Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:20])[C:3]=1[C:21]#[N:22].[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+]>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([NH:34][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4](=[O:20])[C:3]=2[C:21]#[N:22])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Nc2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)C1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Chloro-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0.250 g, 0.80 mmole) in N,N′-dimethylformamide was added commercially available 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.1 eq 0.151 g, 0.88 mmole) and treated with 60% NaH oil dispersion. (1.5 eq, 0.029 g, 1.2 mmole). After stirring for 2 h, reaction was quenched with 10% HCl aq. (1 ml) then H2O (5 ml). A solid formed that was collected and dried. No further purification was necessary, afforded 3-[3-Cyano-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinolin-4-ylamino]-azetidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.322 g, 90%, calc M+H 449, obs M+H 449).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH2:10][CH2:11][OH:12]>C(O)C>[OH:12][CH2:11][CH2:10][CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: NCCCO
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCCCO)CS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of 4-thioxothiazolidin-2-one (2.66 g) in ethanol (50 mL) was added 3-aminopropan-1-ol (1.50 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (2.70 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)=[CH:22][CH:23]=2)[O:18][CH2:17]1>>[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][N:26]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:15])=[CH:22][CH:23]=2)[O:18][CH2:17]1
Reactant: CC(C)c1ccc(NCc2ccc3c(c2)OCO3)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc3c(c1)OCO3)c1ccc(C(C)C)cc1)CCC2
Yield: 58.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(1,3-dioxaindan-5-yl)methyl](4-isopropylphenyl)amine (1.3 g) as starting materials, N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.3 g) was obtained. melting point: 97-98° C.
Reaction SMILES: [CH:1]([N:4]=[C:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11](=[O:22])[C:12](=[CH:18]OCC)[C:13](OCC)=[O:14])[CH3:9]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:5]([N:4]1[C:1]([CH3:3])=[CH:2][CH:18]=[C:12]([C:11]([O:10][CH2:8][CH3:9])=[O:22])[C:13]1=[O:14])([CH3:7])[CH3:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)=NC(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Temperature: 185 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of isopropyl(1-methylethylidene)amine (7.94 g, 80.0 mmol, prepared according to Newcomb, Martin et al., J. Amer. Chem. Soc., 1990, 112, 5186) and diethyl(ethoxymethylene)malonate (17.31 g, 80.0 mmol) in diphenyl ether (48 mL) was stirred in a sealed tube at 180-190° C. for 18 h. After cooling, the mixture was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=1/1˜1/2) to give 12.5 g (70%) of the title compound as brown oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7].[C:21]([O-:24])(=O)C.[Na+].CN(C)[CH:28]=[O:29]>O>[CH2:6]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:28]=[O:29])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH:21]=[O:24])[CH:13]=2)[CH3:7]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: CC(=O)[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
A 271 ml quantity of dimethylformamide (DMF, 3.5 mol) was added to a 1-liter, 3-neck round bottom flask equipped with a mechanical stirrer, a thermometer, and an addition funnel. The contents were cooled in a salt/ice bath. When the temperature inside the flask reached 0° C., 326 ml of phosphorus oxychloride (POCl3, 3.5 mol) was slowly added. During the addition of POCl3, the temperature inside the flask was not allowed to rise above 5° C. After the addition of POCl3, the reaction mixture was allowed to warm to room temperature. After the flask warmed to room temperature, N-ethylcarbazole (93 g) in 70 ml of DMF was added and then the flask was heated to 90° C. for 24 hours using a heating mantle. Next, the reaction mixture was cooled to room temperature and the reaction mixture was added slowly to a cooled 4.5 liter beaker containing a solution comprising 820 g of sodium acetate dissolved in 2 liters of water. The beaker was cooled in an ice bath and stirred for 3 hours. The brownish solid obtained was filtered and washed repeatedly with water, followed by a small amount of ethanol (50 ml). After washing, the resulting product was recrystallized once from toluene using activated charcoal and dried under vacuum in an oven heated at 70° C. for 6 hours to obtain 55 g (46% yield) of N-ethyl-3,6-diformylcarbazole. The 1H-NMR spectrum (250 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 10.12 (s, 2H); 8.63 (s, 2H); 8.07 (d, 2H); 7.53 (d, 2H); 4.45 (m, 2H); 1.53 (t, 3H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1

