Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[C:28]2[C:29]3[C:21]([C:22](=O)[C:23](=O)[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=1.[OH-].[K+]>CO>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:29]3[C:28]=1[CH:27]=[CH:26][CH:25]=[C:24]3[C:23]1[C:22]2=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1C(=O)c2ccc(Br)c3cccc1c23
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(c2ccccc2)=C2C(=C1c1ccccc1)c1ccc(Br)c3cccc2c13
Temperature: 65 °C

Procedure:
1,3-Diphenylacetone (17.5 g, 83 mMole) was dissolved in methanol (240 mL) and heated to 65° C. To the solution was added 5-bromoacenaphthenequinone (2), (20 g, 75 mMole). The resulting well-stirred suspension was then treated with 1M-methanolic KOH (100 ML, 100 mMole) at a fast drip rate, whereupon the dark colored product precipitated immediately. The mixture was then stirred at 65° C. for 1 hour, cooled and filtered. The black solid was washed well with methanol, ether and dried. Yield of product (3), (31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC.[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[C:39](I)[CH:38]=[C:37]([Br:42])[CH:36]=1>[Cu]I.C(#N)C>[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[C:39]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@:10]3([CH2:9][C@@H:8]3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:11]2=[O:19])[CH:38]=[C:37]([Br:42])[CH:36]=1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: O=C1Nc2ccccc2[C@]12C[C@@H]2c1ccc(Cl)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
A Schlenk tube charged with CuI (214 mg, 1.124 mmol, 20 mmol %), (1S,2S) and (1R,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (1.50 g, 5.62 mmol) and K2CO3 (2.30 g, 16.86 mmol) was evacuated and backfilled with argon. N,N′-dimethylethylenediamine (242 μL, 2.25 mmol, 40 mol %), 3-Bromo-5-iodo-benzoic acid methyl ester (2.30 g, 6.75 mmol, 1.2 equiv.) and acetonitrile (5 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 90° C. for 3 hours. HPLC monitor the reaction finished. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 5-15% ethyl acetate in petroleum ether) to give the title compound as white powder (1.3 g, 48%). LC/MS m/e calcd. for C24H17BrClNO3: 482, observed (M+H)+: 483.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)#[N:17]>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: N#Cc1ccc(O)cc1
Product: CCCc1c(COc2ccc(C#N)cc2)ccc(C(C)=O)c1O

Procedure:
The title nitrile intermediate was prepared from 18.12 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 35.7 g. of 4-cyanophenol following the general procedure of Example 1. Crystallization from ethanol/water provided 19.0 g. of the desired intermediate, m.p. 102°-103° C.
Reaction SMILES: [OH-].[OH:2][C:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:19])[C:4]=1[NH+:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].[OH-].[K+]>C(Cl)Cl.O>[C:32]([O:2][C:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:19])[C:4]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: O=c1c([NH+]2CCCC2)c(O)c2cccnc2n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1c(N2CCCC2)c(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C

Procedure:
A mixture of 1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidinium hydroxide, inner salt (3 g) and triethylamine (1.41 g) in CH2Cl2 (50 mL) was stirred at room temperature in an atmosphere of nitrogen. Acetyl chloride (1.09 g) was added dropwise and stirring was continued for a total of about 20-24 hours. The product was poured into water (200 mL) and the pH was adjusted to 7 with 10% KOH solution. The organic layer was separated and dried (Na2SO4). The dry solution was filtered and evaporated to a solid which was recrystallized from isopropanol to yield the desired product, 2.17 g (67%) m.p. 197°-200° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=2[CH3:28])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: Cc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1-c1ccc(F)cc1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A solution of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (3.6 g, 0.014 mol) in toluene (80 mL) and EtOH (40 mL) was degassed 3 times before Pd(PPh3)4 (0.49 g, 0.425 mmol), 4-fluoro-2-methylphenylboronic acid (2.62 g, 0.017 mol) and an aqueous solution of Na2CO3 (2N, 14.2 mL, 0.028 mol) were added. The reaction mixture was stirred at 70° C. for 15 hours, cooled down to RT, filtered and the volatiles evaporated under vacuo. The residue was taken up in EtOAc and washed with aqueous NaOH (1N). The organic phase was dried over Na2SO4, concentrated under vacuo, before a purification on column chromatography (SiO2, EtOAc/Heptane, 1/3) yielded 3.6 g (77%) of the title compound as a colorless oil. ES-MS m/e: 328.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:36][CH3:37])[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH2:36]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:37]
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccccc1
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(=O)(=O)c1ccccc1
Yield: 64.4 %

