Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]1[CH2:24][CH2:23][CH2:22][C:21]21[O:28][CH2:27][CH2:26][O:25]2
Reactant: OCCO
Reactant: O=C1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(OC2CCCC23OCCO3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.2 g. of N-[4-bromo-3-(cyclopentanon-2-yloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 0.68 g. of ethyleneglycol, 0.2 g. of p-toluenesulfonic acid and 30 ml. of benzene was refluxed with stirring under removing water for 8 hours and the reaction mixture was cooled to room temperature and then, 20 ml. of ethyl acetate was added to the reaction mixture to extract the product. The extract was washed with water and dehydrated over sodium sulfate and the solvent was distilled off and the product was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 1:4) to obtain 1.35 g. of Compound No. 9 shown in Table 1.
Reaction SMILES: [CH3:1][N+:2]1([O-])[CH2:18][C:16]2=[C:17]3[C:12](=[C:13]([O:19][CH3:20])[CH:14]=[CH:15]2)[O:11][C@@H:10]2[C@:5]3([CH:6]=[CH:7][C@H:8]([OH:21])[CH2:9]2)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:18][C:16]2[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]3[C:17]=2[C@:5]2([C@@H:10]([O:11]3)[CH2:9][C@@H:8]([OH:21])[CH:7]=[CH:6]2)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CC[N+](C)([O-])C2
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2

Procedure:
A solution of 1.73 g (5.7 mmoles) of galanthamine N-oxide and 3.17 g (11,4 mmoles, 2 eq) of FeSO4 --7H2O in 100ml of methanol is agitated under argon for 1.5 hours at 10° C. After the evaporation of the solvent, the residue is taken up again in dichloromethane, treated with a saturated aqueous solution of sodium hydrogencarbonate and extracted three times with dichloromethane. The organic phases are collected and washed with a saturated aqueous solution of sodium chloride, dried on sodium sulfate and evaporated. The crude product of the reaction is purified by flash chromatography on silica gel using the mixture of dichloromethane/methanol (80:20) as eluant. The least polar fraction yields galanthamine and the most polar fraction yields for the most part norgalanthamine in the form of a white foam (yield=76%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21](=O)[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4](/[C:21](=[N:26]\[OH:27])/[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1
Reactant: CCC(=O)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC/C(=N/O)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A mixture of 1-[7-methyl-1-(2,4,6-trimethyl-phenyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl]-propan-1-one (50 mg, 0.154 mmol), hydroxylamine hydrochloride (43 mg, 0.62 mmol), and sodium acetate (57 mg, 0.693 mmol) in ethanol (4 ml) was stirred at room temperature overnight. The mixture was concentrated to dryness, then diluted with water, and extracted with 3 times with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness to give 51 mg of a mixture of the title (E) and (Z)-isomers as a white solid. Both isomers were separated by preparative thin layer chromatography plate with 40% ethyl acetate in hexane as solvent.
Reaction SMILES: [C:1]([C:5]1[CH:54]=[CH:53][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:33][C:34]2[CH:39]=[C:38]([F:40])[C:37]([O:41][Si](C(C)C)(C(C)C)C(C)C)=[C:36]([F:52])[CH:35]=2)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O=O.[Cl-].[NH4+]>C1COCC1>[C:1]([C:5]1[CH:54]=[CH:53][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:24][CH:23]=2)[CH2:33][C:34]2[CH:39]=[C:38]([F:40])[C:37]([OH:41])=[C:36]([F:52])[CH:35]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(-c3nnn[nH]3)cc2)cc1F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(-c3nnn[nH]3)cc2)Cc2cc(F)c(O)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
442 mg (0.51 mmol, 86%-pure) of E-5-{4-[5-[2-(4-tert-butylbenzyloxy)phenyl]-3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)pent-4-enyl]phenyl}-1H-tetrazole are charged in 12 mol of THF, cooled to 0° C., mixed with 1.18 ml (1.18 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF with exclusion of oxygen and stirred at room temperature for 2 hours. The mixture is then added to ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. 297 mg (0.5 mmol, 98% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:11]([O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=4)[C:7]=3[C:8]=2[CH3:20])[N:3]=1.C=O.[C:37](O)(=O)C.C([BH3-])#N.[Na+]>O>[CH3:37][N:24]([C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=1)[CH:21]1[C:7]2[C:8]([CH3:20])=[C:9]3[C:4](=[CH:5][C:6]=2[CH2:23][CH2:22]1)[N:3]=[C:2]([CH3:1])[N:11]([O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])[C:10]3=[O:19]
Reactant: COC(=O)c1ccc(NC2CCc3cc4nc(C)n(OC(=O)C(C)(C)C)c(=O)c4c(C)c32)cn1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(N(C)C2CCc3cc4nc(C)n(OC(=O)C(C)(C)C)c(=O)c4c(C)c32)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 5-[-((6RS)-2-methyl-4-oxo-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-pyridine-2-carboxylate (0.24 g), an aqueous solution of formaldehyde (37% weight/volume, 0.52 ml) and glacial acetic acid (5 ml) was stirred at ambient temperature for 30 minutes. Sodium cyanoborohydride (0.05 g) was added portionwise during 5 minutes and the mixture was stirred at ambient temperature for 30 minutes. The mixture was poured onto a mixture of ice and water (20 ml) and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using ethyl acetate as eluant. There was thus obtained methyl 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylate as a gum (0.185 g);
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:17](=[S:21])[S:18][S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S-:22][S-].[Na+].[Na+].O>CN(C)C=O>[SH:22][C:20]1[S:19][S:18][C:17](=[S:21])[C:16]=1[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=1
Reactant: CC(C)(C)c1cc(-c2cssc2=S)cc(C(C)(C)C)c1O
Reactant: [S-][S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2c(S)ssc2=S)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
33.8 parts of 4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione and 40 parts of a 2.5 molar solution of sodium disulphide were dissolved in 40 parts of dimethylformamide and warmed at 100°C for 15 minutes. 500 parts of water were then added, the mixture extracted several times with ether to remove any starting material, and then 60 parts of 3N hydrochloric acid solution were added slowly with stirring. The solid was filtered giving 27 parts of 5-mercapto-4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione m.p. 182°C which gave the following elemental analysis:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1N=[CH:22][N:21](C(N2C=NC=C2)=O)[CH:20]=1.CNC>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[CH3:20][N:21]([CH3:22])[C:16](=[O:18])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CNC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Reaction time: 0.83 h

