Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(C(C)C)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
1-(2,4-Dihydroxy-5-isopropyl-phenyl)ethanone (1 eq) was dissolved in DMF and potassium carbonate (2.2 eq) then benzyl bromide (2.2 eq) were added. The suspension was heated, with stirring to 150° C., under nitrogen, for 16 hrs. The solution was cooled to room temperature and the mixture was poured into 1 MHCl (aq) then extracted in to ethyl acetate. The organic phases were combined and washed again with 1 MHCl (aq) then five times with brine solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, to give a solid, which was purified by diethyl ether:hexane (1:1) trituration to give 1-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-ethanone.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:10][OH:11])[CH2:4][C:3]1([CH3:13])[CH3:12].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34]>>[C:33]([O:35][C:5]1([N:10]=[O:11])[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]1)(=[O:34])[C:32]([CH3:37])([CH3:36])[CH3:31]
Reactant: CC(C)(C)C(=O)O
Reactant: CN1C(C)(C)CC(=NO)CC1(C)C
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CN1C(C)(C)CC(N=O)(OC(=O)C(C)(C)C)CC1(C)C

Procedure:
1,2,2,6,6-Pentamethyl-4-nitrosopiperidin-4-yl pivalate was prepared from 1,2,2,6,6-pentamethyl-piperidin-4-one oxime, lead tetraacetate and trimethylacetic acid using conditions of General Method 3. 1H NMR (250 MHz, CHLOROFORM-d) δ 2.43-2.64 (5H, m), 2.09 (3H, s), 1.91 (2H, d, 14.2 Hz), 1.39 (6H, d, 5.9 Hz), 1.30 (9H, s), 1.25 (6H, d, 2.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:25])=[C:19]([NH2:24])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[F:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:25])=[C:19]([NH:24][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=3)(=[O:35])=[O:34])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine (500 mg, 1.313 mmol) and 3-fluorobenzenesulfonyl chloride (0.210 mL, 1.575 mmol), the title compound was obtained as an yellow foam (690 mg, 98% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: CNc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.55 g (78.0 mmol) pyrrolidine are added to a solution of 4.70 g (26.1 mmol) 4-methylamino-3-nitro-benzaldehyde in 100 mL THF and the reaction mixture is acidified with glacial acetic acid. 6.36 g (30.0 mmol) NaBH(OAc)3 are added and the reaction mixture is stirred overnight at RT. The mixture is combined with saturated NaHCO3 solution and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed with 200 mL semisaturated NaHCO3 solution and dried over MgSO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[CH2:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1Cl)(=O)C.[OH-].[Na+].[NH4+].[Cl-:19]>C(O)C>[Cl:19][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][NH:4]2)=[CH:8][C:9]=1[CH:13]=[CH2:14]
Reactant: C=Cc1ccc2c(c1)CC(Cl)N2C(C)=O
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1cc2c(cc1Cl)NCC2

Procedure:
1-Acetylchloro-5-vinylindoline (D61) (0.13 g), and 10% aqueous NaOH (5 ml) were heated at reflux in ethanol (20 ml) for 2.5 hours, cooled and treated with an excess of saturated aqueous NH4Cl. The mixture was partitioned between ethyl acetate and brine. The organic extracts were dried (Na2SO4) and evaporated to dryness under reduced pressure affording the title compound as a brown oil (0.13 g) which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:23])[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH2:21][CH3:22])[C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:5].[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][CH:3]([CH3:23])[C:4]([NH:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH2:21][CH3:22])[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:5])=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CCn1c2ccccc2c2cc(CNC(=O)C(C)CN)ccc21
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)CNC(=O)c3ccc(C#N)cc3)ccc21

