Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+]([O-])=O.[Cl:15]Cl>>[Cl:15][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: ClCl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Product: Fc1ccc(C(F)(F)F)cc1Cl
Temperature: 320 °C

Procedure:
In a continuous process, about 8 parts per hour of 4-fluoro-3-nitrobenzotrifluoride vapors and about 15 parts per hour of chlorine gas were passed simultaneously through a vapor phase reactor maintained at a temperature of about 320° C. and the reaction product vapors were condensed and collected. The process was continued until about 40 parts of 4-fluoro-3-nitrobenzotrifluoride had been passed through the reactor, yielding about 36.3 parts of 3-chloro-4-fluorobenzotrifluoride product. The structure of the product was confirmed by spectral analysis.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Br:16])=[C:11]([O:17][CH2:18][C:19]#[N:20])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[C:25](Cl)(=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[C:8](=[CH:7][C:6]([C:5]3[S:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[C:4]=3[C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[O:17][CH2:18][C:19]#[N:20]
Reactant: CC(C)CC(=O)Cl
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)sc2ccccc12
Temperature: 25 °C
Yield: 7.1 %

Procedure:
To a 0° C. mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetonitrile (11.3 g, 32.4 mmol) in chloroform (560 mL) was added isovaleryl chloride (4.7 mL, 39 mmol) and tin (IV) chloride (5.8 mL, 49 mmol). The reaction mixture was then refluxed for 23 hours. During this time, isovaleryl chloride (12.7 mL, 103 mmol) in three portions and tin (IV) chloride (13.4 mL, 113 mmol) were added in three portions. After cooling to ambient temperature, the reaction mixture was poured into ice water. It was diluted with more chloroform, and the organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was stirred in ether and filtered. The filtrate was concentrated and purified by flash chromatography using 25–50% methylene chloride in hexane and then by HPLC using 89% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 70° C. for 50 minutes yielded {1-bromo-6-[3-(3-methyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetonitrile (1.1 g, 7.10%) as a yellow semi-solid. mass spectrum (−EI, [M−H]−) m/z 476/478. 1H NMR (500 MHz, DMSO-d6): δ8.19–8.25 (m, 2H), 8.16 (d, 1H, J=1.83 Hz), 8.04–8.07 (m, 1H), 7.91–7.94 (m, 1H), 7.78 (dd, 1H, J=8.78 Hz and 1.95 Hz), 7.69 (d, 1H, J=9.15 Hz), 7.42–7.49 (m, 2H), 5.43 (s, 2H), 2.28 (d, 2H, J=6.71 Hz), 1.93–2.00 (m, 1H), 0.64 ppm (d, 6H, J=6.71 Hz). Elemental Analysis for C25H20BrNO2S: Calcd: C, 62.77; H, 4.21; N, 2.93; Found: C, 62.79; H, 4.18; N, 2.82.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[CH:15]1(B(O)O)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.[NH4+].[Cl-]>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:15]3[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1ccn2C1CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 71.7 %

