Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:15]([NH:17][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:21]([O:28][C:29]3[CH:30]=[CH:31][C:32]4[N:33]([C:35]([N:38]5[C@H:43]([CH3:44])[CH2:42][CH2:41][CH2:40][C@@H:39]5[CH3:45])=[N:36][N:37]=4)[CH:34]=3)[CH2:20][CH2:19]2)=[O:16])[N:11]([C:46]2[CH:47]=[C:48]([CH:57]=[CH:58][CH:59]=2)[O:49][CH2:50][CH2:51][O:52]S(C)(=O)=O)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].C1C[O:63]CC1>>[CH:51]([OH:52])=[O:63].[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:15]([NH:17][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:21]([O:28][C:29]3[CH:30]=[CH:31][C:32]4[N:33]([C:35]([N:38]5[C@H:39]([CH3:45])[CH2:40][CH2:41][CH2:42][C@@H:43]5[CH3:44])=[N:36][N:37]=4)[CH:34]=3)[CH2:20][CH2:19]2)=[O:16])[N:11]([C:46]2[CH:59]=[CH:58][CH:57]=[C:48]([O:49][CH2:50][CH2:51][N:3]([CH2:1][CH3:2])[CH3:4])[CH:47]=2)[N:10]=1)([CH3:6])([CH3:8])[CH3:7]
Reactant: CCNC
Reactant: C1CCOC1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: CCN(C)CCOc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)c1
Product: O=CO
Temperature: 60 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
N-Ethylmethylamine (37 μL, 0.43 mmol) was added to a solution of Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60° C. in a sealed vial overnight. N-Ethylmethylamine (37 μL, 0.43 mmol) was added and the reaction continued for a further 24 h. The mixture was cooled, evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in DCM, then triturated with Et2O. Further purification by HPLC (Gemini C18 column, 10-98% MeCN in H2O, 0.1% formic acid) followed by evaporation of the fractions and trituration with Et2O gave the title compound (12 mg, 11%) as an off-white solid. LCMS (Method 5): Rt 3.85 min, ink 734.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6 Hz), 0.58 (3H, d, J=6 Hz), 0.89 (3H, t, J=7.0 Hz), 1.23 (9H, m), 1.33-1.57 (3H, m), 1.62-1.70 (2H, m), 1.71-1.95 (3H, m), 1.96-2.09 (2H, m), 2.13 (3H, s), 2.35 (2H, q, J=7.2 Hz), 2.63 (2H, t, J=5.7 Hz), 3.06-3.20 (3H, m), 3.21-3.36 (2H, m, obscured by solvent), 4.03 (2H, t, J=5.7 Hz), 4.74-4.83 (1H, m), 5.48 (1H, t, J=5.5 Hz), 6.28 (1H, s), 6.88-6.94 (1H, m), 7.00-7.10 (3H, m), 7.16 (1H, dd, J=9.8, 2.0 Hz), 7.18-7.26 (2H, m), 7.26-7.32 (2H, m), 7.35 (1H, t, J=8.0 Hz), 7.62 (1H, d, J=9.8 Hz), 7.81-7.86 (1H, m), 8.09 (1H, s), 8.37 (0.2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH2:53]>CN(C=O)C>[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH:53][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(CN)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (20 g, 0.084 mol), HATU (CAN 148893-10-1, 41.56 g, 0.11 mol) and N-methylmorpholine (CAN 109-02-4, 25.54 g, 0.253 mol) in DMF (400 mL) was stirred at room temperature for 10 min. 2,2-Dimethoxyethanamine (CAN 22483-09-6, 9.75 g, 0.093 mol) was added and the mixture was stirred overnight. After evaporation of solvents, the residue was diluted with methylene chloride (500 mL) and saturated sodium bicarbonate solution (500 mL). After being separated, the organic layer was washed with 5 N citric acid solution (500 mL), brine (500 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil (27 g, 99%) which was used in the next reaction step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.36-7.33 (m, 5H), 6.44-6.38 (b, 1H), 5.31 (s, 1H), 5.09 (s, 2H), 4.34-4.33 (m, 1H), 3.40-3.37 (m, 8H), 2.06-2.03 (m, 6H).
Reaction SMILES: [OH:1][C:2]1([CH3:27])[CH:8](Br)[CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:27])[CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccc(F)cc3)cc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccc(F)cc3)cc2)C1
Yield: 60.4 %

