Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23])[CH2:3][N:4]1[CH:21]=[N:20][C:6]([CH2:7][C@@H:8]([C:17]([OH:19])=O)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:57][C:58]([O:61][C:62](=[O:66])[C@H:63]([CH3:65])[NH2:64])([CH3:60])[CH3:59].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:57][C:58]([O:61][C:62](=[O:66])[C@H:63]([CH3:65])[NH:64][C:17](=[O:19])[C@H:8]([CH2:7][C:6]1[N:20]=[CH:21][N:4]([CH2:3][C:2]([Cl:1])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[O:23])[CH:5]=1)[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([CH3:60])[CH3:59]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(Cl)(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)[C@H](Cc1cn(CC(Cl)(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a stirred mixture of 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (1.14 g), N-methylmorpholine (461 μl), 1-hydroxybenzotriazole hydrate (277 mg) and L-alanine 1,1-dimethylethyl ester hydrochloride (364 mg) in dichloromethane (30 ml) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (422 mg). The resulting mixture was stirred for 18 hours, and concentrated under reduced pressure to yield a residue which was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and then brine and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to yield a foam which was chromatographed on silica gel eluting with methanol/dichloromethane (1:24) to yield N-[1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidyl]-L-alanine 1,1-dimethylethyl ester as a white foam (1.25 g), and as a mixture of diastereoisomers, m.p. 85-90° C. (decomp), (Found: C, 55.57; H, 5.51; N, 7.86%; C33H39Cl3N4O6.H2O requires C, 55.66; H, 5.80; N, 7.87%), having the formula: ##STR35##
Reaction SMILES: N#N.[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11](O)[CH:12]=C>>[C:3]([O:9][CH2:10][CH:11]=[CH2:12])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: C=CCO
Agent: N#N
Product: C=CCOC(=O)CC(C)=O
Yield: 72.8 %

Procedure:
In a 2 l flask equipped with a magnetic stirrer, equipped for a Vigreaux column for distillation, a heating mantle and N2, there was added 4.0 mole (432 ml) of methyl acetoacetate and 8.0 mole (464.6 g) of allyl alcohol. The reaction mixture was distilled for 12 hours at 92° C. There was added 136 ml (2.0 mole) of allyl alcohol and the mixture was distilled 23 hours. There was then added 136 ml (2.0 mole) of allyl alcohol and the mixture was distilled 16 hours. The reaction mixture was then distilled under vacuum and product was collected at 105°-110° C./35 mm Hg. There was obtained 414 g of allyl acetoacetate (73% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[S:28](=[O:35])(=[O:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:36]1([C:25]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:33]3[CH:29]([CH2:30][N:31]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:32]3)[S:28](=[O:34])(=[O:35])[CH2:27][CH2:26]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CC2C(C1)S(=O)(=O)CCC2(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.35 cm3 of triethylamine and a solution of 0.17 cm3 of phenylacetyl chloride in 5 cm3 of dichloromethane are added to a suspension, cooled to 0° C., of 0.46 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride in 10 cm3 of dichloromethane. After stirring for 1 hour at 0° C. and then 1 hour at 20° C., the reaction mixture is diluted with 10 cm3 of dichloromethane, washed twice with 30 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm3 of ethyl ether, the crystals are drained and dried. 0.50 g of (4aRS,7aRS)-4,4-diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:19]2[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]2)=[C:13](N=C=O)[CH:12]=1)=[O:10])[C:2]1[CH:7]=CC=CC=1.C(OC(=O)CBr)C=C.[CH2:31]([O:38][C:39](=[O:42])CC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]([C:13]1[CH:12]=[C:11]([C:9]([O:8][CH2:1][CH:2]=[CH2:7])=[O:10])[N:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[CH:18]2)=[O:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(=O)OCc1ccccc1
Reactant: O=C=Nc1cc(C(=O)OCc2ccccc2)n2ccccc12
Agent: C=CCOC(=O)CBr
Product: C=CCOC(=O)c1cc(C(=O)OCc2ccccc2)c2ccccn12

Procedure:
The title compound was prepared using the protocol described in steps A and B for the preparation of 1-isocyanato-indolizine-3-carboxylic acid benzyl ester scheme A6 using bromo-acetic acid allyl ester in step A and propionic acid benzyl ester in step B. TLC, Rf (c-hexane/EtOAc 1:1)=0.8; MS (LC/MS): 336.1 [M+H]+, 358.1 [M+Na]+, 693.2 [2M+Na]+; tR (HPLC conditions a): 4.55 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:31][O:32][C:33](=[O:59])[NH:34][CH:35]([C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:47][C:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]#[CH:58])=[CH:53][CH:52]=2)=[CH:49][N:50]=1)=[O:40])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>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.CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:58]#[C:57][C:54]4[CH:55]=[CH:56][C:51]([C:48]5[NH:47][C:46]([CH:42]6[CH2:43][CH2:44][CH2:45][N:41]6[C:39](=[O:40])[CH:35]([NH:34][C:33]([O:32][CH3:31])=[O:59])[CH:36]([CH3:38])[CH3:37])=[N:50][CH:49]=5)=[CH:52][CH:53]=4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CSC(C)(C)C1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5N(C(=O)C(NC(=O)OC)C(C)C)CSC5(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 23.8 %