Procedure:
To a stirred solution of 2.51 g (10 mmol) of Cbz-L-Valine (Bachem) in 20 mL of DMF was added 1.46 g (9 mmol) of CDI and the mixture was stirred for 50 min. To this mixture was added 6 mL (12 mmol) of dimethylamine (Aldrich) in 5 mL of THF and the reaction mixture was stirred for 18 hours. The mixture was taken up in 100 mL of ethyl acetate, washed with 10% HCl (3×40 mL), 10 mL of brine, and 20% potassium carbonate (2×50 mL), and dried over MgSO4. The mixture was filtered and concentrated to yield Cbz-L-valine N,N-dimethyl amide, which was hydrogenated under standard conditions with 10% Pd/C as the catalyst to remove the Cbz group and provide the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C2C(=CC=CC=2)CCN1[C:23]([Cl:25])=[O:24]>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([C:23]([Cl:25])=[O:24])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1CCc2ccccc2C1
Reactant: C1=C(c2ccccc2)CCNC1
Product: O=C(Cl)N1CC=C(c2ccccc2)CC1
Yield: 95 %

Procedure:
4-Phenyl-3,6-dihydro-2H-pyridine-1-carbonyl chloride (62A) is prepared from 4-phenyl-1,2,3,6-tetrahydropyridine as described for 24A.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (0.032 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline Were dissolved in 50 ml of pyridine and 6.75 g (0.048 mol) of benzoyl chloride were added dropwise thereto at 0°. After stirring at room temperature overnight the mixture was extracted with water and chloroform, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1:1) and crystallization (chloroform-hexane) gave 4-benzoyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]-quinoline as white crystals of melting point 194°-196°.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([F:19])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[CH:6]=1>CCO.[Ni]>[Br:1][C:2]1[C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[CH:6]=2)=[CH:12][C:13]([F:19])=[C:14]([CH:15]=1)[NH2:16]
Reactant: O=[N+]([O-])c1cc(Br)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Br)c(Oc2ccnc(Cl)c2)cc1F
Yield: 93.7 %