Procedure:
The product obtained by reducing 200 mg of 3-hydroxy-3-methyl-4-bromo-7-[p-(p-fluorobenzyloxy)phenyl]-5-heptanolide with 400 mg of tri-n-butyltin hydride in 2 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was recrystallized from a mixture of acetone and n-hexane (1:5) to give 99 mg of the desired compound melting at 143.5°-144.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.ClCCl>[CH2:15]([NH:22][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH2:12]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)CCCC(=O)C2
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)CCCC(NCc1ccccc1)C2
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Dissolve 2-Methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (prepared according to JCS Perkin Trans. 1, 1992, 1475-1481, 83 mg, 0.44 mmol) in 1 mL of 19:1 methanol/acetic acid as solvent, and treat the solution with benzylamine (60 uL, 65 mg, 0.60 mmol) and NaCNBH3 (80 mg, 1.27 mmol). Agitate the reaction mixture overnight, then dilute with 25 mL dichloromethane. Wash the organic layer with 25 mL 10% aqueous potassium carbonate solution, the 25 mL brine, dry over MgSO4 and evaporate to yield 103 mg product, used in subsequent chemistry without further purification; 80% crude yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.COC1C=C(C=CC=1)C(Cl)=O>>[C:10]([C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Agent: COc1cccc(C(=O)Cl)c1
Product: O=C(c1ccccc1)c1c[nH]c2ncccc12

Procedure:
Compound 41 was prepared from 7-azaindole 2 using aluminum chloride as described previously for the synthesis of Compound 25, with benzoyl chloride substituted for m-methoxy-benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13](Cl)=[C:4]2[CH:3]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]([O:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:4]2[CH:3]=1
Reactant: Oc1ccccc1
Reactant: CN1CCc2nc3ccc(Cl)cc3c(Cl)c2C1
Product: CN1CCc2nc3ccc(Cl)cc3c(Oc3ccccc3)c2C1

Procedure:
A mixture of the compound of Example 6 (5.0 g, 0.018 mol) and phenol (3.38 g, 0.036 mol) is reacted as described for Example 14 to obtain the free base which is recrystallized three times from hexane to afford the title compound as a crystalline solid, m.p. 182°-184° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:32]CCl>>[Cl-:32].[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH2+:8][CH2:13][CH2:12]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccnc(C(F)(F)F)c2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(NC2CC[NH2+]CC2)ccn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-trifluoromethyl-pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.09 g (11.8 mmol) in dichloromethane (20 mL) is added trifluoroacetic acid (10 mL) and the reaction mixture is stirred at room temperature for one hour. More trifluoroacetic acid (2 mL) is added and stirring is continued for 30 minutes. All volatiles are then removed under high vacuum and to the residue is then added a 4 N solution of HCl in dioxane. All volatiles are then removed again and the residue triturated with diethyl ether. The solid is sucked to dryness and taken up with methanol. After evaporation of all volatiles, the residue is again triturated with diethyl ether and after drying under high vacuum, the desired compound is obtained (26% overall yield).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][CH2:28][CH2:29]Cl>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:29][CH2:28][Cl:27])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCl
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Yield: 60 %

Procedure:
6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime was prepared in 60% yield using the method described in example 85A, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 1,2-dichloroethane in dimethylformamide. The title compound was isolated as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([CH2:23][C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=[C:17]4N=N3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:30].[NH4+]>O>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:18]3[C:17]([OH:30])=[CH:22][C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][N:19]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cncc(Cc2cnc3c(c2)nnn3CCCC2CCCc3cccnc32)c1
Reactant: [OH-]
Agent: [NH4+]
Solvent: O
Product: Oc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.83 h

