Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:20]([C:19]3[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=3)=[O:21])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (8.83 g, 47.9 mmol) and 4-bromobenzoyl chloride (10.0 g, 45.6 mmol) were dissolved in anhydrous dichloromethane (240 mL) followed by addition of N,N-diisopropylethyl amine (8.74 mL, 50.2 mmol) dropwise over the course of 30 minutes. After stirring at room temperature for four hours, the reaction mixture was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Recrystallization of the residue from ethyl acetate afforded the title compound (15.4 g) as white crystals.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]([OH:13])=O)[CH2:10][CH2:9]1.[CH:14]1([CH2:20][NH:21][CH2:22][C@H:23]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH:39]4[CH3:43])=[CH:30][CH:29]=3)[C:26](=[O:44])[CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:14]1([CH2:20][N:21]([CH2:22][C@@H:23]2[CH2:24][CH2:25][C:26](=[O:44])[N:27]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[CH3:43])=[CH:30][CH:29]=2)[C:11]([CH:8]2[CH2:10][CH2:9]2)=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CNCC2CCCCC2)cc1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN(CC2CCCCC2)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.6 %

Procedure:
Triethylamine (0.13 ml, 0.93 mmol, 2 eq) is added to a solution of cyclopropanecarboxylic acid (40 mg, 0.47 mmol, 1 eq) and ((5S)-5-{[(cyclohexylmethyl)amino]methyl}-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 1 (200 mg, 0.47 mmol, 1 eq) in dichloromethane (5 ml). The mixture is cooled with an ice bath. 1-Hydroxybenzotriazole (12 mg, 0.093 mmol, 0.2 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.52 mmol, 1.1 eq) are added. The mixture is stirred at room temperature for 5 hours, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 0.246 g of yellow oil that is purified by chromatography over silicagel (dichloromethane/methanol/ammonia 96/4/0.4) to afford 0.135 g of N-(cyclohexylmethyl)-N-[((2S)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-5-oxopyrrolidin-2-yl)methyl]cyclopropanecarboxamide 77 as a yellow lacquer.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[O:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>>[CH2:12]1[O:11][C:5]2[C:4](=[C:3]3[C:2](=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=2)[N:1]=[CH:15][CH:14]=[C:16]3[CH3:18])[O:13]1
Reactant: C=CC(C)=O
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Product: Cc1ccnc2c([N+](=O)[O-])cc3c(c12)OCO3
Yield: 63 %

Procedure:
4-Amino-1,2-methylenedioxy-5-nitrobenzene was made according to the method of Lott, et al.--J. Amer. Chem. Soc., 70, 3621 (1848). It was subjected to a Skraup reaction with methyl vinyl ketone to provide 5,6-methylenedioxy-4-methyl-8-nitroquinoline. The crude compound was crystallized from acetone to give a 63% yield of pure substance; mp 183°-185°.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7])([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 47.5 %

Procedure:
0.25 g (0.000612 mol) of 1-benzyl-piperidin-4-yl 2-nitro-4-trifluoromethyl-benzoate was dissolved in 10 ml of ethanol and treated with 0.15 g of Raney-nickel. The mixture was hydrogenated at room temperature under normal pressure for 2 hrs. The catalyst was filtered off and the solvent was removed completely. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.11 g (48%) of 1-benzyl-piperidin-4-yl 2-amino-4-trifluoromethyl-benzoate was obtained as a yellow oil. MS: me/e=379 (C20H22F3N2 O2 +).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:18]=2)O)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[CH:26]1([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:15][C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)=[N:18]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OC(c1cccc(OCc2ccccc2)c1)c1nn(C2CCCC2)c2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Oc1cccc(Cc2nn(C3CCCC3)c3ccccc23)c1
Yield: 484.5 %

