Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.O.O.Cl>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCc1c(CCCl)sc2c1CCN(C(C)=O)C2
Agent: Cl
Solvent: O
Product: CCc1c(CCN2CCC(c3noc4cc(F)ccc34)CC2)sc2c1CCN(C(C)=O)C2
Yield: 42.6 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.67 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 165°-167° C. (decomposition) as hydrochloride dihydrate thereof.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn3c(NCCCCNS(C)(=O)=O)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 99 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine (0.02 mL, 0.13 mmol) and methanesulfonyl chloride (0.05 mL). The resultant solution was stirred at 0° C. for 1 hour and saturated aqueous sodium bicarbonate was added. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) provided N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)methanesulfonamide (25 mg, 99%) a yellow solid. 1H NMR (CDCl3): δ 8.01 (d, 1 H), 7.79 (d, 1 H), 7.59 (d, 2 H), 7.32 (m, 1 H), 7.01 (d, 2 H), 6.34 (d, 1 H), 6.13 (m, 1 H), 6.00 (d, 1 H), 5.34 (d, 1 H), 5.02 (m, 1 H), 4.38 (m, 1 H), 3.90 (s, 3 H), 3.38 (m, 2 H), 3.13 (m, 2 H), 2.94 (s, 3 H), 2.14–2.06 (m, 2 H), 1.82–1.54 (m, 10 H); MS m/z 550 (M+1).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)nc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)nc(Cl)n1

Procedure:
A solution of 2-hydroxy-4,6-dimethylpyrimidine (5.0 g) in phosphorous oxychloride (19 ml) was refluxed under heating for 9 hr. The reaction mixture was added dropwise to an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (3.0 g). The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=30:1) to give the title compound (2.4 g) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccccc2CO)cc1
Temperature: 250 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and the mixture is stirred for 1 hour at 250° C. The mixture is poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam, which when triturated with diethyl ether provides the desired product as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7]OC(=O)[O:4]1.[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12].C(=O)=O>O>[F:9][C:10]([F:18])([F:17])[C:11]1([C:13]([F:16])([F:15])[F:14])[O:4][CH:3]([CH2:2][OH:1])[CH2:7][O:12]1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: O=C1OCC(CO)O1
Agent: O=C=O
Solvent: O
Product: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 118 °C
Reaction time: 40 h

Procedure:
118 Grams glycerol carbonate (1 mole) is placed in a 500 ml three neck flask, fitted with a thermometer, magnetic stirrer, gas-inlet tube, and a condenser cooled with a dry ice-isopropyl alcohol bath. Hexafluoroacetone gas is added to the vigorously stirred glycerol carbonate at 27° to 60° C. until 142 grams (0.85 moles) has been absorbed. The dry ice condenser is now replaced by a water condenser which is connected to a dry ice trap so that hexafluoroacetone which escapes during reaction may be condensed. The temperature is raised slowly to about 118° C. at which point CO2 evolution begins. The temperature is allowed to rise to 148° C. during a 40 hour reaction period. The resulting product is mixed with water (50 ml) and the organic layer separated and diluted with chloroform. The chloroform solution is washed several times with water and 5% NaHCO3 solution. Vacuum stripping gives crude 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane. This is distilled at 78° - 80° C./25 mm Hg and the yield of pure product is 92%, based on utilized hexafluoroacetone. The twice distilled product has a refractive index of 1.35046 (20° C.) and upon analysis contained 47.19% fluorine, 30.02% carbon, and 2.22% hydrogen.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][C:13](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C=C1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Yield: 66.3 %

