Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[Cl-].C(C1C=CC=C(CCC)C=1[N+:22]1[CH:26]=[CH:25][N:24]([C:27]2[C:32]([CH2:33][CH2:34][CH3:35])=[CH:31]C=CC=2CCC)[CH:23]=1)CC.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:22]2[CH2:35][CH:34]3[CH2:23][N:24]4[CH2:27][CH:32]([CH2:31][CH:26]2[CH2:25]4)[CH2:33]3)=[CH:6][CH:7]=1
Reactant: CCCc1cccc(CCC)c1-n1cc[n+](-c2c(CCC)cccc2CCC)c1
Reactant: Clc1ccc(Cl)nn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccc(N2CC3CC4CC2CN(C4)C3)nn1
Temperature: 90 °C

Procedure:
A solution of the product of Example 2 (0.30 g, 2.0 mmol) in dry toluene (10 mL) was treated with 3,6-dichloropyridazine (0.71 g, 4.8 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3; 0.037 g, 0.04 mmol; Alfa Aesar), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (0.057 g, 0.12 mmol; Strem), and sodium tert-butoxide (0.45 g, 4.0 mmol; Aldrich). The mixture was purged with nitrogen and heated to 90° C. for 8 hours. After cooling to room temperature, the reaction was quenched by pouring into a 5% aqueous NaHCO3 solution. The mixture was extracted with chloroform (3×), washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by preparative HPLC [Waters 30×100 mm XBridge Prep C18, 5 μm, 40 mL/min, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[NH2:15][CH:16]([CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([NH:15][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:24][CH3:25])[CH:21]([CH3:22])[CH3:23]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc2ccccc2c1
Product: CCC(NC(=O)Cc1ccc2ccccc2c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])([C:9]2[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[N:12][CH:13]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[C:9]2[NH:10][CH:11]=[N:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(O)(c1ccccc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C(c1ccccc1)c1cnc[nH]1
Yield: 53 %

Procedure:
Phenyl-o-tolyl-(3-trityl-3H-imidazol-4-yl)-methanol, (Intermediate 8) (620 g, 1.2 mmol) in dichloromethane (30 mL) was reacted with TFA: trifluoroacetic acid (4.0 ml) and triethylsilane (TES) (6.0 ml) at rt for 24 h. The mixture was evaporated under reduced pressure and quenched with solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to yield 5-(Phenyl-o-tolyl-methyl)-1H-imidazole 162 mg (53%). 1HNMR (CD3OD, 300 MHz) δ 7.8 (s, 1H), 7.12-7.38 (m, 9H), 6.82 (s, 1H), 6.40 (s, 1H), 5.60 (s, 1H), 2.21 (s, 1H).
Reaction SMILES: [Li].C[O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH:23]3[CH2:25][CH2:24]3)=[CH:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O1CCOCC1.Cl>O>[CH:23]1([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:26])=[O:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[CH:15]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CC3)c3ccccc32)cc1
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
Add lithium hydroxidemonohydrate (181 mg, 4.31 mmol) to a solution of 4-(3-cyclopropyl-indole-1-sulfonyl)-benzoic acid methyl ester (505 mg, 1.42 mmol) in 3:1 dioxane:water (6.0 mL). Stir the mixture at RT for 4 h, dilute with water (80 mL) and add 1N HCl until mixture reaches pH 2. Collect the white solid by filtration and dry overnight under vacuum to give the title compound (450 mg, 93%). MS (ES) 341.9 (M+1)+, 340.1 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][Si](C)(C)C)[CH:4]=1.C1(O[C:23](Cl)=[S:24])C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]=[C:23]=[S:24])[CH:4]=1
Reactant: COc1cc(N[Si](C)(C)C)nc(OC)c1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: CC#N
Product: COc1cc(N=C=S)nc(OC)c1
Yield: 43.6 %

