Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.C[Si](C)(C)Cl.[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1.[CH:16]1([S:22]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CCCCC>[CH:16]1([S:22][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClSC1CCCCC1
Reactant: c1ccc2[nH]cnc2c1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)ncn2SC1CCCCC1
Reaction time: 10 h
Yield: 85.2 %

Procedure:
NH3 gas was passed into 80.4 g of trimethylchlorosilane in 500 ml of dry toluene at 50° to 60° C. to saturation. 59.1 g of benzimidazole were then added and the mixture was boiled for 10 hours under reflux. To remove excess ammonia, 250 ml of toluene were distilled off in vacuo, and 0.5 mol of cyclohexylsulphenyl chloride in 500 ml of pentane was then added dropwise. The mixture was subsequently stirred for 4 hours and filtered, and the solvent was removed in vacuo. 99 g of 1-cyclohexylthiobenzimidazole were obtained as a red-brown oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][C:17]=1[OH:32]>C1COCC1>[F:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[CH:21][NH:22]2)=[CH:18][C:17]=1[O:32][S:11]([C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1[F:3])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CN1CCC(c2c[nH]c3cc(F)c(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3cc(F)c(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Yield: 27.7 %

Procedure:
By a method similar to Example 31, using 0.2N sodium hydroxide (2.4 mmol, 12.2 mL), 2,6-difluorobenzenesulfonyl chloride (2.9 mmol, 0.625 g), 6-fluoro-3-(1-methylpiperidin-4-yl)-1H-indole-5-ol (2.4 mmol, 0.608 g) in THF (7.7 mL). The crude isolated product was subjected to normal phase silica gel radial chromatography, 4 mm plate eluting with 9:1 methylene chloride:2M ammonia in methanol at 10 mL/minute. Fractions containing product combined, concentrated in vacuo to a white solid. The title compound was crystallized from methylene chloride to afford 0.282 g (27%) of the title compound: mp=202° C.; Mass spectrum (ion spray): m/z=425 (M+1); 1H NMR (DMSOd6): 11.10 (s, 1H), 7.91 (m, 1H), 7.40 (m, 2H), 7.26-7.16 (m, 3H), 2.78 (m, 2H), 2.52 (m, 1H), 2.20 (s, 3H), 1.96 (m, 2H), 1.69 (m, 2H), 1.51 (m, 2H); Calculated for C20H19F3N2O3S: C, 56.12; H, 4.57; N, 6.54. Found: C, 56.13; H, 4.56; N, 6.48.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>CN(C1C=CN=CC=1)C.C(#N)C>[OH:26][C:25]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cccc2nc(O)n(C3CCC(=O)NC3=O)c(=O)c12
Yield: 81.5 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (1.00 g, 3.8 mmol), CDI (0.62 g, 3.8 mmol) and DMAP (0.10 g, 0.82 mmol) in acetonitrile (12 mL) was heated at 150° C. in a microwave oven for 10 minutes. The suspension was filtered and washed with acetonitrile (2×20 mL), water (2×20 mL), HCl (1N, 25 mL), water (25 mL), methanol (2×20 mL), and ethyl acetate (2×20 mL) to give 3-(2-hydroxy-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (0.89 g, 81% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 5.72 min (99%); mp: 373-375° C.; 1H NMR (DMSO-d6) δ 1.90-1.97 (m, 1H, CHH), 2.49-2.58 (m, 2H, CH2), 2.61 (s, 1.5H, CH3), 2.69 (s, 1.5H, CH3), 2.81-2.92 (m, 1H, CHH), 5.55 (dd, J=5, 11 Hz, 0.5H, NCH), 5.72 (dd, J=5, 11 Hz, 0.5H, NCH), 6.99-7.08 (m, 2H, Ar), 7.50-7.55 (m, 1H, Ar), 10.92 (s, 0.5H, OH), 11.42 (s, 0.5H, NH), 11.56 (s, 0.5H, NH) (observed at 350K); 13C NMR (DMSO-d6) δ 20.90, 21.38, 22.11, 22.41, 30.72, 30.77, 49.74, 50.99, 111.52, 112.15, 113.38, 125.67, 134.26, 134.34, 140.29, 140.63, 141.09, 141.45, 148.77, 149.99, 161.60, 162.39, 170.00, 170.38, 172.74; LCMS: MH=288; Anal. Calcd. for C14H13N3O4: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.40; H, 4.32; N, 14.59.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:8]2[C@@H:3]1[CH2:4][C:5]1[C:6]3[C:19]([NH:20][CH:21]=1)=[CH:18][CH:17]=[CH:16][C:7]=32.[Br:22]C1CC(=O)NC1=O>C(Cl)(Cl)Cl>[Br:22][C:21]1[NH:20][C:19]2[C:6]3[C:5]=1[CH2:4][C@H:3]1[C@H:8]([C:7]=3[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][N:2]1[CH3:1]
Reactant: CN1Cc2ccccc2[C@H]2c3cccc4[nH]cc(c34)C[C@@H]21
Reactant: O=C1CC(Br)C(=O)N1
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2[C@H]2c3cccc4[nH]c(Br)c(c34)C[C@@H]21

