Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:6][N:5]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[N:3]=1.[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O.C(OCC)(=O)C>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:4]2[N:3]=[C:2]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:6][N:5]=2)=[CH:23][CH:24]=1)#[N:29]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1-n1cccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
To a solution of tert-butyl (5-(4-chloro-2-((4-cyanophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)carbamate (T5, 30 mg) and pyrazole (7 mg) in N-methylpyrrolidone (1 mL), cesium carbonate (71 mg) was added at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 40% hexane in ethyl acetate) to obtain tert-butyl (5-(2-((4-cyanophenyl)amino)-4-(1H-pyrazol-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)carbamate (T7, 20 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[O:9]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: OC(c1cccc(F)c1)C1CCCCN1
Product: Fc1cccc(C2OC3(CCN(Cc4ccccc4)CC3)N3CCCCC23)c1

Procedure:
Utilizing the procedure described in Example 1 above, 11 g of alpha-(3-fluorophenyl)-2-piperidinemethanol is reacted with 10 g of N-benzyl-4-piperidone to obtain hexahydro-1'-benzyl-1-(3-fluorophenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 113°-115° C. after recrystallizaton from petroleum ether.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 5.47 g of 5-[6-(hydroxymethyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide, 2.57 g of methanesulfonyl chloride, and 2.39 g of triethylamine in 130 ml dichloromethane give [3-(5-carbamoyl-4-{1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[C:23](Br)[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:35]C(C)([O-])C.[K+].CB(O)O.C(O)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[C:23]([CH3:35])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Reactant: CC(C)(C)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(C)c1
Temperature: 160 °C
Yield: 48.3 %

Procedure:
A mixture of {4-[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetra-hydro-indazol-1-yl}-acetic acid ethyl ester (70 mg, 0.123 mmol, prepared as described above in example 2-1), tetrakis(triphenylphosphine)palladium(0) (1 mg, 0.012 mmol), potassium tert-butoxide (2.5 mg, 0.29 mmol), methylboronic acid (12 mg, 0.184 mmol) in N,N-dimethylformamide (1.5 ml) was heated in a microwave oven at 160° C. for 30 minutes, then acidified to pH 6 by addition of acetic acid. The resulting precipitate was filtered through a glass funnel to afford {4-[6-(4-chloro-phenoxy)-5-methyl-pyridine-3-sulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 48%) as a white solid. MS cald. for C23H25ClN4O5S 504, obsd. (ESI+) [(M+H)+] 505.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[N:6][CH:7]=1.[F-].[K+].Br[CH2:21][N:22]1[C:26](=[O:27])[C:25]2[C:28]([CH:34]([CH3:36])[CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=2[S:23]1(=[O:38])=[O:37]>CN(C=O)C>[CH:34]([C:28]1[C:25]2[C:26](=[O:27])[N:22]([CH2:21][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[N:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=3)[S:23](=[O:38])(=[O:37])[C:24]=2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=1)([CH3:36])[CH3:35]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccc(Cl)cn1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cn1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
A mixture of 1-(5-chloro-2-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole (527 mg; 2 mmol) and KF (232 mg; 4 mmol) in 4 ml of DMF was stirred under nitrogen at room temperature for 20 minutes and then 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (609 mg, 1.75 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, filtered, and the solid residue was washed with water. The white solid was dissolved in methylene chloride, dried over magnesium sulfate, partially concentrated in vacuo, and the resulting residue was crystallized from ethyl acetate. The combined solid was dried in vacuo to afford 736 mg (79%) of 4-isopropyl-6-methoxy-2-[1-(5-chloro-2-pyridyl)-3-(trifluoromethyl)pyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =5-chloro-2-pyridyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 173°-174° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][CH2:20][C:21]([OH:23])=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11]3[C:10]=1[CH2:19][CH2:20][C:21](=[O:23])[C:12]=3[CH:13]=[CH:14][CH:15]=2
Reactant: COc1ccc2ccccc2c1CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2cccc3c2c1CCC3=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 250 ml three-necked flask, oxalyl chloride (1.95 ml, 2.19.10−2 mol, 1 eq.) is added dropwise, under argon, to a solution of the acid obtained in Step D (5 g, 2.17.10−2 mol) in anhydrous dichloromethane (225 ml) at 0° C. A few drops of anhydrous dimethylformamide are then added. After 1 hour at 0° C., slight evolution of gas is still observed and the three-necked flask is left at ambient temperature for 40 minutes. After return to 0° C., aluminium chloride (7.5 g, 5.62.10−2 mol, 2.6 eq.) is added using a spatula. The initially yellow solution becomes red, orange and then khaki-green. After 15 minutes' stirring at 0° C., the mixture is poured into an ice/1N HCl mixture. After separation of the phases and washings of the acidic aqueous phase with dichloromethane, the combined organic phases are washed with water, then treated with a saturated NaHCO3 solution and finally washed with a saturated NaCl solution. After drying over MgSO4 and evaporation under reduced pressure, the yellow oil obtained crystallises in a freezer.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1[NH:30][C:31]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:32][N:33]=1>>[CH2:22]([C:21]1[N:32]2[N:33]=[C:29]([CH3:28])[N:30]=[C:31]2[N:34]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:10][C:11]=1[F:27])[CH2:23][CH2:24][CH3:25]
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 71.5 %

