Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5](Br)[C:6](=[O:8])[CH3:7].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([N:11]=[N+:12]=[N-:13])[C:6](=[O:8])[CH3:7]
Reactant: COC(=O)CC(Br)C(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(N=[N+]=[N-])C(C)=O
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a solution of 2.23 g (10.67 mmol) of 3-bromo4-oxo-pentanoic acid methyl ester in 11 mL of DMF at 0° C. was added 690 mg (10.67 mmol) of sodium azide. After warming to RT over 2.5 h, the reaction was diluted with water and extracted with diethyl ether/hexane (1:1). The layers were separated, the organics dried (Na2SO4), and the solvent removed in vacuo. The residue was purified by silica gel chromatography using diethyl ether/hexane (gradient of 1:4 to 2:3) to give 1.07 g (58% yield ) of the title compound: low resolution MS (FAB) m/e 172 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:28][CH2:27]1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Yield: 99 %

Procedure:
Method 1 was followed using 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 55° C. for 1 hour yielding tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-ylcarbamate (99%). LCMS (m/z): 390.1 (MH+); LC Rt=3.51 min.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25]O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:36])=O>C1(C)C=CC=CC=1>[Cl:36][CH2:25][C:21]1[N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][N:22]=1
Reactant: OCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of (1-trityl-1H-imidazol-2-yl)-methanol (9.92 g; CAS 102152-03-4) in toluene (160 ml) was cooled under an argon atmosphere to 0° C. and treated with triethylamine (8.1 ml). Then, thionylchloride (2.96 ml) was added dropwise. The reaction mixture was stirred for 1 hour at 0° C., then treated with 500 ml ice-cold H2O. The mixture was extracted with EtOAc. The organic layer was washed with H2O, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (silica gel; eluent: CH2Cl2/methanol 95:5) to give 2-chloromethyl-1-trityl-1H-imidazole (2.73 g) as off-white solid. MS 359.0 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]C)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:20])=[N:24][CH:25]=1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ccc(Cl)cn1
Product: CN1C(C(=O)Nc2ccc(Cl)cn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 60 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-5-chloro-pyridine with a yield of 60% of theory.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:16])=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[C:10]=1[OH:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:6]1[NH:7][C:8]([CH3:16])=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH2:17][CH:19]1[O:21][CH2:20]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCCc1c(C)[nH]c(C(=O)OCC)c1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C)[nH]c(C(=O)OCC)c1OCC1CO1
Temperature: 50 °C
Yield: 93.8 %

Procedure:
Using the method described in Example V, 35 g of 2-carboethoxy-3-hydroxy-4-butyl-5-methyl-pyrrole, 32 g of epibromohydrin and 41 g of dry potassium carbonate in 100 ml of N,N-dimethylformamide, when heated at 50° C. for 8 hours, give 41 g of 1-(2-carboethoxy-4-butyl-5-methyl-pyrrol-3-oxy)-2,3-epoxypropane, of melting point 125°-127° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[CH3:15]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH3:15])[CH2:11][CH2:12]1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyridyl)piperazine instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:18](=[O:30])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:20]([C:22]4[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=4)[C:28]#[N:29])[CH2:19][C:18](=[O:30])[NH:17][C:9]=3[CH:10]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C4CC4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-cyclopropyl-phenyl}-carbamic acid tert.-butyl ester (Example K78) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (44 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][N:11]=[C:10]1[S:22][CH2:23][CH2:24][CH3:25].[OH-].[K+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][N:11]=[C:10]1[S:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCSc1ncc(CCCC(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCSc1ncc(CCCC(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of ethyl 4-[1 (2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]butyrate (244 mg) was dissolved in ethanol (5 mL) and a solution of potassium hydroxide (950 mg) in water (5 mL) was added. After being stirred at room temperature for 2 hours, the solution was diluted with water, acidified to pH 3.5 to 4.0 with 10% hydrochloric acid solution and the precipitated product was filtered, washed well with water and recrystallized from acetonitrile to afford 0.144 g (64%) of 4-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]butyric acid; mp 98°-99° C.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH:1]1([S:4][C:5]2[CH:13]=[CH:12][C:8]([CH2:9][NH2:11])=[CH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)c1ccc(SC2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(SC2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-cyclopropylsulfanyl-benzamide (preparation 63a, 137 mg, 0.71 mmol) in THF is added to lithium aluminium hydride (1 M in THF, 2.1 mL, 2.1 mmol) precooled at 0° C. The mixture is stirred at 0° C. for 1 h and then heated at reflux for 1 h. The mixture is cooled to room temperature and stirred for 1.5 h. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. Yield: 75 mg (60% of theory); ESI mass spectrum: [M+H]+=180; r.t. HPLC: 0.51 min (X011_S03).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+]>O1CCCC1>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([B:17]([OH:18])[OH:16])=[CH:8][CH:9]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Under nitrogen, 113 mL (181 mmol) of n-BuLi (1.6 M in hexanes) was added to a stirred solution of 30 g (150 mmol) of 4-bromothioanisole (Lancaster) in 1,500 mL of anhydrous tetrahydrofuran (THF) at −78° C. After 30 minutes, 51 mL (450 mmol) of trimethylborate was added. The reaction was warmed to ambient temperature and stirred overnight. The resulting solution was treated with 300 mL of 10% NaOH and stirred vigorously for 1 hour. The THF was removed in vacuo, the pH adjusted to 4-5 and the solid collected by filtration. The solid was washed repeatedly with water and hexane. Drying in vacuo gave 21 g (83%) of 4-methylthiophenylboronic acid as a colorless solid: NMR (DMSO-d6) δ 2.47 (s, 3H), 7.20 (d, J=8 Hz, 2H), 7.71 (d, J=8 Hz, 2H), 7.96 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>CN(C=O)C>[CH3:11][N:12]([CH3:14])/[CH:13]=[C:7](\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)/C(=C/N(C)C)c1ccccc1
Yield: 18.5 %