Procedure:
To 300 ml of acetonitrile are added 45.0 g of 4,6-dimethoxy-2trimethylsilylaminopyridine and 35.0 g of phenylchlorothiocarbonate, followed by refluxing for 10 hours. The reaction solution is concentrated under reduced pressure to remove acetonitrile, and to the residue is added 300 ml of toluene. Insoluble product is filtered off, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography (eluent: ethyl acetate-hexane) to give 17.0 g of the title Compound. mp. 85°-86° C.
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1.Cl>CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:19])[CH2:17][CH2:18][O:14][CH2:15]1
Reactant: O=C1CCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(C(F)(F)F)CCOC1
Temperature: 0 °C
Yield: 44.1 %

Procedure:
Tetrahydrofuran (55 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (2.404 mL, 16.26 mmol) was then added and stirred under N2 and then cooled to 0° C. Dihydrofuran-3(2H)-one (1 g, 11.62 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.116 mL, 0.116 mmol) was added dropwise slowly via syringe and allowed to warm up to RT for 1 hr. The reaction was then cooled back down to 0° C. and added 30 mL of 1N HCl and stirred at RT for overnight. The reaction was then diluted with EtOAc and separated with water. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give the product 3-(trifluoromethyl)tetrahydrofuran-3-ol (800 mg, 44.1% yield) as an orange thin oil. 1H NMR (400 MHz, CHLOROFORM-d) d 4.05-3.92 (m, 3H), 3.80-3.75 (m, 1H), 2.31 (dt, J=13.3, 8.4 Hz, 1H), 2.08-2.03 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 4 h

Procedure:
Preparation according to Example 38: Enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol), 1-bromo-2-methylpropane (0.32 mL, 2.97 mmol). Stirred 4 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 2:1). Yield: 0.16 g. [α]D=−16.1° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 176° C.; MS m/z (relative intensity, 70 eV) 255 (M+3), 182 (45), 213 (12), 127 (6) 212 (bp).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9](C(OCC2C=CC=CC=2)=O)[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:20][C:21]1[C:25]([C:26](OC)=[O:27])=[CH:24][S:23][CH:22]=1)=[O:19])=[CH:14][C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[N:17]1[C:26](=[O:27])[C:25]3=[CH:24][S:23][CH:22]=[C:21]3[NH:20][C:18]1=[O:19])=[CH:14][C:13]([C:30]([F:33])([F:31])[F:32])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1[nH]c2ccc(C(F)(F)F)cc2c1-n1c(=O)[nH]c2cscc2c1=O
Temperature: 100 °C
Yield: 86.9 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-[3-(4-methoxycarbonylthiophen-3-yl)-ureido]-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5G (5.29 g, 8.57 mmol) in anhydrous methanol (50 mL) was added a 0.5 M solution of sodium methoxide (25 mL, 12.5 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 10 minutes. Ethyl acetate (500 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-(2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5H (3.36 g, 7.45 mmol).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([C:17]1[O:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.C(OCC)(=O)C.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>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:20]2[O:21][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Brc1ccc(Cc2ccccc2)cc1
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: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(Cc3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
To a round bottom flask containing 1-benzyl-4-bromo-benzene (700 mg, 2.83 mmol) and 5-formyl-2-furan-boronic acid (595 mg, 4.25 mmol) in dimethoxyethane (30 mL) and ethanol (7.5 mL) was added an aqueous solution of sodium carbonate (900 mg, 8.49 mmol) in water (10 mL) The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium (162 mg, 0.14 mmol). The reaction was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 6% ethyl acetate in hexanes to afford 5-(4-benzyl-phenyl)-furan-2-carbaldehyde (320 mg g, 43%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 3.99 (2H, s), 7.20-7.39 (8H, m), 7.63 (1H, d, J=3.6 Hz), 7.78-7.81 (2H, m), 9.59 (1H, s); APCI-MS: 262.02.
Reaction SMILES: C([NH:4][CH:5]1[CH:19]2[CH:8]([CH2:9][C:10]3[C:18]4[C:17]2=[CH:16][CH:15]=[CH:14][C:13]=4[N:12](S(C2C=CC=CC=2)(=O)=O)[CH:11]=3)[N:7]([CH3:29])[CH2:6]1)(=O)C.O.NN>>[NH2:4][CH:5]1[CH:19]2[CH:8]([CH2:9][C:10]3[C:18]4[C:17]2=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][CH:11]=3)[N:7]([CH3:29])[CH2:6]1
Reactant: CC(=O)NC1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12
Agent: NN
Solvent: O
Product: CN1CC(N)C2c3cccc4[nH]cc(c34)CC21

