the product is treated with water, and the mixture is extracted using ethyl acetate. After the solvent has been distilled off, the crude product which remains is chromatographed over a silica gel column (silica gel 60 Merck, particle size: 0.040 to 0.063 mm) using methylene chloride as the eluent. 4.4 g (56.5% of theory) of 3-(3-chloro-2-methyl-phenoxymethyl)-5-methyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13].CCN(CC)CC>C1COCC1>[OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:3]1
Reactant: OCCCBr
Reactant: OC1CNCC12CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.5 %

Procedure:
To a solution of 7-hydroxy-5-azaspiro[2.4]heptane (1.23 g, 11.0 mmol) in THF (40 mL) was added 3-bromopropanol (2.3 g, 16.65 mmol) and Et3N (2.24 g, 22.2 mmol). The reaction mixture was stirred at rt for 12 hrs and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:50:2(v/v/v) EtOAc/CH3OH/Et3N) to afford the desired compound as orange oil (1.14 g, 60%).
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]([OH:18])=O)=[C:11]3[CH2:12][CH2:13][O:14][C:10]3=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(Cl)Cl>S(Cl)(Cl)=O>[CH2:12]1[CH2:13][O:14][C:10]2[CH:9]=[CH:8][C:7]3[C:1]4[C:2]([C:16](=[O:18])[C:15]=3[C:11]1=2)=[CH:3][CH:4]=[CH:5][CH:6]=4
Reactant: O=C(O)c1c(-c2ccccc2)ccc2c1CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2-c2ccc3c(c21)CCO3
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A magnetically stirred solution of 2,3-dihydro-5-phenyl-4-benzofurancarboxylic acid (0.730 g, 3.04 mmol) in thionyl chloride (250 mL) was heated at reflux for 3 h. The solvent was removed by concentration in vacuo. The residue was digested with CH2Cl2 (150 mL) and the solution concentrated in vacuo. This process was repeated twice. The residue was digested with CH2Cl2 (260 mL) and treated with anhydrous aluminum chloride (0.40 g, 3.00 mmol). The resultant suspension was stirred for 2 h, poured over ice (250 g), treated with 1 N HCl (250 mL) and CH2Cl2 (250 mL), the layers were separated, and the aqueous layer further extracted with fresh CH2Cl2 (3×200 mL). The combined organic extracts were washed with brine (500 mL), dried (K2CO3), filtered, and concentrated in vacuo to give 0.525 g of 2,10-dihydro-1H-fluoreno[2,1-b]furan-10-one: 1H NMR (300 MHz, CDCl3) δ 3.44 (t, J=8.5 Hz, 2H), 4.65 (t, J=8.5 Hz, 2H), 6.78 (d, J=8 Hz, 1H), 7.18 (dt, J=1.5, 8 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.41 (dt, J=2, 8 Hz, 1H), 7.57(d, J=8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 21 h
Yield: 98.6 %

Procedure:
A typical procedure is given for the reaction of Entry 1 in Table 2. A 4 ml vial was charged with bromobenzene (171 mg, 1.10 mmol), diphenylamine (169 mg, 1.00 mmol), Pd(dba)2 (5.9 mg, 1 mol %), Ph5FcP(t-Bu)2(7.1 mg, 2 mol %), and sodium tert-butoxide (144 mg, 1.50 mmol). Anhydrous toluene (1 ml) was added into the mixture, and the vial was then sealed with a cap containing PTFE septum. The reaction mixture was stirred at room temperature for 1 h. After the starting aryl halide was consumed detected, as determined by GC, the reaction solution was directly absorbed onto silica gel, and the product was isolated by eluting with hexane/ethyl acetate to give 244 mg (99%) of triphenylamine as a white solid. Reaction of chlorobenzene (62 mg, 0.55 mmol) with diphenylamine (85 mg, 0.50 mmol) proceeded at 80° C. over 21 h to give triphenylamine (121 mg, 98%).