Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]2(=[O:26])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10](=O)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](#[N:31])[CH2:28][C:29]#[N:30]>C(O)C.N1CCCCC1>[C:29]([C:28]([C:27]#[N:31])=[C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[P:7](=[O:26])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9]1)#[N:30]
Reactant: N#CCC#N
Reactant: O=C1C=C(c2ccccc2)P(=O)(c2ccccc2)C(c2ccccc2)=C1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=C1C=C(c2ccccc2)P(=O)(c2ccccc2)C(c2ccccc2)=C1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a mixture of 0.25 g of 1,2,6-triphenylphospha-2,5-cyclohexadien-4-one P-oxide and 0.060 g of malononitrile in 100 ml of ethanol was added 1 drop of piperidine. The red mixture was heated on a steam bath for about one hour, then allowed to cool to room temperature overnight. The product crystallized as dark greenish brown metallic needles. It was collected and dried to give 0.247 g of 4-dicyanomethylene-1,2,6-triphenylphospha-2,5-cyclohexadiene P-oxide, whose structure was confirmed by 1HNMR and FDMS analyses.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6].[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C>[Si:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC/C=C/c1cc(O)cc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
3-Hydroxy-5-[(1E)-3-methoxyprop-1-en-1-yl]benzaldehyde from the previous step (1 eq.) and tert-butylchlorodimethylsilane (1 eq.) were combined in DMF (0.5 M). To this solution was then added imidazole (1.5 eq.) and the reaction mixture was stirred at RT for 16 h. The resulting solution was quenched with water and extracted with 1:1 (v:v) ether:hexanes. The combined organic extracts were washed with brine, dried over MgSO4 and filtered through a plug of SiO2. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)=[CH:9][C:4]=1[CH2:5][OH:6]
Reactant: COC(=O)c1cc(-c2nnn(C)n2)ccc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(-c2nnn(C)n2)cc1CO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate (130 mg, 0.52 mmol) was dissolved in methylene chloride (2 mL), cooled to −78° C. and treated with diisobutylaluminum hydride (1 M in methylene chloride, 1.5 mL, 1.5 mmol). After stirring at −78° C. for 1 h the reaction was quenched by a few drops of methanol (until no bubbling was observed) followed by addition of excess saturated sodium potassium tartarate (2 mL). The reaction was stirred at room temperature overnight, the layers were separated and the organic layer washed with brine (2×), dried over sodium sulfate and concentrated to afford 100 mg (86%). LC/MS (HPLC method 3): tR=1.68 min, 221.11 (MH)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:16][NH:17][CH2:18][C:19]#[CH:20].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:11][C:6]1[C:7]([C:8]([N:17]([CH3:16])[CH2:18][C:19]#[CH:20])=[O:10])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: C#CCNC
Reactant: O=C(O)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCN(C)C(=O)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
A solution of 4,6-dichloropyrimidine-5-carboxylic acid (Compound 310G, 15.0 g, 77.7 mmol) and thionyl chloride (28.3 mL, 389 mmol) was refluxed in DCM (100 mL) for 2 h. The reaction mixture was concentrated in vacuo, taken up in DMF (200 mL) and charged drop-wise with a solution of N-methyl-2-propyn-1-amine (5.4 g, 78 mmol) and triethylamine (21.7 mL, 155 mmol) in DMF at −60° C. and stirred at rt for 24 h. The reaction mixture was partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash to afford 7.66 g, 40% yield, of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ=9.04 (s, 1H), 4.37 (d, J=2.53 Hz, 2H), 3.08 (s, 1H), 2.95 (s, 3H). MS (ES+): m/z 246.0039 [MH+] (TOF, polar).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:10]([CH3:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:28])=[N+:7]2[O-:27].C(OC[C@@H](OC(C)(C)C)C1C([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)=C2C(=CC=1C)N=C(C)C=C2)(=O)C(C)(C)C>>[C:22]([O:21][C@@H:12]([C:11]1[C:2]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:26])[N+:7]([O-:27])=[C:6]([CH3:28])[CH:5]=[CH:4]2)[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Product: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
Following the procedure used to prepare compound (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethyl pivalate was used instead of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate. LCMS-ESI+ (m/z): 484.3, 486.3 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.[Cl:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=1>C(O)C.CO>[ClH:8].[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=1
Reactant: COc1ccnc(CCl)c1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCO
Product: COc1ccnc(CSCCN)c1
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Cysteamine hydrochloride (7.62 g) was added to a solution of sodium (4.70 g) in ethanol (170 cc) and the mixture was stirred and cooled to 10° and 2-chloromethyl-4-methoxypyridine hydrochloride (11.5 g) in methanol (50 cc) was added over 35 minutes, and the mixture was left overnight at room temperature. The mixture was filtered and the filtrate was evaporated to a residue which was partitioned between chloroform and water. The chloroform extract was evaporated to an oil which was crystallised from 2.1 M ethanolic hydrogen chloride to give 2-(2-aminoethylthiomethyl)-4-methoxypyridine dihydrochloride (12.4 g) m.p. 172.5° (decomp).