Procedure:
To the N-benzenesulphonyl-9-acetamide (Example 10) (0.15 g) was added with stirring hydrazine hydrate (4 cm3) and the mixture heated to reflux under anhydrous conditions. After 24 hours all solid had dissolved to give a clear orange solution. All solvents were removed under high vacuum (<30° C.) to give after trituration with water (10 cm3) and acetone (2×10 cm3) an orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:21]([S:27][CH3:28])[C:22]4[NH:26][N:25]=[N:24][N:23]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:35])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:21]([S:27]([CH3:28])=[O:44])[C:22]4[NH:23][N:24]=[N:25][N:26]=4)=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:35])[CH:3]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=C(SC)c2nnn[nH]2)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=C(c2nnn[nH]2)S(C)=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
To a solution of 0.43 g (0.9 mmol) of the compound obtained in example 50 in 1.5 mL of dichloromethane, cooled to -78° C., was carefully added a solution of 0.27 g (0.81 mmol) of metachloroperbenzoic acid in 1.2 mL of dichloromethane. The cooling bath was removed, the reaction mixture was allowed to warm up to room temperature and was then heated at 30° C. for 90 min. Finally, it was allowed to cool to room temperature, water was added and it was extracted with dichloromethane. The organic phase was dried and the solvent was removed to afford a crude product that was chromatographed on silica gel (ethyl acetate-methanol-acetic acid mixtures of increasing polarity), to give the title compound of the example (yield: 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:13]=1[F:12])=[O:9]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1cc(Cl)ccc1O
Yield: 71.7 %

Procedure:
Using 5-chlorosalicylic acid and 2-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][NH2:12])=O)[CH2:4][CH2:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:17][N:18]=[C:19]=[S:20]>C(O)C>[SH:20][C:19]1[N:18]([CH2:17][C:16]2[CH:21]=[C:22]([F:24])[CH:23]=[C:14]([F:13])[CH:15]=2)[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:11][N:12]=1
Reactant: Fc1cc(F)cc(CN=C=S)c1
Reactant: CN1CCN(CC(=O)NN)CC1
Solvent: CCO
Product: CN1CCN(Cc2nnc(S)n2Cc2cc(F)cc(F)c2)CC1

