Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2ccccc2C1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution of methyl chloroformate (15.45 mL, 200 mmol) in CH2Cl2 (50 mL) was added to a solution of 1,2,3,4-tetrahydroisoquinoline (13.3 g, 100 mmol) and triethylamine (57 mL, 400 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction mixture was stirred for 3 hours then was quenched with water. The organic layer was separated and washed with water (2×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title compound (19.1 g). The crude material thus obtained was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.CS(C)=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(I)c(Cl)cn2)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
A mixture of 5-chloro-2-fluoro-4-iodopyridine (517 mg, 2.008 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (603 mg, 3.01 mmol), DMSO (2 ml) and TEA (0.420 ml, 3.01 mmol) reaction mixture was stirred at 90° C. for 18 hours. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3×), saturated salt solution (1×), dried sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 40 g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 585 mg of the title compound as free base. LCMS (m/z): 438.1 (MH+), retention time=1.00 min.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[H-].[Na+].CS(C)=O>CO>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:2]([CH3:1])([CH2:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:3])=[CH:10][CH:11]=2)[C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)CC(C)(C)c1ccc(Nc2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)CC(C)(C)c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
First, 76.20 mmol of Bis-(4-(2,4,4-trimethylpentan-2-yl)phenyl)amine, 91.45 mmol of 4-Fluoronitrobenzene, 114.31 mmol of sodium hydride, 2.74 g of NaH, and 120 ml of dimethyl sulfoxide (DMSO) were added into a bottle. After stirring at 120° C. for 48 hrs, the reaction mixture was cooled and then poured into 1 L of methanol. The yellow precipitate was collected by filtration and dried under vacuum. The product was purified by silica gel column chromatography (dichloromethane:n-hexane=1:3) and recrystallized from ethyl acetate to afford 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline as a yellow crystal with a yield of 60%. The 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline had a melt point of 167° C. The synthesis pathway was as follows:
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[C:24](O)=[O:25]>>[NH2:12][C:11]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:10]=1[NH:13][C:24]([CH:18]1[CH2:19][CH:20]2[CH2:23][CH:17]1[CH2:22][CH2:21]2)=[O:25]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C1CC2CCC1C2
Product: CCCn1c(N)c(NC(=O)C2CC3CCC2C3)c(=O)n(CCC)c1=O
Yield: 93 %

Procedure:
The substantially same operations as in Example 1 were repeated using 3.0 g (13.3 mmol) of 1,3-dipropyl-5,6-diaminouracil and 2.61 g (18.6 mmol) of bicyclo[2.2.1]heptane-2-carboxylic acid to afford 4.31 g (yield: 93%) of amorphous 6-amino-5-(bicyclo[2.2.1]heptan-2-yl)carbonylamino-1,3-dipropyluracil.
Reaction SMILES: [CH:1]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH2:3][C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=12.C([BH3-])#N.[Na+].[C:21](O)(=O)[CH3:22]>>[CH2:21]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C@H:4]2[CH2:3][C:2]3[C:13]([C@@H:5]12)=[CH:14][CH:15]=[CH:16][CH:1]=3)[CH3:22]
Reactant: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1c2ccccc2[C@H]2Cc3ccccc3[C@H]21
Reaction time: 3 h

