Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:22][C:23]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:25][N:24]=1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:22][C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)[O:25][N:24]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 90 °C
Yield: 12.6 %

Procedure:
4-Chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (0.014 g, 0.068 mmol), Cs2CO3 (0.033 g, 0.102 mmol), and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.027 g, 0.102 mmol) were combined in DMF (10 mL) and heated to 90° C. for 30 min. The cooled reaction mixture was partitioned between Et2O and water. The organic portion was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.0037 g): MS (ESI) m/z 432 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[O:3]1.[OH-:23].[Na+].Cl>CS(C)=O.CN(C=O)C>[OH:23][C:4]1([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH2:11][CH:2]([CH3:1])[O:3]1
Reactant: COc1ccc2c(c1)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
A solution of 3 (1.3 g) in 4 ml of DMSO and 24 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phase was washed with water in order to remove DMF, dried over Na2SO4. Removal of the solvent afforded syrup crude product (1.6 g), which was used directly for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Reaction time: 72 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMSO is added copper (II) acetate (0.71 g, 3.9 mmol), powdered 4A molecular sieves (0.2 g), 3-pyridylboronic acid (4.3 mmol) and triethylamine (2.7 mL, 20 mmol). The resulting mixture is stirred under an oxygen atmosphere for 3 days. After filtering through a plug of Celite and silica gel, the mixture is concentrated in vacuo, adsorbed to silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate-hexanes, affording 5-(5-Nitro-pyridin-2-yloxy)-1-pyridin-3-yl-1H-indazole.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13](=[O:16])[C:12]3=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12](=[O:17])[C:13]1=[O:16]
Reactant: O=C1Nc2c(cccc2-c2ccccc2)C1=O
Reactant: BrCCCCBr
Product: O=C1C(=O)N(CCCCBr)c2c1cccc2-c1ccccc1

Procedure:
The title compound was prepared according to the process step described in the text is from Page 7, line 34 to Page 8, line 5 of WO 94/29272 using 7-phenyl-1H-indole-2,3-dione and 1,4-dibromobutane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:38])[CH2:24][Sn](CCCC)(CCCC)CCCC)[CH3:21]>CN(C=O)C.CCOC(C)=O.[Br-].[Zn+2].[Br-]>[CH2:20]([O:22][C:23](=[O:38])[CH2:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:21]
Reactant: Brc1cc(OCc2ccccc2)cc2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)CC(=O)OCC
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Benzyloxy-1-bromo-naphthalene (5.64 g, 18.01 mmol) is dissolved under an atmosphere of argon in dry DMF (100 ml). Tributylstannanyl-acetic acid ethyl ester (7.47 g, 19.81 mmol) is added, as well as [bis(tri-ortho-tolyl-phosphine)]palladium (II) dichloride (2.83 g, 3.60 mmol) and zinc(II) bromide (5.27 g, 23.41 mmol). The reaction mixture is heated to 80° C. for 3 h. The reaction mixture is diluted with EtOAc and washed twice with diluted brine (back extracted). The combined organic layers are dried over Na2SO4, the solvent is removed, and the residue is purified by FCC (hexane/EtOAc 100:0 to 97.5:2.5 to 95:5 to 90:10). The resulting oil, still containing tin residues, is stirred in a 1:1 mixture of EtOAc/1N NaOH (200 ml) for 1 h. The mixture is extracted twice with EtOAc. The combined organic layers are washed twice with H2O (back extracted), dried over Na2SO4 and concentrated. The residue is purified by FCC (hexane/EtOAc 100:0 to 97:3 to 95:5 to 93:7 to 92:8 to 90:10) to yield the title compound. 1H NMR (DMSO, 400 MHz) δ 1.18 (t, J=7.2 Hz, 3H), 4.10 (q, J=7.2 Hz, 2H), 4.11 (s, 2H), 5.25 (s, 2H), 7.21 (d, J=3.0 Hz, 1H), 7.41 (m, 8H), 7.53 (d, J=6.6 Hz, 1H), 7.84 (dd, J=7.2 Hz, 1H); ES-MS: 320 [M+H]+.
Reaction SMILES: CO.[CH3:3][C:4]([CH3:6])=O.[ClH:7].Cl.Cl.[CH3:10][O:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[NH:23])=[NH:20])=[CH:14][CH:13]=1>C(O)C>[ClH:7].[CH3:3][C:4]1([CH3:6])[N:20]=[C:19]([NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:35][CH:34]=2)[NH:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:23]1
Reactant: CC(C)=O
Reactant: CCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccc(OC)cc2)N1

