Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC=C)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1CCOCC1>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CC#N
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of compound (15) (1 g, 2.7 mmol) in acetonitrile (10 mL) under nitrogen was added (10 mg, 0.008 mmol) of tetrakis(triphenylphosphine) palladium (0) followed by morpholine (0.28 mL, 0.28 g, 3.2 mmol). After one hour, the solvent was removed in vacuo. The resulting oil was dissolved in diethyl ether (50 mL) and the organic phase was washed with 2N HCl (20 mL), water (20 mL) and brine (20 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to give an oil, which was purified by column chromatography on silica gel, eluting with 30% ethyl acetate:hexane. The desired product (11) was isolated as a white crystalline solid (0.75 g, 84% yield), m.p 63–64° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[CH:21]=[C:20]([O:22]CC)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>Cl>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[CH2:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CCOc1cc(NCCSCc2[nH]cnc2C)nc2ccccc12
Agent: Cl
Product: Cc1nc[nH]c1CSCCNC1=Nc2ccccc2C(=O)C1

Procedure:
(found: C, 63.2; H, 6.5; N, 16.1; S, 9.1. C18H22N4OS requires: C, 63.1; H, 6.5; N, 16.4; S, 9.4) 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline (1.69 gms) and concentrated HCl (30 mls) were refluxed together for 17 hours. The solution was evaporated to dryness, the residue dissolved in water and basified with potassium carbonate. The precipitated oil was separated by decantation, washed with water and crystallised from isopropanol-water to give 2[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-quinolone. m.p. 121°-124° C.
Reaction SMILES: [Mg].Br[C:3]1[C:11]2[O:10][C:9]3[CH2:12][CH2:13][CH2:14][CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH2:15]1[C:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:16]([OH:18])=[O:17])[C:11]=3[O:10][C:9]=2[CH2:12][CH2:13][CH2:14]1
Reactant: Brc1cccc2c3c(oc12)CCCC3
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc2c3c(oc12)CCCC3
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of magnesium (345 mg) in tetrahydrofuran (5 ml) was added 6-bromo-1,2,3,4-tetrahydrodibenzofuran (3.39 g) in tetrahydrofuran (15 ml) dropwise. The mixture was refluxed for 1 hour and cooled to 4° C. Dry ice (2.7 g) was added to the mixture and the mixture was stirred at ambient temperature for 30 minutes. To the mixture was added 3.6% hydrochloric acid and chloroform. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from n-hexane to give 1,2,3,4-tetrahydrodibenzofuran-6-carboxylic acid (2.60 g).
Reaction SMILES: [SiH](Cl)(Cl)Cl.[C:5]([CH2:27]OCCC[Si](Cl)(Cl)Cl)([C:8]([C:11]([C:14]([C:17]([C:20]([C:23](F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F.[C:36](OC(=O)C)(=O)[CH3:37].[CH3:43][SiH](Cl)Cl>>[CH3:36][CH2:37][CH2:27][CH2:5][CH2:8][CH2:11][CH2:14][CH2:17][CH:20]([CH3:23])[CH3:43]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COCCC[Si](Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Reactant: C[SiH](Cl)Cl
Agent: Cl[SiH](Cl)Cl
Product: CCCCCCCCC(C)C

