Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])[CH3:12].C(N(C(C)C)CC)(C)C>CCO>[CH2:11]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CC[C@@H](Nc2nc3ccccc3[nH]2)CC1
Temperature: 200 °C

Procedure:
A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200° C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g). Data for (J): 1H NMR (300 MHz, CDCl3) δ7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q, 2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22 (t, 3 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288]. Later fractions gave the trans isomer (K) (0.5 g): 1H NMR (300 MHz, CDCl3) δ7.28 (br s, 2 H), 7.02 (m, 2 H), 4.82 (br s, 1 H), 4.15 (q, 2 H), 3.64 (m, 1 H), 2.20 (br d, 3 H), 1.96 (br d, 2 H), 1.42 (m, 2 H), 1.22 (t, 3 H), 1.20 (m, 2 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)COCCO.O>[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Reactant: COc1ccccc1N
Solvent: OCCOCCO
Solvent: O
Product: COc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 79 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol and 2-methoxyaniline (282 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 242 mg of desired compound as solid in 79% of yield.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[CH3:24])[C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:16]=[N:15][C:9]2[NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:8]=2[CH:7]=1.CCN(CC)CC.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:13]1[CH2:14][C:8]2[CH:7]=[C:6](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:18][C:19]3[O:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]=3[CH3:24])=[O:17])[CH:16]=[N:15][C:9]=2[NH:10][CH2:11][CH2:12]1)(=[O:38])[CH3:37]
Reactant: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCN3)oc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCNc2ncc(/C=C/C(=O)N(C)Cc3oc4ccccc4c3C)cc2C1
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A solution of (E)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-3-(2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (105 mg, 0.280 mmol) in CH2Cl2 (6 mL) was treated with Et3N (0.05 mL, 0.36 mmol) followed by acetic anhydride (27 μL, 0.29 mmol). After stirring for 1.5 h, the mixture was diluted with CH2Cl2 (100 mL) and washed with H2O (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to a tan residue. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 96:4) gave the title compound (89 mg, 76%) as a colorless residue and as a mixture of amide rotamers: MS (ESI) m/e 419 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=O.C1(P(=[CH:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:41]([O:40][C:38](/[CH:37]=[CH:1]/[C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)c1cccc(-n2cccc2C=O)c1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-n2cccc2/C=C/C(=O)OCc2ccccc2)c1
Yield: 48.8 %

Procedure:
The solution of methyl 3-(2-formylpyrrol-1-yl)benzoate (1.0 g) and benzyl (triphenylphosphoranylidene)acetate (1.8 g) in tetrahydrofuran (10 ml) were heated under reflux for 30 hours. After evaporating the solvent, the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-[2-((E)-2-benzyloxycarbonylethenyl)pyrrol-1-yl)benzoate (0.77 g) as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH2:3][CH2:4][OH:5].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH3:7])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)CCO
Product: CCC(C)CCOS(C)(=O)=O

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (384 mg, 67%) from 3-methyl-1-pentanol (300 mg, 2.90 mmol) and methanesulfonyl chloride (500 mg, 4.40 mmol). 1H NMR (CDCl3, 300 MHz) δ0.86-0.95 (m, 6H), 1.15-1.25 (m, 1H), 1.33-1.42 (m, 1H), 1.51-1.60 (m, 2H), 1.76-1.84 (m, 1H), 3.00 (s, 3H), 4.23-4.31 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(COc2cccc(Br)c2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3cccc(Br)c3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 4-((3-bromophenoxy)methyl)benzoic acid (0.1 g, 0.32 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (147 mg, 0.76 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (104 mg, 0.77 mmol) and triethylamine (77 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.4 mmol) was added and the resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water (20 mL). The organic phase was separated and concentrated to give a residue. The residue was purified through column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 4-((3-bromophenoxy)methyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (80 mg, 57%). LRMS (M+H+) m/z: calcd 440.07. found 440.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6](O)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=1.O=P(Cl)(Cl)[Cl:21].CC(=O)OCC>[N+](C)(C)(C)C.[Cl-].CC#N>[Cl:21][C:6]1[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=2[F:1])=[CH:10][N:9]=[C:8]([S:11][CH3:12])[N:7]=1
Reactant: CSc1ncc(Oc2ccc(F)cc2F)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
The title compound of step 1 (5.30 g, 19.63 mmol), POCl3 (18.06 g, 117.78 mmol), (Me)4NCl (3.23 g, 29.47 mmol) in dry CH3CN (60 mL) was refluxed for 12 h. The mixture was poured into ice-water (50 mL) and subjected to EA extractive work up. Concentration under vacuum gave impure title compound (4.0 g), which was carried on to the next step. LCMS: 288.99 (M+1)+
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:8][C:9]([NH2:11])=[S:10]>>[S:10]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:8]=[C:9]1[NH2:11]
Reactant: O=C1CCCC1Cl
Reactant: NC(N)=S
Product: Nc1nc2c(s1)CCC2
Temperature: 70 °C

