Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[N+:29]([C:32]1[CH:45]=[CH:44][C:35]([C:36]([O:38][C@H:39]2[CH2:43][CH2:42][NH:41][CH2:40]2)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(#N)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:41]2[CH2:42][CH2:43][C@H:39]([O:38][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:45][CH:44]=3)[CH2:40]2)=[CH:12][CH:11]=1
Reactant: O=C(O[C@H]1CCNC1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O[C@H]1CCN(CCc2ccc(Cl)cc2)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
4-Chlorophenethyl tosylate (683 mg, 2.20 mmol), sodium carbonate (236 mg, 2.20 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to a solution of (S)-3-(4-nitrobenzoyloxy)pyrrolidine (472 mg, 2.00 mmol) in acetonitrile (10 ml), and they were heated under reflux at 90° C. for 8 hours. The solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-chlorophenethyl)-3-(4-nitrobenzoyloxy)pyrrolidine in the form of a light yellow oil (315 mg, 42%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1([O:11][C:12]2[CH:34]=[CH:33][C:15]3[C:16]4[N:20]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:19]=[C:18]([C:24]2[N:25]([CH:30]([CH3:32])[CH3:31])[N:26]=[C:27]([CH3:29])[N:28]=2)[N:17]=4)[CH2:10][CH2:9]1)=[O:7]>CO.O>[CH:30]([N:25]1[C:24]([C:18]2[N:17]=[C:16]3[N:20]([CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([O:11][C:8]5([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]5)[CH:34]=[CH:33][C:15]=43)[CH:19]=2)=[N:28][C:27]([CH3:29])=[N:26]1)([CH3:32])[CH3:31]
Reactant: COC(=O)C1(Oc2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Yield: 80.9 %

Procedure:
Lithium hydroxide monohydrate (141 mg, 3.44 mmol) was added to a solution of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid methyl ester (730 mg, 1.72 mmol) in MeOH (10 mL) and water (2 mL) and the mixture was heated at 50° C. for 1 h. Volatiles were removed under reduced pressure and the pH of the resulting residue was adjusted to 4 by addition of 1N HCl. A precipitate formed which was collected by filtration and washed with water affording 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid (570 mg, 81%). LCMS: RT 2.71 min [M+H]+ 410.2
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:32])=[C:6]([C:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[C:7]([O:12]C)=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[C:1]([C:4]1[C:5]([CH3:32])=[C:6]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:7]([OH:12])=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCC(O)(c1ccc(F)cc1)c1c(C)c(C(C)=O)c(C)c(C)c1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1c(C)c(C)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.4 %

