Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:42])([F:41])[C:20]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][C@@H:34]2[CH2:39][OH:40])=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([C:20]([OH:25])([C:19]([F:18])([F:41])[F:42])[C:21]([F:24])([F:22])[F:23])=[CH:27][CH:28]=4)[C@@H:34]([CH2:39][OH:40])[CH2:35]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: OC[C@H]1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)[C@@H](CO)C2)cc1
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.487 mmol, 114 mg), (R)-1,1,1,3,3,3-hexafluoro-2-(4-((2-(hydroxymethyl)piperazin-1-yl)methyl)phenyl)propan-2-ol (0.443 mmol, 165 mg) and triethylamine (1.330 mmol, 0.185 mL, 135 mg) in dichloromethane (4 mL) was added 1-propanephosphonic acid cyclic anhydride (0.665 mmol, 0.395 mL, 423 mg, 50% solution in ethyl acetate). The reaction was stirred for 3 hours and then was diluted with dichloromethane/saturated sodium hydrogen carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluting with ethyl acetate to 5% methanol/ethyl acetate and basic reverse phase HPLC to afford the title compound (92 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18]Cl>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[S:18][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: ClSc1cc(Cl)ccc1Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2cc(Cl)ccc2Cl)c1

Procedure:
Under a nitrogen atmosphere, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride and cooled with stirring in an ice-water bath. 2,5-Dichlorobenzenesulfenyl chloride (4.24 g., 20 mmoles) was added dropwise. The bath was removed and the reaction stirred for 1 hour at room temperature, at which time thin layer chromatography (silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant) indicated that virtually all of the starting pyrrole ester had been consumed. An equal volume of ether was added, the mixture filtered and the filtrate evaporated in vacuo to a partially crystalline gum (5.2 g.). The latter was recrystallized from methylene chloride/hexane to yield purified methyl 5-(2,5-dichlorophenylthio)pyrrole-3-carboxylate (2.68 g., m.p. 162°-165° C.).
Reaction SMILES: [Br:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]([O:6][CH:7]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:26].C(N(CC)CC)C.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH:39][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH:7]([O:6][C:5]2[CH:23]=[C:24]([CH3:25])[C:2]([Br:1])=[C:3]([CH3:26])[CH:4]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=1
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a mixture of 4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790 mg, 4.27 mmol) in methylene chloride (43 mL) are added triethyl amine (1.79 mL, 12.82 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (895 mg, 6.4 mmol) and EDCI (2463 mg, 12.8 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving racemic 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (945 mg).
Reaction SMILES: [ClH:1].Cl[C:3]([N:22]([CH3:24])[CH3:23])=[N:4][C:5]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:7]=[CH:8][C:9]=1[C:10]#[N:11]>ClCCCl>[Cl:1][C:10]1[N:11]=[C:3]([N:22]([CH3:24])[CH3:23])[N:4]=[C:5]2[N:6]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:7]=[CH:8][C:9]=12
Reactant: Cl
Reactant: CN(C)C(Cl)=Nc1c(C#N)cnn1-c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCCl
Product: CN(C)c1nc(Cl)c2cnn(-c3ccc(S(C)(=O)=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stream of dry hydrogen chloride was passed through a solution of 1-chloro-N′-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-dimethyl-formamidine (0.600 g, 1.70 mmol) in 1,2-dichloroethane (20 mL) for 1 h. The solution was stirred at rt for 3 days. The solvent was removed under reduced pressure and the crude washed several times with dichloromethane. [4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-dimethyl-amine recrystallized in dichloromethane and it was retrieved by filtration as an off-white solid (0.4 g, 67%). Exact mass calculated for C14H14ClN5O2S 351.06, found 352.20 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[C:5](=[N:32]O)[C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[N:28]O)[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.N.[H][H]>[Ni].C(O)C>[CH3:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][O:10][C:9]2[CH:30]=[CH:31][C:6]([CH:5]([NH2:32])[C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([CH3:1])[CH:3]=3)=[CH:7][CH:8]=2)=[CH:19][CH:18]=1)[NH2:28]
Reactant: [H][H]
Reactant: Cc1cccc(C(=NO)c2ccc(OCCOc3ccc(C(=NO)c4cccc(C)c4)cc3)cc2)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: Cc1cccc(C(N)c2ccc(OCCOc3ccc(C(N)c4cccc(C)c4)cc3)cc2)c1
Reaction time: 7 h
Yield: 42.2 %