Procedure:
100 ml of methanol, 40 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 2.0 g (4.6 mmol) of N1-(4-methoxyphenethyl)-N5-nonyl-biguanide dihydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure to give a residue, which was dissolved in hydrous ethanol. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7)) to obtain 1.2 g of a colorless resinous solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[NH:4][C:5]1[C:6]([C:17]([OH:19])=[O:18])=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]2=O>CO.O>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[N:4]=[C:5]1[C:10](=[CH:11]2)[CH:9]=[CH:8][CH:7]=[C:6]1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cccc2c(=O)c3cccc(Br)c3[nH]c12
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2cc3cccc(Br)c3nc12
Yield: 70 %

Procedure:
Reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-bromo-9-oxoacridan-4-carboxylic acid as above gave 5-bromoacridine-4-carboxylic acid (70%), mp (MeOH/H2O) 327° C. (dec). 1H NMR [(CD3)2SO] δ 7.71 (dd, J=8.3, 7.4 Hz, 1 H, H-2), 7.94 (dd, J=8.4, 7.1 Hz, 1 H, H-7), 8.40 (dd, J=8.7, 0.8 Hz, 1 H, ArH), 8.50 (dd, J=7.3, 1.0 Hz, 1 H, ArH), 8.64 (dd, J=8.3, 1.3 Hz, 1 H, ArH), 8.85 (dd, J=7.1, 1.3 Hz, 1 H, ArH), 9.66 (s, 1 H, H-9), 16.77 (br s, 1 H, COOH). Anal. (C14H8BrNO2) C, H, N, Br.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:31][O-:32].[Na+]>CO.CS(C)=O>[CH3:31][O:32][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: C[O-]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (35 mg, 0.075 mmol) was reacted with sodium methoxide (0.5 M in methanol, 1.0 mL, 0.488 mmol) in a mixture of methanol (4 ml) and DMSO (0.5 mL) at reflux for 16 h to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 70% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (15 mg, 43%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[CH2:26]Cl>C(O)(C)C>[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[CH2:26][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc(N)c(CCl)c1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(N)c(CSc2nc3cc(OC)ccc3[nH]2)c1
Yield: 25.3 %

Procedure:
The title compound was prepared by the method of Example 1 using 1.30 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 1.80 g of ethyl 4-amino-3-(chloromethyl)benzoate hydrochloride (prepared as for Example 70) instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 10% sodium hydroxide instead of sodium carbonate and 1,2-dichloroethane instead of dichloromethane. The 1,2-dichloroethane extract was dried over sodium sulfate, filtered, and concentrated in vacuo to a gum. Recrystallization from diethyl ether-hexane gave 650 mg of the title compound: m.p. 140-146° C. Anal. Calc'd. for C18H19N3O3S: C, 60.49; H, 5.36; N, 11.76; S, 8.90. Found: C, 60.27; H, 5.44; N, 11.39; S, 8.70.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[C:21]([CH2:29]Cl)[N:20]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:29][C:21]3[C:22]([CH3:28])=[C:23]([O:26][CH3:27])[C:24]([CH3:25])=[C:19]([Cl:18])[N:20]=3)[N:10]=[CH:11][C:3]=12
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: COc1c(C)c(Cl)nc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C)c(Cl)nc(Cn2ncc3c(Cl)nc(N)nc32)c1C
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (124 mg), Cs2CO3 (392 mg) and crude 2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (200 mg) in DMF (2 ml) was heated to 80° C. for 1 h, diluted with EtOAc and washed with water. Concentration and purification by preparative TLC (EtOAc) gave the title compound. R.t. 6.43 min. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 5.48 (s, 2H), 5.37 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Mg].[F:2][C:3]([F:27])([F:26])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24]Cl)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:28][O:29][Si:30](OC)([O:33][CH3:34])[O:31][CH3:32]>C1COCC1>[F:2][C:3]([F:27])([F:26])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][Si:30]([O:33][CH3:34])([O:31][CH3:32])[O:29][CH3:28])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: FC(F)(F)Oc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](CCCl)CC3)CC2)cc1
Reactant: CO[Si](OC)(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: CO[Si](CC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OC(F)(F)F)cc3)CC2)CC1)(OC)OC
Reaction time: 2 h