Procedure:
A solution of methyl 7-(3-acetyl-6-methoxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)-7-hydroxyheptanoate (1.6 g) in dichloromethane (15 ml) was added dropwise to a solution of boron tribromide (1.4 ml) in dichloromethane (15 ml) at -78° C. The temperature was raised slowly to room temperature and the mixture was stirred for 5 hours. The reaction mixture was ice-cooled and water was added. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain 7-(3-acetyl-6-hydroxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoic acid (0.87 g) (Compound 35). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[CH:34]([O:37][C:38]([O:40][CH:41](I)[CH3:42])=[O:39])([CH3:36])[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:41]([O:40][C:38]([O:37][CH:34]([CH3:36])[CH3:35])=[O:39])[CH3:42])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)OC(=O)OC(C)I
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)OC(=O)OC(C)OC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 1-(isopropyloxycarbonyloxy)ethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (85 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(COC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(Cc2cc(Br)ccc2I)s1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(Cc2cc(Br)ccc2-c2ccccc2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of the above 5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene (1.0 g) in dimethoxyethane (10 ml) were added phenylboronic acid (310 mg), bis(triphenylphosphine)palladium (II)dichloride (85 mg) and 2M aqueous sodium carbonate solution (3.8 ml), and the mixture was stirred at 50° C. overnight. Added thereto was a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene (683 mg) as oil.
Reaction SMILES: S(C)C.[CH3:4][Li].[CH2:6]([N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:14]([CH2:17][CH3:18])[CH:15]=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH2:19]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:14]([CH2:17][CH3:18])[C@H:15]([OH:16])[CH3:4])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [Li]C
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCOCC
Solvent: CSC
Product: CC[C@@H]([C@@H](C)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a stirred suspension of CuBr.SMe2 (1.54 g, 7.5 mmol) in anhydrous ether under an argon atmosphere at −78° C., was added methyllithium (1.6M in ether, 9.4 ml, 15 mmol) dropwise. After the addition was complete, the reaction was allowed to warm to room temperature. The reaction was recooled to −78° C. and a solution of (S)-2-(dibenzylamino)butanal (1 g, 3.75 mmol) in ether (20 ml) was added dropwise. After the addition, continued stirring for 2 h The reaction was then quenched with a saturated aqueous solution of NH4Cl (10 ml). The reaction mixture was extracted with ether (2×30 ml) and the combined organic phase washed with brine (20 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel gradient column chromatography, eluted with hexane:ethyl acetate (100:0→80:20) to afford the product as a light yellow oil (0.95 g, 89%) as the only isomer. δH (250 MHz, CDCl3) 1.05 (3 H, t, J 7.5, CHCH2CH3), 1.25 [3 H, d, J 7.5, CH(CH3)OH], 1.6-1.49 (1 H, m, CHHCH3), 1.88-1.73 (1 H, m, CHHCH3), 2.41 (1 H, s, br, OH), 2.66-2.59 (1 H, m, CHCH2CH3), 3.85-3.65 (4 H, m, 2×CH2Ph), 4.05-3.9 (1 H, m, CHOH), 7.41-7.25 (10 H, m, ArH) δC (250 MHz, CDCl3) 140.05 (2×C), 128.98 (4×CH), 128.37 (4×CH), 127.3 (2×CH), 66.81 (CH), 63.65 (CH), 55.41 (CH2), 20.63 (CH3) 18.44 (CH2), 12.5 (CH3)
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([O:16][CH:17]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[CH3:18])[CH3:15].CN(C)[CH:31]=[O:32]>CCCCCC.C1COCC1>[CH2:14]([O:16][CH:17]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[C:21]=1[CH:31]=[O:32])[CH3:18])[CH3:15]
Reactant: CN(C)C=O
Reactant: CCOC(C)Oc1ccc2c(c1)OCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(C)Oc1ccc2c(c1C=O)OCO2
Temperature: -78 °C
Yield: 96 %

Procedure:
n-Butyllithium (18.6 ml of a 2.5M solution in hexane, 46.5 mmol) and N,N,N',N'-tetramethylethylenediamine (5.38 g, 46.3 mmol), respectively, were added (using a syringe) to a stirred solution of 5-(1-ethoxyethoxy)-1,3-benzodioxole (8.9 g, 42.4 mmol) in dry THF (100 ml) in a nitrogen atmosphere at -78° C. The resulting solution was allowed to attain room temperature and then cooled to -78° C. A solution of N,N-dimethylformamide (3.70 g, 50.6 mmol) in dry THF (20 ml) was added using a syringe, and the reaction mixture was allowed to attain room temperature. The resulting mixture was quenched with water and extracted with diethyl ether (3times). The combined ether layers were washed with water (2 times), dried over Na2SO4, filtered and evaporated in vacuo to to yield 5-(1-ethoxyethoxy)-4-formyl-1,3-benzodioxole (9.7 g, 96% yield; compound No. 2) as a pale yellow solid, m.p. 48°- 50° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17]([O:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:32][CH2:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:12][CH:11]=3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CCc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCOC2c3ccccc3CCc3ccccc32)cc1)C(=O)O