Procedure:
A mixture of methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (1 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 72%).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:21])[C:11]1([CH3:44])[CH3:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(C)(C)C(=O)N(Br)C1=O.CC1C=C(C)C=C(C)N=1>>[C:1]([O:9][C@H:10]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([CH2:22][O:23][Si:24]([CH:31]([CH3:32])[CH3:33])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:30])[CH3:29])[CH3:21])[C:11]1([CH3:44])[CH3:43])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Yield: 100.1 %

Procedure:
42 g of (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3β-ol benzoate were treated with 13.7 g 1,3-dibrom-5,5-dimethyl-hydantoin and 18 ml 2,4,6-trimethylpyridine as described in Example 1e) to give (without purification by column chromatography) 41.9 g of (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5,7-dien-3β-ol benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N1CCCCC1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(N3CCCCC3)c([N+](=O)[O-])cc2Cl)CC1
Yield: 83.6 %

Procedure:
The procedure of Example 5, step (b) was followed using 968 mg (3.52 mmol) of 1-(4,5-dichloro-2-nitro-phenyl)-piperidine (as prepared in the previous step) and 1.95 mL (17.6 mmol) of 1-methylpiperazine. Crystallization from hexane afforded 997 mg (84%) of the title compound as a yellow-tan solid: Mass spectrum (ESI, m/z): Calcd. for C16H23ClN4O2, 339.2 (M+H), found 339.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:23][CH2:27][CH:29]1[O:31][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(OCC3CO3)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 6.1 g. of 3,4-dibenzyloxyphenol in 10 ml. of water and 1.53 g. of potassium hydroxide pellets is added 5.6 g. of epichlorohydrin in 60 ml. of ethanol. The solution is stirred at room temperature for 24 hours and then concentrated in vacuo. The residue is suspended in water and the mixture extracted with ether. The ether extracts are dried to yield 3-(3,4-dibenzyloxyphenoxy)-1,2-epoxypropane.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:16])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](O)=O>CN(C1C=CN=CC=1)C.ClCCl>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:16][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:9]
Reactant: O=C(O)c1ccccn1
Reactant: N[C@H](c1ccccc1)[C@H](N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N[C@H](c1ccccc1)[C@H](NCc1ccccn1)c1ccccc1
Yield: 71 %

