Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[C:41]([O:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1)(=[O:43])[CH3:42]>CN(C=O)C.O.C(N(CC)CC)C>[C:41]([O:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]4)[CH2:3][CH2:4]2)=[O:50])=[CH:47][CH:46]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril monohydrobromide in 10 ml of DMF was added 296 mg of sodium hydrogencarbonate and stirred at room temperature for 30 minutes to convert the compound to 6-piperazinyl-3,4-dihydrocarbostyril, to which was added 0.62 ml of triethylamine. Then, a solution of 605 mg of 4-acetyloxybenzoyl chloride in 5 ml of DMF was slowly added dropwise to the mixture. After completion of addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed serially with saturated aqueous sodium hydrogencarbonate solution and with water and then dried over anhydrous sodium sulfate. Chloroform was distilled off to give 6-[4-(4-acetyloxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C.[NH:14]1[CH:20]=[CH:19][CH2:18][CH2:17][NH:16][C:15]1=[S:21]>CO>[ClH:1].[CH3:12][C:11]1[C:2]([S:21][C:15]2[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:14]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: S=C1NC=CCCN1
Reactant: Cc1nc2ccccc2nc1Cl
Agent: C
Solvent: CO
Product: Cc1nc2ccccc2nc1SC1=NCCCCN1
Product: Cl
Temperature: 50 °C

Procedure:
2-Chloro-3-methylquinoxaline (5.36 g., 0.03 mole) was dissolved in 150 ml. methanol, treated with Norit and filtered. The filtrate was added to 3.91 g. (0.03 mole) of tetrahydro-1,3-diazepine-2-thione. The mixture was stirred in a waterbath heated at 50° C. for 2 hours. The resulting orange solution was concentrated to a volume of 75 ml., then diluted with 150 ml. acetone. The mixture was chilled and 2.5 g. of a solid collected. An additional 3.2 g. of solid was recovered from the mother liquor. The two solids were combined and recrystallized from methanolacetone to give the product as 1.15 g. (12.4%), white solid, m.p. 170°-173° C. (dec)
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8](O)=[N:9][C:4]2=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]2[N:1]=[CH:2][CH:3]=[C:4]2[N:9]=1
Reactant: Oc1ccn2nccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccn2nccc2n1
Yield: 68 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidin-5-ol (17.0 g, 126 mmol) in POCl3 (100 mL) was heated at reflux for 3 hours. After cooling, the reaction was concentrated under vacuum. To the residue was added dichloromethane. The organic phase was carefully washed with saturated aqueous NaHCO3 solution, dried and concentrated. The crude product was purified by passing through a short silica gel pad eluting with 50% EtOAc in hexane to give 5-chloropyrazolo[1,5-a]pyrimidine (13.1 g, 68%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]([OH:22])=O)[CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].N[CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=1.F[P-](F)(F)(F)(F)F.[N:48]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:52]2C=CC=C[C:51]=2N=N1>CN(C=O)C.CCN(CC)CC.C(Cl)Cl>[CH2:14]([O:13][C:10]1[CH:9]=[C:8]([CH:18]=[CH:19][C:20]([NH:48][CH2:52][CH2:51][CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:29]([OH:36])=[C:28]([C:37]([CH3:39])([CH3:40])[CH3:38])[CH:27]=2)=[O:22])[CH:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=1[OH:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(C=CC(=O)O)cc(OCCCC)c1O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)c1cc(CCN)cc(C(C)(C)C)c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1cc(C=CC(=O)NCCCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(OCCCC)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To the solution of 3-(3,5-dibutoxy-4-hydroxyphenyl) acrylic acid (53 mg, 0.17 mmol) in DMF (0.76 ml) and Et3N (39 μl), was added 4-(2-aminoethyl)-2,6-di-t-butylphenol (50 mg, 0.19 mmol) at 0° C. The obtained solution was added with the solution of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (84 mg, 0.19 mmol) in CH2Cl2 (1 ml). The solution was stirred for 30 minutes at 0° C. and then was stirred for 12 hours at room temperature. The solution was added with BOP (70 mg, 0.16 mmol) and was stirred for 1 hour. And then CH2Cl2 was evaporated in vacuo and the obtained residue was poured into ice water. The residue was extracted with EtOAc and washed with HCl (aq) and NaHCO3 (aq). And then the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:2), yielding 51 mg (91%) of the title compound as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1)(=[O:3])[CH3:2].[C:12]1([CH2:18][S:19][CH:20]([C:24](O)=[O:25])[C:21](O)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][C:8]1[CH:9]=[C:4]([C:1]2[O:3][C:21](=[O:22])[C:20]([S:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:24]([OH:25])[CH:2]=2)[CH:5]=[C:6]([CH3:11])[N:7]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)nc(C)c1
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)n1