Procedure:
The silane C7F15CH2OCH2CH2CH2SiCl3 was prepared as described in Example 1 of U.S. Pat. No. 5,274,159 (Pellerite et al.). The silane C8F17SO2N(C2 H5)CH2CH2CH2SiCl3 was prepared by treatment of C8F17SO2N(C2H5)CH2CH=CH2 (which can be obtained as described in Example 1 of U.S. Pat. No. 3,442,664 (Heine)) with HSiCl3 (obtained from Aldrich Chemical Co., Milwaukee, Wis.) in the presence of 50-100 ppm Pt/divinyltetramethyldisiloxane as catalyst (prepared according to methods described in Example 10 of U.S. Pat. No. 3,814,730 (Karstedt)). The triacetoxysilane C7F15CH2OCH2CH2CH2 Si(OAc)3 was prepared by treating C7F15CH2OCH2CH2CH2SiCl3 with acetic anhydride, heating to distill out byproduct acetyl chloride, and vacuum distilling of the product. The silane C8F17CH2CH2SiCl3 was obtained from PCR Inc., Gainesville, Fla. The silane C7F15CH2OCH2 CH2CH2Si(CH3)Cl2 was prepared as described in Example 1 of U.S. Pat. No. 5,274,159 (Pellerite et al.) except that CH3SiHCl2 (obtained from Aldrich Chemical Co., Milwaukee, Wis.) was substituted for trichlorosilane. The silane C7F15CH2 OCH2CH2CH2Si(OEt)3 was prepared as described in Example 5 of U.S. Pat. No. 5,274,159 (Pellerite et al.), and C8 F17SO2N(Et)CH2CH2CH2Si(OMe)3 was prepared as described in Example 6 of the same document. Isoparaffinic solvents were obtained under the trade designations "ISOPAR G" and "ISOPAR L" from Exxon Chemical, Baytown, Tex. Ethyl perfluorobutyl ether and methyl perfluorobutyl ether were obtained under the trade designations "HFE 7200" and "HFE 7100," respectively, from 3M Company, St. Paul, Minn.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.CC([O-])=O.[Na+]>CCO>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][N:31]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])=[CH:26][CH:25]=1
Reactant: NOc1ccc(F)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 80.4 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (280 mg, 0.84 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (150 mg, 0.92 mmol) and anhydrous NaOAc (75 mg, 0.92 mmol) in EtOH (15 mL) was stirred for 24 hours at RT. The reaction mixture was concentrated under vacuum, the residue purified by column chromatography (eluting with CH2Cl2/PE; 1:1 to 4:1) and the solvent removed under reduced pressure. Recrystallization from CH2Cl2/PE afforded N-{2-[1-(4-fluorophenoxyimino)ethyl]-5-trifluoromethylphenyl}trifluoromethanesulfonamide 200 (300 mg, 81%), as colorless crystals. M.p. 95-96° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.48, br s, 1H; 8.01, s, 1H; 7.76, d, J=8.4 Hz, 1H; 7.55, m, 1H; 7.19-7.04, m, 4H; 2.60, s, 3H.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH:17]=[O:18])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:19])#[N:2].CC(=CC)C.Cl([O-])=[O:26].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([C:17]([OH:26])=[O:18])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: [O-][Cl+][O-]
Reactant: N#Cc1ccc(C2CCc3ncc(C=O)n32)cc1F
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C2CCc3ncc(C(=O)O)n32)cc1F
Reaction time: 16 h

Procedure:
To a solution of aldehyde from Step L (990 mg, 3.88 mmol) in tert-butanol (20 mL)/2-methyl-2-butene (2 mL) was added a solution of sodium chlorite (421 mg, 4.65 mmol) and sodium dihydrogenphosphate monohydrate (642 mg, 4.65 mmol) in H2O (4 mL). The reaction mixture was stirred for 16 hours and the precipitate filtered to yield the title product as a white solid.
Reaction SMILES: [C:1]1([C:10]#[N:11])[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=1.C([O-])(=O)C.[K+].O>CN1CCCC1=O>[C:10]([C:1]1[CH:2]=[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2)#[N:11]
Reactant: N#Cc1ccn2ccccc12
Reactant: COCOc1cc(I)ccc1C(=O)OC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COCOc1cc(-c2cc(C#N)c3ccccn23)ccc1C(=O)OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a solution of indolizine-1-carbonitrile (0.20 g) in N-methylpyrrolidone (5 mL) were added methyl 4-iodo-2-methoxymethoxybenzoate (0.5 g), dichlorobis (triphenylphosphine) palladium (II) (0.05 g), potassium acetate (0.28 g) and water (0.05 mL), and the mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-0/100) to give methyl 4-(1-cyanoindolizine-3-yl)-2-methoxymethoxybenzoate (0.17 g). To a mixed solution of the obtained compound (0.17 g) in tetrahydrofuran (4.5 mL), ethanol (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (0.10 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.5 mL), and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added water. The precipitated solid was collected by filtration, washed with water and n-hexanc, and dried under reduced pressure at 50° C. to give the title compound (0.11 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 500 mg, 1.264 mmol, (3S,4S)-pyrrolidine-3,4-diol (157 mg, 1.517 mmol), DIPEA (442 μL, 2.53 mmol) and iPrOH (1.264 mL) were added to a MW vial, which was sealed and subjected to MW irradiation at 140° C. for 30 min. The solvent was evaporated off under reduced pressure to give a residue which was treated with 0.5 M HCl (10 mL) and extracted with EtOAc. The combined extracts were washed with HCl 0.5 M and brine, diluted with MeOH (20 mL), dried over MgSO4 and the solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/MeOH afforded the title compound as a white solid. UPLC-MS (Condition 1) tR=2.48 min, m/z=462.0/464.0 [M+H]+, m/z=460.0/462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.56 (d, J=11.25 Hz, 2H) 3.94-4.06 (m, 4H) 4.79 (br. s, 2H) 7.34 (d, J=8.80 Hz, 2H) 7.88 (d, J=9.05 Hz, 2H) 8.38 (d, J=1.96 Hz, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.34 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:9]([Cl:11])=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)ccc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: N#Cc1cc(F)cc(Cl)c1N
Temperature: 80 °C
Yield: 51.2 %