Procedure:
A reaction mixture is prepared from 1,2-bis[4-(3-methylbenzoyl)phenoxy]ethane dioxime (10.6 g, 0.022 mole), 400 ml absolute ethyl alcohol saturated with ammonia gas and Raney nickel catalyst W-6 (2 g). This mixture is subjected to 500 psi hydrogen pressure, heated to 90° and stirred for seven hours. The Raney nickel is removed by filtration and the alcohol and ammonia by distillation. The residual crude material is crystallized from ethanol to yield 4.2 g (42%) of material mp 113°-115°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3C1CCCCO1)[CH3:21])=[CH:7]2.C([O-])(O)=O.[Na+]>>[N:31]1[C:23]([NH:22][CH:20]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH3:21])=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: Cc1ccccc1-n1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc2cccc(C)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1-n1c(C(C)Nc2ncnc3[nH]cnc23)cc2cccc(C)c2c1=O
Reaction time: 2 h
Yield: 54.1 %

Procedure:
8-Methyl-3-(1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-2-o-tolylisoquinolin-1(2H)-one 4105 (180 mg, 0.36 mmol) was dissolved in MeOH(HCl) (50 mL) and stirred for 2 h. Aqueous NaHCO3 solution was added to the reaction mixture and the pH value was adjusted to 9. The mixture was then filtered and the filtrate was concentrated in vacuo to afford the desired product, 3-(1-(9H-purin-6-ylamino)ethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one 4106 (80 mg, 54% yield) as a yellow solid.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH3:14].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCOCC1.CCOCC>[N:15]1([C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH3:14])=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=3)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc2[nH]cc(C)c2c1
Reactant: c1c[nH]cn1
Agent: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2[nH]c(-n3ccnc3)c(C)c2c1

Procedure:
A solution of bromine (0.62 ml) in dioxane (25 ml) is added dropwise over a period of 2 hours to a mixture of 5-methoxy-3-methylindole (2.00 g) and imidazole (4.08 g) in dioxane (50 ml) while stirring at 10°. Upon complete addition cooling bath is removed and the suspension is stirred two days at room temperature. The mixture is concentrated in vacuo and the oil obtained is suspended in ether (100 ml) and extracted into 1N hydrochloric acid (2×50 ml). The acid extract is first washed with ether (1×50 ml), the pH is adjusted to pH 6 with 3N sodium hydroxide (38 ml), and the aqueous mixture is then extracted with ether (8×50 ml). This extract is dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil. This oil is purified by flash chromatography on silica gel (eluent: 95% methylene chloride, 5% methanol) to give 2-(1-imidazolyl)-5-methoxy-3-methylindole as a crystalline solid; NMR (CDCl3): δ10.4 (s, 1H), 7.67 (s, 1H), 3.88 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:2]=1
Reactant: OC1CCCCC1
Reactant: Cc1ccc(O)cc1
Solvent: O
Product: Cc1ccc(O)c(C2CCCCC2)c1

Procedure:
To carry out the process, a mixture of zeolite and p-cresol is for example heated to the desired reaction temperature with stirring. Cyclohexanol is then added in accordance with the amount of evolved water. In the case of a reaction batch of 2-4 moles of p-cresol, this generally requires a period of 3-6 hours. After all the cyclohexanol has been added, the reaction mixture is stirred at the reaction temperature for a further 2-4 hours. The 4-methyl-2-cyclohexylphenol can then be isolated from the reaction mixture by separating methods known to the person skilled in the art. For instance, it is possible first to remove the zeolite by filtration or centrifuging. However, it is also possible to leave the zeolite at elevated temperature after the reaction has ended and to decant or siphon off the reaction mixture. Such a procedure leaves the repeatedly reusable catalyst in the reaction vessel, in which, after renewed addition of p-cresol and subsequent addition of cyclohexanol, further reaction products can be obtained. The reaction mixture from which the zeolite has been removed can advantageously be worked up further by distillation. The resulting excess p-cresol is recycled.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:12]1[CH:17]2[CH:13]1[CH2:14][O:15][CH2:16]2.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C@@H:17]1[CH2:16][O:15][CH2:14][C@H:13]1[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: C1OCC2OC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O[C@@H]1COC[C@H]1OCCOCc1ccccc1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Into dichloromethane (5.0 mL), 2-benzyloxyethanol (7.07 g, 46.5 mmol) and 3,4-epoxytetrahydrofuran (1.0 g, 11.6 mmol) were dissolved, to which a boron trifluoride-diethyl ether complex (0.08 g, 0.58 mmol) was added at room temperature, followed by stirring for three hours. To the resulting reaction liquid, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (2.28 g, yield 82%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 50.8 %