Procedure:
Using the compound obtained in Step 2 and 4-cyanobenzoic acid, and by the reaction and purification in the same manner as in the method described in Step 3 of Example 36, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C@@H:32]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:25]=[CH:26][C:27]([O:30][C@H:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:29]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O)cc2)c1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
To a solution of 4-[l-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol (1.40 g, 3.45 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.00 g, 5.18 mmol) and triphenylphosphine (1.36 g, 5.18 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.31 g, 5.18 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.00 g (yield: 49.8%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18](F)[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18]([N:35]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:34])[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)(C)C
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(F)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(R)-[4-fluoro-6-(2-methyl-5-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.36 g, 0.81 mmol), N-methyl-neopentylamine hydrochloride (411 mg, 3 mmol) and DIEA (0.4 mL) in 1,4-dioxane (0.5 mL) was stirred at 90° C. overnight. After removing the solvent under reduced pressure the desired product (81 mg) was purified by silica gel chromatography. C28H43N7O3 MS m/e=526 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:29]4[S:30][CH:31]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:28]=4)[CH2:33][CH2:34]3)=[O:20])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(-n2ccnc2)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(1H-imidazol-1-yl)phenyl]carbamate (200 mg, 0.598 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (147 mg, 0.598 mmol), diisopropylethylamine (0.104 ml, 0.598 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (91.0 mg, 35.4%) as a solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[OH:13].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[C:17]=[O:18].[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1>C1COCC1.N1C=CC=CC=1>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:17](=[O:18])[NH:16][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:26])[NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[CH:21][CH:20]=1
Reactant: Nc1nccs1
Reactant: O=C=Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)Oc1ccnc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-trifluoromethyl-quinolin-4-ol (107 mg, 0.50 mmol) in THF (5 mL) was added 4-isocyanatobenzene-sulfonyl chloride (109 mg, 0.50 mmol) at RT. The resulting mixture was stirred at ambient temperature for 1 h. Then, a solution of 2-aminothiazole (50 mg, 0.50 mmol) in pyridine (5 mL) was added and stirring was continued for 65 h. The solvents were evaporated under a stream of nitrogen, the residue was dissolved in DMSO (2 mL) and purified by preparative LC/MS (gradient of 5-95% CH3CN/water). 1H-NMR (DMSO-d6) δ 9.63 (s, 1H), 9.10 (s, 1H), 8.28-8.22 (m, 2H), 7.97-7.95 (m, 2H), 7.81-7.77 (m, 3H), 7.52-7.51 (m, 1H), 7.41-7.40 (m, 2H), 7.15-7.14 (m, 1H). LC/MS (5-95%) M/Z: M+1 obs=495.4; tR=10.45.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1.C1C(=O)N([Br:30])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:30][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:22])[CH3:1])[N:14]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)CCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.8 %

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (266 mg) in dry chloroform (3.15 mL) at 0° C. was added NBS (163 mg). The reaction was warmed to room temperature and was stirred for 5 h. The reaction was taken up into DCM (20 mL) and extracted with water (20 mL). The organics were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a green/brown solid (314 mg).
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH3:22])[N:18]=[N:17][C:16]=12)=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.CN(C=O)C.[Pd]>[OH:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH3:22])[N:18]=[N:17][C:16]=12)=[O:11]
Reactant: Cn1nnc2c(C(=O)NOCc3ccccc3)ncn2c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C(=O)NO)ncn2c1=O
Yield: 24.9 %

