Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([N:23]3[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[CH:25]=[N:24]3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([N:23]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[N:24]3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)c1
Temperature: 60 °C
Yield: 34.9 %

Procedure:
To a solution of ethyl 1-[6-(3-fluoropyridin-4-yl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-2-yl]-1H-pyrazole-4-carboxylate (0.022 g, 0.05 mmol) in a mixture of THF/ethanol 1:1 (1 mL), 2N sodium hydroxide aqueous solution (0.05 mL) was added. The mixture was heated at 60° C. for 2 hours and then neutralised with 2N hydrogen chloride aqueous solution. The solvent was evaporated and the crude mixture was purified by solid phase extraction, SCX, it was washed with water and eluted with methanol/ammonia (9:1) to give the title compound (0.007 g, 29% of yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]2[C:15]3[N:16]([CH3:19])[CH:17]=[N:18][C:14]=3[CH2:13][CH2:12][NH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28]([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH:10]2[C:15]3[N:16]([CH3:19])[CH:17]=[N:18][C:14]=3[CH2:13][CH2:12][N:11]2[C:34](=[O:35])[CH2:33][CH2:32][NH:31][S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:30])=[O:29])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: Cn1cnc2c1C(c1ccc(C#N)c(F)c1)NCC2
Reactant: COc1cccc(S(=O)(=O)NCCC(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cccc(S(=O)(=O)NCCC(=O)N2CCc3ncn(C)c3C2c2ccc(C#N)c(F)c2)c1
Reaction time: 18 h

Procedure:
2-Fluoro-4-(3-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-4-yl)-benzonitrile (Step E) (0.034 g, 0.132 mmol), 3-(3-methoxy-benzenesulfonylamino)-propionic acid (Step G) 0.041 g, 0.16 mmol), HOBT (0.022 g, 0.16 mmol), EDC (0.031 g, 0.16 mmol) and N-methylmorpholine (0.043 mL, 0.40 mmol) were dissolved in DMF (3 mL) and stirred for 18 h. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2 and saturated NaHCO3 solution and separated. The aqueous layer was washed with CH2Cl2 (2×, the organic layers combined, dried (Na2SO4), filtered and concentrated to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:17]=[C:18]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:19]=[CH:20][C:5]=2[O:4]1.CCN(CC)CC.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl.O>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:17]=[C:18]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=6[CH:40]=5)[CH:19]=[CH:20][C:5]=4[O:4][CH:3]([CH2:2][NH:1][S:55]([CH3:54])(=[O:57])=[O:56])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CNS(C)(=O)=O)O4)cc12
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A mixture of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.08 mmol), and Et3N (11 mg, 0.12 mmol) in dichloromethane (1 mL) was stirred at room temperature under N2 protection. Then MsCl (11 mg, 0.09 mmol) was added and the solution was stirred at room temperature for overnight. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane:MeOH=15:1) to provide 5-(11-fluoro-6-(methylsulfonamidomethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 35.7%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=4.8 Hz, 1H), 7.83 (s, 1H), 7.96˜8.06 (m, 3H), 7.65˜7.70 (m, 1H), 7.59˜7.63 (m, 1H), 7.57 (t, J=6.4 Hz, 1H), 7.37˜7.44 (m, 3H), 7.24˜7.30 (m, 1H), 7.10 (s, 1H), 6.91˜6.97 (m, 1H), 6.77 (dd, J=6.8 Hz, 4.4 Hz, 1H), 3.37 (dd, J=14.0, 7.2 Hz, 2H), 3.29 (br s, 3H), 2.89 (s, 3H), 2.77˜2.87 (m, 6H). MS (M+H)+: 722.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][N:9]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][O:13][C@H:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]1
