Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO.O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCCCCOc1ccc(OCCCCCn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCOc1ccc(OCCCCCn2ccnc2)cc1
Yield: 86.2 %

Procedure:
To a solution of 2.5 g ethyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]hexanoate in 10 ml methanol, was added a solution of 520 mg sodium hydroxide in 5 ml water, and the mixture was heated under reflux for 5 hours. Methanol was distilled off under reduced pressure, and dilute hydrochloric acid was added to the remaining aqueous soluiton to lower its pH down to about 5. The solid which separated out was collected by filtration, washed with water, and recrystallized from methanol, affording 2 g of 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]hexanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2I)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[CH:35]>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.[Cu]I.C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[C:35][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: C#Cc1c(F)cccc1Cl
Reactant: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (847 mg, 2.35 mmol), PdCl2(PPh3)2 (82 mg, 0.12 mmol), copper (I) iodide (22 mg, 0.12 mmol), and THF (50 mL) were added to a pressure tube. Diisopropyl amine (6 mL) and 1-chloro-2-ethynyl-3-fluorobenzene (41) (400 mg, 2.59 mmol) were added to the pressure tube and the reaction was stirred at 50° C. overnight. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to provide ethyl 2-((2-chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (42).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Cl[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.O>CS(C)=O>[CH2:20]([O:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1cccs1
Reaction time: 16 h
Yield: 86 %

Procedure:
Anhydrous potassium carbonate (11.04 g.) was added to a stirred suspension of N-hydroxyphthalimide (17.12 g.) in dry dimethyl sulphoxide (200 ml.). A brown colour developed, 2-Chloromethylthiophene (28.5 g.) was added dropwise and the mixture was stirred for 16 hr., during which time the colour disappeared. The suspension was poured into water (800 ml.) and cooled to 5°. The white precipitate was filtered off, and recrystallised from ethanol to give colourless needles of N-(then-2-yloxy)phthalimide (23.4 g., 83%), m.p. 129.7° - 130.9° τ values (DMSO-d6) are 4.58 (CH2), 2.28, 2.68, 2.90 (thienyl protons) 2.08 (phthalimide protons)
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]3[S:37][C:38]([C:42]([NH2:7])=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 197-198° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.17 (m, 6H), 4.57-4.51 (m, 1H), 4.42 (d, J=5.4 Hz, 2H), 3.60 (dd, J=9.0, 9.0 Hz, 1H), 3.03 (dd, J=9.0, 3.4 Hz, 1H), 2.46 (s, 3H), 1.38 (d, J=6.2 Hz, 3H); MS (ES+) m/z 348.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[C:7]([O:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19](=[O:47])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](OS(C(F)(F)F)(=O)=O)=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:47])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[O:12][CH2:13][O:14][CH3:15])=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29])[CH3:17]
Reactant: COCOc1cccc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OCOC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
6-Methoxy-2-methoxymethoxybenzeneboronic acid (1.92 g) was coupled with N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine ethyl ester in a similar procedure as described in Example 5-3) to afford N-(2,6-dichlorobenzoyl)-4-(6-methoxy-2-methoxymethoxyphenyl)-L-phenylalanine ethyl ester (0.942 mg). ESMS m/Z 532 (MH+), 530 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CN(C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 14 h
Yield: 72.5 %

Procedure:
A solution of compound 112 (0.43 g, 1.506 mmol) in dry ethanol (5 mL) was treated with 10% Pd—C (0.04 g) and purged with hydrogen gas at room temperature. The reaction was stirred at the same temperature under a hydrogen atmosphere (balloon pressure) overnight (14 h). The reaction was filtered through a celite bed and washed with dry ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.85 g, 3.013 mmol) at room temperature and stirred for 24 h. The solvent was evaporated and crude material was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 116 (0.4 g, 72%, over two steps) as a yellow solid. mp 104-106° C.; 1H NMR (DMSO-d6) δ: 1.39-1.60 (m, 3H), 1.66-1.72 (m, 1H), 1.82-1.94 (m, 3H), 2.05-2.08 (m, 1H), 2.23 (s, 3H), 2.34 (s, 3H), 2.64-2.71 (m, 1H), 2.91-2.96 (m, 1H), 6.48 (brs, 1H), 6.64 (dd, 1H, J=1.5, 8.4 Hz), 6.99-7.05 (m, 2H), 7.10 (t, 1H, J=4.2 Hz), 7.27 (d, 1H, J=8.4 Hz), 7.60 (d, 1H, J=5.4 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.57 (s, 1H); ESI-MS m/z (%): 367 (MH+, 31), 322 (18), 184 (100); ESI-HRMS calculated for C21H27N4S (MH+), Calculated: 367.1965; Observed: 367.1950.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:39]#[N:40])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-:42].OO>CO>[Si:1]([O:8][C@H:9]([C:39](=[O:42])[NH2:40])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)O[Si](C)(C)C(C)(C)C)CC4)CC1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)C(N)=O)CC4)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
A 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]-2-cyanoethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (2.2 g, 3.75 mmol, 1.00 equiv) in 20 mL of methanol was added LiOH (315 mg) followed by addition of H2O2 (30%, 3 mL) via syringe at 0° C. with vigorous stirring. The resulting solution was stirred for 3 h at 20° C. The reaction was then quenched by the addition of 50 mL of saturated aqueous Na2SO3 and extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with 2×30 mL of brine, and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-2:1) to afford the desired tert-butyl N-(4-[[(3R)-3-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-2-carbamoylethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (0.9 g) as a white solid. MS: m/z 605 (M+H)+, 627 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:14].C1N2CCN(CC2)C1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[S:26].O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[C:25](=[S:26])[O:14][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: Cc1cc([N+](=O)[O-])c2c(c1O)CCC2
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c2c(c1OC(=S)N(C)C)CCC2
Temperature: 25 °C
Yield: 79.9 %

