Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:16])=[CH:11][CH:10]=1)#[N:8]>>[NH2:8][CH2:7][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH2:16])=[CH:11][CH:10]=1
Reactant: C=C(OCc1ccc(C#N)cc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=C(OCc1ccc(CN)cc1)c1ccccc1

Procedure:
Lithium aluminium hydride reduction of α-(4-cyanobenzyloxy)styrene led to this compound: 1H NMR (CD3OD) δ 3.73 (2H, br s), 4.30 (1H, d, J 3 Hz), 4.70 (1H, d, J 3 Hz), 4.72 (2H, s), 4.87 (2H, s), 7.1-7.7 (9H, m).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[Na+].[C:29]([CH2:32][S:33][C:34]1[S:35][C:36]([SH:39])=[N:37][N:38]=1)(=[NH:31])[NH2:30]>CN(C=O)C>[C:29]([CH2:32][S:33][C:34]1[S:35][C:36]([S:39][CH2:18][C:15]2[CH2:16][S:17][C@@H:12]3[C@H:11]([NH:10][C:8](=[O:9])/[C:7](/[C:4]4[N:3]=[C:2]([NH2:1])[S:6][N:5]=4)=[N:25]\[O:26][CH3:27])[C:23](=[O:24])[N:13]3[C:14]=2[C:20]([OH:22])=[O:21])=[N:37][N:38]=1)(=[NH:30])[NH2:31]
Reactant: N=C(N)CSc1nnc(S)s1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1nsc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc(SCC(=N)N)s3)CS[C@H]12)c1nsc(N)n1
Temperature: -20 °C
Yield: 74.4 %

Procedure:
To a solution of 371 mg of sodium 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate and 309 mg of 2-amidinomethylthio-5-mercapto-1,3,4-thiadiazole in 10 ml of DMF was added 600 mg of ethyl o-phenylenephosphate under stirring at -20° C. After stirring at -20° C. to 0° C. for 60 minutes, the mixture was subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with acetonitrile/water (4:1). The eluate was concentrated under reduced pressure, and the resultant solid was dissolved in dilute hydrochloric acid. This aqueous solution was subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 30% aqueous ethanol. The eluate was concentrated under reduced pressure and lyophilized to give 381 mg of the title compound as a colorless powder.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([NH2:7])[CH2:2]1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.CS(O)(=O)=O>CN1CCCC1=O.C(#N)C>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:7][C@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:1]([NH:8][C:10]4[C:19]5[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=5)[N:13]=[CH:12][CH:11]=4)[CH2:2]3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: N[C@@H]1CCC[C@H](N)C1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: Clc1ccc2c(N[C@@H]3CCC[C@H](Nc4ccnc5cc(Cl)ccc45)C3)ccnc2c1
Yield: 21.9 %

Procedure:
23.2 g of cis-cyclohexane-1,3-diamine and 80.5 g of 4,7-dichloroquinoline are reacted at 150° C. in 400 ml of N-methyl-2-pyrrolidone under argon for 24 hours. After cooling insoluble material is filtered off and the filtrate is treated with 600 ml of water. The separated crude product is introduced into 400 ml of water and 100 ml of glacial acetic acid. The mixture is extracted three times with 200 ml of ethyl acetate each time and then adjusted to pH 12 by the addition of 600 ml of 2N NaOH. The separated crystalline diamine is recrystallized from 270 ml of dimethylformamide, 20.1 g of pure product being obtained. This is converted into the dimethanesulphonate in 200 ml of boiling acetonitrile with 6.4 ml of methanesulphonic acid. 19.5 g of colourless crystalline salt, m.p.:>250° C., are obtained.
Reaction SMILES: C(OC(N[C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:10]([OH:12])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=[O:30]>ClC(Cl)C>[O:26]=[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][C@H:9]([OH:30])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC(Cl)Cl
Product: O=C(O)[C@@H](O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-2-(tert-butoxycarbonylamino)-5-(1,3-dioxoisoindolin-2-yl)pentanoic acid L (1.45 g, 4.0 mmol) in dichloroethane (25 mL) was cooled to 0° C. Trifluoroacetic acid was added in one portion and the mixture was allowed to warm to room temperature and stir for 2 h. The mixture was concentrated to dryness mixed with water (18.5 mL), HOAc (9.5 mL) and aqueous NaNO2 (1.2 g in 25 mL H2O). After 15 min another portion of HOAc (14 mL) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness. The residue was dissolved in water (100 mL), the pH was adjusted to 1 by addition of 10% aqueous HCl, and the solution was extracted with diethyl ether (5×100 mL). The organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure afford (S)-5-(1,3-dioxoisoindolin-2-yl)-2-hydroxypentanoic acid LI (0.98 g, 3.73 mmol, 93%). ESIMS found for C13H13NO5 m/z 262 (M−H)−.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Cn1ccnc1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 1-methylimidazole
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 4 h
Yield: 24.3 %

