Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:24]=1)[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.Cl>[C:35]([NH:38][NH:39][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:22]=[C:23]([CH:24]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:14][CH:15]=1)=[O:19])(=[O:37])[CH3:36]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)O)cc2)c1
Reactant: CC(=O)NN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)NNC(C)=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-[3-(benzyloxy)-5-(methoxycarbonyl)phenoxy]benzoic acid (Intermediate 11) (34 g, 82.87 mmol, 1 equiv) in dry DCM (50 mL), DMF (1.5 mL, catalytic) was added followed by oxalyl chloride (20.1 g, 158.7 mmol, 2 equiv.) dropwise at 0-5° C. The reaction mixture was stirred at room temperature for 2 h. After 2 h, a mixture of acetic hydrazide (8.8 g, 119 mmol, 1.5 equiv.) and dry pyridine (12.4 mL, 158.7 mmol, 2 equiv.) in dry DCM (50 mL) was added to the above prepared acid chloride at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with dil. HCl and extracted with DCM. The organic layer was washed with water, brine and dried over sodium sulphate and concentrated to afford white solid. (32 g).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of ethyl 4-hydroxybenzoate and 3,3-dimethylallyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-(3-Methyl-but-2-enyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.54 (s, —CO2H); 7.81 (d-like, 2 arom.H); 6.95 (d-like, 2 arom.H); 5.38 (m, CH═C(CH3)2); 4.54 (d-like, CH2CH═C(CH3)2); 1.69, 1.64 (2s, CH═C(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 166.96 (C═O); 162.05; 137.66; 131.25 (2 arom. C); 122.78; 119.38; 114.36 (2 arom.C); 64.58; 25.37; 17.99.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:18]1[C:27]2[C:22]3=[C:23]([CH2:28][CH2:29][O:30][C:21]3=[CH:20][CH:19]=1)[CH:24]=[CH:25][N:26]=2)(=O)=O.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.[Li+].[Cl-]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:17][C:16]1[C:7]([CH:33]=[CH2:34])=[C:8]([C:18]2[C:27]3[C:22]4=[C:23]([CH2:28][CH2:29][O:30][C:21]4=[CH:20][CH:19]=2)[CH:24]=[CH:25][N:26]=3)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2ccccc2c(-c2ccc3c4c(ccnc24)CCO3)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ccccc2c1-c1ccc2c3c(ccnc13)CCO2
Yield: 113 %

Procedure:
A solution of 1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yltrifluoromethanesulfonate (5E) (89 mg, 0.194 mmol), tributyl(vinyl)tin (0.23 mL, 0/776 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol) and LiCl (16 mg, 0.39 mmol) in dioxane (3 mL) was stirred at 110° C. under Ar for 5 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCO3 solution (2×), brine and dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 5F as a white solid (74 mg, 91%). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H20NO: 338.42. Found: 338.2.