Procedure:
The title compound was prepared from the condensation of the trimethylsilyl enol ether of 4-acetyl-2,6-dimethylpyridine and the diethyl ester of [(phenylmethyl)thio]propanedioic acid following the same procedure outlined in Method A; m.p. 88-90° C. NMR (DMSO-d6) δ2.55 (s, 6 H), 4.02 (s, 2 H), 6.85 (s, 1 H), 7.16-7.28 (m, 5 H), 7.40 (s, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].C(N(CC)CC)C.Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:24]=[C:23]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.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>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:25]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:21][N:22]=[C:23]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[CH:36][CH:37]=3)[N:24]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: C#Cc1cccc(C(=O)OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 120 °C
Yield: 57.3 %

Procedure:
To a nitrogen de-gassed solution of methyl 3-ethynylbenzoate (I31) (0.105 g, 0.655 mmol) in dry DMF (6 mL) were added triethylamine (0.308 mL, 2.18 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.250 g, 0.546 mmol), triphenylphosphine (0.021 g, 0.082 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.038 g, 0.055 mmol) and Cu(I)I (0.016 g, 0.082 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I32) (0.182 g, 57% yield) as an orange solid; 1H NMR (400 MHz, d6-DMSO) δ 10.28 (brs, 1H), 8.78 (s, 1H), 8.16-8.03 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 3.90 (s, 3H), 3.50-3.41 (m, 4H), 3.11-2.99 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.82 min; m/z 582.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C@@H:9]1[C@@H](CO)[O:12][C@@H:11]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1.C(O)C>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C@H:2]1[O:12][C@@H:11]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10][C@@H:9]1[F:8])(=[O:7])[CH3:6]
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (1.2 ml, 13 mmol) was added to a solution of 2',3'-dideoxy-3'-fluorouridine (1 g, 4.34 mmol) in dry pyridine (10 ml) and the mixture was stirred at room temperature for 24 hours. Ethanol (2 ml) was added and the mixture was evaporated to dryness. Residual pyridine was removed by coevaporation with portions of ethanol and the final residue purified by silica gel column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound which was isolated following trituration with ether.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=O)#[N:2].Cl.C([N:19]([CH2:22][CH3:23])[CH2:20]C)C.CN.Cl[CH2:27]C(=O)C>C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([C:3]1[CH:27]=[C:22]([CH3:23])[N:19]([CH3:20])[C:4]=1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)CCl
Reactant: COC(=O)c1cccc(C(=O)CC#N)c1
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2c(C#N)cc(C)n2C)c1
Reaction time: 2 h

Procedure:
To the stirring mixture of methyl 3-(cyanoacetyl)benzoate (2.0 g), triethylamine (1.4 ml), triethylamine hydrochloride (1.4 g) and 40% aqueous methylamine (0.93 ml) was added chloroacetone (0.86 ml) at ambient temperature and the mixture was stirred for 2 hours at the same temperature. To the reaction mixture was added ethyl acetate and the mixture was washed with water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give methyl 3-(3-cyano-1,5-dimethylpyrrol-2-yl)benzoate (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:27])[N:11]([CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[CH:28]1([CH2:31][N:17]2[CH2:18][CH2:19][C:14]([CH2:13][N:11]([CH3:12])[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[O:27])([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[CH2:15][CH2:16]2)[CH2:30][CH2:29]1
Reactant: O=CC1CC1
Reactant: CN(CC1(c2ccc(I)cc2)CCNCC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN(CC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a solution of 3-(3,5-dichloro-phenyl)-1-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-1-methyl-urea (˜0.10 g, 0.17 mmol) in ClCH2CH2Cl (1 mL) was added cyclopropanecarboxaldehyde (0.016 mL, 0.204 mmol, 1.2 eq.). The mixture was stirred at room temperature for 15 min and then HOAc (0.01 mL, 1% v/v) was added. The reaction was stirred for a further 1 h. Na(OAc)3BH (0.054 g, 0.255 mmol, 1.5 eq.) was added and the reaction was stirred at room temperature for 12 h. It was diluted with EtOAc (10 mL) and washed with saturated NaHCO3 (10 mL) and saturated brine (10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give 1-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-3-(3,5-dichloro-phenyl)-1-methyl-urea (0.094 g, 95%). Crude 1H NMR (CDCl3): δ 7.83 (d, 2H), 7.22 (m, 4H), 7.05 (s, 1H), 6.01 (br.s, 1H), 3.50 (s, 2H), 2.97 (d, 2H), 2.83 (s, 3H), 2.36 (m, 2H), 2.27 (m, 2H), 2.09 (m, 2H), 0.91 (br.m, 1H), 0.58 (d, 2H), 0.15 (d, 2H).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C(=N[NH:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH:29]=2)=[C:22]([Cl:40])[CH:21]=1)C)C.[C:42]([O:45][CH2:46][CH3:47])(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[CH2:46]([O:45][C:42]([C:43]1[NH:19][C:20]2[C:21]([CH:1]=1)=[C:22]([Cl:40])[C:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH:29]=1)=[C:24]([Cl:26])[CH:25]=2)=[O:44])[CH3:47]
Reactant: CCOC(=O)C(C)=NNc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC)c2)c(Cl)c1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(Cl)c(Oc3ccc(O)c(S(=O)(=O)CC)c3)c(Cl)cc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of p-toluenesulfonic acid (169 mg, 0.98 mmol) and 2-{[3,5-Dichloro-4-(3-ethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-hydrazono}-propionic acid ethyl ester (310 mg, 0.65 mmol) in toluene (2.5 mL) was heated to reflux for 16 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (25 mL), washed with saturated NaHCO3 (3 times 10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (4% methanol in methylene chloride) to afford the title compound (100 mg) as a tan solid. 1H NMR (400 MHz, CDCl3) δ10.7 (s, 1H), 7.42 (s, 1H), 7.18 (d, 1H), 7.04-6.98 (m, 2H), 6.88 (d, 1H), 4.36-4.30 (q, 2H), 3.20-3.05 (q, 2H), 1.34 (t, 3H), 1.18 (t, 3H). MS (APCI−) Calc: 457.0, Found: 456.1 (M−1).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:21]2[O:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:28])[C:17](=[O:29])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:21]2[O:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:28])[C:17](=[O:29])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCO)cccc2c1=O
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCCl)cccc2c1=O