Procedure:
Reaction of (RS)-3-[2-(tetrahydropyran-2-yloxymethyl)-pyridin-4-yl]-benzoic acid methyl ester with tert.-butyl acetate according to general procedure K (method d; example K15) yielded compound K9.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([C:7](C)=[O:8])[CH3:6].[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][OH:27])=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-:28].[Na+].[OH2:30]>>[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][OH:27])=[N:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[OH:28][C:5]([CH2:10][CH3:11])([CH3:6])[C:7]([OH:8])=[O:30]
Reactant: O
Reactant: [OH-]
Reactant: CCC(C)=O
Agent: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(C)(O)C(=O)O
Reaction time: 1 h

Procedure:
A solution of 6 ml of chloroform and of 6,8 ml of methyl ethyl ketone is added dropwise in about 30 minutes to a suspension of 5.9 g of 1-benzyl-3-hydroxymethyl-indazole, prepared as described above, of 12 g of NaOH and of 35 ml of methyl ethyl ketone. When the addition is over, the reaction mixture is heated to reflux. After 60 minutes, the reaction mixture is cooled, water is added and the aqueous phase is separated and acidified. The resulting oil is extracted with diethyl ether and the solvent is evaporated to give an oil that hardens and is crystallized from hexane/ethyl acetate 1:1; the ether of 1-benzyl-3-hydroxymethyl-indazole with 2-hydroxy-2-ethyl-propionic acid is thus obtained (Compound I, R=CH3, R'=C2H5, R"'=H), m.p. 115°-116° C.
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3[CH2:20][NH:21][CH2:22][CH2:23][C:18]=3[NH2+:17][N:16]=2)=[CH:11][CH:10]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3[CH2:20][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][CH2:23][C:18]=3[NH:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: Brc1ccc(C2=N[NH2+]C3=C2CNCC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Reaction time: 2.5 h
Yield: 50.8 %

Procedure:
To a stirred solution of 3.11 g (11.1 mmol) of 3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium trifluoroacetate and 4.71 mL (33.5 mmol) of Et3N in DMF (55 mL) was slowly added 1.21 mL (15.6 mmol) of methanesulfonyl chloride. After 2.5 h, the solvent was removed under reduced pressure and the residue was diluted with CH2Cl2 (100 mL) and saturated NaHCO3 (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by column chromatography (silica, 0-5% MeOH/CH2Cl2) afforded 2.01 g (50%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): m/z calculated for C13H14BrN3O2S [M++H] 356.00, observed 356.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:15]1[C:20]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][O:8][C:15]1[C:20]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: OCCOc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(O)c2)CC1
Temperature: 65 °C
Reaction time: 1.75 h
Yield: 94 %