Procedure:
(1-{4-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5,5-dimethyl-thiazolidine-3-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (83 mg, 0.167 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (66.0 mg, 0.167 mmol) and PdCl2(PPh3)2 (11.7 mg, 0.017 mmol) under an argon atmosphere. DMF (2.0 mL degassed with Argon) was added followed by triethylamine (168 mg, 1.67 mmol) and copper(I) iodide (3.2 mg, 0.017 mmol). The mixture was heated at 80° C. After 20 hours, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(4-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (32.1 mg) as a TFA salt.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])O[CH2:12][CH3:13].[NH2:16][C:17]1[S:18][CH:19]=[C:20](C)[N:21]=1>>[NH2:9][C:8]1[N:21]([C:17]2[S:18][CH:19]=[C:12]([CH3:13])[N:16]=2)[CH:20]=[N:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)C(N)C#N
Reactant: CCOC([O-])[O-]
Product: CCOC(=O)c1ncn(-c2nc(C)cs2)c1N

Procedure:
The desired compound was synthesized following the procedures described in Reference Example 7 by using ethyl α-aminocyanoacetate, ethyl orthoformate and 2-amino-4-methylthiazole as raw materials. m.p.: 152° to 155° C.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+].CCOCC.O>[CH2:19]([O:18][CH2:17][CH2:16][CH2:15][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCCC1
Reactant: BrCCCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=C1CCCCC1CCCOCc1ccccc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Example 234 A) To a mechanically stirred mixture of KOt-Bu (10.1 g, 104 mmol) in benzene (100 mL) cooled to 0° C. under nitrogen was added cyclohexanone (7.4 g, 83 mmol) dropwise over 20 min. Ten minutes after the addition was complete, benzyl 3-bromo-propyl ether (20 g, 87 mmol) was added over a twenty minute period. The reaction mixture was warmed to room temperature, refluxed for seven hours, stirred at room temperature or eighteen hours, and diluted with 0.5N potassium hydrogen sulfate (200 mL). The reaction mixture was further diluted with Et2O, 0.5N potassium hydrogen sulfate, and water, until two phases formed. The organic phase was washed with water, brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give 19.2 g of the 2-(3-benzyloxypropyl)-cyclohexan-1-one.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCC1CCCCC1
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CC3CCCCC3)(CC1)C2
Product: [Br-]
Yield: 24.3 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and (bromomethyl)cyclohexane (0.030 mL, 0.215 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0172 g, 24.2%). EI-MS m/z 385 (M+) Rt (1.82 min).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1)#[CH:2].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:12]=2[N:13]=1)[CH3:2]
Reactant: C#Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Yield: 95.7 %

Procedure:
A mixture of 0.34 g of 2-(3-ethynylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.10 g of 5% palladium on carbon and 8 ml of ethyl acetate was stirred under about one atmosphere of hydrogen at room temperature for two hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.33 g of 2-(3-ethylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 35”).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[F:21])=[CH:6][N:7]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: N#Cc1nc(Br)cnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1nc(-c2ccc(Cl)cc2F)cnc1N
Temperature: 80 °C
Yield: 83.8 %

Procedure:
To a solution of 3-amino-6-bromopyrazine-2-carbonitrile (2.00 g, 9.55 mmol) in 1,4-dioxane (48 mL), were added (4-chloro-2-fluorophenyl)boronic acid (1.66 g, 9.55 mmol) and aqueous Na2CO3 (2 M, 24 mL, 48 mmol) and the reaction mixture sparged with N2 gas for 10 min. Pd(dppf)Cl2.CH2Cl2 (0.349 g, 0.477 mmol) was then added and the reaction mixture sparged for an additional 10 min with N2 gas. The reaction vessel was sealed and heated for 3 hours at 80° Celsius. The mixture was cooled to rt, filtered through celite, and the filter cake washed with EtOAc (300 mL). The filtrate was washed with a 1:1 mixture of brine/H2O (2×100 mL). The organic phase was concentrated to dryness and subjected to FCC to give the title compound (1.99 g, 84%). MS (ESI): mass calcd. for C11H6ClFN4, 248.03; m/z found 249.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J=2.0, 1H), 7.83 (m, 1H), 7.25-7.08 (m, 2H), 5.36 (s, 2H).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]1=[O:39])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40](N(CC)C(C)C)([CH3:42])[CH3:41].C(Br)C=C>C(Cl)Cl>[CH2:42]([N:33]([C:34]1[S:35][CH:36]=[CH:37][N:38]=1)[S:30]([C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:22][CH2:23][C@@H:19]([O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]2=[O:39])=[CH:25][CH:26]=1)(=[O:31])=[O:32])[CH:40]=[CH2:41]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1=O)(c1ccccc1)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Yield: 83.9 %

