Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 94.9 %

Procedure:
A solution of tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate (380 mg, 0.705 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 294 mg (95%) of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine. Compound was determined to be 95% pure by 1H NMR and was carried forward into further chemistry. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.54 (m, 2 H) 1.92-2.08 (m, 2 H) 2.92-3.12 (m, 1 H) 3.27 (t, J=11.87 Hz, 2 H) 5.42 (br. s., 2 H) 7.07-7.61 (m, 8 H) 8.38 (s, 1 H), [M+H]+ 439.4.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:37])C(=O)C1>C(Cl)Cl>[Cl:37][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([C:18]3[N:17]=[C:16]([C:9]4[S:10][C:11]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[O:20][N:19]=3)[CH:22]=2)[NH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Solvent: ClCCl
Product: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
D2 (200 mg) and NCS (65 mg) were dissolved in DCM (5 ml) and stirred overnight at room temperature. The reaction mixture was then partitioned between DCM and H2O. The DCM solution was evaporated to dryness and purified on a Biotage silica cartridge, eluting with a 25-75% mixture of diethyl ether in hexane. This gave the title compound (36 mg) as a brown solid. A second batch of the title compound was also obtained from this purification (86 mg) as a brown solid. δH (CDCl3, 400 MHz): 7.28 (1H, m), 7.45-7.54 (6H, m), 7.93 (1H, s), 8.05 (1H, d), 8.28 (1H, br s), 8.49 (1H, s). MS (ES): C21H11ClF3N3OS requires 445; found 444 (M−H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][N:3]=1.[CH3:18][C:19]([CH3:31])([O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[C:20]#[CH:21]>C(NCC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][C:19]([CH3:18])([CH3:31])[C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)#[N:28]
Reactant: O=C(OCc1ccccc1)c1ccc(I)nc1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CC(C)(C#Cc1ccc(C(=O)OCc2ccccc2)cn1)Oc1ccc(C#N)cc1
Yield: 74.9 %

Procedure:
12.2 g of benzyl 2-iodopyridine-5-carboxylate and 5.64 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were stirred with 32 mg of copper(I) iodide, 162 mg of triphenylphosphine and 180 mg of palladium(II) chloride in 280 ml of diethylamine at room temperature for 7 days under a nitrogen atmosphere. The mixture was evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 9.04 g of benzyl 2-[3-(4-cyanophenoxy)-3-methyl-1-butyn-1-yl]pyridine-5-carboxylate which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>C(O)C.[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CN2CCOCC2)c1
Yield: 96.6 %

Procedure:
A solution of 4-(3-nitrobenzyl)morpholine (3.0 g, 14 mmol) in ethanol (40 ml) was treated with 10% palladium on charcoal (150 mg) and hydrogenated at 50 psi until hydrogen uptake ceased (ca. 2 hours). The mixture was filtered through a glass microfibre filter paper (Whatman GF/A) and evaporated to dryness to give 3-(morpholin-4-ylmethyl)phenylamine as a colourless oil (2.6 g, 100%) which was used without purification. m/z (ES+) 193 (M++H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([CH3:12])=[N:7]2.CC1(C)C(C)(C)OB([C:27]2[NH:35][C:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:36])[C:29]=3[CH:28]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(Cl)Cl>[CH3:12][C:6]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:27]2[NH:35][C:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:36])[C:29]=3[CH:28]=2)[N:7]=1
Reactant: Cc1nc2cccc(Br)c2nc1-c1ccccc1
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 31.8 %

Procedure:
A solution of 5-bromo-2-methyl-3-phenylquinoxaline (87.5 mg, 0.292 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 609; 216 mg, 0.585 mmol), K3PO4 (186 mg, 0.877 mmol), XPhos (Strem Chemicals, Inc.; 13.94 mg, 0.029 mmol), and Pd2dba3 (Aldrich; 13.39 mg, 0.015 mmol) in a mixture of 1,4-dioxane (2.0 mL) and water (0.400 mL) was stirred under argon at 100° C. for 45 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(2-methyl-3-phenylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (32.8 mg, 0.093 mmol, 32% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br. s.), 8.06 (1H, dd, J=7.2, 1.4 Hz), 7.77-7.91 (4H, m), 7.53-7.64 (3H, m), 7.26 (1H, d, J=2.2 Hz), 7.00 (1H, s), 3.40 (2H, td, J=6.8, 2.4 Hz), 2.84 (2H, t, J=6.8 Hz), 2.75 (3H, s). m/z (ESI, +ve) 355.0 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:5].[CH3:6][N:7]([CH3:16])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Li]>C1(C)C=CC=CC=1>[CH3:6][N:7]([CH3:16])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Zr:5]([CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[N:7]([CH3:16])[CH3:6])([CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[N:7]([CH3:16])[CH3:6])[CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[N:7]([CH3:16])[CH3:6]
Reactant: [Zr+4]
Reactant: [Li]Cc1ccccc1N(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C)c1ccccc1C[Zr](Cc1ccccc1N(C)C)(Cc1ccccc1N(C)C)Cc1ccccc1N(C)C
Temperature: 50 °C