Reaction SMILES: CC(O[C:5]([CH3:7])=[O:6])=O.[F:8][C:9]([F:25])([F:24])[C:10]([N:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)=[O:11]>C(O)(=O)C.O>[F:25][C:9]([F:8])([F:24])[C:10]([N:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[C:20]([NH:23][C:5](=[O:6])[CH3:7])[CH:21]=[CH:22][C:15]=2[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2.75 mL acetanhydride was added to 5 g 3-trifluoracetyl-7-amino-1,2,4,5-tetrahydro-benzo[D]azepine in concentrated acetic acid. The mixture was stirred 17 h at RT, diluted with water and stirred for another 1 h at RT. The precipitate was filtered, washed with water and dried to give 5.35 g of the desired product. Rf: 0.46 (DCM/MeOH=19/1), (M+H)+=301
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([CH2:34][CH2:35][C:36](O)=[O:37])(=[O:33])=[O:32])[CH:25]=[CH:24]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([CH2:34][CH2:35][C:36]([N:11]1[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH:6]1[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])=[O:37])(=[O:32])=[O:33])[CH:25]=[CH:24]2
Reactant: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Yield: 60.2 %

Procedure:
tert-Butyl 3-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate (0.9 g) was dissolved in dichloromethane (20 mL), and triethylamine (0.92 mL) was added thereto. With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (1.0 g), HOBt (0.55 g) and WSC (0.65 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.1 g) as a pale brown oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]([F:16])([F:15])[CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([F:15])([F:16])[C@H:8]2[CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][CH2:13]2)=[CH:17][CH:18]=1
Reactant: O=C1CCC(C(F)(F)Oc2ccc(Br)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1CC[C@H](C(F)(F)Oc2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-[(4-bromo-phenoxy)-difluoro-methyl]-cyclohexanone (1050 mg, 3.290 mmoles) in ethanol (16.4 mL, 0.2M) was added NaBH4 (249 mg, 6.58 mmoles) 0° C. The solution was stirred at 0° C. for 20 minutes and then warmed to room temperature for 20 minutes. The reaction was quenched with 1N HCl to a pH of ˜7, and extracted three times with ethyl acetate. The organics where combined, dried over magnesium sulfate, filtered and concentrated. Cis/trans isomers were then separated by chiral purification. Isolated 260 mg of trans isomer (24%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.39 (s, 2H) 1.51-1.65 (m, 2H) 1.83-1.96 (m, 2H) 2.01-2.21 (m, 2H) 2.38-2.47 (m, 1H) 7.03-7.14 (m, 2H) 7.41-7.58 (m, 2H)
Reaction SMILES: [CH2:1]([C:4]([CH2:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=C.O=O.[O:28]=[O+][O-].CSC>C(Cl)Cl.O>[CH3:8][O:7][C:5](=[O:6])[C:4]([CH2:1][CH:2]=[O:28])([CH2:13][C:14](=[O:25])[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=[O+][O-]
Reactant: C=CCC(CC(=O)c1ccc(C(F)(F)F)cc1)(C(=O)OC)C(=O)OC
Agent: O=O
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C(CC=O)(CC(=O)c1ccc(C(F)(F)F)cc1)C(=O)OC
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Dimethyl allyl{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonate (20 g, 0.055 mol) was dissolved in DCM (180 ml) and the solution was cooled to −78° C. Oxygen, containing ozone, was bubbled through the solution until a blue coloration persisted. The mixture was then purged with nitrogen for 10 min in then dimethyl sulfide (20 ml, 0.275 mol) was added and the mixture was stirred overnight at room temperature. Water (500 ml) was added and the mixture was extracted with DCM. The organic layer was separated and was washed with brine, then dried (MgSO4) and concentrated in vacuo to give the product as an oil. This was purified by chromatography on silica using hexane/EtOAc (9:1 to 1:1) as eluant to afford the product (4 g). 1H NMR (500 MHz, CDCl3): δ 3.46 (2H, s), 3.77 (7H, s), 3.93 (2H, s), 7.74 (2H, d, J 8.2), 8.06 (2H, d, J 8.1), 9.73 (1H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:25]=1[NH2:26]>C(OCCO)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([C:14]#[N:15])=[C:2]2[NH:26][C:25]1[C:24]([F:23])=[CH:30][C:29]([F:31])=[CH:28][C:27]=1[F:32]