Procedure:
A mixture of 0.33 g (1.70 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.61 g (1.70 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-benzenesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 535 mg of N-ethyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-benzenesulfonamide as a yellow solid (yield 64.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([OH:33])=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:43]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:31]([CH2:30][C:24]1([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:21][CH2:20]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)(=[O:33])[NH2:43]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)nc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(N)=O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.9 %

Procedure:
[1-[2-[4-[N-(5-Methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (909 mg), ammonium chloride (216 mg), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (1.56 g), 1-hydroxybenzotriazole hydrate (470 mg) and N,N-diisoprpoylamine (1.4 mL) were dissolved in N,N-dimethylformamide (8 mL). The solution was stirred at room temperature for 22 hours. Saturated aqueous sodium bicarbonate solution was added to the solution, and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (silica gel, chloroform:methanol=10:1) to give the title compound (652 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 115 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 3-methyl-4-nitrophenol (45 g, 0.294 mol) in dimethylformamide (270 mL) there were added 1-bromodecane (65 g, 0.294 mol) and potassium carbonate (121.8 g, 0.882 mol). The reaction mixture was heated to 115° C. and stirred at that temperature for 48 hours. The reaction mixture was cooled and poured into water (4 L), stirred for 0.5 hour and extracted with two portions of ethyl acetate (1.5 L and 600 mL). The combined organic extracts were washed with 5% aqueous solution sodium bicarbonate (1 L), water (1 L and 0.5 L), dried over sodium sulfate and concentrated to give the crude product (90 g, 0.294 mol, 100% yield). This product was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[C:4]([NH:6][C:7](=[NH:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:5].CC([O-])(C)C.[K+]>>[Cl:24][C:21]1[CH:22]=[N:23][C:2]2[N:19]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:20]=1
Reactant: N=C(CCCCc1ccc(F)cc1)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1[nH]c(CCCCc2ccc(F)cc2)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-[5-(4-fluoro-phenyl)-1-imino-pentyl]-nicotinamide was treated with KOtBu to obtain 6-chloro-2-[4-(4-fluoro-phenyl)-butyl]-3H-pyrido[2,3-d]pyrimidin-4-one as off-white crystals. MS: m/e=332.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.CC1NC2C(C=1[CH2:24][N:25](C)[C:26](=[O:29])[CH:27]=[CH2:28])=CC=CC=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][NH:25][C:26](=[O:29])/[CH:27]=[CH:28]/[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1CCCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)/C=C/c1cnc2c(c1)CCCC(=O)N2
Yield: 57.1 %

Procedure:
A solution of 3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (0.60 g, 2.50 mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (0.85 g, 3.75 mmole), Pd(OAc)2 (0.06 g, 0.25 mmole), tri-ortho-tolylphosphine (0.15 g, 0.50 mmole) and diisopropylethylamine (0.87 mL, 5.00 mmole) in propionitrile (50 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (200 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3). The title compound (0.35 g. 35%) was obtained as a light tan solid after drying in vacuo: MS (ES) m/e 246 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[C:15]4[N:20]=[C:41]([OH:42])[NH:19][C:16]4=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cnc1N
Solvent: C1CCOC1
Product: Oc1nc2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cnc2[nH]1
Yield: 25 %