Procedure:
4 g of trans-4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridine are suspended in 300 ml of chloroform, and the stirred suspension is heated to reflux temperature. A solution of 2.7 g of bromosuccinimide in 100 ml of chloroform is quickly added, and the clear reaction solution is then refluxed for a further hour. The cooled reaction solution is extracted with 1n aqueous sodium carbonate solution, the organic phases dried, concentrated and the evaporation residue chromatographed on silica gel with methylene chloride/methanol=95/5 (methylene chloride 10% saturated with NH3). The title compound is obtained. Its bis[base]fumarate is cryst allised from methanol (m.p. 235°-237°).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11][CH:12]([CH2:18][Br:19])[C:13]([N:15]=[C:16]=[O:17])=[O:14]>C(#N)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16]([NH:15][C:13](=[O:14])[CH:12]([Br:11])[CH2:18][Br:19])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C=NC(=O)C(Br)CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(NC(=O)C(Br)CBr)Nc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
14.0 g of 4-nitroaniline are dissolved in 200 ml of anhydrous acetonitrile, and 26.0 g of 2,3-dibromopropionyl isocyanate are added dropwise with cooling at 5° to 10° C. After stirring for 3 hours at 20° C., the solid precipitated is filtered off and dried. Yield: 35.0 g m.p.: 205° - 206° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=O)=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:6]2[CH2:5][CH2:4][C:3]3[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]2)=[CH:14][CH:13]=1
Reactant: Nc1cccc2c1CCNC2
Reactant: O=Cc1ccnc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
1,2,3,4-tetrahydro-5-aminoisoquinoline (500 mg, 3.37 mmol) was dissolved in tetrahydrofuran (15 mL) then added 4-quinolinecarboxaldehyde (556 mg, 3.54 mmol) and sodium triacetoxyborohydride (786 mg, 3.71 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate then concentrated under vacuum. The remaining residue was dissolved in ethyl acetate then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude material was purified by silica gel chromatography (50% to 80% ethyl acetate/hexane) to afford 2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine (805 mg) as a yellow solid. MS (ESI, pos. ion) m/z: 290.1 (M+1).
Reaction SMILES: [C:1](=[S:11])([S:3][CH2:4][CH2:5][C:6]([F:10])=[C:7]([F:9])[F:8])[NH2:2].Cl.Cl[CH2:14][CH:15]=O>O1CCOCC1>[F:10][C:6](=[C:7]([F:9])[F:8])[CH2:5][CH2:4][S:3][C:1]1[S:11][CH:14]=[CH:15][N:2]=1
Reactant: NC(=S)SCCC(F)=C(F)F
Reactant: O=CCCl
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)=C(F)CCSc1nccs1
Reaction time: 4 h

Procedure:
15.1 g (64.8 mmol; purity 86.3%) of 3,4,4-trifluoro-3-butenyl dithiocarbamate in 100 ml of dioxane are admixed with 0.2 ml of conc. hydrochloric acid and 12.4 g (71.2 mmol) of 45% aqueous chloroacetaldehyde solution. The mixture is boiled for 4 h under argon, and another 1 ml of chloroacetaldehyde solution is added after 2 h. The mixture is then concentrated by evaporation under reduced pressure, the residue taken up in dichloromethane and washed with water, and the organic phase concentrated by evaporation under reduced pressure after drying over MgSO4. 16 g (94.4% of theory; purity by GC/MS: 86.1 area %) of an oil are obtained, which may be distilled at 0.4 T/86° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[Cl:11][C:9]1[CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:6]=[N:7][C:8]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C1CCNC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCCC2)c(Cl)c1
Temperature: 130 °C
Yield: 91.2 %