Procedure:
A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform was added to a boiling solution of 3.37 g of Intermediate XX in 20 ml of chloroform. After refluxing for 90 minutes, the solvent was removed in vacuo and the residue was crystallized from acetonitrile to give 3 g of the title compound with a melting point of 193°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[Cl-:16].CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalkyl chloride and DMF in chloroform at room temperature followed by evaporation in vacua.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[N:25][NH:26][N:27]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][N:25]1[N:26]=[N:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CCCCN1Cc1ccccc1
Reactant: Fc1ccc(-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2nnn(CC3CCCCN3Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Benzyl-2-bromomethylpiperidine (2.1 g), 5-(4-fluoro-phenyl)-2H-tetrazole (1.28 g) and potassium carbonate (6 g) were combined in xylene (100 ml) containing diisopropylethylamine (7 ml) and boiled for 16 h. The reaction mixture was cooled to room temperature, filtered, solvent removed at reduced pressure and the residue column chromatographed (silica gel; diethyl ether/petroleum ether 40:60 eluant) to give after combining appropriate fractions and removing solvent at reduced pressure the title compound 1.44 g.
Reaction SMILES: [ClH:1].N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]>C(O)C>[ClH:1].[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(C)c([N+](=O)[O-])c2)c2c(ccc3nc[nH]c32)n1

Procedure:
A mixture of 10.85 g. (0.05 m.) of the compound of Example I, C., 7.6 g. (0.05 m.) of 4-methyl-3-nitroaniline and 500 ml. of ethanol was refluxed overnight. The reaction mixture was concentrated in vacuo to give 38 g. of crude product. It was then dissolved in 6000 ml. of MeOH and filtered hot. The MeOH filtrate was concentrated in vacuo to yield 27 g., m.p. 344°-345°C.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:34]([CH2:40][CH2:41][CH3:42])=[N:33][C:27]=3[C:28]([NH2:32])=[N:29][C:30]=2[CH:31]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:32][C:28]1[C:27]2[N:33]=[C:34]([CH2:40][CH2:41][CH3:42])[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([CH2:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)(=[O:15])=[O:14])=[CH:31][C:30]=2[N:29]=1
Reactant: O=S(=O)(Cl)CCc1cccc2ccccc12
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cc(OCCCNS(=O)(=O)CCc4cccc5ccccc45)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
2-(1-Naphthyl)ethanesulfonyl chloride (0.358 g, 1.40 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 30 minutes. Triethylamine (0.250 mL, 1.79 mmol) was then added. The reaction mixture was poured into saturated aqueous sodium carbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale yellow oil was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 94:6) and subsequent recrystallization from acetonitrile to yield 0.341 g of N-(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-(1-naphthyl)ethanesulfonamide as white crystals, mp 164-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
3-[2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3yl]-propionic acid (11 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 11.5 g (80%) of 3-[2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:5]=2[C:4]=1[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>ClCCl>[CH:21]1([N:20]2[C:4]3[C:5]4[CH:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:17])[CH3:18])[C:6]=4[N:7]=[CH:8][C:3]=3[CH2:2][NH:1][C:27]2=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(CN)cnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCCCC1
Yield: 68.6 %

Procedure:
5-(Aminomethyl)-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (127 mg, 0.339 mmol) in dichloromethane was stirred with 1,1′-carbonyldiimidazole (65.9 mg, 0.407 mmol) at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a colorless oil (93.2 mg, yield 69%).