Procedure:
A mixture of 3-[3-(5,6,7,8-tetrahydroquinol-8-yl)-propyl]-6-(pyrid-3-ylmethyl)-3H-1,2,3-triazolo[5,4-b]-pyridine (3.56 g) and polyphosphoric acid (17.5 g) were heated with stirring at 188°-197° C. for 50 minutes. Water (30 ml) was added to the hot residue and, after slight cooling, the solution was basified with aqueous ammonium hydroxide to pH 10 and then extracted with chloroform. The combined chloroform extracts were dried over magnesium sulphate, concentrated in vacuo and the residue was chromatographed on silica eluted with 5% v/v methanol in chloroform to give the title compound as a brown gum (0.68 g). The aqueous portion after extraction, was concentrated to dryness, to give a paste, water (100 ml) was then added, the mixture was refluxed for 1 hour and a brown oil which formed was extracted with chloroform (3 x 100 ml). The extracts were dried, combined and concentrated to give a further quantity of the title compound as an oil (0.31 g). The two portions of the product were combined, converted to the trihydrochloride with ethanolic HCl and then recrystallised, first from isopropanol and then from isopropanol/methanol to give the title compound as a buff solid (0.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and pyrrolidine according to conditions described in general procedure C. Mp: 205-207° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.81 (s, 4 H), 3.06 s, 2 H), 3.27 (s, 4 H), 3.41 (s, 2 H), 3.77 (s, 4 H), 6.27-6.19 (m, 1 H), 7.03-7.06 (m, 1 H), 7.27 (d, J=9.1Hz, 1 H), 7.42-7.46 (m, 1 H), 7.51 (s, 1 H), 7.57-7.639 (m, 3 H), 7.86 (d, J=8.4 Hz, 1 H), 8.00 (d, J=8.3 Hz, 1 H), 8.23-8.25 (m, 1 H), 10.47 (s, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:17]2(=[O:29])=[O:28])=[C:12]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:11]=1)(C)(C)C.C(OC(=O)N[C@@H](CC1C=CC=CC=1)CC1C=CC(N2CC(=O)NS2(=O)=O)=C(O)C=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:17](=[O:29])(=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:19](=[O:21])[CH2:20]2)=[C:12]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H](N)Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ((S)-1-benzyl-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester (intermediate from Example 60) (510 mg, 0.78 mmol) in methylene chloride (5 mL) is added TFA (2 mL) and the mixture is stirred at RT for 5 h. The solvent is removed under reduced pressure to give the title compound. This material is used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)cn1

Procedure:
6-Methyl nicotinic acid (138 mg, 1.00 mmol) was dissolved in dichloromethane (15 mL) and N,N-dimethylformamide (0.10 mL), and in an ice bath oxalic chloride (192 mg, 1.51 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was moved to react at room temperature for 3 hours, and concentrated under reduce pressure to obtain 6-methyl nicotinoyl chloride as a white solid.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1>CN(C=O)C>[N+:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3])([O-:29])=[O:28]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cccc(OCCCCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1cccc([N+](=O)[O-])c1
Yield: 55 %

Procedure:
The title compound was synthesized analogously to 83.8, using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 1-(4-bromobutoxy)-3-nitrobenzene (164 mg, 0.6 mmol) in anhydrous. DMF (1 mL). The crude product obtained after workup was purified by flash column chromatography on silica gel (25% ethyl acetate-petroleum ether) to give 83.9 as a white solid (m p 87-89° C.) in 55% yield (95 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][C:18](=[O:24])[NH:19]3)[CH2:10][CH2:9]1)=[O:7].[NH2-].[Na+].[CH2:32](Cl)[CH:33]=[CH2:34]>CN(C=O)C>[OH2:2].[CH2:34]([N:19]1[C:20]2[C:15](=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:9][CH2:10]3)[CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]1=[O:24])[CH:33]=[CH2:32].[CH2:34]([N:19]1[C:20]2[C:15](=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:9][CH2:10]3)[CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]1=[O:24])[CH:33]=[CH2:32]
Reactant: COc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1OC
Reactant: C=CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)CCc2c(N3CCN(C(=O)c4ccc(OC)c(OC)c4)CC3)cccc21
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.8 %

Procedure:
5-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (1.96 g) and 0.20 g of sodium amide were mixed with 60 ml of DMF and stirred at room temperature for 2 hours. Then, to the mixture was added 0.67 g of allyl chloride and the mixture was stirred at room temperature for 10 hours. The reaction mixture was poured into 150 ml of saturated saline solution and organic substances were extracted with chloroform. The chloroform layer was washed with water and dehydrated. Chloroform was distilled off and the residue was purified through silica gel column chromatography followed by recrystallization from methanol-ether to give 1.76 g of 1-allyl-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril hemihydrate, m.p. 120°-122° C., colorless granules.
Reaction SMILES: CO[C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:14]=2[CH:33]=1.[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH2:40]>>[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH:40][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:14]=2[CH:33]=1
Reactant: COCCCN
Reactant: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccc(C)cc3)c2c1
Product: COCCCNC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccc(C)cc3)c2c1