Procedure:
The title compound (70.0 mg) was prepared from 207.0 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 98.5 mg of 4-fluorophenylboronic acid as in Example 199. MS (ESI): exact mass calculated for C19H18FN3, 307.15. found, m/z 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.28-7.24 (m, 2H), 7.22-7.16 (m, 3H), 7.13-7.10 (m, 2H), 7.05-7.01 (m, 2H), 3.12-3.08 (m, 2H), 3.05-3.02 (m, 2H), 3.01-2.98 (m, 2H), 2.68-2.64 (m, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=3[CH2:9][O:8][C:7]=2[CH:28]=1.[CH3:29][C:30]1[N:35]=[C:34]2[NH:36][C:37]([CH2:39][CH3:40])=[N:38][C:33]2=[C:32]([CH3:41])[CH:31]=1>>[CH3:29][C:30]1[N:35]=[C:34]2[N:36]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]4[CH:12]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]5[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=5[CH2:9][O:8][C:7]=4[CH:28]=3)[C:37]([CH2:39][CH3:40])=[N:38][C:33]2=[C:32]([CH3:41])[CH:31]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1c2ccccc2COc2cc(CO)ccc21
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2COc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc21
Yield: 29 %

Procedure:
The same procedures as in Steps C and D of Example 1 were repeated using 367 mg of Compound 23-a and 250 mg of 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine to give 150 mg (31%) of the product as an oily substance.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.CO>[Pd]>[C:7]1([CH:6]2[CH2:5][NH:4][CH2:3][CH:2]2[OH:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CC(O)C(c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: OC1CNCC1c1ccccc1
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A mixture of benzyl 3-hydroxy-4-phenylpyrrolidine-1-carboxylate (125 mg, 0.000420 mol), palladium (25 mg, 0.000023 mol) in methanol (10 mL, 0.2 mol) was stirred under a H2 atmosphere (balloon with H2) over 2 hours. LCMS indicated that the starting material was consumed. The reaction mixture was filtered and the filtrate was concentrated to yield the product (62 mg). LCMS: m/z 163.9 (M+H+).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH2+:16][CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[CH3:23]
Reactant: O=C([O-])[O-]
Reactant: Clc1c(OCC[NH2+]Cc2ccco2)ccc2ccccc12
Agent: [Cl-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCOc1ccc2ccccc2c1Cl)Cc1ccco1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
A solution (32 mg, 0.095 mmol) of 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2 ylmethyl)ethanaminium chloride (1) in 5 mL of THF was treated with 21 mg (0.15 mmol) of K2CO3 and 6 μL (0.100 mmol) of MeI. The resulting mixture was stirred for 14 h at room temperature. The solvent was distilled off under vacuum and the crude was triturated for 1 h in 5 mL of di-isopropyl ether. Pure 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-N-methylethanamine was obtained after decantation of ether as a pale yellow oil in 91% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([NH2:24])=[O:23])[S:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(#N)C.C(OCC)(=O)C.CC#N.CC#N.Cl[Pd]Cl>[NH2:24][C:22]([N:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[C:13]1[C:11]1[S:10][CH:9]=[C:8]([NH:7][C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1csc(C#Cc2ccccc2NC(N)=O)c1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1csc(-c2cc3ccccc3n2C(N)=O)c1
Temperature: 90 °C