Procedure:
Prepared according to general procedure 48. The reaction was set up (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50.0 g, 86.6 mmol), CH2Cl2 (200 mL), N,N-diisopropylethylamine (30.2 mL, 173.2 mmol), and allylbromide (15.0 mL, 173.2 mmol). The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (45.0 g, 72.7 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ. 7.85-7.79 (m, 6H), 7.70 (dd, J=1.6, 7.7 Hz, 2H), 7.49-7.40 (m, 6H), 7.36 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.90-5.82 (m, 1H), 5.16 (dd, J=1.3, 10.3 Hz, 1H), 4.97 (d, J=1.3 Hz, 1H), 4.56-4.52 (m, 3H), 3.76-3.72 (m, 1H), 3.56-3.48 (m, 1H), 2.28-2.25 (m, 1H), 2.19-1.98 (m, 1H), 1.11 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.Cl.Cl.[CH3:31][O:32][C@@H:33]1[CH2:37][NH:36][CH2:35][C@H:34]1[NH2:38]>>[NH2:38][C@H:34]1[C@H:33]([O:32][CH3:31])[CH2:37][N:36]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:35]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: CO[C@@H]1CNC[C@H]1N
Agent: Cl
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C[C@H]1N

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 284 using 2-chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 284.1, 20 h at 80° C. then 24 h at 100° C.). HPLC (Condition 10) tR=5.97 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=492.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62 (br. s, 2H) 2.82-2.90 (m, 1H) 3.02-3.11 (m, 1H) 3.21 (s, 3H) 3.26-3.34 (m, 2H) 3.47-3.57 (m, 2H) 7.35 (d, J=8.99 Hz, 2H) 7.85 (m, J=9.00 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:55])[CH2:5][N:6]([C:8](=[O:54])[C@@H:9]([NH:25][C:26](=[O:53])[C@@H:27]([NH2:52])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:46])([CH3:45])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:36])=[O:35])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].CCN(C(C)C)C(C)C.[CH3:65][C:66](OC(C)=O)=[O:67]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:55])[CH2:5][N:6]([C:8](=[O:54])[C@@H:9]([NH:25][C:26](=[O:53])[C@@H:27]([NH:52][C:66](=[O:67])[CH3:65])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:45])([CH3:46])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:35])=[O:36])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@@H](N)CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@H](CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of compound F (6.6 g, 7.8 mmol) in CHCl3 (50 mL) at 5° C. was added DIPEA (4.8 mL, 27.4 mmol) followed by Ac2O (0.9 mL, 9.4 mmol). The reaction mixture was stirred at ambient temperature for 30 min. Solvents were removed in vacuo, and then the residue was diluted with water (500 mL) and EtOAc (500 mL). The organic layer was separated and washed with water (300 mL), 2% aqueous H2SO4 (200 mL), water (2×300 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to afford compound G (5.5 g, 82%). LC-MS [M+H] 853.4 (C36H52N8O12S2+H, calc: 853.9). Purity >95% (UV/254 nm). Compound G was used without further purification.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C1COCC1.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>[F:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[N:3][CH:4]=1
Reactant: Nc1cc(F)cnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ncc(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a mixture of 2-bromo-5-fluoropyridin-3-amine (3.3 g, 17.3 mmol), TEA (7.3 mL, 51.9 mmol), PdCl2(PPh3)2 (1.2 g, 1.73 mmol), and Cu(I)I (0.33 g, 1.73 mmol) in THF (50 mL) at 0° C. under nitrogen was added a solution of (trimethylsilyl)acetylene (3.39 mL, 34.6 mmol). The mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 2.0 g (915) of 5-fluoro-2-((trimethylsilyl)ethynyl)pyridin-3-amine as a yellow solid. MS (ESI): m/z=209.1 [M+1]+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)CCO2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3-see Preparation 3), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.242 g-see Preparation 20), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.26 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:49])[NH:34][CH2:35][CH2:36][CH2:37][C@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][NH2:40])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH2:13][C:14]([NH:40][CH2:39][C@@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:49])=[O:16])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NC[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.1 g (0.26 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid (J. Med. Chem. (2002) 45:4246-4253) and 0.11 g (0.34 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.065 g (0.34 mmol) of EDC and 0.011 g (0.079 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.