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[S:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[S:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
In 12 ml of 1N aqueous sodium hydroxide solution is dissolved 0.5 g of 3(R)-[1(S)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide, and the solution is allowed to stand at room temperature for 30 minutes. The solution is neutralized with 2 ml of acetic acid, and purified by MCI-gel (CHP 20P, 150 to 300μ, Mitsubishi Chemical Industries, Japan) column chormatography (water:methanol=2:1). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.3 g of 3(R)-[1(S)-carboxy-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH2:7]Cl.[NH3:24].C(=O)([O-])O.[Na+]>C(#N)C>[NH2:24][CH2:7][C:6]1[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:4]([CH3:23])=[N:3][C:2]=1[Cl:1]
Reactant: N
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CCl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CN)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-5-chloromethyl-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (340 mg) in acetonitrile (3 ml) was added gradually to a mixed solvent of 28% aqueous ammonia (6 ml) and acetonitrile (6 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with chloroform/methanol=100/1. The objective fraction was concentrated under reduced pressure to give 5-aminomethyl-4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (82 mg) as a pale-brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]([N:11]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CCC(=O)O)C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To tert-butyl 3-{N-benzyloxycarbonyl-N-(ethoxycarbonylmethyl)amino}propionate (500 mg, 1.37 mmol) was added formic acid (2.5 mL, 66.3 mmol), followed by stirring at an outer temperature set of 40° C. for 3 hours. After leaving to be cooled, to the reaction mixture were added ethyl acetate (10 mL) and water (10 mL), and the organic layer was collected by separation. To the aqueous layer was added ethyl acetate (10 mL), the organic layer was collected by separation, and then the organic layer was combined, washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was dried at room temperature under reduced pressure to obtain 421 mg (yield 99%) of a title compound as colorless oil.
Reaction SMILES: Cl.[C:2]([C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=2)=[C:7]([F:18])[CH:6]=1)([OH:4])=[O:3].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:2]([C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH2:17][CH2:16][N:15]([C:19](=[O:21])[CH3:20])[CH2:14][CH:13]=2)=[C:7]([F:18])[CH:6]=1)([OH:4])=[O:3]
Reactant: O=C(O)c1cc(F)c(C2=CCNCC2)cc1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N1CC=C(c2cc(F)c(C(=O)O)cc2F)CC1

Procedure:
A suspension of 8.51 g (29.1 mmol) 4-(4-carboxy-2,5-difluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in 90 ml acetic anhydride was stirred at reflux for 0.75 hour. The resulting solution was evaporated to dryness and the residue stirred with water, filtered, and crystallized from acetic acid-water to afford the title compound, mp 241°-242° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH:16][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC2CCC(C1)N2Cc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1NC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
5.62 g (27.82 mmol) 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine (u17094-94) and 9.7 ml (55.46 mmoml) of Hunig's base were dissolved in 200 ml NMP. 4.32 g (30.60 mmol) 1-fluoro-2-nitrobenzene was then added and the mixture was stirred at RT for 3 hrs. The reaction mixture was diluted with EtOAc and washed with water and dried over sodium sulfate. The solvent was removed partially under reduced pressure and was left in refrigerator overnight. The solid was filtered off to afford 2.92 g of product as a yellow powder. The solvent was removed from filtration to give additional 5.7 g of product as an orange-yellow residue.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[O:11][CH3:12].C[Si]([N-:17][Si](C)(C)C)(C)C.[Li+].CC(O)C.Cl>C1COCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:17])=[NH:7])=[C:4]([F:10])[C:3]=1[O:11][CH3:12]