Procedure:
5,10-Dihydroindeno[1,2-b]indole (60.0 g, 0.29M) was vigorously stirred in glacial acetic acid (1000 cm3) and to it was added sodium cyanoborohydride (79 g, 1.25M) portion-wise over 40 minutes. After 3 hours stirring the reaction mixture was poured onto ice-water (2000 cm3) and the gelatinous solid which formed was separated and stirred with a mixture of ethyl acetate (75 cm3) and water (100 cm3). A colourless solid remained this was found to be unreacted starting material (19.0 g). The original filtrate was extracted with ethyl acetate (2×75 cm3) and the combined organic phases dried and evaporated. The residue was then partly dissolved in a mixture of 60°-80° C. petroleum ether (20 cm3) and ethyl acetate (40 cm3). The residual solid was removed and shown to be impure starting material (2.5 g). The filtrate was extracted with 2M hydrochloric acid (8×25 cm3) and the combined acid extracts were washed with ethyl acetate (2×15 cm3), prior to basification with 0.89 ammonia. The oil which separated was extracted into ethyl acetate (6×25 cm3) and the combined organic layers were then dried and evaporated to give the title compound as a colourless oil. Yield: 34 g, 75%. 1H NMR (CDCl3) δ: 1.20 (3H, t, J=7.0 Hz), 3.05 (1H, dd, J=16.5 and 5.0 Hz), 3.38 (2H, q, J=7.0 Hz), 3.40 (1, dd, J=16.5 and 9.0 Hz), 4.12 (1H, ddd, J=9.0, 5.0 and 5.0 Hz), 5.11 (1H, d, J=9.0 Hz), 6.33 (1H, d, J=7.0 Hz), 6.57 (1H, dt, J=7.5 and 1.0 Hz), 7.02 (1H, t, J=8.0 Hz ), 7.08 (1H, d, J=8.0 Hz), 7.14-7.20 (3H, m), 7.34-7.40 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:19][CH2:20][CH3:21].C(O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: COc1cccc(C2CCCCC2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCC1(c2cccc(OC)c2)CCCCC1=O
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 2-(3-methoxy-phenyl)-cyclohexanone (2.04 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was added over 10 min to a mixture of sodium hydride (0.29 g, 12.0 mmol) in N,N-dimethylformamide (4 mL), the temperature being kept below 30° C. The reaction mixture was stirred at 20-25° C. for 2 h. A solution of 1-iodo-propane (1.17 mL, 12.0 mmol) in N,N-dimethylformamide (2 mL) was added over 10 min at 20-25° C. The mixture was stirred for 18 h, and then, ethanol (2 mL) was slowly added. The mixture was stirred for 0.5 h and then poured onto ice-water. The mixture was extracted with dichloromethane. The organic layer was separated, washed with water, and dried over sodium sulfate. Solvents were removed under reduced pressure and the remaining oil was purified by column chromatography on silica gel using heptane/diethyl ether (4:1, v/v) as eluent to give the title compound (0.74 g, ca. 30%) as pale-yellow oil. MS ISP (m/e): 247.3 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]3[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=3[Cl:32])=[O:26])[CH2:20][CH2:19]2)[S:13][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([OH:3])=O.Cl.O1CCOCC1>>[Cl:32][C:31]1[C:30]([Cl:33])=[C:29]([CH3:34])[NH:28][C:27]=1[C:25]([NH:24][CH:21]1[CH2:22][CH2:23][N:18]([C:12]2[S:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]([CH2:9][N:8]3[C:6](=[O:7])[C:5]4[C:4](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:1]3=[O:3])[N:11]=2)[CH2:19][CH2:20]1)=[O:26]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNC(=O)c4ccccc4C(=O)O)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CN4C(=O)c5ccccc5C4=O)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Yield: 32.4 %