Procedure:
A solution of compound 6b (220 mg, 0.470 mmol) and CDI (200 mg, 1.23 mmol) in THF (8 mL) was stirred at rt for 18 h. The reaction was quenched with H2O (10 mL). The resulting solids were collected by filtration and washed with Et2O to obtain the title compound 94 as a light yellow solid (57.6 mg, 25% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 11.62 (s, 1H), 11.08 (s, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.97-7.92 (m, 2H), 7.86-7.80 (m, 2H), 7.74 (t, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.60-7.51 (m, 2H), 7.39 (s, 1H), 4.40-4.25 (m, 4H), 3.95-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H22N8O2: 491.2 (M+H). Found 491.0.
Reaction SMILES: C(Cl)CCl.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[CH2:13][C:12]=2[CH:28]=1)(O)=[O:6].Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][CH2:33][CH2:32][NH:31][C:5]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[CH2:13][C:12]=2[CH:28]=1)=[O:6]
Reactant: NCCNc1ccccn1
Reactant: CCOC(=O)CC1Cc2ccc(C(=O)O)cc2Cc2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1Cc2ccc(C(=O)NCCNc3ccccn3)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
EDC (112.7 mg, 0.59 mmole) was added all at once to a solution of ethyl (±)-10,11-dihydro-3-carboxy-5H-dibenzo[a,d]cycloheptene-10-acetate (157.8 mg, 0.49 mmole), 2-[(2-aminoethyl)amino]pyridine dihydrochloride (123.5 mg, 0.59 mmole), HOBt.H2O (79.5 mg, 0.59 mmole), and diisopropylethylamine (0.43 mL, 2.45 mmole) in anhydrous DMF (2.5 mL) at RT. The reaction was stirred at RT for 18 hr, then was concentrated. The residue was reconcentrated from xylenes, then was diluted with H2O (5 mL) and extracted sequentially with EtOAc (2×5 mL) and CHCl3 (2×5 mL). The organic layers were combined and treated with a little MeOH to dissolve a small amount of insoluble material. Drying (MgSO4), concentration, and silica gel chromatography (5% MeOH/CHCl3) gave the title compound (199.1 mg, 92%) as a yellow oil: TLC (5% MeOH/CHCl3) Rf 0.42; 1H NMR (400, CDCl3) δ 8.10 (d, J=3.5 Hz, 1 H), 8.02 (br s, 1 H), 7.60 (app. narrow d, 1 H), 7.53 (app. dd, 1 H), 7.33-7.42 (m, 1 H), 7.08-7.22 (m, 5 H), 6.57-6.65 (m, 1 H), 6.45 (d, J=8.3 Hz, 1 H), 4.79-4.90 (m, 1 H), 4.36 (d,J=15.1 Hz, 1 H), 4.11-4.26 (m, 2 H), 3.92 (d, J=15.1 Hz, 1 H), 3.80-3.95 (m, 1 H), 3.55-3.72 (m, 4 H), 3.38 (dd, J=15.2, 4.1 Hz, 1 H), 3.03 (dd, J=15.2, 9.5 Hz, 1 H), 2.66 (dd, J=15.8,4.8 Hz, 1 H), 2.50 (dd, J=15.8, 9.6 Hz, 1 H), 1.27 (t, J=7.2 Hz, 3 H); MS (ES) m/e 444 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH2:13]([O:20][CH2:21][C:22]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][C:24]2([CH2:27][C:26](=O)[CH2:25]2)[CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([NH:8][CH:26]1[CH2:27][C:24]2([CH2:29][C:22]([CH2:30][O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([CH2:21][O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23]2)[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC2(C1)CC(COCc1ccccc1)(COCc1ccccc1)C2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CNC2CC3(C2)CC(COCc2ccccc2)(COCc2ccccc2)C3)cc1
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
Benzylamine (1.06 ml, 9.70 mmol) and acetic acid (0.56 ml, 9.70 mmol) were added to a dichloromethane (50 ml) solution of the compound (1.70 g, 4.85 mmol) obtained in Step 3 above, the resulting mixture was stirred for 10 minutes under ice cooling and then sodium cyanoborohydride (610 mg, 9.70 mmol) was added to the reaction mixture. After stirring at room temperature for 24 hours, saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=40:1 (v/v)] to give 1.27 g (60%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([Cl:11])=[C:4](Cl)[C:3]=1[Cl:13].[NH2:14][NH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[Cl:11][C:5]1[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([Cl:1])=[C:3]([Cl:13])[C:4]=1[NH:14][NH2:15]
Reactant: NN
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NNc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Temperature: 25 °C