Procedure:
To a mixture of 0.046 g of zirconium tetrachloride and 0.113 g of 2-dimethylaminobenzyllithium was added 3 ml of toluene, and the mixture was warmed to about 50° C with stirring. Reaction slowly took place to give an orange liquid. When there was no further appreciable change in the color of the liquid, the mixture was cooled and filtered to give an orange solution of tetrakis(2-dimethylaminobenzyl)zirconium.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][CH2:18][N:19]2[CH2:37][CH2:36][C:22]3([O:27][CH2:26][CH2:25][N:24]([C:28]([C:30]4[N:31]=[C:32]([CH3:35])[S:33][CH:34]=4)=[O:29])[CH2:23]3)[CH2:21][CH2:20]2)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C>CO>[OH:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][C:22]3([O:27][CH2:26][CH2:25][N:24]([C:28]([C:30]4[N:31]=[C:32]([CH3:35])[S:33][CH:34]=4)=[O:29])[CH2:23]3)[CH2:36][CH2:37]2)=[CH:14][CH:13]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO[Si](C)(C)C(C)(C)C)s4)CC3)C2)cs1
Agent: Cl
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)s4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (0.5 mL) was added to a solution of (9-(2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 4, step i) (0.235 g) in methanol (5 mL) and the resulting solution stirred for 1 h. The solvent was evaporated in vacuo and the residue azeotroped with toluene and re-dissolved in methanol (˜2 mL). The residue was dissolved in methanol (10 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (100 mL) and eluted with 1M ammonia in methanol solution (100 mL). The eluent was evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.12 g.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH3:17][O:18][C:19](=[O:36])[C@@H:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:21]1[C:32](=[O:35])[CH2:33][NH2:34]>CCCCCC.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:36])[C@@H:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:21]1[C:32](=[O:35])[CH2:33][NH:34][C:6](=[O:8])[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CN
Reactant: CC(=O)SC(Cc1ccc(Cl)cc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CNC(=O)C(Cc1ccc(Cl)cc1)SC(C)=O
Yield: 53 %

Procedure:
Condensation of 2-acetylthio-3-(para-chlorophenyl)propanoic acid with N-glycyl-5-(ortho-hydroxyphenyl)proline methyl ester, obtained in accordance with the same protocols as those described in Preparation G, yields the expected product in the form of an oil after chromatography in an n-hexane/ethyl acetate mixture, 1:1.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)=O.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[N+:13]([C:10]1[CH:9]=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:5]=1[NH2:4])([O-:15])=[O:14]
Reactant: CC(=O)Nc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is added gradually with stirring potassium nitrate (55.5 g) at room temperature during which the temperature raises to 60° C. The mixture is stirred at 60° C. for one hour. The reaction mixture is poured into ice water, and the precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate, water and aqueous saturated sodium chloride in this order and dried. The solvent is removed by concentration and washed with n-hexane. The resulting crystals are taken by filtration and dried to give 2-nitro-4,5-difluoroaniline (54 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:26]([O-:28])=[O:27].Cl.[CH:30]1([CH:33]([NH2:36])[CH2:34][CH3:35])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:36][CH:33]([CH:30]2[CH2:32][CH2:31]2)[CH2:34][CH3:35])[C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: CCC(N)C1CC1
Agent: Cl
Product: CCC(Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 43.4 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester (548 mg, 1.76 mmol) and 1-cyclopropyl-propylamine HCl (479 mg, 3.5 mmol) were treated substantially as described in Part C of Example 19a to produce 300 mg (43%) of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (EI) m/z 393.22 [(M+H)+, 100].
Reaction SMILES: O[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.CC1(C)CCC(C)(C)C2C=C(C=CC(Cl)=O)C=CC1=2.[CH3:33][C:34]1([CH3:60])[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[C:40]2[CH:39]=[C:38]([CH:46]=[CH:47][C:48]([O:50]C3C=CC=CC=3C([O-])=O)=[O:49])[CH:37]=[CH:36][C:35]1=2>>[CH3:33][C:34]1([CH3:60])[CH2:43][CH2:42][C:41]([CH3:44])([CH3:45])[C:40]2[CH:39]=[C:38](/[CH:46]=[CH:47]/[C:48]([O:50][C:12]3[CH:13]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[O:49])[CH:37]=[CH:36][C:35]1=2
Reactant: C=CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccccc3C(=O)[O-])ccc21
Agent: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Product: C=CCOC(=O)c1ccccc1OC(=O)/C=C/c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to that of Example 11(b), by reaction of 710 mg (4 mmol) of allyl 4-hydroxybenzoate with 1 g (3.62 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride obtained in Example 1(c), 500 mg (33%) of allyl E)-2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloyloxy]benzoate, with a melting point of 92-3° C., are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[N:26]([S:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:47])=[O:46])[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 70.3 %