Procedure:
5-Methyl-7-nitroindan-4-ol (5.0 g) was dissolved in N,N-dimethylformamide (50 mL). After adding triethylenediamine (5.8 g) and dimethylthiocarbamoyl chloride (4.8 g) with stirring at room temperature, the mixture was stirred at 75° C. for 5 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added to the reaction mixture. The insoluble material was collected by filtration, washed with diethyl ether and dried to give the title compound (5.80 g).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+].[CH2:18]([S:25](Cl)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH2:18]([S:25]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CCC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCC[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a stirred solution of 0.5 g of H-Aad(OtBu)-OH in 4.4 mL of aqueous 1 N sodium hydroxide was added 0.42 g of benzylsulfonylchloride in 2 mL of dioxane. After 16 hours at room temperature, additional 1.4 mL of aqueous 2 N sodium hydroxide, 0.5 mL of dioxane and 0.09 g of benzylsulfonylchloride were added and the reaction mixture stirred for an additional day. The dioxane was removed, water was added, the mixture made acid (pH 3) using hydrochloric acid and extracted twice with diethyl ether. The combined ether layers were dried over sodium sulfate and concentrated to give 235 mg of BzlSO2-Aad(OtBu)-OH.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]1([F:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>>[F:17][C:18]1([F:24])[CH2:23][CH2:22][CH2:21][N:20]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:19]1
Reactant: FC1(F)CCCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(F)(F)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3,3-difluoropiperidine hydrochloride (9.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C16H16F2N2O2: 306.1180, found 306.1177.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:4][CH:3]=1.[CH:13](O)=O>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[N:12][C:10]([OH:11])=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NNc1cccc(F)n1
Reactant: O=CO
Product: Oc1ncn(-c2cccc(F)n2)n1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution was prepared by admixing 17 g (0.10 m) of 2-(6-fluoro-2-pyridinyl)hydrazinecarboxamide and 60 mls of 98 percent formic acid. This mixture was stirred and refluxed for 2 hours and allowed to cool to room temperature. The insolubles were filtered off and dried to produce 3.5 g of the desired 1-(6-fluoro-2-pyridinyl)-1H-1,2,4-triazol-3-ol which melted at 290° C. with decomposition. The excess formic acid in the remaining liquid phase was distilled off under reduced pressure and the solids which precipitated were washed and dried. This product was a second crop of the desired product which also melted at 290° C. The product was recovered in a yield of 60 percent of theoretical and upon analysis, was found to have carbon, hydrogen and nitrogen contents of 46.80, 2.89 and 31.17 percent, respectively, as compared with the theoretical contents of 46.47, 2.80 and 31.10 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)=[C:6]([CH:13]=1)[O:7][CH:8]([CH3:12])[C:9](O)=[O:10].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:9](=[O:10])[CH:8]([O:7][C:6]1[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)O)c2c1C
Reactant: CN(C)CCN
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)NCCN(C)C)c2c1C

Procedure:
Prepared analogously to example 32.3 from 2-(5-fluoro-2-(6-(methoxycarbonyl)-5-methylthieno[2,3-d]pyrimidin-4-ylamino)phenoxy)propanoic acid (200 mg) and 2-dimethylaminoethylamine (70 μl)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH2:16]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29]Cl)[CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:16]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1cc(Cc2ccccc2)ccn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(Cc2ccccc2)ccn1)C(=O)OCC
Yield: 97.6 %