Procedure:
To a reaction flask was added 26.1 grams (0.1 mole) of tetrachloropicolinic acid, 200 milliliters of water, 3.6 grams of 95 percent hydrazine (0.11 mole) and 10.6 grams (0.1 mole) of sodium carbonate. The mixture was heated with stirring and maintained under reflux conditions for about 1 hour. The reaction mixture was cooled to 25° C and 25 milliliters of 5 normal hydrochloric acid was added. The solid which precipitated was recovered by filtration, and washed successively with water, ethanol, benzene and hexane and air dried. The 3,5,6-trichloro-4-hydrazinopicolinic acid product was recovered in a yield of 25.6 grams (93 percent of theoretical) having a melting point of 165°-170° C. After recrystallization from a 50:50 dimethylformamide-water mixture the product (as the mono-hydrate) was found by analysis to have carbon, hydrogen and nitrogen contents of 26.6, 2.1 and 15.3 percent, respectively, as compared with the theoretical contents of 26.2, 2.2 and 15.3 percent, respectively, calculated for the above named compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[CH:4][N:3]=1.C[Mg]Br.C(=O)(O)[O-].[Na+].CC[O:20][CH2:21][CH3:22]>C1COCC1>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:21](=[O:20])[CH3:22])=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(F)nc1
Agent: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.9 %

Procedure:
To a solution of 6-fluoronicotinonitrile (5.00 g, 41.0 mmol) in THF (50 mL) was added 1 N methylmagnesium bromide (16.4 mL, 49.1 mmol) in THF at 0° C. After addition, the mixture was warmed to ambient temperature and stirred at ambient temperature for 4 hours. Saturated sodium bicarbonate solution (50 mL) and ether (100 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 1-(6-fluoropyridin-3-yl)ethanone (0.85 g, 14.9%) as solid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:14][N:15]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[CH2:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:50]=[CH:49][C:26]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=[N:29][C:25]=3[CH:24]=2)[CH:20]=[CH:19][C:18]=1[F:51])=O)(C)(C)C>O1CCOCC1.CO>[NH:27]1[C:26]2[CH:49]=[CH:50][C:23]([C:21]3[CH:20]=[CH:19][C:18]([F:51])=[C:17]([CH:22]=3)[CH2:16][N:15]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)[CH2:14][C@H:10]3[CH2:11][CH2:12][CH2:13][NH:9]3)=[CH:24][C:25]=2[N:29]=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN(Cc1ccc(F)cc1)Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc(CN(Cc2cc(-c3ccc4[nH]nnc4c3)ccc2F)C[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A solution of hydrochloric acid in dioxane (4M, 2 mL) was added to a solution of (R)-2-({(4-fluoro-benzyl)-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (119 mg, 0.15 mmol) in 5 mL of methanol and the resulting solution stirred at ambient temperature for 24 h. The volatiles were removed in vacuo and purified by HPLC. The product obtained was treated with hydrochloric acid to give 40 mg of product. LC/MS (long run): Retention time, 6.20 min; (M+H)=433.
Reaction SMILES: O1CCN(CC[N+]#[C-])CC1.[C:11]([C@H:14]([C@@H:26]([CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[CH2:15][N:16]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH3:24])[C:17]1=[O:25])([OH:13])=O.[OH:41][N:42]1C=CC=CC1=O.C[Si](C)(C)ON>C(Cl)Cl>[CH:36]1([CH2:35][C@H:26]([C@@H:14]([C:11](=[O:13])[NH:42][OH:41])[CH2:15][N:16]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH3:24])[C:17]2=[O:25])[C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reactant: O=c1ccccn1O
Agent: C[Si](C)(C)ON
Agent: [C-]#[N+]CCN1CCOCC1
Solvent: ClCCl
Product: CN1C(=O)N(C[C@H](C(=O)NO)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
0.78 g of 2-morpholino-ethyl isocyanide was added at 22° to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperdine from Example 11 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of t-butyl methyl ether and 0.23 ml of water, stirred for 1½ hrs. at 22°, the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperdine I, MS (EI): 436 (40%).