Procedure:
100 mg of 6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 53 mg was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17]C=2)[CH2:10][CH:9]1[CH3:21])(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([N:32](C(C)C)CC)(C)C.[NH:38]1[C:46]2[C:41](=[CH:42][C:43]([C:47]([OH:49])=O)=[CH:44][CH:45]=2)[CH:40]=C1.CCN=C=NCCCN(C)C>ClCCl.O>[CH3:21][C@H:9]1[CH2:10][C@@H:11]([C:14]2[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][N:8]1[C:1]1[NH:38][C:46]2[C:41]([CH:40]=1)=[CH:42][C:43]([C:47]([NH2:32])=[O:49])=[CH:44][CH:45]=2
Reactant: CC1CC(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccccc2)CCN1c1cc2cc(C(N)=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 10 h
Yield: 54 %

Procedure:
To a solution of 1-BOC-2-methyl-4-benzylpiperidine (0.29 g, 1.0 mMol) in 5 mL of dichloromethane was added trifluoroacetic acid (TFA) (0.5 mL). After stirring at rt for 10 h the reaction mixture was evaporated in vacuo and azeotroped twice with dichloromethane and twice with hexane. The residue was dissolved in 5 mL of dichloromethane and diisopropylethylamine (1.6 mL, 10 mMol) was added. In a separate flask a mixture of 5-indolecarboxylic acid (0.19 g, 1.2 mMol) and EDAC (0.23 g, 1.2 mMol) was dissolved in 15 mL of dichloromethane and stirred at rt for 5 min. To this reaction mixture was added the first solution, and the resulting mixture stirred at rt for 20 h. The reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water and brine. The extract was dried over Na2SO4 and evaporated. The residue was chromatographed on a column of silica gel with 1% MeOH-dichloromethane. Evaporation of the desired fractions gave 0.18 g (54%) of the product as an oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH2:9][C@H:10]1[CH2:22][CH2:21][N:13]2[C:14]3[C:19]([CH:20]=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[C:12]1[CH2:11][C@@H:10]([CH2:9][C:1]#[N:2])[CH2:22][CH2:21][N:13]12
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC[C@H]1CCn2c(cc3ccccc32)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC[C@H]1CCn2c(cc3ccccc32)C1
Temperature: 70 °C
Yield: 52.7 %

Procedure:
18.0 g (367 mmol) of sodium cyanide were added to a solution of 65.0 g (233 mmol) of (6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl)methyl methanesulfonate in 500 ml of dimethylformamide and the mixture was heated at 70° C. for 24 hours. The mixture was partitioned between 1000 ml of water and 600 ml of ethyl acetate. The aqueous phase was extracted twice with 700 ml of ethyl acetate each time and the combined extracts were washed in twice with 500 ml of water each time, dried over magnesium sulfate and evaporated. The brown solid obtained was dissolved in ethyl acetate and the solution was filtered through a pad of silica gel. The solvent was removed in a vacuum and the residue was crystallized from methanol to give 25.8 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-acetonitrile as a light brown solid of melting point 100°-101° C.; [α]D20 -40.6° (c=0.84%, CH2Cl2).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:5][C:2]([NH:1][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])([CH3:6])[CH2:3][OH:4]
Reactant: CC(C)(N)CO
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)(CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (2.0 g, 21.4 mmol) in tetrahydrofuran (15 mL) was added 1,3-propane sultone (2.66 g, 21.4 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The crude product was collected by filtration, washed with acetone (2×25 mL). The solid was suspended in EtOH (50 mL). The suspension was stirred at reflux for 5 minutes. The solid was collected by filtration and dried in a vacuum oven (50° C.), affording compound DH (2.5 g, 58%): 1H NMR (D2O, 500 MHz) 8 ppm 3.48 (s, 2H), 3.04 (t, 2H, J=7.8 Hz), 2.90 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.18 (s, 6H). 13C NMR (D2O, 125 MHz) 8 ppm 64.88, 60.27, 48.19, 40.10, 21.92, 20.02. ES-MS 210 (M−1).