Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (73 mg, 87%), MS (ISP) m/z=338.5 [(M+H)+], mp 243° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([CH:24]=[CH2:25])=[O:23]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:22](=[O:23])[CH:24]([CH3:25])[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: C=CC=O
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: CC1C(=O)Oc2[nH]c(-c3cc(F)ccc3F)nc2C1c1ccccc1
Reaction time: 72 h
Yield: 42 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and acrolein. After 72 h, the reaction only reached 63% conversion by 1H NMR. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 20 as an off-white solid (43 mg, 42%). Analytical data for 20: 1H NMR (500 MHz, CDCl3) δ 9.48 (br s, 1H), 7.91 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.37-7.27 (m, 3H), 7.12-7.03 (m, 3H), 7.02-6.95 (m, 1H), 4.21 (d, J=7.2 Hz, 1H), 3.36 (ap, J=7.0 Hz, 1H), 1.11 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.6, 159.1 (d, JCF=243.9 Hz), 155.4 (dd, JCF=241.1, 2.5 Hz), 149.5, 137.0, 136.5, 129.2, 128.2, 127.8, 118.5 (dd, JCF=12.6, 9.0 Hz), 117.1 (dd, JCF=25.6, 8.7 Hz), 116.6 (dd, JCF=24.8, 9.4 Hz), 114.5 (dd, JCF−1 26.9, 3.9 Hz), 110.1 (d, JCF=3.7 Hz), 41.1, 40.7, 13.4; IR (film) cm−1 3083, 3029, 2987, 1773, 1758, 1636, 1618, 1529, 1482, 1464, 1411, 1236, 1173, 1132, 1084, 1062, 919, 873, 813, 766, 737, 700; LRMS (ESI): Mass calcd for [M+H]+ C19H15F2N2O2: 341.1. found 341.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 12% IPA/hexanes 1.0 mL/min, 280 nm), Rt1 (major)=14.4, Rt2 (minor)=27.6 min; er=>99:1.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 62 mg (0.55 mmol) of 4-fluorophenol and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) of azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed twice with 2N aqueous NaOH solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 100 mg (45%) product as a white solid. MS (ISP) 445.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34]O)[CH:30]=[CH:31][C:32]=1[F:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:34][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)c(Cl)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3-chloro-4-fluorophenyl)methanol (95 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, filtered through a plug of NH silica gel, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). Then the resulting solid was recrystallized from IPA-EtOAc to give the title compound (58.4 mg) as an off-white solid.
Reaction SMILES: Cl.[CH2:2]1[O:14][C:13]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][C:9]([N:15]4[CH2:20][CH2:19][N:18]([C:21]5[N:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[CH:10]3)=[CH:5][C:4]=2[O:3]1>O1CCCC1>[CH2:2]1[O:14][C:13]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][CH:9]([N:15]4[CH2:20][CH2:19][N:18]([C:21]5[N:22]=[CH:23][CH:24]=[CH:25][N:26]=5)[CH2:17][CH2:16]4)[CH2:10]3)=[CH:5][C:4]=2[O:3]1
Reactant: C1=C(N2CCN(c3ncccn3)CC2)CCc2cc3c(cc21)OCO3
Agent: Cl
Solvent: C1CCOC1
Product: c1cnc(N2CCN(C3CCc4cc5c(cc4C3)OCO5)CC2)nc1
Yield: 62.3 %