Procedure:
Diethyl malonate (1.15 mL, 7.60 mmol) was added to a solution of sodium ethoxide (0.106 g of sodium in 5.0 mL of EtOH). To the clear solution was then added gradually a solution of 4-benzyl-2-(chloromethyl) pyridine (0.59 g, 2.7 mmol) in EtOH (5 mL). After the mixture had been heated at reflux for 4.5 h, the EtOH was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with NH4Cl (2×50 mL)), dried over Na2SO4 and was concentrated under reduced pressure. The crude compound was purified by filtration on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a colorless oil (0.9 g, 98%) 1H NMR (CDCl3) δ1.12 (t, J=7.2 Hz, 4H), 1.28 (t, J=7.2 Hz, 2H), 3.25-3.40 (m, 2H), 3.92 (s, 2H), 4.00-4.30 (m, 5H), 6.93 (d, J=4.8 Hz, 1H), 7.00 (s, -H), 7.15 (d, J=7.2 Hz, 2H), 7.20-7.40 (m, 3H), 8.38 (d, J=5.1 Hz, 1H); IR (film) 2984, 1752, 1736, 1606 cm−1.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][S:2]([C:5]3[CH:9]=[CH:8][S:7][C:6]=3[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: COC(=O)c1sccc1S(=O)(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared Procedure Q1 and Scheme AC using methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: Anal. Calcd for C24H33N3O5S.HCl: C, 6.00; H, 5.30; N, 7.72. Found: C, 52.9; H, 6.04; N, 7.59; ESMS m/e: 508.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1)=[O:5].[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1.[BH4-].[Na+]>CCO>[CH3:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[NH:1][CH2:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[CH:12][CH:11]=1)([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)[CH3:22]
Reactant: O=Cc1ccncc1
Reactant: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3N)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3NCc3ccncc3)cc2)CC1

Procedure:
A mixture of 2-amino-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)ethyl]phenyl}benzamide (600 mg, Step B) and 4-pyridinecarboxaldehyde (0.22 mL) was heated at reflux in EtOH (50 mL) overnight. NaBH4 (250 mg) was added and the mixture was heated at reflux for 10 min and evaporated. The residue was mixed with CH2Cl2 and washed with H2O twice, followed by brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography using 10% MeOH/CH2Cl2 to provide the title compound. MS (ES+): 443 (M+H)+. Calc'd. for C28H34N4O-442.27.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.NN>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(OCCc2ccccc2)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1nccc(OCCc2ccccc2)c1N
Yield: 69.3 %

Procedure:
A mixture of 1.11 g of 2-amino-4-(2-phenylethoxy)-3-nitropyridine (starting material K2), 1.0 ml of hydrazine hydrate and 0.130 g of Raney nickel in 30 ml of methanol is heated under reflux until no starting material is detectable by TLC. After filtration and evaporation of the solvent the residue is chromatographed on silica gel (dichloromethane/methanol 20:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 0.68 g of the title compound as an oil, which crystallizes on standing (m.p. 86–87° C.). The mass spectrum shows the molecular peak MH+ at 230.2 Da.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=O)[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[C:6]=2[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([Cl:22])[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[C:6]=2[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Br)c2[nH]c(=O)n(CCCCl)c12
Product: COC(=O)c1ccc(Br)c2nc(Cl)n(CCCCl)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of methyl 7-bromo-3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (490 mg, 1.41 mmol) and phosphoryl chloride (14 mL) was stirred at 100° C. for 2 h. Phosphoryl chloride (9 mL) was added to the reaction mixture and the resultant mixture was stirred at 100° C. for 3 h. Phosphoryl chloride (15 mL) was added to the reaction mixture, and the resultant mixture was stirred at 100° C. for 3 h, concentrated in vacuo, and diluted with ethyl acetate and aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (429 mg, 1.17 mmol, 83%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][C:3]=1[CH2:15]O.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:15][C:3]1[N:4]=[C:5]2[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1]
Reactant: Cc1c(CO)nc2c3c(ccn12)CCCC3
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CCl)nc2c3c(ccn12)CCCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product of (3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2-yl)methanol (200 mg) was dissolved in 5 mL of DCM. To the mixture was added thionyl chloride (0.5 mL) at 0° C. The mixture was stirred overnight at room temperature. After removal of the solvent, the residue was dried under vacuum to give 2-(chloromethyl)-3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinoline (200 mg). ESI MS: m/z 235 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=[O:23].C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C.O>[Br:31][C:5]1[C:4]2[C:3]([CH:22]=[O:23])=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:8]=2[N:7]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(C=O)c(C)cc(C)c32)cc1
Temperature: 60 °C
Reaction time: 18.5 h

Procedure:
To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (2 g, 6.11 mmol) in DMF (10 mL) was added NBS (2.39 g, 13.44 mmol), and then the mixture was stirred at 60° C. for 18.5 h. The reaction mixture was cooled to room temperature. The mixture was diluted with H2O, the layers were separated and the aqueous layer was extracted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography to give the title compound. MS (ESI+) m/z 406.0, 408.0 (M+H).