Procedure:
A mixture of 5,6-dichloronicotinic acid ethyl ester (1.00 g, 4.57 mmol), pyrrolidine (325 mg, 4.57 mmol), potassium carbonate (632 mg, 4.57 mmol) and copper powder (34 mg) in DMF (6.8 mL) was heated at 130° C. in the microwave for 20 min. Further pyrrolidine (163 mg, 2.29 mmol) was added and the reaction heated at 130° C. for 20 min. Water (7 mL) was added and the mixture extracted with ethyl acetate (2×14 mL). The combined organic extracts were washed with water (7 mL) and brine (7 mL) before being dried (phase separator) and concentrated in vacuo to give the title compound as an orange oil (1.06 g, 4.17 mmol). δH (methanol-d4, 400 MHz): 8.45 (1H, d), 7.98 (1H, d), 4.31 (2H, q), 3.82-3.75 (4H, m), 2.0-1.93 (4H, m), 1.36 (3H, t) ppm. MS (ES): C12H15ClN2O2 requires 254, 256; found 255, 257 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[F:32][C:33]([F:42])([F:41])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:37][CH2:36][N:35]([CH2:34][C:33]([F:41])([F:42])[F:32])[CH2:40][CH2:39]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: FC(F)(F)CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCN(CC(F)(F)F)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2,2,2-trifluoro-ethyl)piperazine following General Procedure C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-chlorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11ClN4, 296. Found, 295, 297.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39]Br)[C:33]=2[N:32]=[CH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>CC#N>[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39][N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH2:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[C:33]=2[N:32]=[CH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1cccc2c1ncn2C(=O)OC(C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure A: Reaction of 4-[(3-Methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester in dry CH3CN with 4-Bromomethyl-benzoimidazole-1-carboxylic acid tert-butyl ester, DIPEA and KI gave 4-{[(1-tert-Butoxycarbonyl-piperidin-4-yl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a white foam. Deprotection with TFA using General Procedure F gave (1H-Benzoimidazol-4-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=13)[C:8]([CH2:17][CH3:18])=[C:7]2[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:3])[CH3:2].B(Br)(Br)Br.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl.ClCCl.CO>[C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=13)[C:8]([CH2:17][CH3:18])=[C:7]2[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(C(C)=O)c3cc(OC)cc1n32
Agent: BrB(Br)Br
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: CCc1c(-c2ccc(O)cc2)c2cc(C(C)=O)c3cc(OC)cc1n32
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A solution of 4-acetyl-1-ethyl-6-methoxy-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.3 g, 0.85 mmol) in 7 ml of dry dichloromethane was cooled to -65° C. and stirred in a nitrogen atmosphere while 1.2 ml of a 1 M boron tribromide solution in dichloromethane was added. Stirring was continued for one hour and the cooling source was removed. The reaction mixture was allowed to reach room temperature and then poured into a stirred medium of dichloromethane (100 ml) and a saturated sodium hydrogen carbonate solution (100 ml). The usual work up afforded 200 mg of a substance which was submitted to column chromatography (aluminium oxide) with dichloromethane/methanol (20:1) as eluent. The fractions having RF 0.4 (silica gel 60, dichloromethane/methanol (20:1)) was collected and evaporated to afford 160 mg (58%) of the title compound. M.p. 245-46° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.37 (t, 3H), 2.62 (s, 3H), 3.13 (q, 2H), 4.07 (s, 3H), 7.00 (d, 2H), 7.70 (d, 2H), 7.79 (d, 1H), 7.87 (d, 1H), 8.12 (s, 1H), 9.87 (s, 1H). (Compound 7).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:32])[CH2:22][N:23](C(OC(C)(C)C)=O)[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:32])[CH2:22][NH:23][CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.7 %

Procedure:
N-tert-Butoxycarbonyl-N-methyl-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (2.19 g; 4.99 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 2.5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a white solid. CIMS: MH− 339
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH:9]=1.S(OC)(OC)(=O)=O.Cl>CN(C)C=O>[CH3:1][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
Potassium carbonate (1.244 g) was added to a solution of commercially available 2,6-dihydroxynaphthalene (961 mg) in N,N-dimethylformamide (100 ml), and the admixture was stirred at room temperature for 30 minutes. Dimethyl sulfate (1.14 ml) was slowly added dropwise to the mixture and the resulting mixture was further stirred at room temperature overnight. The reaction mixture thus prepared was neutralized with a 2N HCl solution and then partitioned between water and ethyl acetate, and the ethyl acetate layer was dried with anhydrous magnesium sulfate. After removing the solvent by distillation under reduced pressure, the resulting residue was purified by column chromatography on silica gel (eluting with chloroform/ethyl acetate) to obtain 307 mg of the title compound (yield: 29%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:5]([O:4][CH2:3][CH2:2][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOCCOc1ccc(C=O)cc1
Yield: 64 %