Procedure:
To a stirred solution of 2-(3-hydroxyphenoxy)ethanol (7.71 g, 0.05 mol) in dry DMF (100 mL) at ˜0° C. (ice bath) was added NaH (3.90 g, 0.163 mol) in portions under N2. When the H2-evolution had ceased, a solution of 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (0.05 mol, 14.9 g; from Example 52, Step 1) in dry DMF (70 mL) was added in one portion. The mixture was stirred at 65° C. for 1.75 h. After cooling, the reaction was quenched by addition of H2O in DMF. The mixture was filtered and concentrated. in vacuo. The residue was dissolved in EtOAc, washed with 1 M KHSO4 and water, dried (Na2SO4+ Norit), and concentrated in vacuo to give the title compound as a beige sticky oil. Yield 94%. This product was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.ClCCl.C(O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1F
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 500 mg, 1.64 mmol), tetrabutylammonium iodide (605 mg, 1.64 mmol) and 2,4-difluorobenzyl bromide (840 μL, 6.54 mmol) in dimethylformamide (10 mL) was heated at 100° C. overnight. Dichloromethane (250 mL) was added and the solution was washed with water (3×100 mL), aqueous sodium thiosulfate (100 mL), and brine (100 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 45-50% ethyl acetate/petroleum ether. Fractions homogeneous for the product were concentrated to give an oil which was co-evaporated with ethanol and then held under high vacuum to give (4S,7R)-1-(2,4-difluoro-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (508 mg, 71%). APCI(+)-MS (M+H) 431.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].CN(C)C=O.I[CH2:32][CH3:33]>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:9]=1)([O:3][CH2:32][CH3:33])=[O:2]
Reactant: CCI
Reactant: O=C(C#Cc1ccc(C(=O)O)cc1)Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C#CC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of 1.00 g (3.77 mmol)3 -(4-carboxyphenyl)-N-phenylpropiolamide, 1.00 g (excess) anhydrous sodium bicarbonate and 25 mL dry N,N-dimethylformamide was stirred at room temperature. Added was 1.95 g (excess) iodoethane and the mixture heated at 70°-80° C. for 3 hrs. The mixture was allowed to cool to room temperature and poured into 75 mL water. The resulting solid was filtered and recrystallized from ethanol/water to provide 0.99 g (3.37 mmol, 90%)3-(4-carbethoxyphenyl)-N-phenylpropiolamide as a pale, yellow powder, mp=114°-115° C. NMR (CDCl3 /TMS): 1.40 (t, 3H), 4.39 (q, 2H), 7.16 (t, 1H), 7.36 (t, 2H), 7.60 (d, 4H), 7.90 (s, 1H), 8.03 (d, 2H)). IR (KBr): 3292, 2210, 1692, 1660. High resolution mass spectrum: Calculated; 294.113019. Measured; 294.112376.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br.S([O-])([O-])=O.[Na+].[Na+].O>C(O)(=O)C>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(C(=O)O)c(F)c1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(F)c(C(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
2-Fluoro-4-methoxybenzoic acid (10.0 g) was suspended in acetic acid (80 mL). To the suspension was slowly added dropwise bromine (20.7 g)/acetic acid (20 mL) solution. After completion of the dropwise addition, the mixture was stirred at 25° C. for 3 hr and further at 60° C. for 4 hr, the completion of the reaction was confirmed by HPLC. After cooling to room temperature, to the suspension was added dropwise an aqueous solution of sodium sulfite (9.63 g) and water (100 mL). After completion of the dropwise addition, the mixture was stirred at 25° C. for 2 hr, and then for 2 hr under ice-cooling. The precipitated crystals were collected by filtration, washed four times with water (30 mL), and vacuum dried to give 5-bromo-2-fluoro-4-methoxybenzoic acid as white crystals (14.5 g, 99%).
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([CH2:3][CH3:4])[CH3:2].C(C1CCCC([Cl:22])C1=O)(C)(C)C>>[CH:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([Cl:22])[C:6]1=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Reactant: CCC(C)C1CCCCC1=O
Product: CCC(C)C1CCCC(Cl)C1=O

Procedure:
The chlorination of 2-sec-butylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:21]([NH2:23])=O)=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[N:12]=[CH:13][CH:14]=[N:15]3)[S:5][CH:6]=1.C[N:25](C=O)C.NN.[CH3:31][C:32]([N:34](C)C)=O.CC(N(C)C)=O>>[CH3:1][C:2]1[C:3]([C:21]2[NH:23][N:34]=[C:32]([CH3:31])[N:25]=2)=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[N:12]=[CH:13][CH:14]=[N:15]3)[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)Cc2cccc3nccnc23)c1C(N)=O
Reactant: CN(C)C=O
Reactant: CC(=O)N(C)C
Agent: NN
Product: Cc1n[nH]c(-c2c(C)csc2NC(=O)Cc2cccc3nccnc23)n1
Temperature: 90 °C