Procedure:
A mixture of 2-chlorocyclopentanone (5.0 g, 40 mmol) and thiourea (3.0 g, 40 mmol) was heated at 70° C. for 3 hours. After cooling, the solid was triturated with ethanol and collected by filtration to afford the title compound. MS (ESI) m/z 141 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)CCl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-5-cyano pyridine (2.0 g) in dry dichloromethane (17 mL) under nitrogen at 0° C. was treated with triethylamine (2.6 mL) followed by slow addition of chloroacetyl chloride (1.5 mL). The reaction mixture was allowed to warm up to room temperature. After 2 h, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50% EtOAc/cyclohexane. The relevant fractions were combined and evaporated to give the title compound (2.17 g) as a light brown solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:25])[NH:10][C@@H:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:7]1)=[O:5])C.[Li+].[OH-]>>[CH3:23][CH:22]([CH3:24])[CH2:21][C@H:11]([NH:10][C:9]([C@H:8]1[O:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:25])[C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)Nc1ccccc1
Yield: 84.3 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 17a (70 mg, 0.2 mmol); LiOH (4.8 mg, 0.2 mmol); after extraction afforded the desired product as a white solid (54 mg, 83.9%). 1H NMR (MeOD-d4, 400 MHz): δ 7.57-7.55 (d, 2H); 7.33-7.29 (t, 2H); 7.13-7.09 (t, 1H); 4.64-4.61 (m, 1H); 3.71 (s, 1H); 3.57 (s, 1H); 1.76-1.65 (m, 3H); 1.02-0.98 (t, 6H). 13C NMR (MeOD-d4, 100 MHz): 171.22, 169.07, 167.14, 137.98, 128.41, 124.12, 120.14, 52.90, 52.58, 51.69, 40.70, 29.49, 24.64, 22.04, 20.59. ESI-HRMS (m/z): [M−H]+ calcd. for C16H20N2O5: 319.3404, observed: 319.1332. HPLC Method 3: Rt=21.0 min, purity=96.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=c1c2c(CCc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (216 mg, 0.52 mmol, prepared in Example 15) in DMF (5 ml) and methanol (5 ml) was added activated carbon-palladium (22 mg), and the mixture was stirred overnight under hydrogen atmosphere, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(3-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (189 mg, 94%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:19]=3[CH:20]=[CH:21][CH:22]=2)=[O:13])[CH:5]=1.[OH-].[Na+]>C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[C:14]([C:12]([NH:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:30])=[O:2])=[O:13])[C:15]=3[CH:16]=[N:17]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c1
Temperature: 80 °C

Procedure:
To a solution of 3-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester (430 mg, 1.0 mmol) in ethanol (15 mL) was added a 2 N solution of aqueous sodium hydroxide (3.0 mL, 6.0 mmol). The mixture was heated at 80° C. for 4 hours. The mixture was cooled and concentrated in vacuo to remove the ethanol and then added to a solution of 1 N aqueous HCl (30 mL). The white precipitate was collected by filtration and dried to afford the title compound as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=O)=[CH:12][C:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+].Cl>>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:5][O:4][C:16](=[O:18])[C:15](=[O:19])[C:14]2=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)OCc1[nH]c2ccc(OCc3ccccc3)cc2c1C(=O)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C1OCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1=O