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1c(F)cc(F)cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3c(F)cc(F)cc3F)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 200.0 mg (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 148.6 mg (1.0 mmol) of 2,4,6-trifluoro-aniline in 10 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 112.6 mg (37.4%) of the product as a yellow solid, m.p. 297° C. (dec.), mass spectrum (electrospray, m/e): M+H 330.0.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.N1C2C(=NC=CC=2)N([N:20]2[C:24](/[CH:25]=[C:26]3\[C:27](=[O:36])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[C:23]([CH3:37])[C:22]([C:38]([O-])=[O:39])=[C:21]2[CH3:41])N=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:36])/[C:26]/2=[CH:25]\[C:24]1[NH:20][C:21]([CH3:41])=[C:22]([C:38]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)=[O:39])[C:23]=1[CH3:37]
Reactant: NC1CCC(C(=O)O)CC1
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)O)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
4-Amino-cyclohexanecarboxylic acid (84 mg, 0.573 mmol) was added to a solution of A4 (200 mg, 0.478 mmol) and DIEA (0.125 mL, 0.717 mmol) in 15 mL of DMF. The mixture was stirred at r.t. LC-MS was used to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was triturated with ACN for several times to provide 4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-cyclohexanecarboxylic acid (180 mg, 88.5%).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[C:22]([O:27][CH2:28][CH3:29])(=[O:26])[C:23]([CH3:25])=O.C(O)(=O)C.[BH]C#N.[Na]>C(O)C>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3][CH:2]([NH:1][CH:23]([C:22]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25])[C:8]1=[O:9])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CSc2ccccc21
Agent: [BH]C#N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 2 h
Yield: 50.3 %

Procedure:
1.5 g of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 2.0 g of ethyl pyruvate were dissolved in 15 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 2 hours. Then, a solution of 420 mg of sodium boron cyanide hydride in 8 ml of ethanol was slowly added dropwise thereto. After this mixture was allowed to stand overnight, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 3:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.0 g of the desired compound in the form of an oily material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[N+:22]([O-])=O.C(O)(=O)C.C(O)C.C(#N)C>C1COCC1.[Zn]>[NH2:22][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:17])[CH3:18])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c([N+](=O)[O-])c2)c1
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(N)c2)c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a mixture of N-(4-bromo-3-nitrophenyl)-3-(2-cyanopropan-2-yl)benzamide 61 (400 mg, 1.030 mmol) and ZINC (1.011 g, 15.46 mmol) in THF (10 mL) at −5° C., acetic acid (1.180 mL, 20.61 mmol) was added. The reaction mixture was stirred at −5° C. for 30 min and 1 h at rt. Ethanol and acetonitrile were added and filtered off over filter. To the filtrate was added NaHCO3 solution and extracted with CH2Cl2. Organic layer was dried and evaporated to give crude N-(3-amino-4-bromophenyl)-3-(2-cyanopropan-2-yl)benzamide 62 (319 mg, 86%). (m/z)=358 and 360 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][N:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:88])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C1COCC1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:88][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][N:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccnc(Cl)c2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccnc(N)c2)CC1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 4-(2-chloroisonicotinoyl)piperazine-1-carboxylate (17-1, 524 mg) in dry toluene (10 mL) was added NaOtBu (216 mg, 2.25 mmole), racemic BINAP (150 mg, 0.24 mmole), Pd2(dba)3 (74 mg, 0.08 mmole), and benzophenone imine (0.32 mL, 1.93 mmole) then the mixture was heated to 80° C. After 18 hr the mixture was cooled to RT. A solution of 1N HCl:THF (1:1) was added and stirring continued. After 4 hr the mixture was neutralized with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 50-100% EtOAc/hexanes then 0-10%MeOH/CH2Cl2) gave the titled compound as a yellow solid. 1H-NMR (500 MHz, CDCl3) δ 8.12 (d, 1 H, J=5.13 Hz), 6.58 (d, 1 H, J=5.13 Hz), 6.47 (s, 1 H), 4.55 (bs, 2 H), 3.72-3.36 (m, 4 H), 1.47 (s, 9 H); MS (ES) (M+H)+ 307.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O:20][C:21](=O)[CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]2[CH:32]=1)C>ClCCl.[Cl-].[NH4+]>[Br:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:32]=[C:23]([CH2:22][C:21]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:20])[N:24]=2)[CH:27]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1cn2cc(Br)ccc2n1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cc1cn2cc(Br)ccc2n1)N1CCOCC1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