Procedure:
A Grignard reagent was prepared from 100 ml of THF, magnesium (120 mmole) and 1-trifluoromethoxy-4-(trans-4-(trans-4-chloroethylcyclohexyl)cyclohexyl)benzene (100 mmole) under nitrogen atmosphere. A THF 100 ml solution of tetramethoxysilane (150 mmole) was heated to 65° C., and the Grignard reagent was added dropwise thereto. The solution was stirred at the same temperature for 2 hours, and after left standing for cooling, the reaction mixture was filtered. The solvent was distilled off, and then 1-trifluoromethoxy-4-(trans-4-(trans-4-trimethoxysilylethylcyclohexyl)cyclohexyl)benzene (57 mmole) was obtained by distillation under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].Cl[CH2:16][CH:17]=[CH2:18]>CS(C)=O>[CH3:16][CH:17]1[CH2:18][C:3]2[C:2]([Cl:1])=[C:7]([CH3:8])[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=2[O:12]1
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1Cl
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(C)O2
Temperature: 190 °C
Reaction time: 8 h

Procedure:
A mixture of 93.4 g of 4B, 750 ml of DMSO, 48 g of 50% aqueous sodium hydroxide and 45.9 g of 3-chloropropene was stirred for 8 hours at 75°-80° C., then for 16 hours at room temperature. The resulting mixture was added to 3 liters of ice water and the resulting mixture was extracted with methylene chloride. The extract was washed with water, dried (MgSO4) and evaporated to dryness. The residue, in a nitrogen atmosphere, was heated slowly to 190° C. (one hour) and held at 185°-195° C. for two hours, cooled to room temperature, and dissolved in 250 ml of acetic acid. To this solution 150 ml of 48% aqueous hydrogen bromide solution was added, and the mixture was stirred at reflux for three hours, then mixed with 2 liters of ice water, and the resulting mixture was extracted with a 1:1 v:v mixture of hexane and ether. The extract was washed with water, 5% aqueous sodium bicarbonate solution, dried (MgSO4), charcoaled and concentrated to dryness. The residue was crystallized from 500 ml of 9:1 v:v hexane/-ether mixture, giving 2,3-dihydro-2,5-dimethyl-4-chloro-7-nitrobenzofuran (4C), m.p.: 114°-116° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1ccccc1
Reaction time: 1 h

Procedure:
(±)-trans-2-Aminocyclohexanol (241 gm) was combined with chloroform (2000 ml), water (2000 ml) and sodium bicarbonate (352 gm) and stirred. Benzoyl chloride (352 gm) was added dropwise to the stirred solution and stirring was continued for 1 hr. The product was filtered and washed with water. The white solid was dried at 80° C. to provide the product (mp 172°-173° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20](I)([F:25])[C:21]([F:24])([F:23])[F:22]>[Cu].CS(C)=O>[CH3:13][N:12]([CH3:14])[CH2:11][CH2:10][CH2:9][N:8]([CH3:15])[C:5]1[CH:6]=[CH:7][C:2]([C:20]([F:25])([F:19])[C:21]([F:24])([F:23])[F:22])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 22 h

Procedure:
To a pressure vessel was added N-(4-Bromo-2-nitro-phenyl)-N, N′,N′-trimethyl-propane-1,3-diamine (Step 1, 5.0 g, 15.8 mmol), copper powder (10.0 g, 158 mmol), and 20 mL DMSO. Pentafluoroethyl iodide (7.8 g, 31.6 mmol) was bubbled in and the vessel sealed. The mixture was then heated to 120° C. and vigorously stirred for 22 h. The reaction was cooled to 0° C. and filtered through a Buchner funnel, rinsing with EtOAc. The filtrate was then washed once with saturated aqueous NaHCO3, twice with water, once with brine, and then dried over Mg2SO4. The crude mixture was then purified by silica gel chromatography using a 10% MeOH/CH2Cl2 gradient to yield the title compound as a brown oil. MS (M+H)+=356; Calc'd 355.30 for C14H18F5N3O2.
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCCCBr)cc1
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCCCN2CCC(Oc3ccccc3)CC2)cc1

