Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: Nc1ncccn1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Yield: 21.9 %

Procedure:
Stir a mixture of 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one (500 g, 1.78 mol, 1 equiv), IPA (5 L), 2-aminopyrimidine (205 g, 2.13 mol, 1.2 equiv), and sodium bicarbonate (298.8 g, 3.55 mol, 2 equiv) in a thermally controlled reactor at 80° C. for 18 hours. Cool the suspension, and concentrate in vacuo. Dilute the resulting mixture with DCM (5 L), and the wash with brine (2 L). Re-extract the brine wash with DCM (2.5 L); combine all the organic extracts; dry over MgSO4; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to a red gum. Slurry the resulting red gum in Et2O (1.5 L); filter; and collect the solid. Air dry the solid for 45 min to give the product as a fine off-white solid (108 g, 22% yield). ES/MS (m/z) 278 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24]([OH:26])=O)[N:4]=[N:3]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH3:22][N:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][C:5]=1[C:24]([N:27]1[CH2:30][CH2:29][CH2:28]1)=[O:26])=[O:23]
Reactant: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)nnn1C
Reactant: C1CNC1
Product: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCC2)nnn1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-1H-1,2,3-triazole-4-carboxylic acid (30 mg, 84.7 μmol) and azetidine (6.8 mg, 8 μL, 119 μmol) according to the method described in example 37, step 3 as colorless solid (11 mg, 28 μmol, 33%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li]CCCC.CON(C)[C:20]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:21]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]#[C:11][C:20]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:21])([CH3:5])([CH3:6])[CH3:7]
Reactant: CON(C)C(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#CC(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A −15° C. solution of N-BOC propargyl amine (641 mg, 4.13 mmole, 3.5 eq) in dry THF (12 ml) was treated dropwise with a 1.6M n-BuLi in hexanes solution (5.16 ml, 8.3 mmole, 7.0 eq) and the resulting pale yellow dianion solution stirred at −15° C. for 30 minutes under nitrogen. A dry THF solution (3 ml) of the above-prepared 2,4-Diphenyl-oxazole-5-carboxylic acid methoxy-methyl-amide (365 mg, 1.18 mmole, 1.0 eq) was added dropwise to the dianion solution at −15° C. and the mixture stirred at 0° C. for 2 hours under nitrogen. The mixture was quenched by adding a solution of 2M NaH2PO4 (5 ml), then warmed to room temperature and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a crude brown oil. The crude oil without purification was used immediately in next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])=[O:11])=[CH:4][CH:3]=1)=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)OCC[Si](C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc(O[C@@H](Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1
Yield: 91.2 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using 2-trimethylsilylethyl (S)-3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionate (4.80 g), which is the product of Reference example 29(e), t-butyl 2-methanesulfonyloxyethylcarbamate (7.17 g) and potassium carbonate (8.28 g) and the reaction mixture was treated to afford the desired compound (5.94 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([Br:25])[CH:27]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1cccc(Br)c1
Solvent: CCOCC
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1cccc(Br)c1)S(=O)(=O)c1ccc(OC)cc1
Yield: 92 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.6 g (2.4 nunol) of m-bromobenzyl bromide provided 0.954 g (92%) of the desired product as a white solid after trituration with ether. Electrospray Mass Spec 518.1 (M+H).
Reaction SMILES: C(=O)([O-])OC(C)(C)C[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12](C(=O)C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]=1[CH3:23].[OH2:28].NN.Cl>CC(O)(C)C>[OH:28][C:5]1[C:6]([CH3:23])=[C:7]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]([CH3:11])=[CH:9][CH:10]=1
Reactant: CC(=O)N(C(=O)OC(C)(C)C)c1c(C)ccc(CC(C)(C)OC(=O)[O-])c1C
Reactant: O
Agent: Cl
Agent: NN
Solvent: CC(C)(C)O
Product: Cc1ccc(O)c(C)c1NC(=O)OC(C)(C)C