Procedure:
A solution of 1-phenylpropan-2-one (2.3 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by silica gel column (PE/EtOAc=4:1-2:1) to give the title compound (0.7 g, 18%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]3=[N:9][C:8]=2[CH3:17])=[CH:4][C:3]=1[N+:20]([O-])=O.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:20][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:2]=1[OH:1])[CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[CH3:17]
Reactant: Cc1ccn2c(Cc3ccc(O)c([N+](=O)[O-])c3)c(C)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccn2c(Cc3ccc(O)c(N)c3)c(C)nc2c1
Yield: 70.8 %

Procedure:
A mixture of 3-(4-hydroxy-3-nitrobenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (2.2 g) in ethanol (100 ml) and tetrahydrofuran (50 ml) was hydrogenated over 10% palladium on carbon (0.7 g) under atmospheric pressure of hydrogen gas for 5 hours at ambient temperature. The catalyst was removed by filtration and filtrate was concentrated in vacuo and the precipitate was collected by filtration to give 3-(3-amino-4-hydroxybenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(O)(=O)C>[Br:13][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:12]
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (10.0 g, 54.2 mmol, from Aldrich) in acetic acid (100 mL) was added N-bromosuccinimide (11.6 g, 65.0 mmol) and the resulting mixture was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo, then neutralized with sat. sodium bicarbonate, and the insoluble succinimide was removed by filtration. The filtrate was extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product was recrystallized from a mixture of EtOAc and hexane (11.4 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])=[C:2]([NH2:1])[N:3]=2)[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)c(C)cc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 43) and ethyl-4-amino- 1-piperidine carboxylate (Aldrich 96%) using the procedure described in Step B. Example 6. HRMS, observed: 431.2090, Calcd for (M+H)+: 431.2089.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](I)[CH2:10][CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCn1ncc(C#N)c1N
Temperature: 80 °C
Reaction time: 0.16 h

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 15 g, 0.138 mol), pentyliodide (Acros, 24.45 ml, 0.187 mol) and anhydrous potassium carbonate (Fisher, 25.88 g, 0.187 mol) were suspended in 100 mL anhydrous DMF and heated at 80° C. under nitrogen overnight. HPLC analysis (Method D) showed starting material still present. An additional 9 ml (69 mmol) of pethyliodide and 9.5 g (69 mmol) K2CO3 were added to the reaction and heating continued for 5 more hours. The reaction was permitted to cool and the DMF was removed on a rotary evaporator. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded orange solid which contained both pentyl isomers and residual DMF by NMR analysis (27.65 g, greater than theoretical yield). This was carried on crude. HPLC (1 peak, 63%) elutes at 9.5 minutes (Method D). 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.60 (s, 1H), 6.15 (s, 1H), 5.33 (s, 2H), 3.80 (t, J=7, 2H), 1.68 (m, 2H), 1.25 (m, 4H) 0.75 (t, J=7, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:36])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@H:16]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])[S:10][C:11]=1[CH3:12].NN>O1CCCC1.CO>[NH2:25][CH2:24][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([CH3:12])=[C:7]([C:6]2[N:5]([CH3:36])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:14])[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc(C(=O)N[C@H](CN)CC2CCCCC2)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 61.4 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol) in tetrahydrofuran (2.20 ml) and methanol (2.20 ml) at 25° C. was added hydrazine (0.14 ml, 4.40 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then transferred to the HCl salt adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (124 mg, 0.27 mmol, 60% yield) as a yellow solid: LCMS (ES) m/z=394, 396 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (br. s., 1H) 7.97 (br. s., 3H) 7.86 (s, 1H) 7.70 (s, 1H) 4.24-4.26 (m, 1H) 3.71 (s, 3H) 2.90-2.99 (m, 2H) 2.36 (s, 3H) 1.75-1.79 (m, 1H) 1.61 1.64 (m, 4H) 1.48-1.51 (m, 1H) 1.31-1.36 (m, 2H) 1.10-1.14 (m, 2H) 0.91-0.94 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[CH:12][CH:11]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CN[C@H](CO)C(=O)O)cc1