Reactant: COc1c(Cl)ccc(C#N)c1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1c(Cl)ccc(C(=N)N)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 156.9 %

Procedure:
4-chloro-2-fluoro-3-methoxybenzonitrile (3.0 g, 16 mmol) was dissolved in 7 mL dry THF and added dropwise to a 1M solution of lithium bis(trimethylsilyl)amide (18 mL, 18 mmol). After stirring at 25° C. for 5 h, the mixture was treated with 25 mL of 2-propanol saturated with gaseous HCl. Upon standing at 5° C. for 18 h, the mixture was diluted with 30 mL ether whereupon the product precipitated. The precipitated product was collected by filtration, washed with ether and dried under vacuum to give the title compound (3.0 g, 78.6% yield): 1H NMR (DMSO-d6) δ 9.70 (br d, 3H), 7.58 (m, 1H), 7.46 (m, 1H), 7.39 (br d, 1H), 3.96 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])#[N:2].C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].C(OCC)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:31]([N:30]([CH3:34])[CH3:29])=[O:32])[CH2:17][CH2:18]1)=[O:11])#[N:2]
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N1CCC(CC(=O)NCCOc2cccc(C#N)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]-piperidine-4-carboxyamide (JP2 19-1) was dissolved in 1.6 ml of dimethylformamide, and 0.3 ml (2.06 mmol) of triethylamine and 0.16 ml (1.74 mmol) of dimethyl carbamoyl chloride were added thereto at 0° C. and stirred at room temperature for 2 hours. It was treated in an ordinary manner with ethyl acetate as the extractant to obtain the title compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:20][N:19]=1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: COc1ccc(C=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A suspension of 0.65 g (1.1 eq) of 95% NaH in 22 ml of toluene was slowly added to 3.8 g (1 eq) of methyl diethylphosphonoacetate in 5 ml of dry toluene below 35° C. The clear yellow solution was allowed to stir under nitrogen at room temperature for 30 min and a solution of 2.5 g (18.2 mmol) of 2-methoxy-pyridine-5-carboxaldehyde in 10 ml of toluene was added dropwise while maintaining the reaction temperature below 40° C. After the addition, the mixture was heated at 65° C. for 30 min, cooled, and filtered through solka floc and concentrated in vacuo to yield 3 g (85.7%) of methyl β-(2-methoxypyridin-5-yl)acrylate (cis/trans mixture).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[OH:10])[C:5]#[N:6].C.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[C:9]=1[OH:10])[C:5]#[N:6]
Reactant: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Product: N#Cc1cc(N)c(O)c(Br)c1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
To a 22-L, 3-neck round-bottom flask fitted with a stirring paddle, a Claisen adapter fitted with a thermocouple and a condenser blanketed with nitrogen, and an addition funnel capped with a septum was added a mixture of 3-bromo-4-hydroxy-5-nitrobenzonitrile (96.9 g, Step A) in methanol (14 L). To this mixture was added iron (III) chloride (9.3 g) and activated charcoal (38 g, Darco 6-60, 100-mesh powder). The mixture was heated to reflux (65° C.) and stirred for 15 min at this temperature. Hydrazine (80 ml) was added to the refluxing mixture dropwise via addition funnel. Once the addition was complete, the mixture was stirred at reflux for 2 h. The mixture was then allowed to cool, filtered through Celite, washing with methanol, and concentrated to a red oil. A mixture of 300 ml of acetic acid and 700 ml of methanol was added and the mixture was concentrated again and then co-concentrated twice with 800 ml of toluene. The residue was purified by flash chromatography on an Isco Companion XL, 1.5 kg column, eluting with 3 column volumes of 30% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 30 to 60% over 6 column volumes, followed by 2 column volumes of 60% EtOAc in hexanes to provide 40 g (55%) of the title compound. Mass spectrum (ESI) 214.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH2:14][CH2:15][OH:16])(O)[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.COC1C=CC(C(O)(C)C(F)(F)F)=C(CCOS(C)(=O)=O)C=1.Cl>ClCCl.CC#N>[CH3:13][O:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:3]([CH3:4])([C:2]([F:18])([F:17])[F:1])[O:16][CH2:15][CH2:14]2