Procedure:
To a solution of 2-amino-5-fluorobenzonitrile (15.0 g, 110 mmol) in anhydrous acetonitrile (300 mL) was added N-chlorosuccinimide (16.0 g, 120 mmol) portionwise. The reaction mixture was heated at 80° C. for 18 hours under nitrogen. The resultant mixture was allowed to cool, concentrated under reduced pressure and then partitioned between EtOAc and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (10-20% diethyl ether in pentane) to afford the title compound as an off-white solid (9.6 g, 51% yield). 1H NMR (300 MHz, CDCl3): δ 7.27 (dd, J=7.9, 2.9 Hz, 1H), 7.08 (dd, J=7.6, 2.9 Hz, 1H), 4.67 (br s, 2H).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:14]([CH3:16])[CH3:15]>>[CH2:18]([N:17]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CCCCCCCCCC1CO1
Reactant: CC(C)CNCCCCCCNCC(C)C
Product: CCCCCCCCCC(O)CN(CCCCCCN(CC(C)C)CC(O)CCCCCCCCC)CC(C)C

Procedure:
Condensation of 1-undecene oxide and N,N'-di(isobutyl)hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-isobutyl 2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = (CH3)2CHCH2, X = (CH2)6, Z = H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:7]([Cl:21])[C:6]=1[Cl:22])=O.[C:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[S:25])[NH2:24].N>>[Cl:22][C:6]1[C:7]([Cl:21])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]1[N:24]=[C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[S:25][CH:2]=1
Reactant: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Reactant: NC(=S)N1CCCCC1
Agent: N
Product: CC(C)c1ccccc1Sc1ccc(-c2csc(N3CCCCC3)n2)c(Cl)c1Cl

Procedure:
The title compound 42 was prepared according to the procedure of Example 11 from compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl piperidine. Yield: 21 mg, 65.6%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 1.65 (m, 6H), 3.44-3.52 (m, 5H),), 6.48 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 7.21 (m, 1H), 7.44-7.51 (m, 3H), 7.61 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 463 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(C)=O
Temperature: 85 °C
Yield: 79.1 %

Procedure:
Dissolve 5′-chloro-2′-hydroxyacetophenone (15.3594 g, 90.03 mmol) in 100 mL of anhydrous acetonitrile in a pressure vessel. Add K2CO3 (13.7541 g, 99.52 mmol) and MeI (25.56 mL, 180.06 mmol) to the vessel. Seal the vessel and heat the reaction mixture to 85° C. for 18 hours. Cool the reaction and concentrate it in vacuo. Partition the residue between Et2O and H2O. Wash the organic layers with 2N NaOH (2×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 13.15 g of 1-(5-chloro-2-methoxy-phenyl)-ethanone (79%).
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=O)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:27][NH2:28]>CO.C(O)C>[CH3:27][NH:28][C:20]([C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[CH:26][CH:25]=1)=[O:22]
Reactant: CN
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A 2M solution of sodium methoxide in methanol (0.89 ml) was added to a suspension of ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (500 mg) in a 33% solution of monomethylamine in ethanol (15 ml). The mixture was stirred at 40° C. for 18 hours. The mixture was cooled and the solid was collected by filtration. The solid was washed with ethanol and ether to give 1-(4-methylcarbamoylphenyl)-4-(4-pyridyl) piperazine (374 mg) as a cream solid, mp 239-242° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24](O)(=O)[CH2:25][CH3:26]>CN(C=O)C>[CH2:16]([O:9][C:3]1[C:2]2[NH:1][C:24]([CH2:25][CH3:26])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(O)c1N
Reactant: CCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2cccc(OCc3ccccc3)c2[nH]1
Temperature: 150 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
2,3-diaminophenol (5 g, 40.3 mmol) was dissolved in propionic acid (10 mL) and stirred at 150° C. for 3 h. The reaction mixture was cooled to room temperature and the volume reduced under high vacuum to give a brown solid which was partitioned between chloroform and a saturated solution of bicarbonate, the chloroform layer was separated, dried and concentrated to give a brown solid. The brown solid (1.3 g, 8.0 mmol) was dissolved in DMF (40 mL) and K2CO3 (2.8 g, 0.02 mmol) was added followed by benzylbromide (1.5 g, 8.8 mmol). The reaction mixture was stirred at room temperature overnight, partitioned with water and ethyl acetate, ethyl acetate layer was separated, dried (MgSO4), concentrated, and purified by flash chromatography to give 7-benzyloxy-2-ethyl-1H-benzimidazole (0.9 g, 44%). LCMS 253 (M+)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]#[N:12])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C([OH:24])C>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[C:6]2[C:5](=[CH:4][C:3]3[O:2][CH2:1][O:9][C:8]=3[CH:7]=2)[CH2:10][C:11](=[O:24])[NH:12]1
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1Cl
Reactant: CCO
Product: O=C1Cc2cc3c(cc2C(c2ccccc2Cl)N1)OCO3