Procedure:
A solution of [3-(acetyl(tert-butoxycarbonyl)amino)-2,4-dimethyl-phenyl]tert-butyl carbonate (800 mg, 2.11 mmol, 1.0 eq) and hydrazine hydrate (5 mL) in t-BuOH (5 mL) was stirred under N2 at 110° C. overnight. The solution was adjusted to pH 6 by addition of diluted HCl and the aqueous layer extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and evaporated in vacuo. The crude solid was used in the next step without further purification (657 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19]>>[C:21]([O:20][C:18](=[O:25])[NH:19][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cccc(-c2nc3cc(Br)ccn3n2)c1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 102.4 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.42 mmol) and tert-butyl carbamate (481 mg, 4.11 mmol) as starting materials. The reaction affords 2-(3-fluoro-phenyl)-[[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (1.15 g, 102%) as light yellow foam. MS: m/z=329.0 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][O:11]2)=[CH:6][CH:5]=1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:32])=O>>[CH2:16]([CH:13]1[CH2:14][O:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([Cl:32])=[O:2])=[CH:5][CH:6]=2)[O:11][CH2:12]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCC1COC(c2ccc(C(=O)O)cc2)OC1
Solvent: CN(C)C=O
Product: CCCCCCCCCC1COC(c2ccc(C(=O)Cl)cc2)OC1

Procedure:
A solution of 2-(4-carboxyphenyl)-5-n-nonyl-1,3-dioxane (2.00 g) in thionyl chloride (10 g) was heated under refluxing for 4 hours with a small amount of N,N-dimethylformamide. Excessive amount of thionyl chloride was distilled to obtain the titled compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([B:22]4[O:26]C(C)(C)C(C)(C)[O:23]4)=[C:18]([CH:31]=O)[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]4[B:22]([OH:26])[O:23][CH2:31][C:18]=4[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OC4CCCC4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2-cyclopentyloxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (2.0 g, 4.60 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (0.26 g, 6.90 mmol). After 1 h at rt, 2 M HCl was added to it at 0° C. until pH reached to 3˜4. The resulting mixture was stirred at 0° C. for 30 min and then sonicated to give white solid which was filtered and lyophilized to yield D100 (0.85 g, 56%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1 H), 8.20 (d, J=8.2 Hz, 1 H), 7.77 (d, J=7.8 Hz, 1 H), 7.27 (d, J=1.2 Hz, 1 H), 7.18 (dd, J=8.2, 1.9 Hz, 1 H), 6.69 (d, J=8.2 Hz, 1 H), 4.97 (br. s., 3 H), 1.75-1.54 (m, 6 H), 1.52-1.33 (m, 2 H); MS (ES) m/z: 337 (M+1)+; HPLC purity 99.36% (Maxplot), 99.35% (220 nm); Elemental analysis for C18H17BN2O4.0.25H2O: Calculated C=63.46%, H=5.18%, N=8.22%. Found C=63.34%, H=5.17%, N=8.34%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.C(Cl)Cl>CCCCCC>[C:15]([Si:12]([O:5][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][Cl:1])([CH3:14])[CH3:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: OC(CCCl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CCCl)c1ccccc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
3-Chloro-1-phenyl-propan-1-ol (3.87 g, 22.6 mmol), tert-butyldimethylsilyl chloride (3.75 g, 24.9 mmol), imidazole (2.00 g, 29.3 mmmol), and methylene chloride (50 mL) are combined and stirred for 1 hour. The mixture is quenched with saturated aqueous sodium bicarbonate and diluted with methylene chloride (100 mL). The mixture is washed with saturated aqueous ammonium chloride, water, and brine, then is dried over magnesium sulfate, filtered, and concentrated to a crude oil. Purification by flash chromatography, eluting with ethyl acetate:hexane gave 4.82 g (75% yield) of the title compound as a transparent oil. 1HNMR (DMSO-d6) 7.76–7.84 (m, 4H), 7.68–7.74 (m, 1H), 5.39 (dd, J=4, 4 Hz, 1H), 4.19–4.22 (m, 1H), 4.00–4.08(m, 1H), 2.55–2.65 (m, 1H), 2.38–2.48 (m, 1H), 1.34 (s, 9H), 0.53 (s, 3H), 0.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([OH:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)Cl>C(Cl)(Cl)Cl>[C:14]([S:21][CH2:11][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC(=S)c1ccccc1
Reactant: C=C(Cc1ccc(Cl)cc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(SCC(Cc1ccc(Cl)cc1)C(=O)O)c1ccccc1