Reactant: COc1ccc(C(C)(O)C(F)(F)F)c(CCO)c1
Agent: COc1ccc(C(C)(O)C(F)(F)F)c(CCOS(C)(=O)=O)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of 1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol (5.00 g, 18.9 mmol) in dichloromethane (30 mL) was added triethylamine (9.20 mL, 66.3 mmol). The solution was cooled to 0° C. and methanesulfonyl chloride (1.61 mL, 20.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred 12 hours. The formation of methanesulfonic acid 2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl ester is rapid and its disappearance was monitored by HPLC (retention time=4.5 minutes, Zorbax Rx-C6 column 4.6×150 mm, 40° C., 50% CH3CN/50% (0.2% Et3N, 0.1% H3PO4 aqueous pH=3.2 buffer), 1 mL/min). At the end of the reaction, the mixture was poured into 1N aqueous hydrochloric acid (30 mL) and was extracted with dichloromethane (20 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman as an oil (3.40 g, 73%). 1H NMR (300 MHz, CDCl3) δ1.69 (s, 3), 2.85-2.90 (m, 2), 3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1), 6.72 (d, 1, J=2.6), 6.85 (dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7). 13C NMR (100 MHz, CDCl3) δ23.25, 29.42, 55.19, 61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96 (q, J=289), 127.86, 136.49, 158.98. IR 2946, 2839, 1738, 1611, 1505, 1162, 1137, 1101 cm−1. Analysis calculated for C12H13F3O2: C, 58.54; H, 5.32. Found: C, 58.27; H, 5.35.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26].[CH3:33][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:21])([CH3:22])[CH3:23])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:33])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:27]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (150 mg, 0.294 mmol) and dimethyl zinc in toluene (0.294 mL, 0.589 mmol), the title compound was obtained as a yellow solid (113 mg, 78% yield). MS (ESI): 489 [M+H]+.
Reaction SMILES: C(N1CCC2C(=C(N)C=CC=2)C1C(F)(F)F)(=O)C.C([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[C:25]([N+:36]([O-:38])=[O:37])[C:26]([C:32]([F:35])([F:34])[F:33])=[CH:27][CH:28]=2)[CH2:23]1)(=O)C>>[N+:36]([C:25]1[C:26]([C:32]([F:35])([F:33])[F:34])=[CH:27][CH:28]=[C:29]2[C:24]=1[CH2:23][NH:22][CH2:31][CH2:30]2)([O-:38])=[O:37]
Reactant: CC(=O)N1CCc2ccc(C(F)(F)F)c([N+](=O)[O-])c2C1
Agent: CC(=O)N1CCc2cccc(N)c2C1C(F)(F)F
Product: O=[N+]([O-])c1c(C(F)(F)F)ccc2c1CNCC2

Procedure:
2-Acetyl-8-amino-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, prepared as in Example 20, is converted to 2-acetyl-8-nitro-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline by the procedure of Example 24. Removing the 2-acetyl group by acid hydrolysis according to the procedure of Example 15 gives 8-nitro-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH3:13])[S:5]([C:8]([F:11])([F:10])[F:9])(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:12]([N:4]([CH2:1][CH2:2][CH2:3][P:17]([O:18][CH2:19][CH3:20])(=[O:21])[O:16][CH2:14][CH3:15])[S:5]([C:8]([F:11])([F:9])[F:10])(=[O:7])=[O:6])[CH3:13]
Reactant: CCOP([O-])OCC
Reactant: C=CCN(CC)S(=O)(=O)C(F)(F)F
Product: CCOP(=O)(CCCN(CC)S(=O)(=O)C(F)(F)F)OCC

Procedure:
Following the procedure of Example 1, N-allyl-N-ethyltrifluoromethanesulfonamide (b.p. 395° C. at 1.50-0.35 torr) was reacted with diethylphosphite to produce diethyl 3-(N-ethyltrifluoromethanesulfonamido)propanephosphonate (b.p. 147°-155° C. at 0.25 torr). Following the procedure of Example 2, this phosphonate was hydrolyzed to produce the corresponding phosphonic acid (m.p. 137.5°-139.5° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]=[CH:12]2.[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[CH2:24]([N:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]=[CH:12]2)[CH2:27][CH2:28][OH:29])[CH3:25]
Reactant: BrCCCCCCOc1ccc2c(ccn2-c2ccccc2)c1
Reactant: CCNCCO
Product: CCN(CCO)CCCCCCOc1ccc2c(ccn2-c2ccccc2)c1

Procedure:
In analogy to example 4.4, 5-(6-Bromo-hexyloxy)-1-phenyl-1H-indole and 2-(ethylamino)ethanol were converted to yield 2-{Ethyl-[6-(1-phenyl-1H-indol-5-yloxy)-hexyl]-amino}-ethanol as colorless oil, MS: 381(MH+).