Procedure:
A mixture of [3-(benzyloxy)phenyl](1-cyclopentyl-1H-indazol-3-yl)methanol (0.24 g, 0.6 mmol) and 10% palladium on carbon in ethanol/cyclohexene (3:1, v/v) was heated at reflux for 1 hour. The catalyst was filtered (celite) and the filtrate concentrated in vacuo to give 0.85 g of product as a white solid.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([O:32]C)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[C:1]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)c1ccccc1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
In 50 ml of methanol, 4.4 g of methyl N-benzoylphenylalanyltyrosinate was dissolved. After addition of 23 ml of 1 N sodium hydroxide, the solution was stirred for 1 hour. The reaction mixture was neutralized with hydrochloric acid, concentrated and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 3.8 g of N-benzoylphenylalanyltyrosine with a mp. 191°-192° C., in a yield of 87%. Analysis, calculated for C25H24O5N2 : C, 69.43; H, 5.59; N, 6.48; found C, 68.98; H, 5.72; N, 6.37.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH:28]1(NC(C)C)CCCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]([CH3:28])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC1CCCCC1
Reactant: CCCCC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Solvent: CI
Product: CCCCC(C)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 7(c), a reaction was carried out using ethyl 2-(4-benzyloxybenzyl)caproate (2.04 g) and methyl iodide (1.12 ml) instead of 4-benzyloxybenzyl chloride and cyclohexylisopropylamine (1.48 ml) instead of diisopropylamine and the reaction mixture was treated to afford the desired compound (1.80 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]3)[N:11]([CH2:26][C:27]3[CH:40]=[CH:39][C:30]([C:31](NC4NN=NN=4)=[O:32])=[CH:29][CH:28]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)(C)[CH:43]=[O:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH2:18][CH2:19]3)[N:11]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:44][CH3:43])=[O:32])=[CH:39][CH:40]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)C(=O)N1CCC(c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCN(CC(C)(C)C)CC2)cc1

Procedure:
To a solution of the intermediate from Example 142 step F (100 mg, 0.225 mmol) in 1,2-dichloroethane (3 mL) was added trimethyl acetaldehyde (29 mg, 0.337 mmol) and sodium triacetoxy borohydride (71 mg, 0.337 mmol). After 16 hours the reaction was diluted with DCM (10 mL) and washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This material was used in the next step without any further purification. LC-MS: 3.44 min; (M+H)=514.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-(3-nitrophenyl)piperazine-1-carboxylate in EtOH (20 mL) and THF (10 mL) was added Pd/C (500 mg), the mixture was charged with H2 (1 atm) and stirred for 16 h. Pd/C was filtered off, the filtrate was concentrated to give tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1.71 g).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C:5]1(C(OC)=O)[CH:10]([CH3:11])[CH2:9][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:7][C:6]1=[O:16].[Cl-].[Li+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH:13]([O:12][C:8]1[CH2:9][CH:10]([CH3:11])[CH:5]([CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[C:6](=[O:16])[CH:7]=1)([CH3:15])[CH3:14]
Reactant: COC(=O)C1(CC=C(C)C)C(=O)C=C(OC(C)C)CC1C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCC1C(=O)C=C(OC(C)C)CC1C
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Reaction: ##STR31## To a solution of methyl 1-(3-methyl-2-butenyl)-2-oxo-4-isopropoxy-6-methyl-3-cyclohexene carboxylate (29.4 g, 0.1 mol) in anhydrous hexamethylphosphoric triamide (220 mL) was added anhydrous lithium chloride (6.4 g, 0.15 mol). The mixture was stirred at 130° C. in a nitrogen atmosphere for 1.5 hours and then added to water (800 mL). The aqueous solution was extracted with ether. The combined ether extracts were washed with water and dried (Na2SO4). The ether was removed on a rotary evaporator and the residue vacuum distilled, yielding 20.1 g of 3-isopropoxy-5-methyl-6-(3-methyl-2-butenyl)-2-cyclohexen-1-one, bp 104°-108° C./0.05 mm. The product was shown by glc/ms to be a mixture of "cis" and "trans" isomers in a ratio of 76:24.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\OCC)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.CC([O-])=O.[Na+]>CC(O)=O.O>[NH2:2][C:1]1[N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:15]([F:25])([F:26])[F:14])=[CH:22][CH:21]=2)[N:24]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CCO/C=C(\C#N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)c1N
Temperature: 100 °C
Yield: 94.1 %