Procedure:
In a oven dried 100 ml RBF equipped, stir bar, septum and Nitrogen inlet was added methyl 6-bromo-1H-indole-4-carboxylate (0.508 g, 2.0 mmol) and 1,2-dichloroethane (7 mL). The solution was stirred for 15 min, then cyclopropylboronic acid (0.344 g, 4.00 mmol) and sodium carbonate (0.424 g, 4.00 mmol) were added. Diluted copper(II) acetate (0.363 g, 2.000 mmol) and 2,2′-bipyridine (0.312 g, 2.000 mmol) in 1,2-dichloroethane (12 mL), heated the mixture, and added the hot suspension to the reaction. The reaction was heated at 70° C. and monitored by LCMS. Stopped heating after 6 h and allowed to sit for 3 days at RT. Added to reaction saturated NH4Cl and water. Extracted with DCM (2×). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (24 g Isco silica column; gradient B: 3-25%. A: hexane. B: ethyl acetate) to give methyl 6-bromo-1-cyclopropyl-1H-indole-4-carboxylate (0.43 g, 1.433 mmol, 71.6% yield) as a yellow residue. 1H NMR (400 MHz, DMSO-d6) δppm 0.96-1.01 (m, 2H) 1.06-1.12 (m, 2H) 3.52 (dt, J=7.20, 3.47 Hz, 1H) 3.90 (s, 3H) 6.85-6.91 (m, 1H) 7.57 (d, J=3.03 Hz, 1H) 7.82 (d, J=1.77 Hz, 1H) 8.04 (d, J=1.01 Hz, 1H).
Reaction SMILES: [CH2:1]([N:13]=[C:14]=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:16]([OH:19])[CH2:17][OH:18]>O1CCCC1>[CH2:1]([NH:13][C:14](=[O:15])[O:18][CH2:17][CH2:16][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCCO
Reactant: CCCCCCCCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)OCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.2 ml dodecyl isocyanate and 2.4 ml of ethylene glycol are combined in tetrahydrofuran at room temperature and stirred overnight at room temperature. The resultant material is evaporated under reduced pressure (<30° C.), dried in vacuo, and purified by chromatography on a silica gel column using ethyl acetate as elutant. Fractions 74-94 are combined (Rf 0.75 TLC Silica gel ethyl acetate iodine detection), evaporated under reduced pressure (<30° C.) and dried in vacuo to yield 546 mg of title product.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23]>>[C:1]([NH:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[N:20]\[NH:21][C:22]([NH2:24])=[O:23])/[C:9]1=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCCN1C(=O)C(=O)c2ccccc21
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)(C)NCCN1C(=O)/C(=N/NC(N)=O)c2ccccc21
Yield: 40.3 %

Procedure:
By using 1-(2-tert-butylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 10 was carried out, and the reaction product was recrystallized from ethanol to obtain (E)-1-(2-tert-butylaminoethyl)isatin 3-semicarbazone having a melting point of 173°-176° C. (decomposition) (yield: 40.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl>C(O)C>[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCC(O)CC2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of ethanol, 1.52 g of 4-hydroxypiperidine was added, and the mixture was refluxed for 6 hours. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.00 g of the desired compound as pale yellow crystals, m.p. 259.5°-261° C. (decomp.).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:8][CH:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:25]([O-])=O)=[C:15]([CH:17]=[C:18]3[NH:22][C:21](=[O:23])[NH:20][C:19]3=O)[CH:16]=2)[O:6][C:5]1=[O:28])[CH3:3].CO.II>CN(C)C=O.[Pd]>[CH3:1][CH:2]([N:4]1[CH2:8][CH:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:25]=[C:19]4[NH:20][C:21](=[O:23])[NH:22][C:18]4=[CH:17][C:15]=3[CH:16]=2)[O:6][C:5]1=[O:28])[CH3:3]
Reactant: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)OC1=O
Agent: [Pd]
Agent: II
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)N1CC(COc2ccc3nc4[nH]c(=O)[nH]c4cc3c2)OC1=O
Reaction time: 21 h
Yield: 55.5 %