Procedure:
3-(4-[2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethoxy]-phenyl)-2-ethoxy-propanoic acid ethyl ester (example 8) (1.5 g, 3.2 mmol) was dissolved in ethanol (30 ml) and 20% sodium hydroxide (3 ml) was added. After 3 days ethanol was evaporated in vacuo, water (50 ml) and hydrochloric acid (2 ml) were added and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo. The residue (1.1 g, 78 %) was dissolved in ethanol and treated with (L)-lysine monohydrate (0.41 g). Ethanol was evaporated and the residue triturated with diethyl ether. The crystalline product was filtered off and dried in the air. This afforded 1.45 g of the title compound as salt with (L)-lysine (dihydrate). M.p. 148-150° C. 1H NMR (250 MHz, DMSO-d6 δ7.00-7.35 (m, 10 H); 6.75 (bd, J=8.2 Hz, 2 H); 6.26 (bs, 8 H); 5.91 (t, J=6.6 Hz, 1 H); 4.02 (t, J=6.2 Hz, 2 H); 3.76 (m, 1H); 3.59 (m)+3.31 (m), 2 H; 3.07 (bs (4 H); 2.70-2.95 (m, 4 H); 2.51 (bq, 2 H); 1.66 (bm, 6 H); 1.03 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(4′-hydroxyphenyl)benzoate (2.02 g), n-butylbromide (3 ml) and sodium carbonate (3.6 g) in N,N-dimethylformamide was stirred for 17 hours at 80° C. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After dried over magnesium sulfate, the solution was evaporated in vacuo. The residue was triturated with n-hexane to afford methyl 4-(4′-butyloxyphenyl)benzoate (2.45 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1C=CO[N:7]=1)=[O:4].[N:11]1[CH:16]=NC=[N:13][C:12]=1N>>[Br:1][CH2:2][C:3]([NH:5][C:6]1[N:7]=[CH:16][N:11]=[CH:12][N:13]=1)=[O:4]
Reactant: O=C(CBr)Nc1ccon1
Reactant: Nc1ncncn1
Product: O=C(CBr)Nc1ncncn1

Procedure:
This compound is prepared by an analogous method to 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) by replacing 3-aminoisoxazole with [1,3,5]triazin-2-ylamine.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1>O>[CH3:38][C:34]1[N:33]=[C:32]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]3)=[CH:27][CH:28]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO)cc2)CC1
Reactant: Cc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(OCCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1

Procedure:
To a DMF (10 mL) solution of tert-butyl 4-[4-(2-hydroxyethyl)benzyl]piperazine-1-carboxylate (1.000 g) was added NaH (112 mg, 60% in mineral oil) at 0° C., then the resultant mixture was stirred for 1 hour. To the mixture was added 2-fluoro-6-methylpyridine (0.419 mL), then the resultant mixture was stirred at 70° C. over night. The mixture was poured into water, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=4/1 to 1/1) to afford tert-butyl 4-(4-{2-[(6-methylpyridin-2-yl)oxy]ethyl}benzyl)piperazine-1-carboxylate as a pale yellow amorphous powder (350 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43]>>[CH2:42]([NH:44][C:45]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:46])[CH3:43]
Reactant: CCN=C=O
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Product: CCNC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and ethyl isocyanate by the procedure described in Example 2, Step C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]3[CH2:19][CH2:18][CH2:17][CH:11]3[C:12](=S)[NH:13][C:14]=2[CH:15]=1.[NH3:20]>>[NH2:20][C:12]1[CH:11]2[CH2:17][CH2:18][CH2:19][CH:10]2[C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:15][C:14]=2[N:13]=1
Reactant: S=C1Nc2cc(-c3ccco3)ccc2C2CCCC12
Reactant: N
Product: NC1=Nc2cc(-c3ccco3)ccc2C2CCCC12
Yield: 82 %

Procedure:
Analogously to Example 4, 7-(2-furanyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (95 mg, 0.35 mmol) in 7N methanolic ammonia solution (30 ml) is reacted to form 72 mg (82%) of product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:23][CH:22]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.34 g, 0.0117 mol), 4-trifluoromethylphenyl isothiocyanate (2.85 g, 0.014 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 3.06 g (65%), m.p. 165°-167 ° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3[CH2:12][CH2:11]3)[C:5]=2[CH:13]=[C:14](Br)Br)[CH2:3][CH2:2]1.[CH2:17]([NH2:20])[CH2:18][NH2:19]>>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3[CH2:12][CH2:11]3)[C:5]=2[CH2:13][C:14]2[NH:19][CH2:18][CH2:17][N:20]=2)[CH2:3][CH2:2]1
Reactant: BrC(Br)=Cc1c(C2CC2)cccc1C1CC1
Reactant: NCCN
Product: c1cc(C2CC2)c(CC2=NCCN2)c(C2CC2)c1