Procedure:
A mixture of 4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine (1.16 g, 3.34 mmol) and Raney Ni (0.5 g) in EtOH (40 mL) was hydrogenated (1 atm) overnight, the solids removed via filtration and washed with EtOH. The filtrate was concentrated to dryness, the residue dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness to afford 5-bromo-4-((2-chloropyridin-4-yl)oxy)-2-fluoroaniline (994 mg, 94%). MS (ESI) m/z: (M+H+): 318.9.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([O:32]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH3:28][O:27][C:24]1[N:23]=[C:22]([O:29][CH3:30])[C:21]([C:20]2[CH:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:6][CH:7]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:31])=[CH:17][CH:16]=[C:15]([OH:32])[CH:14]=3)=[CH:26][N:25]=1
Reactant: COc1ncc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)c(OC)n1
Reactant: C1CCNC1
Product: COc1ncc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCCC3)cc2)c(OC)n1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chrome n-3-yl]-2,4-dimethoxy-pyrimidine and pyrolidine as the starting material.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].S(=O)(=O)(O)O.[CH3:14][C:15]([CH3:21])=[CH:16][C:17](OC)=[O:18]>>[CH3:14][C:15]1([CH3:21])[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:17](=[O:18])[CH2:16]1
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)Oc2cc(O)ccc21
Temperature: 130 °C
Yield: 24.6 %

Procedure:
A mixture of 103 g of resorcinol and 4.6 g of conc. sulfuric acid was heated at 130° C. with stirring, and 58 g of methyl 3,3-dimethylacrylate was added. The mixture was heated at 130° C. for 3 hours with stirring. The reaction mixture was worked up in a customary manner, and the residue after concentration was purified by column chromatography to give 24 g (yield 27%) of 4,4-dimethyl-7-hydroxycoumarin (melting point 84°-85° C.). The product was worked up in the same way as in Referential Example 16 to give 16.8 g (yield 75%) of the desired product as colorless crystals (melting point 88°-88.5° C.).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][Cl:23])[CH3:19]>>[ClH:23].[CH3:17][N:18]([CH3:19])[CH:20]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH2:21][CH3:22]
Reactant: CN(C)CCCCl
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Agent: Cl
Product: CCC(c1cccc2[nH]nc(-c3ccccc3)c12)N(C)C
Yield: 55.5 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenylindazole (3.88 g) and dimethylaminopropyl chloride hydrochloride (4.74 g) to obtain 3.5 g of 1-dimethylaminopropyl-3-phenylindazole hydrochloride (m.p. 140°-143° C).
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]([O:32][CH2:33]Br)(=[O:31])[CH3:30]>>[ClH:1].[CH3:33][O:32][C:29](=[O:31])[CH2:30][N:17]1[C:16](=[O:26])[C:15]2([CH2:27][CH2:28][N:12]([CH:2]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:13][CH2:14]2)[N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18]1
Reactant: CC(=O)OCBr
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: COC(=O)CN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m. p. 178° C. and MS: m/e=442.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromomethyl acetate.
Reaction SMILES: CC(OC(N[C@H](C(O)=O)C1C=CC=CC=1)=O)(C)C.Cl.C(OC(=O)[C@@H]1CCCN1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]([C@@H:45]1[CH2:49][CH2:48][CH2:47][N:46]1[C:50](=[O:66])[C@H:51]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]([C@@H:45]1[CH2:49][CH2:48][CH2:47][N:46]1[C:50](=[O:66])[C@@H:51]([NH:58][C:59]([O:61][C:62]([CH3:64])([CH3:63])[CH3:65])=[O:60])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1