Procedure:
A mixture of 4-phenoxypyridine and benzylbromide in acetone was stirred overnight at room temperature. After removal of the solvent, the residue was dissolved in methanol, cooled to -20° C. and treated portionwise with sodium borohydride, and warmed to 0° C. After a standard workup and purification, the resulting tetrahydropyridine adduct was dissolved in methanol and hydrogenated using 20% Pd-C as a catalyst to provide 4-phenoxypiperidine. A mixture of 4-phenoxypiperidine and 1-bromo-3-(4-fluorophenoxy)propane in acetone with excess potassium carbonate was heated at reflux for 12 hours to give the title compound.
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O[C:20](=[O:22])[CH3:21])(=O)C>>[CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][N:7]([CH3:8])[C:20](=[O:22])[CH3:21])[CH2:3][CH2:2]1
Reactant: CNCCC(=O)C1CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N(C)CCC(=O)C1CC1
Temperature: 25 °C

Procedure:
A crude solution of 1-cyclopropyl-3-methylamino-1-propanone was cooled to 8°-10°C. and 8.2 g. (0.06 mole) of potassium carbonate was added, followed by 50 g. (0.5 mole) of acetic anhydride. The mixture was stirred until it warmed to room temperature. The benzne layer was separated, dried over magnesium sulfate, concentrated, and the residual oil distilled at 99°-150°C./0.1 mm. The distillate weighed 65 g. It was calculated to contain 80% of 1-cyclopropyl-3-(N-methylacetamido)-1-propanone by the nuclear magnetic resonance spectrum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH:19]=[CH2:20])=[O:18]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:20][CH2:19][C:17](=[O:18])[CH3:16])[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: C=CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)CCN1[C@H](C)CN(C(=O)OC(C)(C)C)C[C@@H]1C

Procedure:
Cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.00 g; prepared according to the method E. Jon Jacobson et. al.: J. Med. Chemistry. 1999, Vol. 42, 1123-144) in 47 mL chloroform was treated with methylvinylketone (1.7 mL) at room temperature and heated at reflux for two days. The reaction was then concentrated, diluted with THF and heated at reflux for 1 day before purifying by column chromatography (0 to 10% MeOH/DCM) to afford 0.865 g of the title compound as a clear, colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm 1.08 (d, 2H, J=6.07 Hz), 1.47 (s, 9H), 2.17 (s, 3H), 2.52 (m, 6H), 3.10 (m, 2H), 2.86 (bs, 2H); 13C NMR (CDCl3, 75 MHz) 17.6 (2C), 28.62 (5C), 30.8, 37.34, 42.46, 53.57 (4C), 79.85, 154.49, 208.29.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CS(O[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)(=O)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: COc1ccc2c(c1)C(C(=O)Nc1ccc(C(C)C)cc1)CCC2
Product: COc1ccc(CCCN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1
Yield: 57.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-3-(4-methoxyphenyl)propane (0.40 g) as starting materials, N-(4-isopropylphenyl)-N-[3-(4-methoxyphenyl)propyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[C:28](Cl)(=[O:30])[CH3:29].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:28](=[O:30])[CH3:29])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(N)cc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (100 mg, 0.249 mmol) (intermediate 1) was treated with acetyl chloride (22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (23 mg, 0.299 mmol) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 30 min. THF was evaporated and the residue was washed with saturated sodium bicarbonate solution and water. The solid obtained was purified by silica gel column chromatography using 30% acetone-chloroform as eluent to obtain 25 mg of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 252° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([N:16]([CH3:34])[CH3:15])=[CH:22][CH:21]=1)[C:25]1[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=1)=[O:14]
Reactant: O=C(O)C1CCOc2ccc(Br)cc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3ccc(Br)cc32)cc1
Yield: 48.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-bromochroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as starting materials, 6-bromo-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.52 g) was obtained.