Procedure:
To a suspension of 1H-indazol-5-ol (134 mg, 0.999 mmol) in tetrahydrofuran (4 ml) were added tert-butyl 4-hydroxy-1-piperidinecarboxylate (201 mg, 0.999 mmol) and triphenylphosphine (262 mg, 0.999 mmol) at room temperature, followed by adding thereto diethyl azodicarboxylate (0.46 ml, 1.01 mmol) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. Subsequently, the solvent of the reaction mixture was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=7/3) to obtain tert-butyl 4-(1H-indazol-5-yloxy)-1-piperidinecarboxylate (77 mg, 24%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]1)=[O:14])[CH2:6][CH2:5]2.[N:25]1[NH:26][C:27](=[O:31])[CH:28]=[CH:29][CH:30]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>Cl[Cu].CN(C=O)C>[CH:21]1([N:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([N:26]5[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=[N:25]5)[CH:3]=4)[CH2:8]3)[CH2:20][CH2:19]2)[CH2:22][CH2:23][CH2:24]1
Reactant: O=c1cccn[nH]1
Reactant: O=C(CN1CCc2cc(Br)ccc2C1)N1CCN(C2CCC2)CC1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CN(C)C=O
Product: O=C(CN1CCc2cc(-n3ncccc3=O)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 140 °C

Procedure:
To a sealed tube charged with 6-bromo-2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline (128 mg, 0.326 mmol), CuCl (3.2 mg, 0.0163 mmol, 0.05 eq.), pyridazin-3(2H)-one (47 mg, 0.489 mmol, 1.5 eq.), 8-hydroxyquinoline (9.5 mg, 0.0326 mmol, 0.1 eq.) and K2CO3 (90 mg, 0.652 mmol, 2.0 eq.) is added anhydrous DMF (3 ml). The mixture is degassed with nitrogen for 5 min. The tube is sealed and heated at 140° C. overnight. The mixture is cooled to rt and filtered through Celite. The Celite bed is washed with EtOAc, the combined organics are concentrated, and 5N HCl (30 mL) is added. The mixture is extracted with EtOAc (2×30 mL). The aqueous layer is basified with 10N NaOH, and extracted with DCM (3×40 mL), and the combined organics are dried and concentrated. The crude reaction mixture is purified by preparatory LC/MS to yield the title compound. 1H NMR (300 MHz, CDCl3) δ 7.87 (1H, dd), 7.32 (2H, m), 7.24 (1H, d), 7.12 (1H, d), 7.04 (1H, d), 3.72 (2H, s), 3.67-3.63 (4H, m), 3.36 (2H, s), 2.94 (2H, t), 2.81 (2H, t), 2.69 (1H, m), 2.27 (4H, m), 1.66-2.08 (6H); MS (+VE) m/z 408.14 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[S:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:20]([CH3:19])(=[O:22])=[O:21])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1nc2cc(Br)cnc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1nc2cc(Br)cnc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a cooled (ice-water) solution of (6-bromothiazolo[5,4-b]pyridin-2-yl)methanamine (800 mg, 3.28 mmol) and pyridine (800 mg, 9.85 mmol) in CH2Cl2 (10 mL) is slowly added methanesulfonyl chloride (380 mg, 3.28) and stirred at room temperature for 3 hours. Reaction mixture is washed with water (2×10 mL) dried over Na2SO4 and concentrated. Obtained crude product purified on silica gel column using 0 to 5% methanol/CH2Cl2 to give the title compound (800 mg): m/z (CI) M+2 324.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:11]
Reactant: CCOCCn1c(Cl)nc2ccccc21
Reactant: C1CNCCN1
Agent: O=C(O)/C=C/C(=O)O
Product: CCOCCn1c(N2CCNCC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]benzimidazole (5.00 g), piperazine (19.00 g) and fumaric acid (3.19 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(ethoxy)ethyl]-2-(1-piperazinyl)benzimidazole.3/2 fumarate (2.29 g), as colorless needles, m.p. 167°-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28].C1CCC([N:56]=C=NC2CCCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:33]([NH:24][C@H:25]([C:30]([NH2:56])=[O:32])[CH2:26][CH:27]([CH3:29])[CH3:28])([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Yield: 74.9 %