Procedure:
PtO2 (30 mg) is added to a solution of a E/Z isomers mixture of ethyl (1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-ylidene)acetate (1.5 g, 4.27 mmol) in acetic acid (25 mL); the mixture is maintained under stirring under a pressure of 1 H2 atm. A sample is next extracted and a 1H NRM is done. The mixture is then filtered, diluted with AcOEt, and washed with H2O and with a saturated solution of NaHCO3. The solvent is next evaporated at reduced pressure, giving ethyl 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)acetate (1.0 g, 2.83 mmol, purity 66%, oil).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:22]=[CH:23][C:24]=4[F:26])[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1>CO.O1CCCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:20]2[C:25]=1[C@H:17]([O:16][C:14]1[CH:13]=[CH:12][C:11]3[C@H:7]([CH2:6][C:5]([OH:34])=[O:4])[CH2:8][O:9][C:10]=3[CH:15]=1)[CH2:18][CH2:19]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 M aqueous NaOH solution (3.0 mL) is added to a solution of {(S)-6-[(R)-7-fluoro-4-phenoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.18 g) in methanol (6 mL) and tetrahydrofuran (6 mL) at room temperature. The mixture is stirred at room temperature for 4 h. The organic solvent is evaporated, water (2 mL) is added, and the resulting solution is neutralized with 1 M aqueous HCl solution (3 mL). The solution is stirred at room temperature for 1 h. The precipitate is separated by filtration, washed with water and dried to give the title compound (if the compound does not precipitate, the solution is concentrated and the residue is purified by HPLC on reversed phase using acetonitrile, water and ammonia as eluent). LC (method 3): tR=1.14 min; Mass spectrum (ESI−): m/z=419 [M−H]−.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[C:24]([O:26]C)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH3:28].CO>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[C:24]([NH2:28])=[O:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCC(=O)c1cnc2c(C(=O)OC)cccc2c1Nc1ccccc1C
Solvent: CO
Product: CCCC(=O)c1cnc2c(C(N)=O)cccc2c1Nc1ccccc1C
Yield: 49 %

Procedure:
Methyl 3-butyryl-4-(2-methylphenylamino)quinoline-8-carboxylate (1.03 g, 2.8 mmol) and saturated methanol ammonia (50 ml) were heated to 140° in a pressure vessel for 4 hours. The solid which crystallised on cooling was filtered off and recrystallised from ethanol to give 3-butyryl-4-(2-methylphenylamino)quinoline-8-carboxamide (0.48 g, 49%), m.p. 185-187° .
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C-:13]#[N:14].[K+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1.75 h
Yield: 101.3 %

Procedure:
A stirred solution of 250.0 grams (1.05 moles) of 4-trifluoromethylphenylmethyl bromide in 1000 mL of ethanol was heated to about 80° C., and a solution of 109.0 grams (1.67 moles) of potassium cyanide in about 275 mL of water was added. Upon completion of addition, the reaction mixture was stirred at 80° C. for about 1.75 hours. After this time the reaction mixture was cooled to ambient temperature and extracted with three portions of diethyl ether. The combined extracts were washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was added with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 197 grams of 4-trifluoromethylphenylacetonitrile.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
1-Isopropyl-4-hydroxypiperidine (1 g, 6.98 mmol), DCM (10 ml) and triethylamine (1.08 ml, 7.68 mmol) were cooled to 0-5° C. and mesyl chloride (0.54 ml, 6.98 mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with sat. NaHCO3 (20 ml) and the aqueous phase extracted with DCM (2×5 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.55 g, 100%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12][CH2:13]2)[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 1 h

Procedure:
To 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (50 mg, 0.194 mmol) in DCM (2 mL) in ice bath was added DIEA (340 μl, 1.945 mmol) and methanesulfonyl chloride (16.67 μl, 0.214 mmol). The reaction mixture was stirred for 60 min. The reaction mixture was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. (30 mg, 46%). LCMS (m/z): 335.2/337.2 (MH+), 0.572 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccnc(F)c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccnc(F)c3)ccn2c1=O
Yield: 89.3 %

Procedure:
Methyl 8-(2-fluoro-pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-pyridin-4-yl-boronic acid (72 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (107 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Cn1cc(C2C(=O)Nc3cc(Cl)ccc32)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cn1cc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cn1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one (0.1 g, 0.4 mmol) (from Example 14b supra), 3-chlorobenzyl bromide (0.098 g, 0.48 mmol) (Aldrich), potassium iodide (0.08 g, 0.481 mmol) and potassium carbonate (0.12 g, 0.87 mmol) in acetone (4 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, the mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (ethyl acetate: dichloromethane, 1:1 V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-methyl-1H-pyrazol-4-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield, 0.05 g, 33%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=3)[CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2cc(C#N)c3cc(OC)ccc3c2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(-c2cccc(O)c2)cc2ccc(O)cc12
Yield: 61.8 %