Procedure:
To a solution of {4-[(1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.215 g, 0.51 mmol) in CH2Cl2 (10 mL) was added Et3N (0.30 mL, 2.15 mmol) followed by benzenesulfonyl chloride (0.13 ml, 1.02 mmol) and the resultant solution was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (40 mL), washed with brine (3×10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (15:1 CH2Cl2-MeOH) provided 0.202 g (70%) of {4-[(1-Benzenesulfonyl-1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin−2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as an orange-brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[K+].Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A mixture of 8.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.1 g of potassium hydroxide and 100 ml of dimethylsulfoxide is stirred at room temperature for 30 minutes. Then, 4 g of 2-(dimethylamino)ethyl chloride hydrochloride are added to the mixture, and said mixture is stirred at room temperature for 20 hours. After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is extracted with ethyl acetate, and the ethyl acetate layer is further extracted with 20% hydrochloric acid. The hydrochloric acid layer is alkalized with conc. aqueous ammonia, and the precipitated crystals are collected by filtration, washed with water and then dried. 6.4 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:38][CH3:39].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:38][CH3:39]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCCCC#Cc1cncs1)C(C)(C)C)CC2
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A solution of 530 mg of 16k in 9 ml of dioxane was mixed with a solution of 300 mg of KOH in 3 ml of water and stirred at 55° C. for ½ hr. The reaction mixture was diluted with 25 ml of water and acidified with 0.5N HCl to pH3 and the product was extracted with ethyl acetate. The extract was once washed with water, dried and concentrated, to give 480 mg of 16l as colorless oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[Cl:13]N1C(=O)CCC1=O>O1CCCC1>[Cl:13][C:6]1[S:5][C:4]([NH:3][CH:1]=[O:2])=[N:8][C:7]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=CNc1nc(CC(=O)O)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: O=CNc1nc(CC(=O)O)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 2-formamido-4-carboxymethylthiazole (2.0 g) in tetrahydrofuran (20 ml) was added N-chlorosuccinimide (1.58 g) and stirred at room temperature overnight. The reaction mixture was added N-chlorosuccinimide (0.5 g) and stirred at the same temperature overnight. The reaction mixture was evaporated under reduced pressure and purified by column chromatography on silica gel (SiO2 =200 ml, chloroform:methanol:acetic acid=20:1:0.1) to give two fractions. The fraction 1 (upper spot by TLC) was purified by column chromatography on silica gel (SiO2 =200 ml, methanol:chloroform=2:8), then the elution was evaporated under reduced pressure. The residue was dissolved in a mixture of water and ethyl acetate, adjusted to pH 8.7 with saturated sodium hydrogencarbonate, and washed with ethyl acetate (×2). The aqueous layer was adjusted to pH 3.0 with 1N-hydrochloric acid, extracted with ethyl acetate (×2), dried over magnesium sulfate, and evaporated under reduced pressure to give white solid which was precipitated from ethyl acetate and N-hexane to give 5-chloro-2-formamido-4-carboxymethylthiazole (694 mg, 29.3%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50](O)=[O:51])=[CH:37]1>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:50](=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[CH2:8][CH2:7]1
Reactant: O=C(O)CCCCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCCCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h
Yield: 59.7 %

Procedure:
The non-polar diastereoisomer of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (232 mg, 1.0 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (415 mg, 1.5 mmol.) were added to a solution of 6-(1H-indol-3-yl)hexanoic acid (231 mg, 1.0 mmol.) in abs. methanol, and stirring was carried out for 24 h at RT. For working up, the mixture was concentrated and the residue was suspended in water (10 ml), adjusted to pH 11 with 5M NaOH and extracted with EE (4×10 ml). The combined organic extracts were washed with 1M NaOH (2×2 ml), dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (50 g) with methanol/EE (1:3, 440 ml) and the non-polar diastereoisomer of 6-(1H-indol-3-yl)hexanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide (266 mg) was isolated in the form of a crystalline solid. 265 mg (6 mmol.) thereof were dissolved in 2-butanone, and chlorotrimethylsilane (113 μl, 0.9 mmol.) was added thereto. A colourless, tacky precipitate immediately formed and was converted into a fine pale-pink solid by the addition of ether. The solid was filtered off, washed with cold ether (3×2 ml) and dried in vacuo. The hydrochloride of 6-(1H-indol-3-yl)hexanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide was thus obtained in a yield of 274 mg (pale-pink solid, m.p. 120–125° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:13]=[CH:14][CH:15]=2.[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6]([NH:24][CH2:23][CH2:22][CH2:21][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[C:5]=3[CH:13]=[CH:14][CH:15]=2
Reactant: NCCCn1ccnc1
Reactant: SC1=Nc2c(Cl)cc(Cl)c3cccc1c23
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2cccc3c2c1N=C3NCCCn1ccnc1
Yield: 43.4 %

Procedure:
A mixture of 5.0 g of 6,8-dichloro-benz[cd]indole-2-thiol, 35 ml of dimethylformamide, 2.6 g of 3-(1H-imidazol-yl)propanamine and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 2.95 g of the desired product, mp 182°-183° C.