Procedure:
Compound 21 was synthesized from Boc-L-phenylglycine and L-proline benzyl ester hydrochloride, following the procedure as described for compound 2a, as a white crystallized solid. MS (ESI, EI+) m/z=439 (MH+).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].N1C=CC=CC=1.C[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:15]2[CH:24]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]4[O:37][CH2:36][CH2:35][NH:34][CH2:33][C:32]=4[CH:38]=3)[CH:26]=[CH:27][C:14]=2[N:13]=1>C(Cl)(Cl)Cl>[Cl:4][C:1]([N:34]1[CH2:33][C:32]2[CH:38]=[C:28]([C:25]3[CH:26]=[CH:27][C:14]4[N:13]=[CH:12][N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:15]=4[CH:24]=3)[CH:29]=[CH:30][C:31]=2[O:37][CH2:36][CH2:35]1)=[O:2]
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OC(C)(C)C
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)n1cnc2ccc(-c3ccc4c(c3)CN(C(=O)Cl)CCO4)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Phosgene (20 W % in toluene) (190 uL, 0.38 mmol) was added by syringe to a 0° C. cooled solution of pyridine (100 uL, 1.2 mmol) in chloroform (3 mL) followed by addition of 1,1-dimethylethyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazole-1-carboxylate as obtained in step 7 as a solution in chloroform (1 mL). The mixture was stirred for 15 minutes at 0° C. then partitioned with 10% aqueous citric acid. The organic phase was dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel chromatography to give 1,1-dimethylethyl 6-[4-(chlorocarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1H-benzimidazole-1-carboxylate (62.6 mg, 59% yield) as a yellow amorphous residue. MS (EI) for C23H24ClN3O4: 442 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)CCO3)S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-(3-{[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12w, and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.79 (m, 2H), 7.14 (m, 3H), 7.03 (d, 1H), 6.88 (m, 2H), 6.79 (s, 1H), 6.71 (d, 1H), 6.58 (d, 1H), 4.51 (t, 2H), 4.25 (s, 2H), 4.21 (s, 2H), 3.64 (s, 3H), 3.08 (t, 2H), 2.80 (t, 2H), 2.50 (t, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:17][O:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CI
Reactant: CC(C)n1ccc2ccc(CO)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc2ccn(C(C)C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A solution of 6-hydroxymethyl-1-(2-propyl)indole (0.214 g, 1.13 mmole) in 2 mL of anhydrous N,N-dimethylformamide was added dropwise to a slurry of 95% NaH (35.2 mg, 1.36 mmole) in 6 mL of anhydrous N,N-dimethylformamide at 0° C. under argon and the reaction mixture was stirred at 0° C. for 1 h followed by addition of methyl iodide (84.7 mL, 1.356 mmole). The reaction was then stirred at 20° C. under argon for 17 h. It was poured into ice-water (50 mL) and extracted with ethyl acetate. The ethyl acetate layers were dried over anhydrous magnesium sulfate and evaporated. Purification by flash chromatography using ethyl acetate (2-5%)/hexanes gave 107 mg of 6-methoxymethyl-1-(2-propyl) indole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)OCc1ccccc1

Procedure:
Benzyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzyl chloroformate in a similar manner as described above to give a white solid (16% yield). 1H-NMR (CDCl3): δ 8.69 (s, 1H), 7.60 (s, 1H), 7.43-7.31 (m, 5H), 7.27-7.21 (m, 1H), 7.17 (d, 1H), 5.16 (q, 2H), 5.08 (m, 1H), 4.92 (m, 1H), 2.66 (m, 2H), 2.20 (m, 1H), 1.89 (m, 2H), 1.80 (m, 1H); MS m/z 400 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 23.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.090 g, 0.190 mmol) obtained in step 2 and methanesulfonamide (0.094 g, 0.951 mmol), the title compound (0.025 g, 24%) was obtained.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Pd].[Zn].O.CC(C)=O>[CH2:16]([O:15][C:9]1[CH:10]=[C:11]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[C:9]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOc1ccc(I)cc1OCCCCCC
Agent: [Pd]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Temperature: 50 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A mixture of 1200 mL of distilled water/acetone (1/1), 194 g of Pd/C (Pd: 10%), 194 g of zinc powder, and 200 g (495 mmol) of 1,2-bishexyloxy-4-iodobenzene was stirred at 50° C. for 24 hours. The resulting reaction mixture was filtered with a glass filter and extracted with chloroform. The organic phase was washed with distilled water and dried over MgSO4. Then, the solvent was evaporated and 123 g of a yellow solid was obtained. The yellow solid was recrystallized from ethanol and 58.5 g of a white solid was obtained.