Procedure:
The title compound was prepared from D-serine (29.6 g, 0.3 mmol) and p-methoxybenzaldehyde (68.0 mL, 0.6 mmol) according to Method W and was obtained as a white solid (36.2 g, 57%) that required no further purification. δH (DMSO-d6) 7.37 (2H, dd, J 8.7 and 1.9 Hz), 6.93 (2H, dd, J 8.7 and 1.9 Hz), 3.99 (2H, s), 3.55 (3H, s), 3.73 (3H, m), 3.15 (1H, t, J 4.7 Hz). Some exchangeable protons were not observed. LCMS (ES+) 225.8 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCc1ccoc1
Product: N#Cc1c(OCc2ccoc2)cccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and 3-furanmethanol in 100% yield. 1H NMR (400 MHz, d-DMSO) δ 5.27 (s, 2H), 6.59 (s, 1H), 7.69 (s, 1H), 7.91-7.84 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:27][CH2:28]2)=[O:22])=[CH:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1ccc(F)cc1)CC2
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 25.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluorophenylamino)-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.100 g, 0.209 mmol) obtained in Example 116, step 2 and ethanesulfonamide (0.113 g, 1.04 mmol), the title compound (0.031 g, 25%) was obtained.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[C:26]([C:27](O)=[O:28])[C:20]=4[N:19]=3)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:64][S:65]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH2:73])=[CH:70][CH:69]=1)(=[O:67])=[O:66]>CN(C=O)C>[CH3:64][S:65]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH:73][C:27]([C:26]2[C:20]3[N:19]=[C:18]([NH:17][C:15]([C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:8]#[C:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:14]=4)=[O:16])[NH:22][C:21]=3[CH:23]=[CH:24][CH:25]=2)=[O:28])=[CH:70][CH:69]=1)(=[O:66])=[O:67]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(Nc1nc2c(C(=O)O)cccc2[nH]1)c1cccc(C#Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc3[nH]c(NC(=O)c4cccc(C#Cc5ccccc5)n4)nc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
To a solution of 30 mg (0.07 mmol) of above 2-[(6-Phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid in DMF (1 mL) was added 40 mg (0.1 mmol) of HBTU and DIEA (0.1 mL), the resulting mixture was stirred at room temperature for 10 min, then 40 mg (0.1 mmol) of 4-methanesulfonyl-benzylamine HCl salt was added. After usual work up as described in general procedure A, 21 mg (48%) of 2-[(6-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid 4-methanesulfonyl-benzylamide was obtained after column chromatography purification eluting with DCM/EtOAc (v/v from 5:1 to 1:1). LCMS: 550 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]1[CH2:24][CH:16]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[OH:15][CH:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:24][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: c1ccc(CC2CO2)cc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: C1COCCO1
Product: N#CC1(c2ccccc2)CCN(CC(O)Cc2ccccc2)CC1

Procedure:
A mixture of 4-phenyl-piperidine-4-carbonitrile (6.3 g, 34 mmol) and (2.3-epoxypropyl)benzene (5.0 g, 37 mmol) in dioxane was refluxed for seven days. The solvent was evaporated and the residue was shaken between dilute sodium hydroxide and diethyl ether. The ether extract was dried over potassium carbonate, filtered and the product was converted to the hydrochloride as described in Example 5. Recrystallization from a mixture of ethanol and acetonitrile gave 10.0 g with m.p. 246-249° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:33]C1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:33])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 250.0 mg (0.522 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 249.0 mg (1.827 mmol) of zinc chloride, 24 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF, and 4-ethylphenyl lithium (prepared by adding 167.7 mg (1.54 ml, 2.62 mmol) of tert-butyllithium (1.7M solution in pentane) to a cold solution (-78° C.) of 244.0 mg (1.305 mmol) of 4-ethylbromobenzene in 2.0 ml of THF). 1H NMR (CDCl3): δ 7.99 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz), 7.42-7.24 (7H, m), 5.99 (1H, t, J=4.7 Hz), 4.37 (2H, q, J=7.1 Hz), 2.71 (2H, q, J=7.6 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).