Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:26][N:27]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNCCc1ccccc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCO
Product: CN(CCc1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Yield: 11 %

Procedure:
A mixture of [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.072 g, 0.194 mmol), N-methyl-2-phenylethylamine (0.052 g, 0.388 mmol), ammonium chloride (0.01 g, 0.194 mmol) in n-butanol (4 mL) was refluxed for 48 hours. The reaction mixture was cooled to room temperature, then added 10% potassium carbonate solution, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (10 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 7.73, 7.61-7.64, 7.53-7.56, 7.36, 7.26-7.29, 7.19-7.21, 6.91, 6.75, 3.95, 3.75, 3.30-3.50, 0.92. MS (ES+) m/z 470.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[C:5]1([C:3]([C:2]([F:12])([F:11])[F:1])=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(C=C(c2ccccc2)C(F)(F)F)cc1
Yield: 90 %

Procedure:
2,2,2-Trifluoroacetophenone is reacted with triphenyl-(4-fluorobenzyl)-phosphonium chloride (R. A. Jones: Australian J. Chem. 18, 903-6 (1965) in ethanol in the presence of sodium ethoxide. 2-Phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-propene is obtained with a yield of 90%; b.p.: 105°-107° C./0.2 mm Hg, m.p.: 35°-41° C.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][N:11]=[C:7]2[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=2)[N:4]=1.[OH-:29].[Na+].Cl>O1CCOCC1>[OH:29][C:3]1[N:8]2[CH:9]=[N:10][N:11]=[C:7]2[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=2)[N:4]=1
Reactant: CSc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12

Procedure:
1 g of crude 5-methylthio-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine and 15 ml of 2M NaOH in 15 ml 1,4-dioxane in a 150-ml r.b.flask with a stir bar was stirred at 80° C. The basic solution was cooled down to room temperature and neutralized to pH 7.5 with 10% HCl. A precipitate was formed, filtered off and washed with water (2×10 ml). The solid was dried under vacuum at 70° C. overnight to give a solid product; MS m/z (M+H)+ 392.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.3 %

Procedure:
To a solution of 3′-chloro-4′-fluoroacetophenone (5.2 g, 30.1 mmol) in 30 mL TFA, was added triethylsilane (14.4 mL, 90.4 mmol). The mixture was stirred at rt for 15 h, then concentrated. The crude product was purified by flash chromatography (100% hexanes, 2×) to afford 1.35 g of Intermediate 221.1 as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([N+:18]([O-])=O)[CH:17]=1)[NH:14][C:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12]2)(=[O:4])=[O:3]>[C].[Pd].O1CCCC1>[NH2:18][C:16]1[CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12]2
Reactant: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc([N+](=O)[O-])c2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N)c2[nH]1
Yield: 76.2 %

Procedure:
A mixture of ethyl 5-[3-(methylsulfonyl)propoxy]-7-nitro-1H-indole-2-carboxylate (200 mg), 10% palladium-carbon (50% containing water, 100 mg) and tetrahydrofuran (20 mL) was subjected to catalytic reduction at room temperature under hydrogen atmosphere at normal pressure. The catalyst was filtered off, and the filtrate was concentrated. The obtained crystals were washed with hexane to give the title compound (140 mg, yield 78%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 187-188° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8])=[O:14]
Reactant: COC(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A solution of L-iso-Leucine (7.43 g, 56.6 mmol) in a mixture of dioxane (28 mL) and aqueous NaOH solution (93.5 mL, 2N) was treated with methyl chloroformate (8.75 mL, 113.3 mmol) dropwise, not allowing the internal temperature to rise above 50° C. The mixture was warmed to 60° C. and stirred for 18 hours, cooled to 25° C., and extracted with dichloromethane. The aqueous phase was cooled to 0° C., and its pH was adjusted to 1-2 with HCl (4 N). The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product (10 g).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[CH3:12].[C:13]([C:16]1[CH:36]=[CH:35][C:19]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[CH3:37])(=[O:15])[CH3:14]>CCO>[OH:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:14]/[C:13]([C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]3)=[CH:18][C:17]=2[CH3:37])=[O:15])=[CH:6][C:5]=1[CH3:12]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(/C=C/C(=O)c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cc2C)ccc1O
Temperature: 80 °C
Yield: 47.5 %