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-5-(benzyloxy)-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide in substantially the same manner, as described in step 6 of Example 1, followed by the treatment with aqueous HCl, as described in step 7 of Example 1. The product was obtained as a yellow solid; mp: >291° C. (dec.). Mass spectrum (ESI, [M−H]−) m/z 306. 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 7.48 (d, 2H, J=8.86 Hz), 7.39 (t, 2H, J=7.64 Hz), 7.32 (d, 1H, J=7.18 Hz), 7.04 (dd, 1H, J=8.71 and 2.59 Hz), 5.82 (s, 2H), and 5.16 ppm (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=O.[CH3:11][NH:12][NH2:13]>CS(C)=O.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:13][N:12]2[CH3:11]
Reactant: O=Cc1c(F)cccc1Br
Reactant: CNN
Solvent: O
Solvent: CS(C)=O
Product: Cn1ncc2c(Br)cccc21
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A solution of crude 2-bromo-6-fluorobenzaldehyde (42 g, 0.2 mol) (XXV) in DMSO (44 mL) was added to methylhydrazine (63 g, 7 eq) while maintaining the internal temperature to less than 35° C. The mixture was then heated to 80° C. for 22 hours, after which the internal temperature was adjusted to 25° C. The mixture was diluted with water (160 mL) and heptanes (160 mL) while maintaining the internal temperature at less than 40° C. The layers were separated, and the aqueous layer was extracted with heptanes (40 mL). Combined organic layers were washed with 10% citric acid (100 mL) and concentrated in vacuo. The product solidified on standing to give a yellowish solid (27.5 g, 70% yield)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C@H:5]1[C@H:9]([OH:10])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1.[OH-].[K+]>CCO>[O:4]1[C@@H:5]2[CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:8][C@H:9]2[O:10][CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](OCCBr)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C[C@H]2OCCO[C@@H]2C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(2-bromoethoxy)-4-hydroxypyrrolidine-1-carboxylate (0.20 g, 0.58 mmol) in EtOH (5 mL) was added a solution of KOH (32.0 mg, 0.58 mmol) in EtOH (5 mL). The reaction mixture was stirred for 0.5 h at 85° C., then quenched with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 5:1 (v/v)PE/EtOAc) to give the title compound as colorless oil (0.11 g, 73.33%).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([C:17]4([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:10](=[O:30])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(OC([NH:40][CH2:41][CH2:42][CH2:43]Br)=O)(C)(C)C>C1(C)C=CC=CC=1.O.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[NH2:40][CH2:41][CH2:42][CH2:43][N:9]1[C:10](=[O:30])[C:11]2([CH2:16][CH2:15][N:14]([C:17]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:13][CH2:12]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1(c3ccccc3)CCCCCC1)CC2
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: NCCCN1CN(c2ccccc2)C2(CCN(C3(c4ccccc4)CCCCCC3)CC2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
This was prepared according to the procedure of A. Petric et al. (Bioorg. Med. Chem. Lett. 1998, 8, 1455). To a stirred solution of 1-phenyl-8-(1-phenylcycloheptyl)-1,3,8-triazaspiro[4.5]decan-4-one (54.3 mg, 0.135 mmol) in toluene (0.3 ml) was added a solution of NaOH (23.8 mg, 0.595 mmol) in water (0.5 ml), n-Bu4NHSO4 (70.8 mg, 0.209 mmol), and a solution of N-(t-butoxycarbonyl)-3-bromopropylamine (65.3 mg, 0.274 mmol, this was reported by B. H. Lee et al. J. Org. Chem. 1983, 48, 24) in toluene (0.7 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h, then at 90° C. for 2 h. The reaction mixture was cooled down to room temperature, diluted with water, and extracted with CH2Cl2. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (1 mm plate×2, CH2Cl2/MeOH:95/5, two times developed) to afford 54.2 mg (71.8%) of colorless solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][Cl:25].[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N2CCNCC2)nc(C(C)(C)C)n1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1
Reaction time: 5 h
Yield: 82 %

Procedure:
40 g of 2-tert-butyl-4-[piperazin-1-yl]-6-tert-butyl-pyrimidine and 45.6 g of 1-bromo-3-chloro-propane were dissolved in 160 ml toluene. 13.3 g of 50% aqueous sodium hydroxide and 2.3 g of tetrabutylammonium bromide (dissolved in 40 ml water) were added. The mixture was kept at 50° C. for 5 h under vigorous stirring. The reaction mixture was then extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The product was purified by chromatography on silicagel (cyclohexane/0-10% ethyl acetate) to yield the title compound in 82% yield.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:21][C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:13]1.NN>CCO>[NH2:3][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:21][C:22](=[O:26])[N:23]([CH3:24])[CH3:25])[CH:18]=2)[CH2:13]1
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: CCO
Product: CN(C)C(=O)Sc1ccc2c(c1)CC(N)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
A 3-neck flask, equipped with a reflux condensor and mechanical stirrer, is charged with EtOH (98 mL) and dimethylthiocarbamic acid S-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl] ester (6.9 g; 20.6 mmol). Hydrazine (5.8 mL; 186 mmol) is added in 1-portion at RT and the reaction was refluxed with mechanical stirring for 30 min. The reaction is cooled to RT and the gelatinous, white solid is filtered and washed with ether several times. The ether washes are combined, evaporated under reduced pressure and the crude residue was further triturated with ether, filtered and the ether evaporated under reduced pressure to afford 4.6 g (95%) of dimethylthiocarbamic acid S-[2-aminoindan-5-yl) ester as a brown oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[Si:32]([O:22][CH2:21][CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
In N,N-dimethylformamide (20 ml) were dissolved 1,4-dibenzyl-2-hydroxymethylpiperazine (1.11 g) and imidazole (347 mg). Under ice cooling, tert-butylchlorodiphenylsilane (1.17 ml, 1.24 g) was added to the reaction mixture, followed by stirring at room temperature for 14.5 hours. The solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was then washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (hexane:ethyl acetate=9:1→8:2) using as a carrier silica gel, whereby the title compound (1.42 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26]1(O)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCCC2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and cyclopentanol in analogy to Example 9c): MS (ISP): 466.1 and 468.3 (M+H)+, 366.0 and 368.0 ((M-Boc)+H)+ (100%).