Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(NS(C3C=C4C(C=CC(C(O)=O)=C4)=CC=3)(=O)=O)=O)=CC=2C(N2CCC3C(=CC=CC=3)C2)=O)C=1C.[CH2:56]([N:60]([CH2:109][C:110]1[CH:115]=[CH:114][C:113]([Cl:116])=[C:112]([Cl:117])[CH:111]=1)[C:61]([C:63]1[C:67]([Cl:68])=[C:66]([CH3:69])[N:65]([C:70]2[CH:96]=[CH:95][C:73]([C:74]([NH:76][S:77]([C:80]3[CH:89]=[C:88]4[C:83]([CH:84]=[CH:85][C:86]([C:90]([O:92]CC)=[O:91])=[CH:87]4)=[CH:82][CH:81]=3)(=[O:79])=[O:78])=[O:75])=[CH:72][C:71]=2[C:97]([N:99]2[CH2:108][CH2:107][C:106]3[C:101](=[CH:102][CH:103]=[CH:104][CH:105]=3)[CH2:100]2)=[O:98])[N:64]=1)=[O:62])[CH2:57][CH2:58][CH3:59]>>[CH2:56]([N:60]([CH2:109][C:110]1[CH:115]=[CH:114][C:113]([Cl:116])=[C:112]([Cl:117])[CH:111]=1)[C:61]([C:63]1[C:67]([Cl:68])=[C:66]([CH3:69])[N:65]([C:70]2[CH:96]=[CH:95][C:73]([C:74]([NH:76][S:77]([C:80]3[CH:89]=[C:88]4[C:83]([CH:84]=[CH:85][C:86]([C:90]([OH:92])=[O:91])=[CH:87]4)=[CH:82][CH:81]=3)(=[O:79])=[O:78])=[O:75])=[CH:72][C:71]=2[C:97]([N:99]2[CH2:108][CH2:107][C:106]3[C:101](=[CH:102][CH:103]=[CH:104][CH:105]=3)[CH2:100]2)=[O:98])[N:64]=1)=[O:62])[CH2:57][CH2:58][CH3:59]
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)OCC)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 82.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 46A, ethyl 7-(N-(4-(3-(butyl(3,4-dichlorobenzyl)carbamoyl)-4-chloro-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)-2-naphthoate (91 mg, 0.10 mmol) was converted to the title compound (73 mg, 83%). 1H NMR (DMSO-d6, mixture of amide rotamers) δ 8.49 (s, 0.5H), 8.45 (s, 0.5H), 8.38 (s, 0.5H), 8.09 (dd, J=11.9, 8.4 Hz, 1.5H), 8.01-7.79 (m, 3H), 7.60-7.41 (m, 2H), 7.29-6.92 (m, 3.5H), 6.81 (d, J=8.4 Hz, 0.5H), 4.80-4.16 (m, 3H), 3.68-2.91 (m, 10.5H), 2.81-2.60 (m, 2H), 2.39-2.30 (m, 0.5H), 2.21-2.06 (m, 3H), 1.42-1.06 (m, 3H), 1.01-0.88 (m, 1.5H), 0.86-0.76 (m, 1H), 0.71-0.50 (m, 1.5H); MS(ESI+) m/z 803.4 (M+H)+.