Procedure:
To a round bottomed flask was added EtOH (10 mL) and potassium hydroxide (507 mg, 9.05 mmol). The mixture was stirred until homogeneous before adding commercially available 4-hydroxy-3-methyl benzaldehyde (247 mg, 1.81 mmol) and tert-butyl 4-((4-acetyl-3-methylphenoxy)methyl)piperidine-1-carboxylate (630 mg, 1.81 mmol). The reaction was heated to 80° C. for 5 h, cooled to rt, and concentrated via rotary evaporation. The product was dry-loaded onto a silica gel column and purified through flash chromatography (1:1 EtOAc:Hexanes) to afford (E)-tert-butyl 4-((4-(3-(4-hydroxy-3-methylphenyl)acryloyl)-3-methylphenoxy)methyl)piperidine-1-carboxylate (400 mg, 47% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][CH:20]1[O:22][CH2:21]1)[CH:2]=[CH2:3]
Reactant: ClCC1CO1
Reactant: C=CCc1cc(C2=NNC(=O)CC2)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Yield: 47.6 %

Procedure:
A mixture of finely ground 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (50 g, 0.22 mole), epichlorohydrin (200 g, 2.2 mole) and piperidine (2 g) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane and stirred for 10 minutes with dilute sodium hydroxide (500 ml). The organic phase was washed with water, dried and evaporated to an oil which slowly solidified. Addition of ethanolether gave 6-[3-allyl-4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (30 g, 47%, m.p. 92.5°-95°C) which was recrystallised from aqueous ethanol to give the pure pyridazinone (m.p. 93.5°-95°C).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#N)[CH3:12].C(O)(=[O:23])C.O>C1(C)C=CC=CC=1>[CH2:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:23])[CH3:12]
Reactant: CC(=O)O
Reactant: CCc1cccc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Add a 1 M solution of diisobutylaluminum hydride in toluene (76 mmol) dropwise to a solution of m-ethylbenzonitrile (38 mmol) in toluene (50 mL) under nitrogen in a dry ice-acetone bath. Stir for 30 minutes then add acetic acid (20 mL) dropwise followed by water (100 mL). Stir the reaction for 2 hours. Separate the layers and extract the aqueous with toluene. Dry the combined organic layers over sodium sulfate, and evaporate to give the title compound (4.5 g, 88% yield). 1HNMR (400.43 MHz, CDCl3): δ 9.97 (s, 1H), 7.69-7.66 (m, 2H), 7.46-7.40 (m, 2H), 2.71 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=O.NN>C(O)COCCO>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CCC(=O)c1cccc(Cl)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: O=C(O)CCCc1cccc(Cl)c1
Yield: 90.8 %