Reactant: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.175 mL, 2.26 mmol, 1.2 equiv) was added to a solution of (2S,4R)-2-(hydroxymethyl)-4-methoxy-1-pyrrolidinecarboxylate (3-3, 0.500 g, 1.88 mmol, 1 equiv) and triethylamine (0.394 mL, 2.83 mmol, 1.50 equiv) in dichloromethane (30 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 1 hour. The reaction mixture was partitioned between saturated sodium bicarbonate solution and dichloromethane (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane initially, grading to 100% EtOAc) to provide benzyl (2S,4R)-4-methoxy-2-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylate (3-4) as a light yellow oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ 7.37–7.25 (br m, 5H), 5.17 (d, 1H, J=11.8 Hz), 5.10 (d, 1H, J=11.8 Hz), 4.65 (dd, 1H, J=8.3, 3.8 Hz), 4.24 (br m, 2H), 3.95 (m, 1H), 3.68 (br d, 1H, J=12.0 Hz), 3.45 (dd, 1H, J=12.0, 4.4 Hz), 3.30 (s, 3H), 2.88 (s, 3H), 2.39 (m, 1H), 2.12 (m, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][N:34]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[CH3:16])=[O:13])[CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 76.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (271 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (390 mg) was obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH:41][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCC1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCN(C(=O)OCc5ccccc5)C4)ncc3Cl)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.10 g, 0.27 mmol), racemic 3-(2-aminoethyl)-pyrrolidine-1-carboxylic acid benzyl ester (0.14 g, 0.55 mmol) and triethylamine (0.11 mL, 0.81 mmol) in 1,4-dioxane (1.5 mL) in a sealed reaction vessel is stirred at 90° C. overnight. The reaction is cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer is separated, dried over Na2SO4, filtered and concentrated. The crude solid is washed with ethyl acetate, dried under vacuum to provide 3-{2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-pyrrolidine-1-carboxylic acid benzyl ester as a white solid (90 mg, 56% yield). A stirred solution of this intermediate (16 mg, 0.028 mmol) in TFA (0.5 mL) and water (0.1 mL) is heated in a sealed tube at 100° C. for 20 minutes. At room temperature the mixture is concentrated and the residue is dissolved in methanol, passed through a SCX column, washed with methanol and 2 M NH3/methanol to give the crude product. It is further passed through a short pad of silica gel to afford the title compound as a solid (11 mg, 90% yield). ES+(m/z) 442 (35Cl) and 444 (37Cl) [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[CH2:25][C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Se](=O)=[O:37]>O1CCOCC1.O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[C:25](=[O:37])[C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)cc1OC
Reactant: O=[Se]=O
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4C(=O)C3=O)C2)cc1OC

Procedure:
3.8 g (0.0079 mol) of 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7, 8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one are added at 70° C. to a suspension of 1.4 g (0.0128 mol) of selenium dioxide and 0.8 g of kieselguhr in dioxan/water and refluxed for 16 hours. After cooling, the mixture is diluted with a little ethanol and suction filtered The filtrate is evaporated down in vacuo and purified over 310 g of aluminium oxide (neutral, activity II-III) with methylene chloride and increasing amounts of ethanol (up to 1%).
