Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[N+:15]([O-])=O)(=[O:5])[O:3][CH3:4]>C(O)(=O)C.[Fe]>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[NH2:15])(=[O:5])[O:3][CH3:4]
Reactant: CCSc1ccc([N+](=O)[O-])c(P(C)(=O)OC)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCSc1ccc(N)c(P(C)(=O)OC)c1

Procedure:
To a solution of methyl P-methyl-2-nitro-5-ethylthiophenylphosphinate (3.6 g) in 5% aqueous acetic acid (40 ml) is added 3.0 g of iron by portions at reflux temperature. After addition is complete, the mixture is heated under reflux for another 2 hours. The reaction mixture is filtered and the filtrate is extracted with methylene chloride (3X). The combined extracts are washed, dried and concentrated to dryness to yield methyl P-methyl-2-amino-5-ethylthiophenylphosphinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[OH-].[Na+].[CH2:14](I)[CH3:15]>CS(C)=O.O>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:11][CH2:14][CH3:15]
Reactant: CCI
Reactant: COc1cccc(OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1c(OC)cccc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To a stirred solution of 2,6-dimethoxyphenol (10 g) in dimethylsulfoxide (100 ml) under nitrogen was added a solution of sodium hydroxide (3.2 g) in water (20 ml). The mixture was warmed to 50° C., ethyl iodide (12.4 g) added, and stirring continued at 50° C. for 4 hours. The product was poured into 1 liter of water and the mixture extracted with diethyl ether. The extract was washed sequentially with 20% potassium hydroxide, water, and brine, and then dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 1,3-dimethoxy-2-ethoxybenzene as a colorless oil (6.71 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: ClCc1ccccn1
Reactant: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: Cl
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 7 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound in 7% yield; NMR spectrum (DMSO-d6) 1.18 (d, 3H), 1.83 (s, 3H), 2.84 (s, 3H), 4.19-4.43 (m, 2H), 5.14-5.24 (m, 1H), 5.30 (s, 2H), 7.16-7.27 (m, 2H), 7.32-7.38 (m, 2H), 7.45-7.50 (m, 1H), 7.58 (d, 1H), 7.72 (t, 1H), 7.87 (t, 2H), 8.43 (s, 1H), 8.59 (d, 1H), 9.53 (s, 1H); Mass spectrum MH+ 492.3.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:5][C:6](=[O:34])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH3:42]>CO>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([NH2:42])=[O:2])[CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)=[O:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:13])([CH3:17])([CH3:16])[CH3:18]
Reactant: N
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl-L-histidine methyl ester (2 g) is dissolved in a methanol solution saturated with ammonia, and the solution is stirred in a pressure bottle at room temperature for three days. The reaction mixture is concentrated under reduced pressure and the residue is crystallized with ether to give N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl-L-histidine amide (1.7 g) as white crystals. Yield: 87.2%
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Mg].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.Cl>C(OCC)C>[CH2:1]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Brc1ccsc1
Reactant: CCCCCCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCc1ccsc1
Temperature: 0 °C
Yield: 65 %

Procedure:
0.125 mole of n-hexylbromide was dissolved in 40 ml of ethyl ether. Then, 10 ml of ethyl ether was added in drops and also 0.13 mole of magnesium chip was added. The mixture was refluxed for 5 to 6 hours and the Grignard agent was obtained. The Grignard reagent was added to a solution consisting of 70 mg of NiDPPPCl2 and 0.106 mole of 3-bromo thiophene in drops at 0° C., then the mixture was refluxed for 12 to 15 hours. After that, the mixture was hydrolyzed with 40 ml of 1N hydrochloric acid and 150 ml of ice water. Then, ethyl ether was used to extract the mixture for a few times, and the mixture was washed with water until the solution was neutral. The extract was dried by sodium sulfate to remove the solvent. The product of 3-hexylthiophene was obtained with a yield of 65% after distillation under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])CCC.[Cl:15][Si:16](Cl)([CH3:18])[CH3:17]>O1CCCC1.CCCCCC>[CH3:1][C:2]1[C:3]([CH3:9])=[C:4]([CH3:8])[C:5]([Si:16]([CH3:18])([CH3:17])[Cl:15])([CH3:7])[CH:6]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a two-necked round-bottomed flask, the atmosphere in which was replaced with nitrogen, were charged 15 g of tetrahydrofuran, 12 g of n-hexane and 1.10 g of tetramethylcyclopentadiene. The mixture was cooled to 0° C. with stirring and 4.90 ml of n-butyl lithium (1.6M solution in n-hexane) (7.84 mmol as n-butyl lithium) was gradually added dropwise thereto over 20 minutes. The obtained reaction mixture in the form of a white slurry was stirred for at 0° C. for 3 hours, and a pre-cooled tetrahydrofuran (10 g) solution containing 1.01 g (7.84 mmol) of dichlorodimethylsilane was added in several divided portions. The mixture was then gradually heated to room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:14]=3)=[CH:11][C:10]([C:24]([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=[O:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(OCCCO)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OCCCO)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 116A in analogy to the synthesis of the compound of Example 23. 54 mg (69% of theory) of the title compound are obtained.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:8]([F:14])([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:4]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)C(F)(F)c1ccn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C(F)(F)C(F)(F)F)n1
Yield: 42.4 %

