Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:43])[C:17]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([O:27][C:28](=[O:42])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:23][CH2:22]2)=[O:18])=[O:11])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[NH2:48][CH2:49][C@@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53].C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:55]([Si:52]([CH3:54])([CH3:53])[O:51][C@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[CH2:49][NH:48][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:43])[C:17]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([O:27][C:28](=[O:42])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:25][CH2:26]2)=[O:18])=[O:11])=[CH:7][CH:8]=1)([CH3:58])([CH3:57])[CH3:56]
Reactant: CN(CCCCC(=O)Nc1ccc(C=O)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCC(=O)Nc1ccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-formyl-phenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (2.83 g, 4.84 mmol) and 5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one acetic acid salt (1.91 g, 4.84 mmol) in a 1:1 mixture of MeOH:DCM (40.0 mL, 312 mmol) was added sodium triacetoxyborohydride (3.08 g, 14.5 mmol). The reaction mixture was stirred at room temperature for 2 h and then the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. The solid was purified by silica gel flash chromatography (0-30% MeOH in DCM+0.5% NH4OH) to give the title compound (3.60 g, 82% yield) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][C:16]1[O:20][N:19]=[CH:18][CH:17]=1.CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9]([O:14][CH2:15][C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCc1ccno1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCc1ccno1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
A 631 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride in 2 mL of methylene chloride was added to a solution of 310 mg (3.13 mmol) of 5-hydroxymethyisoxazole and 0.344 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 4 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 2% ethyl acetate in methylene chloride. The solvent was removed and the product dried to afford 0.473 g of the title compound, which was taken directly to the next step.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH2:21][C:22]([CH3:25])([CH3:24])[N:23]=2)=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH3:11])[C:7]=2[CH:12]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(#N)C>[CH3:24][C:22]1([CH3:25])[CH2:21][O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:2]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[C:3]3[CH:4]=[CH:5][C:6]4[N:10]=[N:9][N:8]([CH3:11])[C:7]=4[CH:12]=3)=[CH:14][CH:15]=2)=[N:23]1
Reactant: c1c[nH]cn1
Reactant: Cn1nnc2ccc(C(Cl)c3ccc(C4=NC(C)(C)CO4)cc3)cc21
Solvent: CC#N
Product: Cn1nnc2ccc(C(c3ccc(C4=NC(C)(C)CO4)cc3)n3ccnc3)cc21
Yield: 65.6 %

Procedure:
A solution of 10 parts of 6-[chloro[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]methyl]-1-methyl-1H-benzotriazole and 10 parts of 1H-imidazole in 80 parts of acetonitrile was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated and the product was extracted with ethyl acetate. The extract was washed with a diluted potassium carbonate solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 7.1 parts (65.6%) of 6-[[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl](1H-imidazol-1-yl)methyl]-1-methyl-1H-benzotriazole as a residue (int. 231).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([NH2:45])=[N:35][C:36]=1[C:37]#[C:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH:3]([CH3:7])[C:4]([NH:45][C:34]1[CH:33]=[CH:32][C:31]([Br:30])=[C:36]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:35]=1)=[O:6])[CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)c(C#Cc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (36 g, 177 mmol) and N,N′-dicyclohexylcarbodiimide (22.5 g, 109 mmol) in DCM (150 ml) is stirred with ice bath cooling for 30 minutes. A solution of 5-bromo-6-(2-phenylethynyl)pyridin-2-amine B2a (20 g, 73.2 mmol) in DCM (100 ml) is added. After stirring for 7 days at RT the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 25 g (74%). HPLC-MS: M+H=458/460; tR=2.33 min (*Method—1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([CH:49]([CH3:51])[CH3:50])[N:31](/[CH:40]=[CH:41]/[C@@H:42]([OH:48])[CH2:43][C:44](OC)=[O:45])[C:32]=2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:24][CH:23]=1>C1CCCCC1.C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:29]=[C:30]([CH:49]([CH3:51])[CH3:50])[N:31](/[CH:40]=[CH:41]/[C@@H:42]([OH:48])[CH2:43][C:44](=[O:45])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:32]=2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)CC(=O)CC(=O)OC(C)(C)C