Procedure:
4-{[(2-Carboxybenzoyl)amino]methyl}-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 244; 100 mg; 0.17 mmol) was stirred with 4 N HCl/Dioxane (3 ml) at room temperature for 8 h. The mixture was concentrated in vacuo and the resulting solid was purified by reversed phase HPLC eluting with water/acetonitrile/ammonium acetate buffer mixtures giving the title compound (31 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=3)[CH2:33][CH2:32]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:30]=[CH:29][C:14]([CH2:15][N:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:31]2[CH2:32][CH2:33][N:34]([CH2:37][C:38]3[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=3)[CH2:35][CH2:36]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:30]=[CH:29][C:14]([CH2:15][N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCNCC5)cc4)nc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
tert-Butyl 4-(4-(6-bromo-7-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (0.028 g, 0.043 mmol) was suspended in DCM (2.3 mL) and the mixture cooled in an ice bath. TFA (0.56 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The mixture was passed through an SCX column (2 g), the filtrate collected and the solvent removed in vacuo to give the title compound as a off-white solid (0.021 g, 89%); 1H-NMR (500 Mz, DMSO-d6): 2.27-2.36 (m, 4H), 2.55-2.62 (m, 4H), 2.72 (t, J=4.8 Hz, 4H), 3.50 (s, 2H, NCH2), 3.54 (s, 2H, NCH2), 3.61-3.66 (m, 4H), 3.68 (s, 3H, imidazole Me), 6.80 (s, 1H, imidazole 4-H), 7.45 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.14 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 1.66 min—550/552 [(M+H)+], Br isotopic pattern]; ESI-HRMS: Found: 550.2044, calculated for C26H33BrN9 (M+H)+: 550.2042.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][NH2:26])[CH3:24]>C(O)C>[CH2:23]([O:25][N:26]=[C:1]([C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:24]
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Reactant: CCON
Solvent: CCO
Product: CCCC(=NOCC)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of ethanol was dissolved 1.6 g of 2-butyryl-3-hydroxy-5-(4-methylsulfinylphenyl)-2-cyclohexen-1-one and to the solution was added 0.5 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with methanol. Thus, 1.3 g of colorless objective crystals having a melting point of 72°-74° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:33][C:34]([CH3:39])([CH3:40])[C:35]([O:37][CH3:38])=[O:36])=[CH:41][CH:42]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
Methyl 3-[N-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (3.77 g, 6.27 mmol) from Step D of Example 1, was dissolved in 75 mL of dry CH2Cl2 and the solution was charged with 6.27 g (47.0 mmol) of AlCl3 and the mixture was stirred at RT, under Ar, for 1.75 hours. The reaction was then quenched by the addition of 0.5N Na, K tartrate (150 mL) and the resulting mixture was extracted with EtOAc (3×). The organic extracts were washed with 0.5N Na, K tartrate (1×) and with brine (1×), and dried (MgSO4). Filtration and removal of solvents provided a brown oily residue which was chromatographed on silica gel using EtOAc-hexane (1:3) to give the title compound.
Reaction SMILES: [Br:1][C:2]1([Br:15])[C:13](=[O:14])[N:4]2[C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[Br:15][C:2]1([Br:1])[C:13](=[O:14])[N:4]2[CH:5]([C:10]([O:12][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12
Reactant: BrCc1ccccc1
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)C1C(=O)OCc1ccccc1
Yield: 85 %

Procedure:
To a stirred solution of 1646 g. of 6,6-dibromo-2,2-dimethyl-(5R)penam-3α-carboxylic acid in 10.1 liters of N,N-dimethylacetamide was added 709 ml. of triethylamine during 10 minutes at ca. 0° C. The temperature was adjusted to 10° C., and 602 ml. of benzyl bromide was added during 4 minutes. To the reaction mixture was then added 941 g. of 4A molecular sieves, and then the reaction mixture was stirred overnight without external cooling. At this point, the reaction mixture was filtered and the filtrate was added to a mixture of 44 liters of ice-water and 14 liters of ethyl acetate. The pH of the aqueous phase was adjusted to 2.0 using 6 N hydrochloric acid, and the layers were separated. The aqueous layer was extracted with further ethyl acetate and the combined ethyl acetate solutions were washed sequentially with 14 liters of saturated, aqueous sodium bicarbonate and 14 liters of saturated, aqueous sodium chloride. The ethyl acetate solution was dried (Na2SO4), and then it was evaporated in vacuo at 25° C. The residue was dissolved in 5.5 liters of isopropyl alcohol at 60° C., and then the isopropyl alcohol solution was cooled slowly with stirring. The solid which precipitated was recovered by filtration, washed with cold isopropyl alcohol and then air dried. This afforded 1777 g. (85% yield) of the title product. The NMR spectrum (CDCl3) showed absorptions at 1.40 (s, 3H), 1.55 (s, 3H), 4.55 (s, 1H), 5.20 (s, 2H), 5.75 (s, 1H) and 7.35 (s, 5H) ppm.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:13]
Reactant: CCCCCCC=O
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(Cl)CC(O)CCCCCC

Procedure:
58.30 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 30.00 g of heptanal, 90 g of toluene, 120 g of 5% acetic acid and 34.35 g of zinc powder at 45° C., and then the mixture was allowed to react at the same time temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution an dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 46.31 g of 2-chloroallyl-n-hexylcarbinol. The yield thereof was 92.4%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][C:23]([F:26])([F:25])[F:24])[CH:16]=1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[CH:16][C:17]=1[O:22][C:23]([F:24])([F:26])[F:25]
Reactant: FC(F)(F)Oc1cc(CBr)ccc1Cl
Reactant: O=C(O)CCc1cccc(O)c1
Product: O=C(O)CCc1cccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)c1