Reaction SMILES: [C-]#N.[Li+].P([C:12]#[N:13])(OCC)(OCC)=O.O=[C:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])=[CH:16]1>O1CCCC1>[C:12]([C:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:17](=[CH:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])[CH:16]=1)#[N:13]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.0 g of lithium cyanide and 16 ml of diethyl cyanophosphate were dissolved in 200 ml of dry tetrahydrofuran, and 10 g of methyl 3-oxo-4-androstene-17β-carboxylate were added little by little at room temperature to the resulting solution. The reaction mixture was stirred at room temperature for 15 minutes, after which the tetrahydrofuran was removed by distillation under reduced pressure. The residue was dissolved in 300 ml of a 1:1 by volume mixture of ethyl acetate and benzene, and the resulting solution was washed four times with water and then once with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 100 ml of dry benzene, and 2 ml of a boron trifluoride-diethyl ether complex was added to the resulting solution, which was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with 300 ml of diethyl ether. The diluted mixture was washed with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 100 g of silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane in ratios ranging from 4:96 to 12:88 by volume as the eluent, to give 9.5 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][NH2:43])[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][NH:43][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15]([CH3:18])(=[O:17])=[O:16])[C:31]([F:32])=[CH:30][N:29]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3cccc(Cl)c3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with 2-(3-chloro-phenyl)-ethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 518. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.18 (s, 1H), 7.97 (d, 1H), 7.49 (m, 2H), 7.15 (m, 4H), 4.56 (s, 2H), 3.93 (m, 1H), 3.64 (t, 2H), 3.33 (m, 2H), 3.04 (s, 3H), 2.98 (m, 2H), 2.91 (t, 2H), 1.91 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc(F)cc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(4-fluorobenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>>[C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]([CH2:29][C:30]([OH:32])=[O:31])[S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[CH2:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
prepared by reaction of 2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid p-tolylamide with tert-butyl bromoacetate
Reaction SMILES: CC1C=CC(B(O)O)=CC=1.ClC1C(C)=C(Cl)N=CN=1.[Cl:20][C:21]1[C:26]([CH3:27])=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](F)(F)F)=[CH:30][CH:29]=2)[N:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([CH3:27])=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:24]=[CH:23][N:22]=1
Reactant: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Agent: Cc1c(Cl)ncnc1Cl
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ncnc(Cl)c2C)cc1

Procedure:
Prepared from 4-methylphenylboronic acid and and 4,6-dichloro-5-methylpyrimidine using the procedure described for Intermediate 62.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:18])([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[C:27]([CH3:32])([CH3:31])[C:28](Cl)=O.C[CH2:34][O:35]CC>>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:34](=[O:35])[C@H:28]([CH:27]([CH3:32])[CH3:31])[O:18][C@:8]([C:13]#[C:14][CH:15]3[CH2:16][CH2:17]3)([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: CC(C)(Br)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Reactant: CCOCC
Solvent: c1ccncc1
Product: CC(C)[C@@H]1O[C@](C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 14, Part A) in 15 mL of dry ether was added 0.100 mL of dry pyridine and 228 mg of α-bromoisobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and etracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated. Since TLC. showed the reaction had only gone halfway to completion, the crude product was redissloved in 15 mL of DMF and subjected to the same reaction conditions as above for another 24 h. After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) and then recrystallized from ethyl acetate/hexanes to give 45 mg of the title compound as colorless crystals: mp 167°; Anal. Calcd. for C18H17NO2F3Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 58.11; H, 4.59; N, 3.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=O.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]3([CH3:16])[CH2:15][O:14][CH2:13]3)/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC1(COc2ccc(Cl)cc2C=O)COC1
Solvent: C1CCNC1
Solvent: CO
Product: CC1(COc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)COC1
Temperature: 70 °C
Yield: 77.5 %

Procedure:
To the mixture of 5-chloro-2-(3-methyl-oxetan-3-ylmethoxy)-benzaldehyde (2 g, 8.3 mmol) and 6-Chloro-1,3-dihydro-indol-2-one (1.27 g, 7.6 mmol) in methanol (20 mL) was added pyrrolidine (0.6 g, 9.1 mmol) dropwise. The mixture was then heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered and resulting precipitate was collected, dried to give title compound as a yellow solid (2.3 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]#[N:30])=[CH:19][CH:18]=2)[CH:7]=[C:8]([CH2:10][CH2:11]C(OC)=O)[CH:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:31].[Na+].Cl.[CH3:34][OH:35]>>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]#[N:30])=[CH:21][CH:22]=2)[CH:7]=[C:8]([CH:10]([CH3:11])[C:34]([OH:35])=[O:31])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: [OH-]
Reactant: CCCCc1cc(CCC(=O)OC)cn1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Product: CCCCc1cc(C(C)C(=O)O)cn1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-[2-(n-butyl)-1-(2"-cyanobiphenyl-4'-ylmethyl)pyrrol-4-yl]propionate (AG) (5.8 g) (prepared, e.g., as described in Preparation 23), in methanol (100 ml) was added 10% sodium hydroxide solution (35 ml), and the resulting solution was gently heated under reflux for 4 hours. After cooling to 0° C., the solution was acidified to pH 6 with hydrochloric acid solution (6N), and the product thoroughly extracted into methylene chloride. The combined methylene chloride extracts were washed with cold water, brine, and then dried with magnesium sulfate. Removal of the solvent under vacuum gave 3-[(2-(n-butyl)-1-(2"-cyanobiphenyl-4'-ylmethyl)pyrrol-4-yl]propionic acid (5.51 g), a compound of Formula (AH), as a slightly pinkish gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1C(Cl)=O.[CH2:26](N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12]1[N:15]=[C:26]([C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)[O:14][N:13]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccs1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Solvent: C1COCCO1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1noc(-c2ccsc2)n1
Temperature: 150 °C

Procedure:
A suspension of {(S)-1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2.4 g, 9.7 mmol) in dioxane (15 ml) was treated with thiophene carbonyl chloride (1.45 g, 9.9 mmol) and triethylamine (1.36 ml, 9.8 mmol) and the mixture heated at 150° C. in a microwave (Smith Creator, S00219) for 15 minutes. Solvent evaporated under reduced pressure. The residue was subjected to flash chromatography eluting with a mixture of ethyl acetate and heptane to give {(S)-1-[hydroxy-(5-thiophen-3-yl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-carbamic acid tert-butyl ester, a mixture of diastereoisomers, (144 mg) as a brown solid. 1H NMR (CDCl3): 8.21 (m, 1H), 7.66 (m, 1H), 7.45 (m, 1H), 4.92-4.69 (m, 2H), 5.02-4.80 (m, 2H), 4.10-3.85 (2×m, 1H), 1.80-1.45 (m, 2H), 1.46 & 1.38 (2×s, 9H), 1.01 & 0.99 (2×t, J=7.5 Hz, 3H). MS: 340 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:15][C:13]1[N:14]=[C:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(CCN2CCOCC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: ClCc1cccc(CCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[6-(2-Morpholin-4-ylethyl)pyridin-2-yl]methanol (122 mg) and diisopropylethylamine (104 mg) were dissolved in 2.5 mL of dichloromethane, and 47 μL of methanesulfonyl chloride was added dropwise to the solution at ice temperature, and then the mixture was stirred at room temperature overnight. After removing the solvent from the reaction mixture under reduced pressure, the residue was purified by chromatography on silica gel (chloroform-methanol-aqueous ammonia=300:10:1) to give 80 mg of 4-[2-(6-chloromethylpyridin-2-yl)ethyl]morpholine as a yellow oil.
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:16]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>O.C(O)C>[C:21]([O:20][C:18](=[O:19])[C:17](=[N+:2]=[N-:3])[C:16]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.9 %

Procedure:
A mixture of sodium azide (1.37 grams, 21.0 mmol), p-toluenesulfonyl chloride (4.0 grams, 21.0 mmol), and 70% aqueous ethanol (60 mL) was stirred at room temperature for 1 hour. Di-t-butyl malonate (4.48 mL, 20.0 mmol) and triethylamine (2.92 grams, 21.0 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then poured into deionized water (200 mL). The mixture was extracted with petroleum ether (2×200 mL). The extracts were combined and then washed with a saturated aqueous sodium chloride solution. The organic solution was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 6.10 grams of di-t-butyl-2-diazomalonate as a yellow oil. IR(film): 2110 cm-1. Decomposition temperature: 178° C. (by DSC).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18](Cl)=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH3:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:23])[C:15]=1[O:14][C:9]1[C:8]([NH2:24])=[C:7]([NH:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:12]=[C:11]([CH3:13])[N:10]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cccc2C)c1N
Yield: 54.2 %