Procedure:
A solution of 5-[[5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (8.80 g, 22 mmol) in dimethylformamide (150 mL) was hydrogenated at 60 p.s.i. over 10% palladium on charcoal (0.88 g) in a low pressure hydrogenation apparatus. After 21 hours, the mixture was filtered through kieselguhr and the solvent evaporated in vacuo at about 40° C. to leave a foamy solid. Methanol (180 mL) was added, the mixture heated to reflux and iodine (5.72 g 22 mmol) added portionwise over 15 minutes. After refluxing for a further 15 minutes, the mixture was concentrated to about 50 mL and diluted with 10% sodium sulfate solution and 10% sodium carbonate solution. A grey solid was filtered off, washed with water and air dried to give (4.18 g, 54%) of product. Three further crops amounting to (3.41 g, 46%) were subsequently collected. An analytical sample was purified by dissolving 2 g in 10% hydrochloric acid in methanol. Addition of diethyl ether afforded 1,3-dihydro-7-[[3-(1-methylethyl)-2-oxo-5-oxazolidinyl]methoxy]-2H-imidazo[4,5-b]quinolin-2-one hydrochloride (1.1 g, 50%) m.p. 264°-266° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:11])[CH:6]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[Br:12][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]([OH:11])=[CH:9][CH:8]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Oc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of naphthol (12, 5.0 g, 35 mmol) in CH3CN (125 mL) at 0° C. was added N-bromosuccinimide (7.9 g, 45 mmole) in several portions. The reaction mixture was warmed to room temperature, stirred for 1 h, and concentrated. The residue was dissolved in EtOAc (500 mL) and the solution was washed with water (300 mL) and brine (300 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 4:1 hexanes/EtOAc) to afford 4-bromonaphthol (13, 5.0 g, 64%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.22-8.16 (m, 2H), 7.62-7.26 (m, 3H), 6.71 (d, J=8.0 Hz, 1H), 5.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:23])([NH2:22])[CH3:21])=[CH:15][C:14]=1[F:24].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:22][C:20]([CH3:23])([CH3:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([F:24])[CH:15]=1
Reactant: CC(C)(N)Cc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 90 °C
Reaction time: 38.5 h
Yield: 57.2 %

Procedure:
A mixture of 3-chloro-4-fluoro-1-nitrobenzene (421 mg, 2.40 mmol) and 1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-amine (484 mg, 2.40 mmol) in DMSO (10 mL) was heated at 90° C. under N2 for 3 h. The mixture was cooled to rt and stirred at rt for 38.5 h. It was then heated and stirred further at 90° C. for 81.5 h. The mixture was cooled to rt and 80 mL of water was added. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 (10 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=20:1) to give the title compound as yellow oil (490 mg, 57.2%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 76.2 %

Procedure:
Methyl 4-(2-aminoethoxy)benzoate (19.5 g) and 13.8 g of anhydrous potassium carbonate were added to 200 ml of chloroform and the mixture was stirred with cooling. p-Chlorobenzoyl chloride (17.5 g) was dropped thereinto at 10°-20° C. The mixture was stirred for 3 hours. The reaction solution was washed with water, the chloroform layer was dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and the crystals were recrystallised with ethyl acetate/n-hexane to give 25.4 g of crystals of m.p. 125°-127° C., yield 76%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]([C:15]([O:17]CC)=[O:16])[C:5]2=[O:20].[OH-].[Na+].Cl>CO>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:20]
Reactant: CCOC(=O)c1cn(C)c2nc(OC)c(I)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2c(cc1I)c(=O)c(C(=O)O)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate (3.63 g) is dissolved in MeOH (200 mL). To this is added 6N NaOH (60 mL) and the resulting mixture is stirred at room temperature for 4 h. The white suspension is poured into a seperatory funnel and the organic layer is made acidic with HCl, extracted several times with CH2Cl2 (total volume 4 L), washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to afford 3.2 g (96%) of 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid. Physical characteristics are as follows: 1H NMR (CDCl3) δ 14.62, 9.09, 8.81, 4.19, 4.05; IR (diffuse reflectance) 2497, 2350, 2338, 2086, 1990, 1720, 1716, 1628, 1525, 1482, 1464, 1448, 1385, 1278, 810, cm−1; MS (EI) m/z 360, 316, 185, 159, 158, 142, 86, 84, 63, 53, 51; Anal calcd for C11H9IN2O4: C, 36.69; H, 2.52; N, 7.78. Found: C, 36.93; H, 2.57; N, 7.77.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (231 mg, 50%).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.O1CCCC1.[F:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[C:21]([NH:29][CH3:30])[CH:20]=1>CCCCCC.O>[F:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](=[O:24])[CH2:12][C:11]2[N:7]([CH3:6])[N:8]=[N:9][N:10]=2)=[C:21]([NH:29][CH3:30])[CH:20]=1
Reactant: CNc1cc(F)ccc1C(=O)OC
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CNc1cc(F)ccc1C(=O)Cc1nnnn1C
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (50 ml of 1.6M solution) was added slowly to a stirred mixture of 1,5-dimethyltetrazole (7.84 g) and dry tetrahydrofuran (170 ml) at 0°-5° under nitrogen. The mixture was stirred at 0°-5° for 0.5 hour and then methyl 4-fluoro-2-methylaminobenzoate (4.84 g) was added in portions at 0°-5°. The mixture was stirred at room temperature for 3 hours and then poured into water (500 ml). The resulting mixture was extracted with dichloromethane (5×60 ml). The extract was dried and evaporated to give an oil which partially solidified overnight. The solid was collected by filtration, washed with toluene and dried in vacuo to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 132°-134°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)[N:7]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cc(Cl)cc(Cl)c2)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cc(Cl)cc(Cl)c3)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(3,5-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (250 mg, 0.50 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (33 mg, 1.51 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 36 hr. Water was added and the resulting precipitate was collected by filtration to afford the title compound (213 mg, 0.469 mmol, 94%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([Cl:24])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(OCC)=O)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:18]([Cl:24])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOC(=O)C=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl

Procedure:
reacting 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde with ethyl diethylphosphonoacetate in a solvent in the presence of a base to form ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate;
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:24][N:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=3)[C:22](=[O:34])[NH:21]2)=[CH:13][CH:12]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[CH3:32])[CH2:25][N:23]1[CH2:24][CH:20]([CH2:19][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:35])=[O:5])=[CH:12][CH:13]=2)[NH:21][C:22]1=[O:34]
Reactant: Cc1ccc(CN2CC(CCCc3ccc(OC(C)(C)C(=O)OC(C)(C)C)cc3)NC2=O)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CN2CC(CCCc3ccc(OC(C)(C)C(=O)O)cc3)NC2=O)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.4 %

Procedure:
A solution of 2-(4-{3-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester (0.051 g, 0.106 mmol) in CH2Cl2 (3 mL) was treated with trifluoroacetic acid (0.5 mL) and stirred at room temperature under N2 for 5 h. The solvent removed in vacuo to give crude acid that was purified by flash chromatography using 94:6 CH2Cl2:MeOH to afford 0.011 g (24%) 2-(4-{3-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy) -2-methyl-propionic acid. MS (ES+) Calc'd for C25H33N2O4 (M+1) 425. Found m/z 425 (100%). 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O-:22].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([O:22][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Agent: [Na+]
Product: COc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester [example 4.11 a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 5 ml of methanol). The mixture was stirred at room temperature for 1 hour, concentrated and the title compound purified by recrystallisation from ethyl acetate/cyclohexane. MS (m/e): 296.3 (MH+, 100%)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCCCBr)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCCC(=O)c2ccccc2)CC1
Yield: 34.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 8-bromo-1-phenyl-1-octanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 0.70 g of 4-amino-5-chloro-2-methoxy-N-((1-(8-oxo-8-phenyloctyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl.CO>[C:11]([N:9]1[CH:10]=[C:6]([CH2:5][CH2:4][CH:3]=[O:2])[N:7]=[CH:8]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C

Procedure:
3-(1-Trityl-1H-imidazol-4-yl)propionic acid methyl ester (7.75 g, 19.5 mmol), J. Org. Chem. 2000, 65, 2229-2230, is dissolved in DCM (300 mL) and cooled to −78° C. To this is added a toluene solution of DIBAL (21.0 mL, 1.5 M). After 2 h MeOH (20 mL) is added followed by saturated aqueous Rochelle salt solution (50 mL). The mixture is partitioned between DCM and saturated aqueous Rochelle salt solution. The organic phase is dried (Na2SO4) and evaporated. The crude residue is purified via flash column chromatography (MeOH/DCM 1:99→MeOH/DCM 5:95) to give the aldehyde, 3-(1-trityl-1H-imidazol-4-yl)propionaldehyde as a yellow gum (cas # 184030-88-4). 1H NMR (CDCl3) δ 9.83 (s, 1H), 7.38-7.31 (m, 10H), 7.16-7.12 (m, 6H), 6.58 (s, 1H), 2.90 (t, J=8.0 Hz, 2H), 2.83-2.79 (m, 2H).