Procedure:
There were added 2 ml of a solution 5 N of HCl in tetrahydrofuran to a solution of 3.35 g of 1-(6,7-methylenedioxy-3,4-dihydro-2-naphthyl)-4-(2-pyrimidinyl) piperazine previously obtained, in 100 ml of anhydrous tetrahydrofuran. The hydrochloride of the enamine precipitated, and there were added, to the so-obtained suspension, 10 ml of a normal solution of sodium cyanoborohydride in tetrahydrofuran. The precipitate was then immediately dissolved and the solution was decolourised. 30 minutes later, the solvent was evaporated off and the residue was taken up with a normal sodium hydroxide solution, then extracted with chloroform. The chloroformic solution was then evaporated under reduced pressure and the viscous residue was taken up with 30 ml of anhydrous ethanol. The product crystallized and there were obtained 2.1 g of 1-(6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthyl)-4-(2-pyrimidinyl) piperazine, beige crystals melting at 134°-135° C. The corresponding monomethanesulfonate melts at 218°-225° C.
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.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([NH2:75])[CH:70]=1)[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([NH:75][C:28]([C@H:9]2[C@H: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])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])[CH:70]=1)[CH3:66]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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: CCOC(=O)c1cccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 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, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-aminobenzoic acid ethyl ester (Aldrich, 43 mg, 0.26 mmol). The mixture was stirred at rt overnight. 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 an ISCO machine (24 g column, eluent, 10% EtOAc/methylene chloride) to give a white solid. 55 mg.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:46])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:40]1([CH2:39][CH2:38][C:37]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)=[O:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.125 g, 0.34 mmol) and triethylamine (0.18 mL, 1.36 mmol) in 2 mL methylene chloride was added hydrocinnamoyl chloride (0.152 mL, 1.02 mmol), dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 529.2 (M+1)+
Reaction SMILES: C([O:4][C:5]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[CH:17]=[CH:16][C:6]=1[C:7]([N:9]([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[O:8])(=O)C.[OH-].[Na+]>C(O)C>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:6]([C:7]([N:9]([CH:13]([CH3:14])[CH3:15])[CH:10]([CH3:12])[CH3:11])=[O:8])=[C:5]([OH:4])[CH:19]=2)=[CH:32][CH:31]=1)#[N:34]
Reactant: CC(=O)Oc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2-acetoxy-4-[5-(4-cyanophenoxy)pentyloxy]-N,N-bis(1-methylethyl)benzamide (10 g, 21.5 mmol) in 250 mL of ethanol is treated with 1N sodium hydroxide solution (25 mL, 25 mmol). After stirring at room temperature for 2 hours, the reaction is concentrated in vacuo. This material is partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (200 g) with 40-50% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as a colorless foam.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([O:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])(=[O:6])[CH3:5].O>CS(C)=O>[C:4]([O:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:1]#[N:2])(=[O:6])[CH3:5]
Reactant: CC(=O)Oc1c(CBr)cccc1Oc1ccccc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Oc1c(CC#N)cccc1Oc1ccccc1Cl
Temperature: 25 °C
Yield: 101.8 %

Procedure:
Powdered sodium cyanide (3.65 g) was added to a solution of 2-chlorophenyl 2-acetoxy-3-bromomethylphenyl ether (22 g) in dimethylsulfoxide (80 ml) with stirring at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Water (200 ml) was added to the reaction mixture and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated to give oily 2-[2-acetoxy-3-(2-chlorophenoxy)phenyl]acetonitrile (19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]>>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[N:13]1([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cccc(Cl)c2C1
Reactant: C1CNCCNC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: Clc1cccc2c1CC(N1CCCNCC1)CC2

Procedure:
Employing the procedure of Example 3, 2.0 g (11.1 mmol) of 8-chloro-2-tetralone were reacted with 2.2 g (22.2 mmol) of homopiperazine, and the resulting product was reduced with sodium borohydride and the reduced product treated with maleic acid to obtain 0.13 g of the title compound as colorless crystals, m.p. 146°-148° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[N:5]1.C([O-])([O-])=O.[Na+].[Na+].Cl>>[N+:12]([C:6]1[C:7]([C:9]([NH2:11])=[O:10])=[CH:8][N:4]([CH:3]=[CH2:2])[N:5]=1)([O-:14])=[O:13]
Reactant: NC(=O)c1cn(CCBr)nc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=Cn1cc(C(N)=O)c([N+](=O)[O-])n1
Reaction time: 5 h

Procedure:
A suspension of 5 gm. of 1-(2-bromoethyl)-3-nitro-4-pyrazolecarboxamide in 100 ml. of 5 percent Na2CO3 solution was refluxed with stirring for 5 hours. The mixture was cooled in an ice bath and acidified to ph 2 with concentrated HCl. The product precipitated and was separated by filtration. The solids were washed with cold water and recrystallized from methanol-water to product 2 gm. of 3-nitro-1-vinyl-4-pyrazolecarboxamide, m.p. 150°-52° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:10][CH2:11]3)=[O:2])=[CH:29][CH:28]=1)(=[O:26])[CH3:24]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 35.8 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminoacetophenone (46.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-acetylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.4 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([N+:26]([O-])=O)=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCCC1.CO.O.[Fe]>[NH2:26][C:10]1[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][C:13]([NH:15][C:16](=[O:24])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:12]([CH3:25])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)cc1NC(=O)Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(N)c(Sc2ccc(O)cc2)cc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
The product of Example 265B (0.282 g, 0.715 mmol), iron powder (0.160 g, 2.86 mmol, 4.0 eq), and ammonium chloride (0.0469 g, 0.858 mmol, 1.2 eq) in tetrahydrofuran (6 mL), methanol (6 mL) and water (2 mL) was heated under reflux for 1.5 h and then cooled to room temperature. The reaction mixture was then filtered through Celite and the Celite pad rinsed with methanol (50 mL). The filtrate was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to provide an orange oil that was triturated with dichloromethane to provide the title compound as a yellow powder (0.246 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]1(NN)[CH:15]=CC=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]=[CH:10][C:11]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: NNc1ccc(Cl)cc1
Product: Cc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 8 with 4-chlorophenyl hydrazine · HCl substituted for phenyl hydrazine and 2-amino-5-(2-N-t-butylaminosulfonylphenyl)pyridine was used in the coupling step. There was obtained the title compound; HRMS (M+H)+ : calc. 468.089714; found 468.088873.
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([O:30][CH3:31])[CH:29]=1)[O:26][CH2:25][CH2:24][CH2:23]2)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:31][O:30][C:28]1[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=[C:22]2[C:27]=1[O:26][CH2:25][CH2:24][CH2:23]2
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCCC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 281 mg of {2-(8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanyl-ethylidene}carbamic acid methyl ester in 2 ml of DMF there were added 58 mg of 2-hydrazinopyrimidine and 130 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 8.75 ml of a methanol:acetic acid=10:1 mixed solvent. After adding 265 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.O=S(Cl)[Cl:18]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:18])=[O:15]
Reactant: O=C(O)CCCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCCCCCCCCCBr
Yield: 95 %