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13]Cl)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>C(O)C>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)OCC(CNC1CCCCC1)O2
Temperature: 180 °C
Yield: 98 %

Procedure:
6.5 g (0.0250 mol) of 8-t-butyl-2-chloromethyl-1,4-dioxaspiro[4.5]decane and 4.5 g (0.0450 mol) of cyclohexylamine are dissolved in 50 ml of 95% ethanol in the presence of 5.65 g (0.040 mol) of K2CO3 and 0.42 g (0.0025 mol) of KI in an autoclave. The mixture is heated to 180° C. for 8 hours with stirring. After returning to room temperature, the reaction medium is poured into 500 ml of water and extracted with 200 ml of CH2Cl2. The organic phase is dried over magnesium sulphate and concentrated under vacuum. The brown oil is used directly in the following step (yield: 98%; NMR analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCOc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-4-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, 1H, J=3.2, 5.7 Hz), 7.53 (dd, 1H, J=3.2, 5.7 Hz), 7.50 (m, 1H), 7.31 (m, 1H), 7.24-7.20 (m, 2H), 6.94 (d, 1H, J=7.9 Hz), 6.85-6.82 (m, 2H), 4.00 (t, 2H, J=6.1 Hz), 3.07 (d, 2H, J=10.9 Hz), 2.55 (m, 3H), 2.50 (sept, 1H, J=6.2 Hz), 2.08 (dt, 2H, J=3.1, 10.9 Hz), 2.00 (m, 2H), 1.83 (m, 3H), 1.69 (qt, 1H, J=6.2 Hz), 1.24 (d, 6H, J=6.8 Hz); Anal. Calcd for C24H31ClN2O2+HCl: C, 63.8; H, 7.09; N, 6.21. Found: C, 63.3; H, 7.04; N, 6.27; ESMS m/e: 415.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH2:11]([NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C1COCC1>[ClH:1].[Cl:8][C:7]1[C:2]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH2:18])=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: NCCCCCCN
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Solvent: C1CCOC1
Product: Cl
Product: NCCCCCCNc1nc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.2 grams (0.112 mole) of 2,3,5,6-tetrachloropyridine was added portionwise to a stirring solution of 1,6-hexanediamine (23.2 grams; 0.2 mole) in 300 ml. of THF. The mixture was stirred overnight at room temperature, then evaporated to dryness under reduced pressure. A solution of the residual material in water was made alkaline with K2CO3 and extracted with CH2Cl2. The organic layer was dried and evaporated to dryness and the residue dissolved in diethyl ether. Acidification with hydrogen chloride (in ether) precipitated 24.6 grams (66% of theory) of the title compound, a white solid melting at 124°-5° C.:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrCC[C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:29]([NH:31][C:32](=[O:33])[C:27]=12)=[O:30].[C:37](#N)[CH3:38]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:37][CH2:38][N:31]4[C:32](=[O:33])[C:27]5=[CH:26][CH:36]=[CH:35][CH:34]=[C:28]5[C:29]4=[O:30])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: CC#N
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.15 gm, 23.4 mmol), K2CO3 (4.2 gm, 30.4 mmol) and 2-bromoethyl phthalimide (7.13 gm, 28 mmol) in acetonitrile (250 ml) was heated at reflux for 3.5 hr. The solids and solvent were removed. The residue was purified by flash chromatography (SiO2, 110 gm, eluted with 2-4% CH3OH:DCM). The product thus obtained weighed 7.8 gm (84%). Part of the material was recrystallized to give 2.35 gm of off white crystals, m.p.=148°-149° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:12]O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>N1C=CC=CC=1>[Cl:23][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: OCc1cc(-c2ccccc2)cs1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCc1cc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Phenyl thiophene-2-methanol (0.21 g), toluene (2.0 mL), and a catalytic amount of pyridine were added, and thionyl chloride (0.16 mL) was added dropwise thereto under ice-cooling. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried at 60° C. under reduced pressure to obtain 2-(chloromethyl)-4-phenylthiophene (0.22 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=32)[CH2:4][CH2:3]1.[I:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(O)=O>[I-:15].[CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N+:11]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[CH:12][C:13]=32)[CH2:4][CH2:3]1
Reactant: CCCCCCCCCCCI
Reactant: CN1CC[C@H]2CCc3ccncc3[C@H]21
Solvent: CC(=O)O
Product: CCCCCCCCCCC[n+]1ccc2c(c1)[C@@H]1[C@H](CC2)CCN1C
Product: [I-]
Yield: 69.7 %

Procedure:
To a stirred solution of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinoline (120 mg, 0.64 mmol) in AcOH (2 ml) was added 1-iodoundecane (542 mg, 1.92 mmol). The mixture was heated at reflux under nitrogen for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 210 mg (70%) of cis-1-methyl-8-undecyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACU) as a brown oil. 1H NMR (300 MHz, CDCl3) δ9.16 (1H, s, C9-H), 9.07 (1H, d, J6.0 Hz, C7-H), 7.81 (1H, d, J6.0 Hz, C6-H), 4.82 (2H, m. pyCH2), 3.44 (1H, d, J8.4 Hz, C9b-H), 2.29 (3H, s, NCH3), 1.50-3.10 (9H, m, CH2+CH), 1.95 (2H, m, pyCH2CH2), 1.00-1.40 (16H, m, 8×CH2), 0.76 (3H, t, J6.9 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ161.5, 143.2, 142.4, 138.8, 127.5, 63.1, 61.0, 55.7, 41.0, 35.6, 32.0, 31.8, 30.0, 29.51, 29.48, 29.4, 29.2, 29.1, 28.1, 27.3, 26.0, 22.6, 14.1.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:28]=[CH:27][C:6]2[O:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23]C=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[C:5]=2[CH:4]=1.S(OCCCC1C2C=C(F)C=CC=2OC=1)(C1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=[N:57]C=NC=1>>[ClH:1].[F:2][C:3]1[CH:28]=[CH:27][C:6]2[O:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][N:57]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)[C:5]=2[CH:4]=1
Reactant: COc1cccnc1N1CCN(CCCc2coc3ccc(F)cc23)CC1
Reactant: COc1cncnc1N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)OCCCc2coc3ccc(F)cc23)cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCCc2coc3ccc(F)cc23)CC1

Procedure:
The title compound was prepared (0.31 g, 87%, mp 196°-198° C.) in a manner analogous to the preparation of 1-[3-(5-fluorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine hydrochloride (Example 20) by the reaction of 5-fluoro-3-benzo[b]furanpropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:28](O)=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:27])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1.[O:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:27])[CH:21]=3)[C:28](=[O:29])[N:44]3[CH2:43][CH2:42][N:41]([CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH2:46][CH2:45]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: O=C(O)[C@@H](Cc1ccc(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Product: O=C(O[C@H](Cc1ccc(O)c(Br)c1)C(=O)N1CCN(C2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example 7i from 100 mg (0.19 mmol) (R)-2-(3-bromo-4-hydroxy-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 35.1 mg (0.21 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[CH3:27]>CN(C)C=O>[CH2:26]([N:13]([S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH3:27]
Reactant: CCBr
Reactant: COC(=O)C(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(C(C)C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Methyl 2-(2-nitrobenzenesulfonylamino)propionate (17 g; 59 mmol) is dissolved in 600 ml of dimethylformamide, and caesium carbonate (1.5 eq.; 88 mmol; 28.6 g) is then added. The reaction medium is stirred for 30 minutes at room temperature, followed by dropwise addition of ethyl bromide (4 eq.; 236 mmol; 17.6 ml) and the resulting mixture is stirred overnight at room temperature. The reaction medium is evaporated to dryness, taken up in dichloromethane, filtered and evaporated to dryness. The crude product is chromatographed on silica (eluting with dichloromethane) to give 17.1 g of the expected product.
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O)#N.C[CH2:15][N:16]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[C:48](=[NH:51])[NH:49]O)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(OCC)(=O)C.CN(C=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[C:48]1[N:51]=[C:5]([C:4]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[C:11]([C:15]#[N:16])[CH:3]=2)[O:7][N:49]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: COc1ccc(C#N)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=N)NO
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(-c2nc(C3CCCCN3C(=O)OC(C)(C)C)no2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
DMF (2.0 mL) was added to a mixture of cyano-5-methoxybenzoic acid (160 mg, 0.90 mmol), EDCI (176 mg, 0.92 mmol), HOBt (124.3 mg, 0.92 mmol) and 2-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (224 mg, 0.92 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried anhydrous sodium sulfate, filtered and concentrated. DMF (3 mL) was added to the residue and then heated 135° C. for 2.5 h to effect cyclization to oxadiazole. The reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel, eluted with a mixture of ethyl acetate in hexanes afforded 179 mg (56%) of the title compound as a colorless oil. 1H NMR (CDCl3), δ(ppm): 7.99 (s, 1H), 7.84 (d, 1H), 7.35 (s, 1H), 5.56 (bs, 1H), 4.06 (m, 1H), 3.93 (s, 3H), 3.01 (m, 1H), 2.84 (m, 1H), 1.92 (m, 1H), 1.70 (m, 2H), 1.49 (m, 11H).