Procedure:
A solution of 2-(p-chlorobenzyl)acrylic acid (3.93 gm., 22 mmoles) and thiobenzoic acid (2.6 ml., 20 mmoles) in 40 ml. of methylene chloride was heated at reflux for 16 hours. The reaction mixture was evaporated to dryness and product crystallized from hexane (4.5 g.). Additional product was obtained by evaporation of the hexane mother liquor and chromatography of the residue (7.1 g.) on 200 g. of silica gel (230-400 mesh) with chloroform as eluant; 1.8 g., m.p. 111°-114° C.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([O:18][CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])[CH:11]=1>C(O)C>[CH3:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([O:18][CH:19]([CH3:24])[C:20]([F:23])([F:21])[F:22])[CH:11]=1
Reactant: Cc1cc(OC(C)C(F)(F)F)cc(C#N)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(OC(C)C(F)(F)F)cc(C(N)=O)n1
Reaction time: 8 h
Yield: 94 %

Procedure:
To 6 ml of ethanol were added 0.53 g of sodium bicarbonate and 0.44 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.72 g of 6-methyl-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 8 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.73 g of 6-methyl-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19]1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)CCCO
Yield: 797.2 %

Procedure:
A mixture of 59.45 g of hexadecylamine, 10.60 g of gamma butyrolactone, 200 ml of toluene, and 20 mg of zinc chloride was refluxed under nitrogen for three days. Upon cooling, the reaction mixture formed a precipitate which was recrystallized twice from toluene to yield 321.5 g (78.12%) of N-hexadecyl-4-hydroxybutyramide, m.p. 89.5°-90°
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6])[CH3:2].CO[C:13](=[O:35])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:25]=2[C:26]#[N:27])[C:17]([Cl:32])=[CH:16][C:15]=1[O:33][CH3:34]>C1(C)C=CC=CC=1.ClCCCl.N#N>[Cl:32][C:17]1[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:25]=2[C:26]#[N:27])=[CH:19][C:14]([C:13]([N:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:1][CH3:2])[CH3:6])=[O:35])=[C:15]([O:33][CH3:34])[CH:16]=1
Reactant: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Reactant: CNc1ccccc1OC
Agent: N#N
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1ccccc1OC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
To a mixture of 2-methoxyl-N-methylaniline (27.7 mg, 0.2 mmol) and Et3AI (196 μL, 1.9 M in toluene, 0.2 mmol) in 1,2-dichloroethane (1 mL) which was preheated at 50° C. for 10 min under N2 atmosphere, was added 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (50 mg, 0.14 mmol). The mixture was sealed in N2 atmosphere and heated at 80° C. for 16 hrs. Upon cooling to rt, the mixture was quenched with 2 N HCl (5 mL) and diluted with 1,2-dichloroethane. The organic layer was separated and concentrated. The residue was purified via reverse phase preparative LCMS to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide 38-1 (4.9 mg). MS [M+H]+ 475.9; tR=5.91 min (method 3)
Reaction SMILES: C(O)(=O)C[CH2:3][C:4]([OH:6])=[O:5].O[CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[NH:17].C(OC(=O)C)(=O)C.C([O-])(=O)C>C(N(CC)CC)C>[C:4]([O:6][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[NH:17])(=[O:5])[CH3:3]
Reactant: N=C(N)NCCOCCO
Reactant: O=C(O)CCC(=O)O
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCOCCNC(=N)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
2.06 g (9.99 mmol) of 2-(2-hydroxyethoxy)ethylguanidine succinate, 8 ml of triethylamine, 0.122 mg (1.0 mmol) of 4-N,N-dimethylaminopyridine and 1.02 g (9.99 mmol) of acetic anhydride were placed in a 50 ml two neck flask and were stirred for 1 hour at room temperature. After the upper phase was removed by decantation, the obtained crude product was washed five times with 50 ml of diethylether. The product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 1.00 g of the title compound (starch syrup-like, 4.0 mmol, 40.0% in yield) in the form of acetate. Results of the analysis of this compound are as follows.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)Cc1ccccc1CNS(C)(=O)=O)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 8a in dichloromethane (0.1 M) at 0° C. under nitrogen was added triethylamine (3.5 eq) and methanesulfonyl chloride (1.1 eq). The reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane) to afford the product. (41%) 1H NMR (400 MHz, CDCl3) δ 7.16-7.46 (m, 9H), 6.79 (m, 1H), 6.12 (m, 1H), 4.32 (m, 2H), 4.03 (m, 1H), 3.70 (m, 1H), 3.36-3.17 (m, 1H), 2.90 (s, 2H), 2.47-2.83 (m, 6H), 1.74 (m, 6H), 1.25 (m, 1H). Mass Spectral Analysis m/z=430.3 (M+H)+ tR=3.70 min (96%)
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.C(N(CC)CC)C.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2([NH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:29](=[O:46])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2([NH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:36][N:37]([C:3]3[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=3)[CH2:38][CH2:39]2)[C:29](=[O:46])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Yield: 53.8 %