Procedure:
2-(2,6-Dicyclopropyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1,3-dicyclopropyl-2-(2,2-dibromo-vinyl)-benzene and ethylenediamine in analogy to Example 1e): light yellow crystals; MS (ISP): 241.4 ([M+H]+, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[S:37][C:38]([CH3:41])=[N:39][N:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25])=O)(C)(C)C>CCOCC>[NH2:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[S:37][C:38]([CH3:41])=[N:39][N:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC4=C(CNC(=O)OC(C)(C)C)CCCC4)[C@H]3SC2)s1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC4=C(CN)CCCC4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of trifluoroacetic acid (2 ml.) and 5d (1.20 g., 2 mmoles) was stirred for 30 min at room temperature and diluted with ether (50 ml.) to precipitate the trifluoroacetate of 6d. The trifluoroacetate was slurried in water (2 ml.), adjusted at pH 6 with ammonium hydroxide and diluted with acetonitrile (200 ml.) to precipitate 6d. Yield 0.75 g. (76%). M.p. 215° - 220° C. (dec.).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]([CH3:33])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].ON1C(=O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:23]([CH3:33])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CNCCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: ClCCl
Product: CN(CCC(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
Z-Phe-OH (29.9 g, 100 mmol), MeβAla-O-t-Bu (16.0 g, 110 mmol), and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (17.9 g, 110 mmol) was dissolved in methylene chloride (200 ml). This solution was cooled to −10° C., added with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.1 g, 110 mmol), and then stirred at −10° C. for one hour and further at room temperature for 20 hours. After the solvent was evaporated under reduced pressure, the reaction mixture was added with ethyl acetate (100 ml), and washed with 1N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate. The solvent was concentrated under reduced pressure to obtain an oily product, which was purified by silica gel column chromatography (benzene: ethyl acetate=10:1 (v/v)) to obtain 42.6 g of Z-Phe-MeβAla-O-t-Bu as a colorless oily product.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:19]([NH:18][CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:33])=[CH:23][CH:24]=1)=[O:30]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](C=O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OC[C@H](C)N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@H](C)NC[C@@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Preparation 29, but using 1.5 g of (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 26), 1.1 g of methyl 4-[2(S)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 28), 10 ml of absolute methanol and 950 mg of sodium cyanoborohydride, the title compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:4]=[N:3][CH:2]=1.O.NN>C(O)C>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:4]=[N:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCc1cncnc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCc1cncnc1
Yield: 89.3 %

Procedure:
A solution of 23.2 g of 2-[6-(5-pyrimidinyl)hexyl]-1H-isoindole-1,3-(2H)-dione and 14.6 ml of hydrazine hydrate in 320 ml of ethanol was heated to reflux for 3 hours. The cooled mixture was filtered and the filtrate was concentrated and dissolved in dichloromethne. The solution was washed with 5% sodium hydroxide, dried and evaporated to an oil which was evaportively distilled to yield 12.0 g (90%) of 5-pyrimidinehexanamine, bp 120°-128° C./0.6 mm.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[CH2:11][O:12]C(C)=O>C(OCC)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:11]=[O:12])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(C)=O
Solvent: CCOC=O
Product: O=CNCc1ccc(F)cc1
Yield: 71 %

Procedure:
A solution of 4-fluorobenzylamine (20 g, 160 mmol) in ethyl formate was heated at reflux for 4 h. After cooling, the solvent was evaporated to afford a yellow solid. Trituration with cold EtOAc afforded the title compound as a white solid (17.46 g, 71%). 1H NMR (CDCl3): □8.24 (s, 1H), 7.25 (m, 2H), 7.00 (m, 2H), 5.91 (br s, 1H), 4.42 (d, 2H).