Procedure:
A solution of dry diisopropylamine (0.77 ml) in dry cyclohexane (15.6 ml) at 3° under nitrogen was treated dropwise with n-butyl lithium solution (1.55M in hexanes, 3.54 ml). After 15 min t-butyl acetate (0.74 ml) was added dropwise. After 30 min the mixture was cannulated into a solution of methyl (3S,E)-5-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3-hydroxy-4-pentenoate (334 mg) in dry THF (7.8 ml) at 3° under nitrogen over 15 min. After 1 h the mixture was quenched with saturated aqueous ammonium chloride solution (3.5 ml) and then diluted with water. The mixture was then and extracted with ethyl acetate (3×20 ml). The combined extracts were dried and evaporated to a gummy solid (518 mg) which was treated with ether (4 ml) and then cyclohexane (4 ml) and cooled in an ice bath. The solid was collected, washed and dried to give the title compound (239 mg) as a white powder; δ(CDCl3) 1.41 (d, J7.5 Hz, 6H, CH(CH3)2), 1.46 (s, 9H, C(CH3)3), 2.59 (d, J7.5 Hz, 2H, C(OH)CH2CO), 3.02 (bs, 1H, OH), 3.14 (septet, J7.5 Hz, 1H, --CH(CH3)2), 3.35 (s, 2H, CH2CO2R), 4.63 (m, 1H, CHOH), 5.39 (dd, J14 and 7 Hz, 1H, N--CH=CH--C), 6.70 (d, J14 Hz, 1H, N--CH=CH--C), 6.90 and 7.10 (2t, J9 Hz, each 2H, C-3 and C-5 protons of 4-fluorophenyls), 7.17-7.47 (m, 4H, C-2 and C-6 protons of 4-fluorophenyls). Also present was a trace of the enol form, δ values include 1.52 (s, --C(CH3)3), 4.51 (m, CHOH), 4.89 (s, C(OH)=CHCO2), 5.38 (dd, J14 and 7 Hz, --N--CH=CH), 6.64 (d, J14 Hz, NCH=CH). Chiral hplc detected none of the other enantiomer. A second crop of title compound (56 mg) was also obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1>CO.C(Cl)Cl.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#Cc2cccc(N)c2)ccn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(N)c2)ccn1
Yield: 98.1 %

Procedure:
To a mixture of tert-butyl {4-[(3-aminophenyl)ethynyl]pyridin-2-yl}carbamate (328 mg, 1.06 mmol) in methanol (8 mL) and methylene chloride (8 mL) was added 10% palladium on carbon (100 mg, 0.09 mmol). The resultant mixture was hydrogenated at 30 psi for 18 hours. The reaction mixture was filtered, washed with MeOH/DCM and concentrated to give the desired product (326 mg, 98%) as a light brown powder. LCMS for C18H24N3O2 (M+H)+: m/z=314.1.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])[CH2:5][CH2:4]1.Br[CH2:35][C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CCCCC.O1CCCC1>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[N:10]([CH2:35][C:36]3[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=3)[C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[C:13]([CH3:14])=[C:8]2[C:6]([CH:3]2[CH2:5][CH2:4]2)=[O:7])=[CH:33][CH:32]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(Cc2cccc(C(=O)OC(C)(C)C)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (12.1 mg, 0.31 mmol; 60% suspension in mineral oil) is washed with pentane (3×3 ml), then treated with a solution of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (100 mg, 0.235 mmol) in tetrahydrofuran (5 ml). After 5 minutes, the reaction is treated with a solution of tert.-butyl 3-(bromomethyl)benzoate (77 mg, 0.28 mmol) in tetrahydrofuran (5 ml) and then stirred at room temperature overnight (16 h). The reaction mixture is quenched with water (50 ml) and extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: [F:1][C:2]1[C:3]([O:27][CH3:28])=[C:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][CH2:13][CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:27][CH3:28])[C:2]([F:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl 4-[2-(5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.0245 g, 0.0623 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0100 g, 0.0685 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(2{-2-[(1H-indazol-3-yl)methylene]-5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0231 g, 71%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:21]1[C:17]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:15])=[CH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]1=2
Reactant: Brc1cc2ccccc2s1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc3ccccc3s2)CCN1c1cnccc1C1CC1
Yield: 34.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 150 mg, 0.738 mmol) was reacted with 2-bromobenzo[b]thiophene (188 mg, 0.886 mmol), 1,4-dioxane (6 mL), copper iodide (14.0 mg, 0.0739 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (10.5 mg, 0.0739 mmol) and potassium phosphate (470 mg, 2.21 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in CHCl3) afforded 85 mg of the product (34% yield).
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[C:9]1([CH2:15][C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:4]([CH:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:16]#[N:17])=[O:5]
Reactant: CCOC=O
Reactant: N#CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CC(C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a suspension of sodium methoxide (10.8 g) in benzene (300 ml) is added dropwise with stirring a mixture of ethyl formate (16.28 g) and phenylacetonitrile (23.4 g) under ice cooling. After 30 minutes, the ice bath is taken off. After reacting for 3 hours, ice water is added to the reaction mixture, and the aqueous layer is separated. The organic layer is washed with 0.5 N sodium hydroxide solution (100 ml×3), and the aqueous layer and the washings are combined and adjusted to pH 3-4 with conc. hydrochloric acid. The mixture is stirred under ice cooling for 20 minutes, and the resulting precipitate is separated by filtration and washed with water to give α-formylphenylacetonitrile (21.13 g). The product is used in the subsequent procedure without further purification.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:22]=[C:10]3[N:11]=[C:12]([CH3:21])[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:14](O)[N:9]3[N:8]=2)[CH:2]=1.P(Cl)(Cl)([Cl:31])=O.C([O-])(O)=O.[Na+]>>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:22]=[C:10]3[N:11]=[C:12]([CH3:21])[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:14]([Cl:31])[N:9]3[N:8]=2)[CH:2]=1
Reactant: COC(=O)Cc1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)Cc1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1Cl
Yield: 87.1 %