Procedure:
2.01 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole and 1.39 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 25 ml of N,N-dimethylformamide. 2.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.31 g of {[3-(pentafluoroethyl)-1H-pyrazole-1-yl]methyl}(3,3, 3-trifluoropropyl)malononitrile (referred as the compound of the present invention (36), hereinafter) shown by below formula.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[C@@H:17]([CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH:15]=[CH:14][CH2:13]2)(=O)=O)=CC=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:28]([CH2:11][C@H:12]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:16][CH:15]=[CH:14][CH2:13]1)#[N:29]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CC[C@@H]2COCc2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
The p-toluene sulphonyl ester/benzyl ether (3) (12 g) in dimethylsulphoxide (DMSO) (15 ml) is added with stirring to potassium cyanide (3 g) in DMSO (20 ml). The mixture is heated at 100° C. under nitrogen for 6 hours and is then cooled, poured into water and the product extracted with ether. The solvent is removed and the residue purified on a Florisil column, eluting with petroleum ether-benzene (1:1) to give the title compound as an oil (6.5 g, ca. 80%) νmax (film) 2220 and 1600 cm-1.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.CC#N.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH:17]1([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][NH:31][CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:8]=3[CH:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Reactant: NC1CCCC1
Solvent: CC#N
Solvent: O
Product: Cc1nc(CNC2CCCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (500 mg) and CH3CN (10 mL) was added cyclopentylamine (1.0 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) and silica gel column (hexane/EtOAc) to obtain N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]cyclopentaneamine (326 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](=[NH:10])OC.[C@@H:14]1(N)[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH2:20]>CCO>[Br:1][C:2]1[CH:11]=[C:6]([C:7]2[NH:20][C@@H:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]3[N:10]=2)[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: COC(=N)c1cc(Br)cnc1OC
Solvent: CCO
Product: COc1ncc(Br)cc1C1=N[C@@H]2CCCC[C@H]2N1
Temperature: 80 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
To a solution of methyl 5-bromo-2-methoxynicotinimidate (6.1 g, 18.5 mmol) in EtOH (100 mL) was added trans-Cyclohexane-1,2-diamine (2.1 g, 18.5 mmol) at room temperature, the mixture was stirred at 80° C. for 12 hours. The solvent was removed and the resulting residue was washed with dichloromethane (50 mL*2), then dry to provide trans-2-(5-bromo-2-methoxypyridin-3-yl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazole (4 g, yield 70.2%). 1HNMR (400 MHz, CDCl3) δ 8.56 (d, J=2.4 Hz, 1H), 8.43 (s, J=2.4 Hz, 1H), 4.14 (s, 3H), 3.51˜3.53 (m, 2H), 2.45˜2.49 (m, 2H), 1.91˜1.93 (m, 2H), 1.61˜1.63 (m, 2H), 1.36˜1.41 (m, 2H), 1.25 (s, 1H). MS (M+H)+: 310/312.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH2:10][CH2:9]1
Reactant: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCNCC1

Procedure:
Step 1): 10% Pd/C was added to a solution of the N-(1-benzylpiperidin-4yl)-2-(N'-n-heptylureido)benzamide (1.4 g, 3.1 mmol) obtained in Example 41 in methanol (25 ml) under nitrogen. The mixture was shaken under 50 psi hydrogen pressure for 5 hours, and then filtered under nitrogen. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (50% methanol and 0.8% NH4OH in dichloromethane) to give N-(piperidin-4-yl)-2-(N'-n-heptylureido)benzamide: 48.4%: mp 159° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:5][CH2:4][N:3]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1COCC1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:9])[CH2:5][CH2:4][N:3]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a pre-dried RB flask, 1-tert-butyl 4-(9H-fluoren-9-ylmethyl) 2-oxopiperazine-1,4-dicarboxylate (6.5 g, 15.39 mmol) was dissolved in CH2Cl2 (150 mL) and THF (15 mL) under N2 and was cooled down to −78° C. DIBAL-H (23.08 mL, 23.08 mmol) was added slowly. Let reaction stir at −78° C. for 2 hours. Then saturated Rochelle's salt water solution (150 mL) was added to quenched reaction. Reaction was slowly warmed up to room temperature. Then it was passed through a Celite® pad. Filtering pad was washed with ether (100 mL×2). Then layers were separated and aq. layer was extracted with 50 mL of EtOAc twice. Organic phases were combined and were washed with water and brine (50 mL) respectively. Then it was passed anhydrous Na2SO4. Concentration gave crude product as white solid that was used directly in next step. LC/MS: (M+23)+=447.16
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([OH:16])=O.[Cl:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][C:22]([NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)=[C:21]([N+:44]([O-:46])=[O:45])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[Cl:18][C:19]1[C:24]([N:25]2[CH2:26][CH2:27][N:28]([C:14]([C:13]3[N:12]([CH3:17])[N:11]=[N:10][C:9]=3[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:16])[CH2:29][CH2:30]2)=[CH:23][C:22]([NH:31][C:32](=[O:43])[C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([CH3:42])[CH3:41])=[CH:37][CH:38]=2)=[C:21]([N+:44]([O-:46])=[O:45])[CH:20]=1
Reactant: CN(C)Cc1ccc(C(=O)Nc2cc(N3CCNCC3)c(Cl)cc2[N+](=O)[O-])cc1
Reactant: COc1ccccc1-c1nnn(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COc1ccccc1-c1nnn(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(CN(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Reaction time: 3 h
Yield: 25.6 %