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene (1.92 g, 6.1 mmols), 2.58 g (7.3 mmols) of Fmoc-L-Leu, 1.5 g (7.3 mmols) of DCC and 1.1 g (7.3 mmols) of HOBtH2O were dissolved in 40 ml of N,N-dimethylformamide, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, then filtered and concentrated. The product was purified through silica-gel column chromatography (mixture of ethyl acetate and hexane at a ratio by volume of 1:2) to produce 3.05 g of the final product in a yield of 76.9%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:17]=[N-:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([O:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:16]=[N+:17]=[N-:18])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN=[N+]=[N-])cc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCCCCN=[N+]=[N-])cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
5-(6-Azidohexoxy)isophthalic Acid Dimethyl Ester was prepared as follows: A mixture of dimethyl 5-hydroxyisophthalate 4 (1.05 g, 5 mmol), 6-azido-1-(p-toluenesulfonyloxy)hexane (1.57 g, 5 mmol) and K2CO3 (1.38 g, 10 mmol) in DMF (15 mL) was stirred for 17 h at 80° C. After cooling down, H2O (150 mL) was added and the mixture was extracted with EtOAc, washed with water, dried (MgSO4), and the solvent was evaporated off. The pure title compound was obtained as a colorless oil (1.51 g, 90%) after column chromatography (SiO2: CH2Cl2).
Reaction SMILES: Cl[O-].[Na+].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:24][C:18]=3[N:17]=2)[CH:9]=1.S([O-])([O-])(=[O:34])=S.[Na+].[Na+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:24][C:18]=3[N:17]=2)=[O:34])[CH:9]=1
Reactant: COc1ccnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1
Reactant: O=S([O-])([O-])=S
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A mixture of 8.5 ml of commercially available sodium hypochlorite solution (about 15% of active chlorine) and 6 ml of 10% strength sodium hydroxide solution is added dropwise to a solution of 1.5 g 2-[(4-methoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole in 30 ml of ethyl acetate at 0° C. in the course of 20 min., stirring is continued at this temperature for 20 min. and 0.6 ml of 10% strength sodium thiosulfate solution is then added. 1.5 g of ammonium sulfate are added and the organic phase is separated off, washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated to a small volume. 1.3 g (85%) of the title compound of melting point 131°-132° C. (decomposition) are obtained by precipitation with diisopropyl ether.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].Br[CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22].Cl>CO.O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(SC2CCOC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
Sodium hydroxide (0.20 g, 5 mmole) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.11 g, 4.6 mmole) in methanol (20 ml) and stirred at room temperature until dissolved. 2-Bromobutyrolactone (0.82 g, 5 mmole) was added and the mixture was stirred at room temperature for 48 hours. The mixture was diluted with water, acidified with 1 N hydrochloric acid, and extracted with diethyl ether. The ether extract was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a minimum of hexane and cooled to induce crystallization. Chromatography of the solid on silica gel and recrystallization from hexane gave the title compound, m.p. 98°'100°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:16][N:17]([CH3:21])[C:18]([NH:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:7][CH:8]=1)[CH3:15])=[O:19]
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: CN(C)C(=O)Cl
Product: CC(CNC(=O)N(C)C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and N,N-dimethylcarbamoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].N([O-])=[O:11].[Na+]>C(O)(=O)C.O>[O:11]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 50 g portion of ethyl acetoacetate in 60 ml of acetic acid was stirred at 0° C. to 10° C., as a solution of 30 g of sodium nitrite in 50 ml of water was added dropwise. When addition was complete, the mixture was stirred at 0° to 10° C. for 30 minutes and then diluted with 300 ml of ice water. The mixture was stirred for 2 hours and then extracted with 500 ml of dichloromethane. The dichloromethane layer was separated, washed with two 500 ml portions of ice water, dried, filtered and evaporated in vacuo. The residual oil was stirred vigorously with 200 ml of hexane and the resulting solid collected, washed with hexane and air dried, giving 31.4 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:11])[CH3:2].C[Al](C)C.N#N.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])=[CH:6][C:5]=1[F:11])[CH3:13]
Reactant: CCN(CC)c1ccc(N)cc1F
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: CCN(CC)c1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.2 %