Procedure:
Nine grams (0.05 mole) of 1-bromo-2-butoxy-ethane and 6.1 grams (0.05 mole) of 4-hydroxybenzaldehyde were dissolved in 75 mls. of acetonitrile. Into the mixture were added 13.8 grams (0.1 mole) of finely ground potassium carbonate and the resulting reaction mixture was stirred under reflux for ten hours. The reaction mixture was allowed to cool, was filtered, washed with acetonitrile and evaporated to an amber oily product. The product was passed through a silica gel chromatographic column for recovery of a colorless oil (64% yield) having the following structure: ##STR20##
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH3:6])C)[CH3:3].[ClH:7].[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12]CC>>[ClH:7].[CH3:1][NH+:2]([CH2:4][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3]
Reactant: CC(C)N(C)C
Reactant: CCCCCCC
Agent: Cl
Product: C[NH+](C)Cc1ccccc1

Procedure:
6 g of N,N-dimethylisopropylamine and 300 ml of heptane were placed under argon in a 500 ml three-necked flask fitted with internal thermometer and gas inlet stopcock. HCl gas from a gas generation apparatus was passed into this reaction mixture for 1 hour. The N,N-dimethylbenzylammonium hydrochloride formed was separated off via a G4 frit, washed with 100 ml of heptane and dried in an oil pump vacuum. 7.4 g (87%) of the desired product were isolated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][C:72]=1[C:73]1[NH:77][N:76]=[N:75][N:74]=1)[NH2:69]>C(Cl)Cl>[Cl:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])[CH:70]=[CH:71][C:72]=1[C:73]1[NH:77][N:76]=[N:75][N:74]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(-c2nnn[nH]2)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)c(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-chloro-4-(1H-tetrazol-5-yl) aniline (made below, 67 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 52 mg.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([NH2:16])[CH:12]=[CH:11][CH:10]=2>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[CH3:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([N:16]=[C:1]=[O:2])[CH:12]=[CH:11][CH:10]=2
Reactant: O=C(Cl)Cl
Reactant: Cc1cc2c(N)cccc2cn1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc2c(N=C=O)cccc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phosgene (20% in toluene, 2.9 mL, 5.5 mmol) of dichloromethane (30 mL)was cooled to 0° C. and treated dropwise with a solution of 4-dimethylaminopyridine (1.43 g, 11.7 mL) in dichloromethane (15 mL). A thick white suspension formed. A solution of 3-methyl-isoquinolin-5-ylamine (0.79 g, 5 mmol) in tetrahydrofuran (20 mL) was then added dropwise to this suspension. The reaction mixture was allowed to warm to ambient temperature and stirred overnight, the solvent was removed under reduced pressure, and the residue titurated with 50 mL of diethyl ether to give an approximately 0.1 M solution of 3-methyl-5-isocyanato-isoquinoline.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])CCC.[C:22](=[O:24])=[O:23].Cl>C(OCC)C.CCCCCC>[F:10][C:4]1[C:5]([C:22]([OH:24])=[O:23])=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=O
Reactant: Fc1cc(F)c(-c2ccccc2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1c(F)c(F)c(F)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a dry argon atmosphere, a stirred solution of 2,3,4,6-tetrafluoro-[1,1'-biphenyl] (23.0 g, 0.102 mole) in 400 ml of diethyl ether was cooled to -65°. During a 11/4 hour period 63.4 ml of a 1.6M solution of n-butyl lithium in hexane was added to the reaction mixture, which was then stirred at -65° for 23/4 hours. During a one hour period, freshly crushed dry ice (750 g) was added to the mixture. The stirred reaction mixture was then allowed to warm to room temperature. The mixture was cooled; 400 ml of 6N aqueous hydrochloric acid was added and the resultant mixture stirred vigorously for two hours. The mixture was poured into a separatory funnel, the aqueous phase separated and extracted with three 300 ml portions of diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid residue. The solid was recrystallized from toluene:n-heptane (1:1) to give 2,4,5,6 -tetrafluoro-[1,1'-biphenyl]-3-carboxylic acid (mp, 189°-190.5°).