Procedure:
A mixture of 4-(2-methoxyphenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (44.7 mg, 0.192 mmol), N-(4-chloro-2-nitro-5-(piperazin-1-yl)phenyl)-4-((dimethylamino)methyl)benzamide (85 mg, 0.160 mmol), HATU (79 mg, 0.208 mmol), and DMAP (78 mg, 0.639 mmol) in NMP (2 mL) was stirred for 3 h. HPLC purification, then silica column purification afforded the title compound (28 mg, 0.041 mmol). 1H-NMR (CDCl3, 500 MHz): δ11.62 (1H, s), 8.57 (1H, s), 8.31 (1H, s), 8.06 (2H, d, J=8.24 Hz), 7.81 (1H, d, J=7.24 Hz), 7.69 (2H, d, J=7.93 Hz), 7.43 (1H, t, J=8.24 Hz), 7.13 (1H, t, J=7.32 Hz), 7.01 (1H, d, J=7.24 Hz), 4.28 (2H, s), 4.20 (2H, s), 3.94 (2H, m), 3.83 (3H, s), 3.25 (4H, s), 2.83 (6H, s), 2.68 (2H, m). HPLC/MS (Method J): (ES+) m/z (M+H)+=633; Rt=1.52 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[C:22]([F:31])[CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:33])([CH3:32])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[C:22]([F:31])[CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:33])([CH3:32])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)S3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 4-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-2-fluorobenzoate (Compound 236, 100.0 mg, 0.219 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 40° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 78.0 mg (83%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.94 (1H, d, J=7.8 Hz), 7.43-7.17 (9H, m), 5.93 (1H, s), 2.38 (3H, s), 1.47 (6H, s).
Reaction SMILES: [C@H:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C@H:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)[C@@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)[C@@H]2CCCc3ccccc32)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of (R)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (300 mg, 1.7 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (349 mg, 1.7 mmol), HATU (760 mg, 2.0 mmol) in anhydrous DMF (10 mL) is added DIPEA (330 μL, 2 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (67) as white solid (615 mg, 100%).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[F:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]=[CH:22][O:21]2)=[CH:16][CH:15]=1>C(OCC)C.O=P(Cl)(Cl)Cl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@@H:20]2[O:21][C@@H:22]([O:12][CH:3]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[CH2:2][Br:1])[CH2:23][CH2:24][CH2:25]2)=[CH:26][CH:27]=1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Reactant: Fc1ccc(OCC2CCC=CO2)cc1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(OC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
389 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and 300 mg of 2-(4-fluorophenoxymethyl)-3,4-dihydro-2H-pyran, prepared as described above, were dissolved in 10 ml of diethyl ether. A catalytic amount (2 drops) of phosphorus oxytrichloride was added to the resulting solution and the mixture allowed to react at room temperature for 4 days, after which it was treated and the product purified essentially as described in Example 34(a), to give 214 mg of the isomer of lesser polarity of trans-6-(4-fluorophenoxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran, 211 mg of the isomer of greater polarity and 143 mg of a mixture of these isomers.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]4[O:32][C:33](=[O:36])[NH:34][N:35]=4)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:37]>CO.O1CCOCC1>[ClH:37].[ClH:37].[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]4[O:32][C:33](=[O:36])[NH:34][N:35]=4)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(c2n[nH]c(=O)o2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCNCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 250 mg of tert-butyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate in 4 ml of methanol was added 4 ml of 4 M hydrogen chloride in 1,4-dioxane at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and concentrated in vacuo to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>CCCCCC>[C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCC#Cc1ccoc1C=O
Solvent: CCCCCC
Product: CCCCCCC#Cc1ccoc1/C=C/C(=O)O
Yield: 87.7 %

Procedure:
Reaction of 3-(1-octynyl)furan-2-carboxaldehyde (1.02 g, 5 mmole from example 14) with malonic acid (1.04 g, 10 mmole) as described in Example 2 gave 1.08 g (88%) of the title compound, mp (Hexane) 81°-81.5° C., νmax (mull) 2600(broad), 1690, 1670(sh), 1620, 1410, 1320, 1270, 970, 890, 770 cm-1 ; δ(CDCl3) 0.91(3H, t, J=6.9 Hz), 1.34(2H, m), 1.46(2H, m), 1.62(2H, m), 2.45(2H, t, J=7.0 Hz), 6.40(1H, d, J=15.9 Hz), 6.46(1H, d, J=1.8 Hz), 7.41(1H, d, J=1.8 Hz), 7.66(1H, d, J=15.9 Hz), 11.60(1H, broad).