Procedure:
7-Methoxy-3-(3-methoxyphenyl)-1-naphthonitrile (110 mg, 0.39 mmol, 1 eq) and pyridinium hydrochloride (4.76 mmol, 12.2 eq) are boiled under reflux for 3 h. After cooling the reaction mixture, it is acidified with 1 N HCl, the resulting precipitate is filtered and dissolved in a small amount of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. The residue formed is the desired product (yield 62%, 63 mg).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:27])[N:22]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(-c2c(-c3nc(CCC(=O)O)cs3)cnn2C(C)(C)C)cc1
Reactant: NC1CCOCC1
Product: COc1ccc(-c2c(-c3nc(CCC(=O)NC4CCOCC4)cs3)cnn2C(C)(C)C)cc1

Procedure:
Using the compound obtained in step 1 and 4-aminotetrahydropyran and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(OCc2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
1-Acetylpiperidin-4-ol (Preparation 193, 10 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (50% wt dispersion in oil, 4.8 g, 0.1 mol) in N,N-dimethylformamide (50 ml) at room temperature under nitrogen. After stirring the reaction mixture for 3 hours, 4-chlorobenzyl chloride (12.8 g, 80 mmol) in N,N-dimethylformamide (50 ml) was added dropwise and the reaction mixture was stirred for a further 4 h. The solution was filtered and the filtrate was evaporated to give an orange oil. Water was added and the mixture was extracted with petroleum ether (3×50 ml) and then with diethyl ether (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound as an orange oil (15.8 g, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=S)=[O:5])[CH3:2].[NH2:9][C:10]1[C:11]([NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])=[N:12][C:13]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:14][C:15]=1[NH2:16].C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C(#N)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:13]1[N:14]=[C:15]2[C:10]([N:9]=[C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])[NH:16]2)=[C:11]([NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[N:12]=1
Reactant: CCOC(=O)N=C=S
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2c(N[C@H](C)CO)nc(SCc3ccccc3F)nc2[nH]1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethoxycarbonylisothiocyanate (0.48 ml) in dry acetonitrile (20 ml) at 0° C. under an atmosphere of nitrogen was added a suspension of the product from example 4, step (e) (1.15 g) in dry acetonitrile (20 ml) containing 2.5 eq triethylamine. After stirring at 0° C. for 5 min, diisopropylcarbodiimide (0.8 ml) was added and the reaction warmed to 70° C. for 1 hr. The reaction mixture was concentrated in vacuo and the residue purified twice by silica gel chromatography, eluting both times with 3:1 ethyl acetate:DCM, to afford the subtitled product as a white solid (0.045 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1C(=O)N([I:17])C(=O)C1>>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[I:17]
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Product: Nc1nc(N)c(I)c(Cl)n1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 25 g (173 mmol) 6-chloro-pyrimidine-2,4-diamine and 39 g (173 mmol) NIS. Yield after precipitation of the product from water: 38.8 g (83%).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8])[C:2]#[CH:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CC(O)C/C=C\CC
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C#CC(C/C=C\CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 22 g. of cis-oct-5-en-1-yne-3-ol, prepared according to the procedure of J. Fried, C. H. Lin, J. C. Sih, P. Dalven, G. F. Cooper, J. Amer. Chem. Soc., 94, 4342 (1972), with 58 g. of triphenylmethyl bromide in 100 ml. of pyridine and purification of Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:14])[F:13].CN(C)[CH:18]=[O:19].Cl>O1CCCC1>[OH:4][C:5]1[C:6]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][CH:8]=[CH:9][C:10]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COCOc1ccccc1OC(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cccc(OC(F)(F)F)c1O
Reaction time: 1 h

Procedure:
1-methoxymethoxy-2-trifluoromethoxybenzene (12.21 g) was dissolved in tetrahydrofuran (120 mL), and a 1.59M n-butyllithium-n-cyclohexane solution (40 mL) was added to the solution at −60° C. over 15 minutes under an argon gas flow, and then the mixture was stirred for 1 hour. N,N-dimethylformamide (6.30 mL) was added to the solution, and then the mixture was stirred at room temperature for 30 minutes. 2N hydrochloric acid (100 mL) was added to the solution, and then the mixture was stirred at 60° C. for 15 hours. The organic solvent was distilled off under reduced pressure, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.38 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:40]([NH2:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:45][CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Reactant: CC(C)(C)CN
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCC(C)(C)C)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and neopentylamine.