Procedure:
A solution of N-(benzyloxy)-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (200 mg, 0.67 mmol) and 10% Pd/C (20 mg) in ethyl acetate:DMF (5:1) (36 mL) was put under an atmosphere of hydrogen for 3 days. The mixture was filtered through a pad of Celite™ and the filtrate was concentrated under vacuum. The residue was suspended in ethyl acetate and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether to give the pure title compound as a pale orange solid (35 mg, 25% yield). δH (DMSO-d6): 11.2 (1H, s), 9.18 (1H, s), 8.82 (1H, s), 3.86 (3H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:19][CH3:20])[N:15]=[N:14]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:26]#[N:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH2:12][N:13]4[CH:17]=[C:16]([C@:18]([OH:25])([C:21]([F:22])([F:24])[F:23])[CH2:19][CH3:20])[N:15]=[N:14]4)=[CH:9][CH:10]=3)[N:5]=[C:4]([C:26]#[N:27])[CH:3]=2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCC(O)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)c(F)c4)cc(C#N)nc3c2)nn1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carbonitrile (100 mg, 0.25 mmol) in DME (3 mL) was added tetrakis(triphenylphosphine)palladium (14 mg, 0.013 mmol), 3,4-difluorophenylboronic acid (59 mg, 0.38 mmol) and aq. 2M Na2CO3 (0.38 mL, 0.75 mmol). After 2 h at 100° C., the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with EtOAc/hexanes, 4:6) gave the title compound. MS (+ESI): 474 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([C:23](OCC)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([CH2:23][OH:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(CO)cc(-c2ccc(F)cc2)n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
Ethyl 5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (2.70 g) was dissolved in tetrahydrofuran (30 mL), and the mixture was cooled to −78° C. A 1.5 mol/L toluene solution (13.1 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was further stirred at −78° C. for 2 hr. 1 mol/L Hydrochloric acid (15 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate. The insoluble material was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:3) to give the title compound as an oil (yield 1.09 g, 45%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:24][CH2:25]1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: c1coc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1coc(N2CCN(CCCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-furyl) piperazine (4.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.0 g compound (I-12) with a yield of 61.5%. ESI-MS [M+H]+: m/z 325.2.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[N:16]([C:20]2[N:32]([CH3:33])[C:23]3=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:22]3[N:21]=2)[CH:17]=[CH:18][CH:19]=1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[N:16]([C:20]2[N:32]([CH3:33])[C:23]3=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]3[N:21]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:38])=[O:36])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.32 g of 2-(2-ethylthiopyrrol-1-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 8 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 3 hours and then allowed to stand overnight at room temperature. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.33 g of 2-(2-ethylsulfonylpyrrol-1-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (24)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C[C@@H](N)CO
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (R)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+]525.2290, observed 525.2294.
Reaction SMILES: [CH3:1][P:2]([O:6][CH3:7])(=[O:5])OC.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].COC>CO>[CH3:7][O:6][P:2]([CH3:1])([CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])=[O:5]
Reactant: C=CC(=O)OC
Reactant: COP(C)(=O)OC
Agent: COC
Solvent: CO
Product: COC(=O)CCP(C)(=O)OC
Yield: 97.7 %

Procedure:
80 g of methanol are mixed at room temperature under nitrogen with 216 g of dimethyl methanephosphonate and the mixture is treated dropwise at room temperature with 172 g of methyl acrylate, the temperature rising to 70° C. At the end of the dropwise addition the mixture is further stirred for 1 hour, at the end of which period about 90 g of dimethyl ether have separated in a fitted cooling trap. Excess methanol used as solvent is then removed by vacuum distillation. The crude product is obtained in a yield of 365 g with a 96.4% purity, which represents a theoretical yield of 97.7%. The boiling point of a distilled sample is 96° C. at 0.027 mbar. The 1H-NMR spectrum and the CHP analysis of the product correspond to those of a comparison sample, synthesized by an independent route.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[C:29]([O:33][C:34](=[O:47])[NH:35][CH2:36][CH2:37][C:38]([NH:40][NH:41][C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])=O)([CH3:32])([CH3:31])[CH3:30]>ClCCl>[C:29]([O:33][C:34](=[O:47])[NH:35][CH2:36][CH2:37][C:38]1[O:46][C:42]([CH:43]([CH3:45])[CH3:44])=[N:41][N:40]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)C(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nnc(CCNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
20.00 g (43.00 mmol) PS-triphenylphosphine are placed in 240 ml dichloromethane, 10.88 g (42.87 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 12.10 ml (87.29 mmol) triethylamine are added dropwise. 5.83 g (21.33 mmol) tert-butyl[3-(N′-isobutyryl-hydrazino)-3-oxo-propyl]-carbamate dissolved in 150 ml dichloromethane are added. The reaction mixture is stirred for 24 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down and purified by chromatography.