Procedure:
To a 300 ml round-bottomed flask equipped with magnetic stirrer and reflux condenser was charged 23.7 g of 87% potassium hydroxide and 150 ml of diethyleneglycol, With stirring, 23 g of 3-(3-chlorobenzoyl)-propionic acid was added followed by 24 g of 85% hydrazine. The mixture was heated to reflux for 2 hours when 50 ml of solvent was azeotroped off into a Dean-Stark trap. The reaction was refluxed for an additional 2 hours, cooled, and poured into 500 g of ice with 50 ml of con. hydrochloric acid. A white precipitate was formed which was extracted into 400 ml of ethyl ether, and washed with 100 ml of water and 100 ml of saturated sodium chloride solution. The ether extract was dried over anhydrous magnesium sulfate, filtered, and stripped to yield 19.5 g of product as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[NH:27]1[CH2:37][CH2:36][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH2:28]1>CS(C)=O>[CH2:34]([O:33][C:31]([CH:30]1[CH2:36][CH2:37][N:27]([C:11]2[CH:12]=[C:13]3[C:18](=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=4)[N:10]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[CH2:28][CH2:29]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CSc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2cc3cccnc3c(-c3cccc(SC)c3)n2)CC1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 8-(3-methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl ester (160 mg, 0.4 mmol) in DMSO (1 ml) is added ethyl isonipecotate (138 mg). The solution is stirred at 60° C. for 23 hours and then partitioned between ethyl acetate and water. The organic layer is separated and washed with brine 3×., then dried over magnesium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel, eluting with 8% isohexane:DCM, increasing polarity to 2% methanol:DCM. The product is obtained as an amorphous solid. MS (ES+) 408.0893
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(OCC)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:17])[CH:10]=1)[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OC(C)C)cn1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(C)C)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 217.2 %

Procedure:
5-(1-methylethoxy)-2-methylpyridine (227 mg, 0.661 mmol) was dissolved in dichloromethane (7.5 mL), added 3-chloroperoxybenzoic acid (408 mg, 0.733 mmol) under ice-cold conditions, and the mixture was stirred at 0° C. for 45 minutes. The reaction solution was added ethyl acetate, saturated aqueous solution of sodium metabisulfite, and an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (ethyl acetate), and 5-(1-methylethoxy)-2-methylpyridine 1-oxide (240 mg (yield 6%)) was obtained as a colorless oil.
Reaction SMILES: CS(O[C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[O:17]([C:16]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C(=O)O)c1cccc(Oc2ccccc2)c1OS(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 95 %

Procedure:
To a solution of 33 g. of 2-methane-sulphonyloxy-3-phenoxy-hydratropic acid in 200 ml. of methanol 28 ml. of triethyl amine and 2 g. of a 5% palladium on charcoal catalyst are added at 25° C. The mixture is then hydrogenated under atmospheric pressure until a calculated amount of hydrogen is used up. The catalyst is filtered off and the solution is evaporated. The evaporation residue is taken up in water, acidified with a 20% aqueous hydrochloric acid solution and the separated oil is extracted with chloroform. The chloroform solution is evaporated after drying over sodium sulphate, and the residue is distilled off. 23 g. (95%) of 3-phenoxy-hydratropic acid are obtained, boiling at 190° C. to 192° C. (0.4 mmHg.). nD25 =1.5751. Melting point of the corresponding cyclohexylamine salt amounts to 153° C. to 154° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][CH2:14][CH2:15][CH3:16].[Li+].[OH-]>C1COCC1.CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:17])=[O:2])=[C:7]([NH:13][CH2:14][CH2:15][CH3:16])[CH:8]=1
Reactant: CCCNc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCNc1cc(F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid methyl ester (0.23 g, 0.95 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (0.17 g, 79%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (50 mg, 0.22 mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethylamine hydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33 mmol) in THF (5 mL) was added 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, and the aqueous layer was washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (35 mg, 34%) after purification by crystallization form EtOAc and hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1nc(-c2ccc(N)cc2)cs1
Yield: 72.4 %

Procedure:
In 500 ml of ethyl acetate, was dissolved 4 g of ethyl N-(4-p-nitrophenyl-2-thiazolyl)carbamate, followed by an addition of 3 g of a 10% palladium/carbon catalyst. The mixture was then subjected under normal pressure to reduction with hydrogen gas. The catalyst was filtered off. The filtrate was concentrated and subjected to column chromatography on silica gel. The reaction product was eluted with a chloroform/ethylacetate mixed solvent. The resulting product was then recrystallized from methanol to obtain 2.6 g of ethyl N-(4-p-aminophenyl-2-thiazolyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][N:10]1[CH3:18].[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[C:22]([F:42])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:20]([NH:19][C:15]([C:12]5[C:13](=[O:14])[N:9]([C:3]6[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=6[Cl:1])[N:10]([CH3:18])[CH:11]=5)=[O:17])=[CH:21][C:22]=4[F:42])=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1c(Cl)cccc1Cl
Yield: 72 %