Procedure:
To a degassed solution of tert-butyl[5-({2-[(aminocarbonyl)amino]phenyl}ethynyl)-3-thienyl]carbamate (112 mg, 0.314 mmol, 1 eq) in anhydrous acetonitrile (2 mL) was added bis(acetonitrile)dichloropalladium(II) (16.3 mg, 0.2 eq). After the reaction mixture was heated at 90° C. for 50 minutes, it was cooled to room temp, and diluted with ethyl acetate. The mixture was washed with aqueous ammonium chloride, water, and brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the dark brown mixture was subject to a gradient column chromatography (EtOAc-hex from 1; 100 to 1:5) to yield tert-butyl {5-[1-(aminocarbonyl)-1H-indol-2-yl]-3-thienyl}carbamate as white powder in amount of 23 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:22])([C:18]([F:21])([F:20])[F:19])[C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:22])([C:18]([F:19])([F:20])[F:21])[C:14]([OH:16])=[O:15])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(Oc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (±)-methyl 2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionate (20 g.), methanol (120 ml.) and 5.2 N-aqueous potassium hydroxide (13 ml.) is stirred at ambient temperature for 18 hours. Most of the methanol is evaporated in vacuo, and water is added. The mixture is washed with light petroleum, and concentrated hydrochloric acid added to the aqueous phase. The mixture is extracted with ether, and the extract is dried with sodium sulphate, treated with carbon and evaporated. The residue is crystallised from toluene to give (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid, m.p. 198°-199° C. (8.35 g.).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]([CH3:36])([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)[CH3:13])C1C=CC=CC=1>CO>[CH3:36][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)([CH3:13])[CH2:11][NH2:10]
Reactant: CC(C)(CNC(=O)OCc1ccccc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CO
Product: CC(C)(CN)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 66 using benzyl(2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)carbamate (CB68) and methanol as solvent; isolated as a clear oil (0.427 g, 80%): 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.84-7.77 (m, 2H), 7.49-7.42 (m, 2H), 7.39 (dt, J=7.9, 1.0 Hz, 2H), 2.85 (s, 2H), 1.78 (s, 2H), 1.36 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 377 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](CCC)[N:4]=1)#[N:2].[Na].[C:13](O)(=[O:15])C>C[O-].[Na+].CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:15][CH3:13]
Reactant: CCCc1cccc(C#N)n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 8 h
Yield: 618.6 %

Procedure:
2-Cyano-6-n-propylpyridine (10 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (100 ml) and metallic sodium (0.32 g). After standing overnight, acetic acid (0.82 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (200 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picolineimidate (11.5 g, yield: 94 %).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].O1CCCC1>[Pt](=O)=O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/c1ccc(OC)cc1F
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of ethyl (2E)-3-(2-fluoro-4-methoxyphenyl)acrylate (7.07 g, 31.5 mmol), tetrahydrofuran (50 mL), ethanol (5 mL) and platinum dioxide (300 mg) was stirred overnight under a hydrogen atmosphere at room temperature. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (5.97 g, yield 84%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[O-]CC.[Na+].[Na]>C(O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:12]#[N:13])[C:14]([O:15][CH2:16][CH3:17])=[O:18])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(CC#N)cc1
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)c1ccc(CC(C)C)cc1
Reaction time: 1 h

Procedure:
A mixture of 52 grams (0.31 mol) of 4-isobutylphenylacetonitrile (Preparation 1) and 230 grams (1.95 mols) of diethyl carbonate was heated in a flask provided with a thermometer, stirrer, dropping funnel, and distillation column having a length of 19 centimeters filled with Fenske rings. When the temperature of the mixture had reached 90° C, a solution of sodium ethoxide in ethanol that was freshly prepared from 9.2 grams (0.4 mol) of sodium metal and 200 milliliters of ethanol was added drop by drop from the dropping funnel while the vapors formed were permitted to distill through the distillation column. After the temperature reached between 120° and 130° C, no further vapors were distilled and the mixture was stirred vigorously for an additional period of 1 hour. Thereafter, the mixture remaining in the flask was cooled and the flask was surrounded with cracked ice and a solution of 35 milliliters of glacial acetic acid in 130 milliliters of water was added thereto with stirring. The organic phase was then separated from the aqueous phase. The aqueous phase was extracted with ether and the extract was combined with the organic phase, which was then successively washed with a saturated aqueous solution of sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The dried liquid was then filtered to separate the solids therefrom and the filtrate was distilled under vacuum, the fraction distilling between 150° and 155° C at a pressure of 1 millimeter of mercury, which is the ethyl 2-(4-isobutylphenyl)cyanoacetate, was collected.