Procedure:
A mixture of ethyl (2E)-2-cyano-3-ethoxy-2-propenoate (113) (1.87 g, 11.1 mmol), 4-(trifluoromethoxy)phenylhydrazine hydrochloride (114) (2.286 g, 10.00 mmol) and NaOAc (0.90 g, 11.0 mmol) in AcOH (7.5 mL) and water (2.5 mL) was heated to 100° C. under N2 for 15 h. The mixture was poured onto ice, and the resulting precipitate was filtered and recrystallised (MeOH/water) to give ethyl 5-amino-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-4-carboxylate (115) (2.965 g, 94%) as white flakes: mp 102-103° C.; 1H NMR [(CD3)2SO] δ 7.73 (s, 1H), 7.68 (d, J=9.1 Hz, 2H), 7.53 (d, J=9.1 Hz, 2H), 6.41 (br s, 2H), 4.22 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). APCI MS m/z 316 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:13])[CH:3]=1.[I:14]Cl.O.S([O-])([O-])=O.[Na+].[Na+]>CCCCCCC>[F:1][C:2]1[C:12]([I:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:13])[CH:3]=1
Reactant: ClI
Reactant: CCOC(=O)c1ccc(F)cc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Product: CCOC(=O)c1cc(I)c(F)cc1O
Reaction time: 1 h

Procedure:
Ethyl 4-fluoro-2-hydroxybenzoate (10.2 g, 55 mmol)) was dissolved in n-heptane. Iodo monochloride (12 g, 74 mmol) was added dropwise at ambient temperature with sniffing. After 1 h, water was added and then solid sodium sulfite in small portions until the suspension was decolourized. More n-heptane was added to clear solution and the phases separated. The organic phase was dried and concentrated. The product crystallized on cooling. It was collected by filtration and washed with cold n-heptane. The crude yield was 10 g. The product was a mixture of ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (about 80%) and the 5 chloro analogue (about 20%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([O:21]CC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:26]([CH2:29][CH2:30][NH2:31])[CH2:27][CH3:28])[CH3:25].C(N(C(C)C)CC)(C)C>CCOCC>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:29][CH2:30][NH:31][C:19](=[O:21])[CH2:18][N:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8]1)[CH3:25]
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCN(CC)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCN(CC)CCNC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 18 h
Yield: 55.2 %

Procedure:
A mixture of 10 g (0.033 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 6.9 mL (0.049 mol) of diethylaminoethylamine and 39 mL of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The reaction was stripped, the residue taken up in about 300 mL of ether and washed twice with water. The ether layer was extracted twice with a total of 150 mL of cold water containing 20 mL of 10% HCl. The combined water extracts were washed once with ether, cooled, made basic with solid sodium carbonate, extracted several times with methylene dichloride, dried over sodium sulphate, treated with decolorizing carbon, filtered and stripped. The oily red residue was crystallized from ether to yield 6.86 g of N-[2-(diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide, mp 80°-83° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[C:16]([F:34])[CH:15]=2)=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:36][NH2:37]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[C:16]([F:34])[CH:15]=2)=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:36][NH2:37])(=[O:3])[NH2:2]
Reactant: NN
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(NN)c(C(N)=O)c(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 15D (3.53 mg, 0.69 mmol) in 1,4-dioxane (5 mL) was added hydrazine hydrate (0.3 mL). After stirring at ambient temperature for 4 hours, the mixture was concentrated. The residue was washed with hexane and dried under vacuum to give the crude title compound, which was used in the next step without further purification (281 mg, 80%). MS: 511 (M+H+).
Reaction SMILES: C(O[CH:5]([C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7])(=O)C.[H][H]>C(O)C.[Pd]>[CH2:5]([C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: CCC(OC(C)=O)c1cccnc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cccnc1F