Procedure:
In the same manner as in Example 46 and using 2-(2,6-dichlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (370 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (330 mg, 72%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[NH:1][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1sccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccccc1
Yield: 92.4 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (3.14 g, 20 mmol) was dissolved in pyridine (10 mL) at room temperature. The flask was sealed with a septum and a nitrogen inlet. The solution was treated slowly with a benzenesulfonyl chloride (2.5 mL, 19.5 mmol). The reaction was followed by thin layer chromatography. The reaction was diluted with ethyl acetate and washing with 2N HCl. The organic layer was washed with saturated, aqueous sodium chloride solution and dried over sodium sulfate. The solution was decanted and evaporated under reduced pressure to give 3-benzenesulfonylaminothiophene-2-carboxylic acid methyl ester (5.36 g, 90%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:19]Br.S(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Br:19])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(Sc2cccnc2N)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Sc2cc(Br)cnc2N)cc1
Temperature: 0 °C
Yield: 68 %

Procedure:
Placed methyl 4-(2-aminopyridin-3-ylthio)benzoate (5.50 g, 21.1 mmol) in acetic acid (25 mL) and cooled to 0° C. Slowly added bromine (1.35 mL, 26.4 mmol) and stirred for an hour. Poured reaction mixture onto saturated sodium bisulfite and ice. Extracted with dichloromethane three times, washed with 2N NaOH, water, brine, dried, and concentrated. Subjected to MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate to afford the title compound (4.87 g, 68.0% yield).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[N:18]=2)[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1.[ClH:38]>>[ClH:38].[CH:31]1([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:19]3[N:18]=[C:17]([N:11]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:37])=[O:2])[CH:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)[CH:22]=[CH:21][N:20]=3)=[CH:28][CH:27]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1cccc(CN(c2ccnc(-c3ccc(OCC4CCCCC4)cc3)n2)C2CCCC2)c1
Agent: Cl
Product: O=C(O)c1cccc(CN(c2ccnc(-c3ccc(OCC4CCCCC4)cc3)n2)C2CCCC2)c1

Procedure:
This product was hydrolyzed according to general procedure T. The 3-({[2-(4-cyclohexylmethoxy-phenyl)-pyrimidin-4-yl]-cyclopentyl-amino}-methyl)-benzoic acid produced was then converted to its corresponding HCl salt following general procedure G2 to give 3-({[2-(4-cyclohexylmethoxy-phenyl)-pyrimidin-4-yl]-cyclopentyl-amino}methyl)-benzoic acid hydrochloride (22 mg). LCMS m/z: 487 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([N:27]2[CH:31]=[C:30]([CH:32]=O)[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[N:28][N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:31]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cnn(-c2ccccc2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cnn(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1-phenyl-1H-pyrazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 392.03 g/mol.
Reaction SMILES: ClC(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7]C=1)=O.[C:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13]>CC1C(CN2CCC(N3CCC(N4C(=O)NC5C4=CC=CC=5)CC3)CC2)=CC=CC=1>[C:11](=[O:16])([O:14][C:15]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=1)[O:12][C:13]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)OC
Agent: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Product: O=C(Oc1ccccc1)Oc1ccccc1
Temperature: 150 °C
Yield: 98 %

Procedure:
A mixture of 7.83 g (0.05 mole) of phenyl chloroformate, 2.48 g (0.0275 mole) of dimethyl carbonate, and 0.85 g of TBPB was heated at 150° C. under a reflux condenser for 4 hours when all gas evolution had ceased. Distillation of the reaction mixture gave 5.25 g (98 percent yield based on chloroformate) of diphenyl carbonate.