Procedure:
4-Chloro-2-methylpyridine hydrochloride (941 mg), triethylamine (1.93 g) and ethanol (50 ml) were added to 4-benzyloxycarbonyl-1-[(4-ethoxycarbonylamino-4-piperidinyl)methyl]-2-piperazinone (2.0 g), and the mixture was reacted at 150° C. for 10 hours in a sealed tube. The reaction mixture was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, and the mixture was extracted with dichloromethane, dried, and concentrated. The resulting residue was purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the colorless amorphous title compound (1.31 g).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:41].O>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:41])[S:27]([C:30]([CH3:31])([CH3:33])[CH3:32])(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)(C)C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide (100 mg, 0.177 mmol; Example 181, Step A) was dissolved in DMF (2.5 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.45 mmol) was added in a single portion. After 25 minutes, this mixture was cooled to 0° C. in an ice-water bath, and iodomethane (0.04 mL, 0.643 mmol) was added dropwise by syringe. The mixture was allowed to gradually warm to ambient temperature, gradually becoming a pale yellow suspension. After 2 h water (2 mL) was added very carefully. The resulting mixture was partitioned between ethyl acetate and saturated aq. NH4Cl solution. The aqueous phase was back-extracted (2×) and the combined organics were washed with sat. aq. NaCl solution (2×), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to an oily residue that was chromatographed on a 12 g silica column, eluting with a gradient of 0 to 35% EtOAc in hexanes. Fractions containing the sulfonamide product were pooled and concentrated to give the title compound. MS (ESI) m/z=579 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[S:5])[NH2:4].CC(O)(C)C.Cl[CH:14]([C:20](=O)[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCOC(C)=O>[CH3:21][C:20]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[S:5][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)C(F)(F)F
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(C(F)(F)F)nc1C

Procedure:
To a mixture of 2,2,2-trifluoroethanethioamide (200 mg) and t-BuOH (10 mL) was added ethyl 2-chloro-3-oxobutanoate (0.217 mL) at room temperature. The mixture was refluxed for 2 days. After cooling, EtOAc was poured into the mixture, and the mixture was washed successively with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (133 mg).