Add 2M trimethylaluminum in toluene (1.94 mL, 3.88 mmol) to a solution of morpholine (0.34 g, 3.88 mmol) in dichloromethane (10 mL). Stir for 10 min and add a solution of (6-bromo-imidazo[1,2-a]pyridin-2-yl)-acetic acid ethyl ester (1.1 g, 3.88 mmol) in dichloromethane (12 mL). Heat at 40° C. for 1 h, carefully dilute with saturated aqueous ammonium chloride and extract into dichloromethane. Concentration followed by filtration gives the titled compound (0.55 g, 43%) as a white solid. TOF MS ES+ exact mass calculated for C13H14BrN3O2 (p+1): m/z=324.0348; Found: 324.0330. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (m, 1H), 7.77 (s, 1H), 7.45 (d, J=10 Hz, 1H), 7.29 (dd, J=10, 2.0 Hz, 1H), 3.81 (s, 2H), 3.55-3.4 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[N:4]=[N:3]1.CON(C)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1)=[O:16].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl.C(=O)([O-])O.[Na+]>ClCCl.CO.O1CCCC1>[CH3:23][C:19]1[N:18]=[C:17]([C:15](=[O:16])[CH2:11][C:8]2[N:7]=[C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]3=[CH:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1cccc(C)n1
Reactant: Cc1ccc2nnn(C)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C(=O)Cc2ccc3nnn(C)c3n2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
To a stirred solution of 3,5-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine of Step B (200 mg, 1.35 mmol), 6-methylpyridine-2-carboxylic acid methoxy-methyl-amide (268 mg, 1.49 mmol), and tetrahydrofuran (5 ml) a 1.0 M solution of lithium hexamethyldisilazide (3.0 ml, 3.0 mmol) was added −78° C. in 10 min. The mixture was warmed up to ambient temperature in 90 min and stirred at the same temperature for 3 h. Methanol (10 ml) and 10% hydrochloric acid (1.5 ml) were added and stirring continued for 18 h. Sodium hydrogen carbonate (5 g) and dichloromethane (10 ml) were added and stirring continued for 10 min. After filtering off solids, the obtained mixture was concentrated. Chromatography on silica gel, eluting with ethyl acetate-hexane (2:3) yielded the title compound (110 mg, 30%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[S:36](Cl)(=[O:38])=[O:37])[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:35]=4[N:26]=[CH:27][CH:28]=[CH:29]5)(=[O:37])=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5cccnc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and quinoline-8-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:43]1([O:49][C:50]([O:52][CH:53]([O:55][C:56](=[O:77])[C@@:57]([CH2:75][OH:76])([CH3:74])[CH2:58][C@H:59]([NH2:73])[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)[CH3:54])=[O:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C>[CH:43]1([O:49][C:50]([O:52][C@H:53]([O:55][C:56](=[O:77])[C@@:57]([CH2:75][OH:76])([CH3:74])[CH2:58][C@H:59]([NH:73][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:63][CH:62]=2)[CH3:54])=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: CC(OC(=O)OC1CCCCC1)OC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](OC(=O)OC1CCCCC1)OC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,2,3-Triazole-4-carboxylic acid (45.2 mg, 400 μmol), DIPEA (209 μL, 1.2 mmol) and HCTU (165 mg, 400 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (193 mg, 400 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The products were purified and separated by preparative HPLC, then lyophilized to yield to yield compound ZC (20 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O2, 579.27. found 579.6, and compound ZD (15 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O2, 579.27. found 579.6.
Reaction SMILES: ClCCl.[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=4[O:30][CH3:31])=[N:14][C:13]=3[N:12]([CH3:32])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>O>[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)(=[O:28])=[O:27])=[CH:22][C:21]=4[O:30][CH3:31])=[N:14][C:13]=3[N:12]([CH3:32])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)N2CCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
To a 2 ml anhydrous dichloromethane solution of 87.2 mg (0.2 mmol) of the compound obtained in Example 48, 26.6 μl (0.24 mmol) of N-methylpiperazine and 70 μl (0.5 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 20 hours. Then, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1˜30/1) to obtain 87 mg (87%) of the captioned compound.