Procedure:
This analog was made from 4-methyl-2-(2-(quinoxalin-5-yl)acetamido)thiophene-3-carboxamide using protocol D except that the DMF was also used in the DMA-DMA step with heating to 95° C. (rather than 110° C.) and the hydrazine step was heated at 95° C. (rather than 90° C.). Method[7], MS(ESI) 365.1 [M+H], Retention time=3.58 min; 1H-NMR (300 MHz, CDCl3) δ 11.9 (s, 1H), 8.87 (s, 2H), 8.17-8.14 (m, 1H), 7.92-7.83 (m, 2H), 6.50 (s, 1H), 4.53 (s, 2H), 2.45 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][NH:11][CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1)[CH3:30].C(N(CC)CC)C.O>ClCCl>[CH2:29]([O:31][C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:11]2[CH2:12][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:28])[C@:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[C@@H:10]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:41])=[CH:35][CH:34]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)N2C[C@H](c3cccc(Cl)c3F)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile prepared in Example 3 (0.44 g, 1.04 mmol) in dichloromethane (5 mL) was added 4-isocyanato-benzoic acid ethyl ester (Aldrich, 0.22 g, 1.14 mmol) and triethylamine (0.22 mL, 1.56 mmol). The reaction mixture was stirred at room temperature for 30 min. Water was added, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25% EtOAc in hexanes) to give rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid ethyl ester as a white solid (0.59 g, 92%)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][N:31]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: O=C(NCc1cccnc1)c1ccc(Nc2ccc(Cl)n3ncnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3ncnn23)ccn1
Temperature: 110 °C
Yield: 77.2 %

Procedure:
A suspension of 4-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-N-pyridin-3-ylmethyl-benzamide (50 mg, 132 μmol), 2-methoxypyridin-4-boronic acid (40 mg, 260 μmol), Pd(PPh3)4 (46 mg, 40 μmol) and NaOtBu (51 mg, 530 μmol) in 1.2 mL of DMF/water (5:1, degassed) is degassed for 1 min in a sealed tube. The tube is sealed and the reaction mixture heated at 110° C. for five hours. After evaporation of the solvents, the residue is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 97:3) affording the title compound (46 mg), which is isolated as a mixture containing 50% of product.
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:34])[CH2:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:33])([F:32])[F:31])[C:23]=2[N:22]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:36][C:37]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:38]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[CH3:36][C:37]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:38]=1[CH2:9][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:34])[CH2:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:33])[F:32])[C:23]=2[N:22]=1)[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)Cc1nc2c(C(F)(F)F)cccc2[nH]1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)Cc1nc2c(C(F)(F)F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of {(2S,3S)-3-hydroxy-2-[2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (87 mg, 0.18 mmol) in MeOH (3 mL) was charged with 5% Pd/C, Degussa style (17 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.024 mL, 0.16 mmol) and sodium cyanoborohydride (12 mg, 0.2 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=477.4.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([C@@H:20]1[C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C@H:31]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[O:33])[CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C@@H:20]4[C@@H:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:23][N:22]([C@H:31]([CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)[C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)=[O:33])[CH2:21]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(C3CCNCC3)s2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4cnc(-c5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To 12 mg of 4-(2-phenyl-thiazol-5-yl)-piperidine (from Step B) in 3 ml of DCE was added 35 mg of a-(R)-(3-(R)-formyl4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, p-methoxybenzyl ester (prepared above as Aldehyde 5) followed by 19 mg of sodium triacetoxyborohydride. The reaction was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane followed by 50% EtOAc in hexane to give 28 mg of the title compound.