Procedure:
A solution of (1R,2R)-1,2-diphenylethylenediamine (1.16 g, 4.74 mmol), picolinic acid (596 mg, 4.79 mmol, 1.01 eq.), N,N-dimethyl-4-aminopyridine (100 mg, 0.82 mmol, 0.17 eq.) and 1,3-dicyclohexycarbodiimide (1.07 g, 5.2 mmol, 1.1 eq.) in dichloromethane (40 ml) was stirred at room temperature under N2 for 18 hours. The reaction mixture was filtered and washed with water. Column chromatography on silica gel using EtOAc/CH2Cl2 (4:1) afforded 1.06 g of white solids as title compound (71% yield). NMR and GCMS confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]2[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=1)[C:30]#[N:31]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3Cl)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 156, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3-chloro-4-fluorobenzonitrile and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=511.2 [M+H+].
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[N:36]([O-])=[O:37].[Na+]>O>[OH:37][N:36]=[C:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]#[N:11]
Reactant: O=N[O-]
Reactant: N#CCC(=O)c1ccccc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Solvent: O
Product: N#CC(=NO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of benzoylacetonitrile (11.7 g, 80.7 mmol) in a mixture of glacial acetic (34 ml) and water (1 ml) was stirred vigorously at 10° C. whilst an aqueous solution of sodium nitrite (6.1 g, 88.4 mmol in 7 ml) was added dropwise over 30 minutes. The mixture was stirred for 1 hour at room temperature and then poured into iced water (600 ml). The yellow solid which precipitated was filtered off, washed with water (100 ml) and dried, giving the title compound, 7.8 g (56%). m.p. 126°-128° C. (literature m.p. 117°-119° C.; Ger. Offen. 2,722,416 (1978).
Reaction SMILES: [CH3:1][C:2]12[CH2:28][CH:5]([C:6]3([CH3:27])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]12[CH2:28][CH:5]([C:6]3([CH3:27])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:17])[C:18]4[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:25][CH:26]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(=O)c4ccc(C(=O)O)cc4)cc3C21C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC12CCC(C1)C1(C)Oc3ccc(C(O)c4ccc(CO)cc4)cc3C21C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A solution of 3.76 g (10 mmol) of the acid obtained in Example 9 was added dropwise to a suspension of 1.14 g of lithium aluminium hydride in 10 ml of tetrahydrofuran and the reaction mixture was maintained under stirring for 3 hours at room temperature. The reaction mixture was neutralized at 0° C. by dropwise addition of a saturated ammonium chloride solution. The precipitate was filtered off, washed with hexane and dried to yield 3.13 g (86%) of the expected compound, melting at 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:26])[N:3]=[CH:4]1
Reactant: COc1cccc(Cn2cnc(N)c2C(N)=O)c1
Reactant: O=C(O)c1cccnc1
Product: COc1cccc(Cn2cnc(NC(=O)c3cccnc3)c2C(N)=O)c1
Yield: 62 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 2.96 g (12.0 mmol) of 4-amino-1-(3-methoxybenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 81 and nicotinic acid instead of cyclopentylacetic acid to obtain 2.61 g of 1-(3-methoxybenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 62%).
Reaction SMILES: [C:1]([CH2:6][C:7]([CH3:19])([CH3:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:18])([CH3:19])[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(C)(C)CCCCC1CCCC1=O
Product: CCOC(=O)CC(C)(C)CCCCC1=C(OC(C)=O)CCC1

Procedure:
This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 10.
Reaction SMILES: [CH:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:13]([O:15][SiH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:14]>C(Cl)Cl>[CH2:13]([O:15][Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:1]=[O:12])[CH3:14]
Reactant: C=CCCCCCCCCC=O
Reactant: CCO[SiH](OCC)OCC
Solvent: ClCCl
Product: CCO[Si](CCCCCCCCCCC=O)(OCC)OCC
Yield: 30 %

Procedure:
To a solution of 16.8 g 10-undecenal in 25 ml methylene chloride, crystals of di-μ-chlorodichlorobis(ethylene)-diplatinum (II) were added and the solution heated to 40°-45° C. A solution of 16.4 g triethoxysilane in 25 ml methylene chloride was added dropwise over a period of 90 minutes. After reagent addition was completed, the rection mixture was heated for an additional 30 minutes. The mixture was fractionated and the product, 11-triethoxysilylundecanal (I) was obtained at 65° C. at 0.2 mm Hg at a 30% yield.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[C:7]([Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[K+]>C(O)C>[Cl:15][C:7]1[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[NH2:11]
Reactant: CCCCc1ccc(NC(C)=O)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(N)c(Cl)c1
Temperature: 120 °C
Yield: 84.6 %

Procedure:
To a suspension of 68 (8.54 g; 37.9 mmol) in ethanol (20 mL) was added concentrated hydrochloric acid (20 mL). The resulting mixture was heated at 120° C. for 5 hours, allowed to cool to room temperature, then made basic with aqueous potassium hydroxide, and extracted with methyl tert-butyl ether (3×75 mL). The combined organic extracts were washed with aqueous saturated sodium chloride, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title product as a dark oil (5.89 g).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21].[OH-].[Ca+2].[OH-].[CH3:30]OS(OC)(=O)=O>CN(C)C=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:22][C:23]([O:25][CH3:26])=[O:24])[S:21][CH3:30]
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=S)NC(=O)OC)C(=N)C=C1
Reactant: COS(=O)(=O)OC
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSC1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (3.88 g.; 0.01 mol) in dimethylformamide (40 ml.) and water (10 ml.) there is added calcium hydroxide (0.74 g.; 0.01 mol). The mixture is stirred at room temperature for four hours and to it there is added dimethylsulfate (1.26 g.). The mixture is stirred at room temperature for four hours and the precipitate collected and dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=3[OH:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)c(O)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(O)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-hydroxy-4-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 513.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6](O)[CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[BrH:13]>>[Br:13][CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: Br
Reactant: CC(C)C(O)c1ccc(Cl)cc1
Product: CC(C)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of p-chloro-α-isopropylbenzyl alcohol (33.08 g) in 48% hydrobromic acid (330 mL) is stirred at room temperature for 1 hour and extracted with hexanes. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a yellow oil (42.98 g) which is identified by NMR spectral analysis.