Procedure:
To a solution of N1,N1-diethyl-2-fluorobenzene-1,4-diamine (1.50 g, 8.23 mmol) in anhydrous CH2Cl2 (60 mL) was added trimethylaluminium (33 mL, 33 mmol, 1 M in heptane) dropwise slowly under N2. Upon the end of addition the mixture was stirred at rt for 40 min. To this mixture was added a solution of methyl 3-acetaminocrotonate (2.58 g, 16.40 mmol) in anhydrous CH2Cl2 (20 mL). The resulting reaction mixture was stirred at rt for another 6 h, then quenched with water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was recrystallized from EtOAc to give the title compound as a pale yellow solid (1.60 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:17]1(B(O)O)[CH2:19][CH2:18]1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[Cl:1][C:2]1[C:3]([CH:17]2[CH2:19][CH2:18]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccnc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cccnc1C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 123.2 %

Procedure:
3-Chloro-2-bromopyridine (5.0 g, 26 mmol) and potassium phosphate tribasic (19.3 g, 90.9 mmol) were suspended in toluene (40.0 mL) and water (2.0 mL). The mixture was sonicated for 10 minutes, then cyclopropylboronic acid (1.12 g, 13.0 mmol), palladium diacetate (0.093 g, 0.414 mmol) and tricyclohexylphosphine (0.243 g, 0.867 mmol) were added to the reaction mixture, which was heated into a pre heated DrySyn® at 100° C., under a nitrogen atmosphere for 2 hours. Then cyclopropylboronic acid (1.12 g, 13.0 mmol), palladium diacetate (0.093 g, 0.414 mmol) and tricyclohexylphosphine (0.243 g, 0.867 mmol) were added to the reaction mixture and the mixture was stirred for 2 hours. Then cyclopropylboronic acid (1.12 g, 13.0 mmol), palladium diacetate (0.093 g, 0.414 mmol) and tricyclohexylphosphine (0.243 g, 0.867 mmol) were added to the reaction mixture and the mixture was stirred for 2 hours more. The reaction mixture was stirred at room temperature for 16 hours, diluted with EtOAc (40.0 mL) and water (40.0 mL) and filtered on a pad of Arbocel® under a stream of nitrogen. The organic layer was separated and washed with aqueous citric acid (10%, 3×25.0 mL), followed by aqueous hydrochloric acid (1 M, 3×20.0 mL). The organic layer was discarded and the aqueous layer basified again with careful addition of a saturated aqueous solution of sodium hydrogen carbonate (100.0 mL). The product was extracted with TBME (3×20.0 mL). The combined organics were washed once more with aqueous citric acid (10%, 25.0 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound as a pale brown oil (2.45 g, 16.02 mmol, 62%).
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH3:33])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:34])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:36]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH3:33])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:36])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:34])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Product: COc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 222) but using compound 11.2 HCl salt in place of compound 1.5. m/z (ES+) 474 (M+H)+.