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(4-chloro-2,6-dimethyl-phenoxy)-pyridin-4-yl]-amine (800 mg, 2.12 mmol) and 160 mg of 10% Pd/C in 150 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through Celite® and the filtrate was concentrated to dryness to give a purple glass form (810 mg) which was purified through silica gel column chromatography using 1:1 chloroform:hexane as eluent to give the title compound as tan crystals (360 mg), mp 98-100° C. 1H NMR (CDCl3) δ7.05 (m, 3H), 6.11 (s, 1H), 4.00 (brs, 1H), 3.28 (m, 11H), 3.09 (brs, 2H), 2.14 (s, 9H), 1.45-1.75 (m, 4H), 0.98 (t, 6H) ppm. The corresponding HCl salt was prepared as white solid, mp 158-162° C., 1H NMR(D2O) δ7.27 (s, 3H), 6.67 (s, 1H), 3.65 (m, 1H), 2.27 (s, 3H), 2.16 (s, 6H), 1.45-1.80 (m, 4H), 0.93 (t, 6H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])([CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCOCC1.CO>[ClH:29].[F:27][C:24]([F:25])([F:26])[C:23]([NH:22][C:11]1([CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)(NC(=O)C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC1(NC(=O)C(F)(F)F)CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2,2,2-trifluoro-acetylamino)-4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (5.25 g, 12.5 mmol) in dioxane (50 ml) is added 4 M HCl in dioxane (15 ml) and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo and the off-white solid obtained dissolved in the minimum amount of MeOH and re-precipitated by adding diethyl ether. The supernatant solvent mixture is decanted and the product is washed again with diethyl ether and dried under vacuum to afford 2,2,2-Trifluoro-N-{4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidin-4-yl}-acetamide hydrochloride; [M+H]+ 322.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH3:15][S:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2nc(S)oc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc2nc(SC)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a stirred mixture of methyl 2-mercaptobenzo[d]oxazole-6-carboxylate (5 g, 23.92 mmol) and solid K2CO3 (9.9 g, 71.76 mmol) in anhydrous DMF (50 mL) at rt was added methyl iodide (10.2 g, 71.76 mmol). The mixture was stirred at rt for 15 h. The reaction mixture was diluted with water then extracted with DCM (×3). The combined organic layers were washed with water and 2 M aq HCl. The organic layer was separated and dried over MgSO4, filtered, and concentrated under reduced pressure to afford methyl 2-(methylthio)benzo[d]oxazole-6-carboxylate (4.24 g, 80%) as a light pink solid that did not require further purification. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.1 Hz, 1H), 8.04 (dd, J=1.1, 8.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 3.95 (s, 3H), 2.79 (s, 3H). LCMS (ESI) m/z 224 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]([CH3:25])[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][NH2:20])[C:14]=2[C:21]([F:24])([F:23])[F:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:32][C:33]([F:39])([F:38])[CH2:34][C:35](Cl)=[O:36]>CCOC(C)=O.C1COCC1>[F:32][C:33]([F:39])([F:38])[CH2:34][C:35]([NH:20][NH:19][C:15]1[C:14]([C:21]([F:24])([F:22])[F:23])=[C:13]([N:12]([CH2:11][C@@H:9]2[CH2:10][C@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:25])[CH:18]=[CH:17][N:16]=1)=[O:36]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(NN)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(NNC(=O)CC(F)(F)F)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a mixture of trans-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-N-methyl-3-(trifluoromethyl)pyridin-4-amine (0.5 g, 1.411 mmol) in EtOAc (6 mL), THF (6 mL) and 2.0 M of aqueous sodium carbonate (3.53 mL, 7.06 mmol) was added 3,3,3-trifluoropropionyl chloride (0.248 g, 1.693 mmol) dropwise at rt. The resulting mixture was stirred at under nitrogen for 10 min. The reaction mixture was partitioned between EtOAc/aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-30% EtOAc/hexane as the eluent to give trans-3,3,3-trifluoro-N′-(4-(((2-(4-fluorophenyl)cyclopropyl)methyl)(methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)propanehydrazide (0.46 g, 66.7% yield) as a white solid. 1H NMR (500 MHz, METHANOL-d4) δ 7.88 (d, J=6.0 Hz, 1H), 7.08-7.01 (m, 2H), 6.99-6.91 (m, 2H), 6.58 (d, J=6.1 Hz, 1H), 3.41 (dd, J=14.0, 5.6 Hz, 1H), 3.36-3.24 (m, 2H), 3.13 (dd, J=14.0, 7.6 Hz, 1H), 1.81-1.71 (m, 1H), 1.32-1.21 (m, 1H), 0.99 (dt, J=8.6, 5.2 Hz, 1H), 0.87 (dt, J=8.8, 5.4 Hz, 1H). LCMS: M+1=465.13.
Reaction SMILES: [C:1]([C:6](=[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH2:7][C:8](O)=[O:9])([O:3][CH2:4][CH3:5])=[O:2].B>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[C:6]([CH2:7][CH2:8][OH:9])=[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:5]
Reactant: CCOC(=O)C(CC(=O)O)=C(c1cccc(OC)c1)c1cccc(OC)c1
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)C(CCO)=C(c1cccc(OC)c1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
As described in Example 135, a solution of 3-carboethoxy-4,4-bis(3-methoxyphenyl)-3-butenoic acid (20.5 g) in dry tetrahydrofuran (100 mL) was treated with a solution of 1M borane in tetrahydrofuran (57 mL) and the reaction was stirred at room temperature overnight. After the usual work up, the crude product was purified by HPLC (diethyl etherhexane; 65:35) to provide 15.4 g of 2-hydroxyethyl-3,3-bis(3-methoxyphenyl)-2-propenoic acid ethyl ester, mp 102.5°-103.5° C. Anal. Calcd for C19H20O3 : C, 77.00; H, 6.80 Found: C, 77.12; H, 6.69