Procedure:
3.50 g (17.7 mmol) of the product from example 49A are dissolved in 30 ml of ethanol and admixed with 2.00 g of 10% palladium on activated carbon. Hydrogenation is effected overnight in a hydrogen atmosphere under standard pressure. The mixture is filtered with suction, washed with ethanol and concentrated cautiously under reduced pressure. This affords 1.9 g of approx. 89% pure product (69% of theory), which is converted further without purification.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C2N=NN(O)C2=CC=1.O.C1CCC(N=C=NC2CCCCC2)CC1.[C:48]1([CH2:54][O:55][CH2:56][CH2:57][NH:58][C:59](=[O:77])[CH2:60][NH:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[CH:65][CH:64]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:5]1([CH2:4][O:3][C:1]([NH:11][C@@H:12]([C:19]([N:61]([CH2:62][C:63]2[CH:64]=[CH:65][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[CH:67][CH:68]=2)[CH2:60][C:59]([NH:58][CH2:57][CH2:56][O:55][CH2:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:77])=[O:21])[CH2:13][C:14]2[N:18]=[CH:17][NH:16][CH:15]=2)=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CNCc1ccc(OCc2ccccc2)cc1)NCCOCc1ccccc1
Reactant: O=C(N[C@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a suspension of CBZ-D-histidine (0.093 g, 0.32 mmol) in DMF (2 mL) was added HOBT hydrate (0.059 g, 0.39 mmol) followed by DCC (0.080 g, 0.39 mmol). A solution of the compound from Step 3 above (0.13 g, 0.32 mmol) in DMF (2 mL) was added and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was diluted with CHCl3, washed twice with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (2-5% MeOH/CHCl3) gave 0.10 g (45%) of the title compound as a white powder; ES-MS 676 (m+1).
Reaction SMILES: [C:1]([O:13]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>C1COCC1>[C:16]1([C:1]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCCCCCCCCC(=O)OCC
Reactant: Br[Mg]c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a solution of 10.6 g of ethyl undecylenate in 100 mL of THF at 0° C. was added, over 1 hr, 40 mL of 3M phenyl magnesium bromide. The mixture was warmed to room temperature and stirred for 75 hrs. Methanol, 10 mL, was added to quench the excess Grinard reagent and the solvent was distilled in vacuo. The residue was shaken with diethyl ether and dilute hydrochloric acid. The ether layer was washed with water and saturated sodium hydrogen carbonate, dried, and concentrated in vacuo to give 18.3 g of crude product, which was then chromatographed on silica gel with chloroform as the eluent, to give 13.7 g of 1,1-diphenyl-10-undecen-1-ol which is characterized by:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5](I)[C:3]=1[NH2:4].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:3]=1[NH2:4]
Reactant: CS(=O)(=O)c1cc(Cl)c(N)c(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(S(C)(=O)=O)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 1308.5 %

Procedure:
To the suspension of 2-chloro-6-iodo-4-methanesulfonylaniline (886.9 mg, 2.7 mmol.), Pd(PPh3)2Cl2 (94.5 mg, 0.13 mmol), and CuI (24.3 mg, 0.13 mmol.) was added triethyl amine (2 mL), and the suspension was slowly treated with (trimethylsilyl)acetylene (0.22 mL, 0.16 mmol.) at 0° C. The reaction mixture was stirred at room temperature for ˜16 h. Solvent was removed under vacuum. The residue was diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with saturated NaCl, water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using 20% ethyl acetate—hexane to give 2-chloro-4-methanesulfonyl-6-trimethylsilanylethynyl-phenylamine (632 mg, 78%). The 1H NMR (500 MHz, CDCl3) spectrum was: 0.27 (s, 9H), 3.01 (s, 3H), 5.17 (s, 2H), 7.77 (d, J=2.5 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]1([CH3:27])[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[C:19]2[CH:18]=[C:17]([CH:25]=[O:26])[CH:16]=[CH:15][C:14]1=2.[Cl-].[NH4+]>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:18]1[C:19]2[C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22][C:13]([CH3:27])([CH3:12])[C:14]=2[CH:15]=[CH:16][C:17]=1[CH2:25][OH:26]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c1ccc(CO)c2C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
17.13 ml (0.121 mol) of trimethylsilylacetylene and 100 ml of THF were introduced into a three-necked flask. A solution of 48.5 ml (0.121 mol) of n-butyllithium (2.5M in hexane) was added dropwise at -78° C. under a stream of nitrogen and the mixture was permitted to heat to room temperature. This solution was introduced dropwise into a solution of 23.8 g (0.11 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehyde in 100 ml of THF at -78° C. The reaction mixture was permitted to heat to room temperature, was poured into an aqueous ammonium chloride solution and was extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporating the solvents, 29.9 g (86%) of the expected alcohol were recovered in the form of a yellow oil.