Procedure:
Compound 37.3 was synthesized using the alkylation and hydrolysis procedure of Example 13 above using compounds 37.1 and 37.2. 3-(3-Hydroxyphenyl)propanoic acid is available from Alfa Aesar Avocado, and Lancaster). 4-(Bromomethyl)-1-chloro-2-(trifluoromethoxy)benzene is available from Alfa Aesar, Lancaster, and Avocado. MS ESI (neg.) m/e: 373 (M−H).
Reaction SMILES: C1O[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]#[N:19])[CH2:7][CH2:6]2)[O:4]C1C.Cl>CCOCC>[C:18]([C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)#[N:19]
Reactant: Cc1ccc(N2CCC3(CC2)OCC(C)O3)c(C#N)c1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(N2CCC(=O)CC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 29 (549 mg, 2.00 mmol) in ether (20 mL) was treated with 3N aqueous HCl (25 mL). The mixture was stirred at room temperature (24 h). The solvent was removed in vacuo and the residue dissolved in 6N HCl (25 mL) and acetic acid (10 mL). The mixture was stirred at room temperature (3 h). The reaction mixture was neutralized with sodium carbonate solution and the aqueous layer was extracted with three portions of ether. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (30).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CCCCCN1C(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Under a stream of nitrogen, 200 g of ε-caprolactam are introduced into a 1 l four-necked flask fitted with stirrer and thermometer and melted. 226 g of N,N-diisopropyl-N-ethylamine (Hunig base) and 250 g of benzoyl chloride are then added dropwise simultaneously over the course of 2 hours, with stirring. The temperature is maintained initially at 90° C.and then increased further to 110° C. When the reaction is complete, the melt, at 80° C., is introduced into 350 ml of water at room temperature and stirred. After one hour, the precipitated benzoylcaprolactam is filtered off and dried. The N-benzoylcaprolactam is obtained in a yield of 95% and a purity of >99% by GC. The Hunig base is worked up as in Example 1. The precipitated N,N-diisopropyl-N-ethylamine (water content: 0.13%) can again be reused without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]1([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of ethyl 3-aminobenzoate (0.200 g; 1.21 mmol), benzeneboronic acid (0.295 g; 2.42 mmol), copper acetate (0.439 g; 2.42 mmol) and pyridine (0.196 mL; 2.42 mmol) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 35% ethyl acetate in heptane) to yield 0.255 g (87%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:5].C=O.[CH2:30](O)C>[OH-].[Na+].O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:1][CH2:30]3)[CH2:14][CH2:13]2)=[O:23])=[CH:21][CH:20]=1
Reactant: Nc1ccccc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CCO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2CNc3ccccc3C2=O)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 6.5 parts of 2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 0.5 parts of paraformaldehyde, 3 drops of sodium hydroxide solution 50%, 80 parts of ethanol and 10 parts of water is stirred and refluxed overnight. The reaction mixture is allowed to cool to room temperature while stirring. The precipitated product is filtered off, washed with ethanol and crystallized from 200 parts of ethanol, yielding 3.3 parts (50%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-4(1H)-quinazolinone; mp. 203.4° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:13][CH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(Cl)c(Cl)c1
Product: ClCc1cnc(Cl)c(Cl)c1

Procedure:
2,3-Dichloro-5-hydroxymethyl-pyridine is reacted in a known manner with thionyl chloride to give 5-chloromethyl-2,3-dichloro-pyridine and the latter is reacted with sodium cyanide, without additional purification (for example analogously to L. A. Carlson et al., Acta Pharm. Suecica 9, 411 (1972)). 5,6-Dichloro-pyridine-3-acetonitrile, thus obtained, melts at 72°-75° C. after recrystallisation from ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][N:12]([CH3:13])[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1cc(Br)ccc1OCc1ccccc1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)N(C)Cc1cc(Br)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 6 g (19.6 mmol) of N-(2-benzyloxy-5-bromo benzyl)-N-methylamine with 3.4 ml (19.6 mmol) of octanoyl chloride, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 8 g (95%) of the expected product are obtained in the form of a colorless oil.