Procedure:
This compound was prepared in an analogous manner to that described in DESCRIPTION 18, from 3,4-methylenedioxyphenylacetonitile and 2-chlorobenzaldehyde. m.p. 207°-9° C. (Ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)C>[Si:15]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccnc1Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.3 %

Procedure:
To a solution of 2-chloro-3-(hydroxymethyl)pyridine (Read, M. W; and Ray, P. S.; J. Heterocyclic. Chem., 1995, 32, 1595-1597., 2.81 g, 19.1 mmol) and imidazole (3.25 g, 47.7 mmol) in N,N-dimethylformamide (30 ml) was added tert-butyldimethylsilyl chloride (3.74 g, 24.8 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 17 h. The solution was diluted with diethyl ether (200 ml), and the resulting solution was washed with water (100 ml×3), and dried (MgSO4). Removal of solvent gave an oily residue. Purification by flash column chromatography eluting with ethyl acetate/hexane (1:15) afforded 3.61 g (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and i-Pr2NEt (6.67 g, 51.6 mmol) were added to the DMF solution (50 mL of 3-{(tert-butoxycarbonyl)amino}pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 ml). The reaction mixture was stirred at 70° C. for 15 hours, and the solvent was then removed under reduced pressure. The residue was recrystallized (CH3CN, 50 mL) to obtain the objective 3-{(tert-butoxycarbonyl)amino}-1-(4-chlorobenzyl)pyrrolidine (6.43 g, 80%) as the yellowish white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].O(C)S([C:42](F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.C(Cl)[Cl:57]>>[ClH:57].[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]([CH3:42])[CH:16]=[N:17][CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:9]([S:33]([CH3:36])(=[O:34])=[O:35])[CH2:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: Cn1cncc1CN1C[C@@H](Cc2ccccc2)N(S(C)(=O)=O)Cc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 200 mg (0.38 mmol) of (R)-7-cyano-2,3,4,5-tetrahydro-1-[(((1,1-dimethylethoxy)carbonyl)-1H-imidazol-4-yl)methyl]-4-(methylsuIfonyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine (prepared from Example 224 as described for Compound A of Example 225) in 2 mL of methylene chloride, at −78° C. and under argon, was added dropwise 59 μL (0.48 mmol) of methyl triflate. The reaction was allowed to warm to rt, during which time a white precipitate was obtained. Stirring was continued at rt for 3 hr, after which time 140 μL (0.8 mmol) of DIEA was added and stirring continued overnight at rt. The mixture, without workup, was subjected to flash chromatography on a 30 cc column of silica gel. Elution with 2% MeOH-CHCl3 afforded 122 mg (0.28 mmol, 74%) of a clear colorless oil which crystallized on standing. This material was converted to its hydrochloride by the addition of 0.28 mL of 1M HCl in ether to a methylene chloride solution (2 mL) of the free base. A white precipitate was obtained which on filtration afforded 90 mg of Example 235 as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:11].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[Si]([C:23]#[N:24])(C)(C)C>C(OCC)(=O)C>[CH3:1][NH:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13]2([C:23]#[N:24])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:5]=1[F:11]
Reactant: O=C1CCCC1
Reactant: C[Si](C)(C)C#N
Reactant: CNC(=O)c1ccc(N)cc1F
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(NC2(C#N)CCCC2)cc1F
Temperature: 80 °C
Reaction time: 13 h
Yield: 63.1 %

Procedure:
A mixture of N-Methyl-2-fluoro-4-aminobenzamide (Formula 39) (62 mg, 0.37 mmol), cyclopentanone (0.07 mL, 0.74 mmol) and TMSCN (0.1 mL, 0.74 mmol) was heated to 80° C. and stirred for 13 h. To the medium was added ethyl acetate (2×20 mL) and then washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5) to give N-Methyl 2-fluoro-4-(1-cyanocyclopentyl)aminobenzamide (Formula 43) (61 mg, 63%) as a white solid. 1H NMR δ 7.95 (dd, 1H, J=8.8, 8.8 Hz), 6.65 (br s, 1H), 6.59 (dd, 1H, J=8.8, 2.3 Hz), 6.50 (dd, 1H, J=14.6, 2.3 Hz), 4.60 (br s, 1H), 2.99 (dd, 3H, J=4.8, 1.1 Hz), 2.36-2.45 (m, 2H), 2.10-2.18 (m, 2H), 1.82-1.95 (m, 4H).