Procedure:
A suspension of methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (748 mg, 1.998 mmol) in phosphoryl trichloride (15 ml, 1.998 mmol) was heated to reflux for 16 hrs. Concentrated to remove most of phosphoryl chloride to leave an oil, which was carefully neutralized w/sat'd NaHCO3 to PH=˜7. The precipitates was filtered and washed w/water, dried in vacuo to afford methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (720 mg, 1.741 mmol, 87% yield). The crude was used for the next reaction directly. 1H-NMR (500 MHz, CDCl3) δ ppm 2.75 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 7.43-7.44 (1H, m), 7.49-7.52 (2H, m), 7.62-7.63 (1H, m), 7.74-7.78 (3H, m), 8.36-8.38 (1H, m), 8.65 (1 H, s).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].[BH4-].[Na+].Cl>C(Cl)Cl.CO>[C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1/[CH:19]=[CH:20]/[C@@H:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C(=O)C3CCCCC3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: Cl
Agent: [BH4-]
Agent: [Ce+3]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C1CC2C(CC(OC(=O)c3ccccc3)C2/C=C/[C@H](O)C2CCCCC2)O1
Reaction time: 2 h
Yield: 15.7 %

Procedure:
To a solution of enone 4 (150 g, 392 mmol), cerium trichloride heptahydrate (152 g, 408 mmol), methanol (500 mL), and CH2Cl2 (1.5 L) at 0° C. was added NaBH4 (14.4 g) in 0.2 g portions over 1 h. After stirring for 2 h, the reaction was poured into 1M HCl (500 mL), the layers were separated, the aqueous layer was extracted with CH2 Cl2 (2×300 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated to provide 150.4 g (100%) of a 1:1 mixture of the two diastereomeric allylic alcohols. Separation of 200 g of the mixture (from several combined reactions) by HPLC (40% ethyl acetate in hexane) afforded 23.7 g (12%) of alcohol 42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:54]=[CH:53][C:16]([C:17]([N:19]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:45][C:46]([OH:48])=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:53][CH:54]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Prepared using General Procedure 8: To a stirring solution of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-34 (54.0 mg, 0.068 mmol) in DCM (2 mL) was added TFA (2 mL). After stirring at room temperature for 2 h, the solvent was concentrated and the reaction mixture was further concentrated from acetonitrile (2×3 mL). The solid was re-slurried from DCM (4 mL), washed with DCM (2 mL) and acetonitrile (2 mL) to afford 44 mg (87%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 354. LCMS-ESI (m/z) calculated for C41H33F3N4O6: 734; found 735 [M+H]+, tR=9.40 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.34 (s, 1H), 8.33-8.22 (m, 2H), 8.15-8.06 (m, 2H), 8.02-7.91 (m, 2H), 7.76-7.69 (m, 2H), 7.69-7.56 (m, 3H), 7.53-7.33 (m, 6H), 7.26-7.14 (m, 2H), 4.77 (s, 1H), 4.69 (s, 1H), 4.04 (s, 1H), 3.98 (s, 1H), 3.90-3.77 (m, 5H), 2.39 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[ClH:6].[CH3:7][N:8]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)O)[CH3:9].[OH-].[Na+]>>[ClH:6].[CH3:7][N:8]([CH3:9])[CH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)CC1CCCCC1(O)c1cccnc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(C)C[C@@H]1CCCC[C@H]1c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.2 %

Procedure:
40 ml 96% strength sulfuric acid were added to 7.8 g dimethylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride, while cooling with ice. When the evolution of gas had ended, the mixture was stirred at room temperature for 45 minutes. The solution was subsequently poured on to approx. 400 g of crushed ice. It was then rendered alkaline by addition of sodium hydroxide lozenges, while cooling with ice, and the mixture was extracted 3× with a total of 600 ml ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness on a rotary evaporator in vacuo at 50° C. 4.2 g of the title compound were obtained in this way.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.Cl.[NH2:22][OH:23].[OH-].[Na+]>CCO.O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:22][OH:23])=[CH:9][CH:8]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-(2-Trifluoromethyl-benzyloxy)-benzaldehyde (which may be prepared as described in Panetta, J. A. et al. U.S. Pat. No. 6,251,928 Column 25; 28.8 g, 102.7 mmol) was combined with 9:1 EtOH/H2O (210 mL) and hydroxylamine hydrochloride (11 g, 158 mmol) was added. A solution of 3.15 M NaOH in 9:1 EtOH/H2O (70 mL, 221 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h and then heated at 50° C. for 1 h. The mixture was partitioned between EtOAc and H2O, and the organic layer was dried, filtered, and evaporated to give 4-(2-trifluoromethyl-benzyloxy)-benzaldehyde oxime (14 g, 46%).