Procedure:
Following a general procedure for preparing 21 (Creager et al. (1994) J. Electroanal. Chem., 370: 203-211), a solution of 12-bromododecanoic acid (4.2 g, 15 mmol) in SOCl2 (50 mL) was heated at 50° C. under argon for 1 h. The excess SOCl2 was removed by water pump distillation with benzene (3×50 mL). 4.3 g (95%) of 12-bromododecanoyl chloride was obtained as a colorless oil and used in the subsequent reaction without further purification. In a 50 mL flask anhydrous AlCl3 (2.8 g, 21 mmol) was added to a stirred solution of 12-bromododecanoyl chloride (4.0 g, 13.6 mmol) in dry CH2Cl2 (30 mL) at 0° C. under argon for 20 min. Then the mixture was added dropwise over 10 min to a solution of ferrocene (2.6 g, 14 mmol) in CH2Cl2 (50 mL) at 0° C. The mixture was stirred and allowed to warm to rt. After 2 h water (30 mL) was added slowly into this mixture. Then the phases were separated, and the organic layer was washed with water (3×100 mL) and NaHCO3 (2×50 mL) and over (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:3) to afford a red oil (4.3 g, 85%). 1H NMR δ 1.28 (s, 16H), 1.64 (m, 2H), 2.63 (m, 2H), 3.29 (m, 2H), 4.19 (s, 5H), 4.48 (A2B2, J=1.5 Hz, 2H), 4.78 (A2B2, J=1.5 Hz, 2H); 13C NMR δ 25.0, 28.5, 29.0, 30.1, 30.9, 33.3, 34.5, 40.5, 70.0, 70.4, 72.9, 89.0, 205.0; FAB-MS obsd 446.0955, calcd exact mass 446.0958 (C12H31.BrFeO).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH:13][C:14]([C@H:16]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[O:15])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1>Cl>[NH2:24][C@H:16]([CH2:17][CH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:8][CH2:7][C:6]=2[CH:9]=1)=[O:15]
Reactant: CN1CCc2ccc(NC(=O)[C@@H](CCc3nnn[nH]3)NC(=O)OC(C)(C)C)cc2CC1
Agent: Cl
Product: CN1CCc2ccc(NC(=O)[C@H](N)CCc3nnn[nH]3)cc2CC1

Procedure:
49.8 mg (90 μmol) tert.butyl(R)-[1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-3-(1H-tetrazol-5-yl)-propyl]-carbamate are stirred in 1 ml of 2 molar aqueous hydrochloric acid at 50° C. for 2.5 h and then evaporated to dryness.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[NH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:31])[C:8](=[O:7])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CNCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)N(C)CCCN)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-methyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 432 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCCCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)CCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 96.8 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 4-aminobutyric acid (0.134 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.35 g (98%) 142 as very pale yellow powder: mp=176–178° C.; Rf 0.82 (A): Rf 0.83 (B): Rf 0.71 (D): IR (cm−1): 3000–3300 (OH), 3122 (C═CH), 1775 (C═O), 1707 (bs, C═O), 1617 (C═C), 1545 (N═O), 1446 (C═C), 1399 (C—O), 1349 (N═O), 1167 (C—O), 722 (C—CH); MS m/z (rel intensity) 291 (100), 191 (8).