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid, hydrazide (3.44 g., 0.020 mole) and 3,5-difluorobenzylisothiocyanate (3.70 g., 0.020 mole) in ethanol (40 ml.) was refluxed for 17 hours and the solvent was removed under vacuum. The residue was triturated with ethyl acetate-ether and the resulting solid was filtered and recrystallized twice from ethanol to give 3-mercapto-4-(3, 5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole as a solid melting at 200°-201° C. (4.60 g., 68%).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[O:4]1[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5]1.S(=O)(=O)(O)O.[CH2:24]([OH:28])[CH:25]([OH:27])[CH3:26].C(=O)([O-])O.[Na+]>O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:28][CH2:24][CH:25]([OH:27])[CH3:26]
Reactant: CCCCCCCCCCCCC1CO1
Reactant: CC(O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: O
Product: CC(O)COCCCCCCCCCCCCCCO
Temperature: 62.5 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Separately, a 500 ml mixing vessel equipped with a calcium chloride-containing tube was charged with 318.6 g (1.50 moles) of 1,2-epoxytetradecane. While the charged 1,2-epoxytetradecane was stirred and cooled with water, a concentrated sulfuric acid was gradually dropped in an amount of 2.7 g (0.027 mole) into the cooled 1,2-epoxytetradecane. After stirring for 15 minutes, the resultant mixture was placed into the dropping apparatus attached to the reaction vessel and was dropped into the 1,2-propanediol contained in the reaction vessel and maintained at a temperature of 60 to 65° C. over a time of 2 hours. Then the reaction of the mixture was carried out at a temperature of 60 to 65° C. for one hour. After the exhaustion of the starting material, namely 1,2-epoxytetradecane was confirmed by a thin-layer chromatography, the reaction was stopped. A powdered sodium hydrogen carbonate was mixed in an amount of 2.5 g (0.03 mole) into the resultant reaction liquid in the reaction vessel, the resultant mixture was stirred for 30 minutes to neutralize the reaction liquid. From the reaction liquid, the resultant precipitated crystals were separated by filtration. A 1,2-propanediol monohydroxydodecyl ether mixture was obtained in an amount of 432.0 g (yield: 97.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[C:31]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:29]3[CH:28]=[CH:27][C:26]4[CH2:25][CH2:24][CH2:23][C:22]([CH3:41])([CH3:21])[C:31]=4[CH:30]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/176722) and 2-(8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][Cl:16])=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(NC(N)=O)c1CO
Solvent: ClCCl
Product: Cc1cccc(NC(N)=O)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 6-methyl-2-ureidobenzyl alcohol (1 g) and thionyl chloride (0.66 g) in methylene chloride (20 ml) was stirred for 2 hours at room temperature and evaporated in vacuo. The residue was washed with water and dried in a desiccator to give 6-methyl-2-ureidobenzyl chloride (0.66 g).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.IC1SC2C=CC([O:43][C:44]([F:47])([F:46])[F:45])=CC=2N=1>>[NH:25]1[CH2:26][CH2:27][CH:22]([N:20]2[CH:21]=[C:17]([C:15]3[CH:16]=[C:11]([C:8]4[S:9][C:10]5[CH:2]=[CH:3][C:4]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:5][C:6]=5[N:7]=4)[C:12]([NH2:28])=[N:13][CH:14]=3)[CH:18]=[N:19]2)[CH2:23][CH2:24]1
Reactant: FC(F)(F)Oc1ccc2sc(I)nc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(OC(F)(F)F)ccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-5-trifluoromethoxy-1,3-benzothiazole and conducting the Suzuki coupling at 50° C. for 2 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.84 (d, J=1.6 Hz, 1H), 8.43 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.15 (m, 1H), 8.09 (s, 1H), 7.55 (m, 1H), 4.68 (m, 1H), 3.61-3.68 (m, 2H), 3.28-3.30 (m, 2H), 2.35-2.42 (m, 4H). MS(ES+): m/z=461.15 [MH+]. HPLC: tR=1.84 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26]CC4C=CC=CC=4)[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OCc4ccccc4)cc23)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(O)cc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the product from Step D (1.10 g, 2.46 mmol) in 20 mL of methanol was added 20% palladium hydroxide on carbon (940 mg). The solution was stirred at room temperature under an atmosphere of hydrogen for 1.5 hours, then purged with argon. The mixture was filtered through celite, the filter pad was washed with methanol, and the filtrate was concentrated in vacuo to produce the crude material as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][CH3:10].Cl.Cl.Cl.[N:14]1([CH2:18][CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=3)[N:22]=[C:21]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:14]1([CH2:18][CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=3)[N:22]=[C:21]2[CH:33]2[CH2:34][CH2:35][N:36]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[CH2:9][CH3:10])[CH2:37][CH2:38]2)[CH2:15][CH2:16][CH2:17]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Reactant: CCc1c(N)ncnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
The reaction mixture of 6-chloro-5-ethyl-pyrimidin-4-ylamine (30.0 mg; 0.19 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine trihydrochloride (86.0 mg; 0.19 mmol; 1.0 eq.), and Cs2CO3 (310.1 mg; 0.95 mmol; 5.0 eq.) in DMSO (1.5 ml) was stirred at 120° C. for 48 hr. The crude was purified by prep HPLC to afford the title compound. LC-MS (M+H=464, obsd=464). 1H NMR (400 MHz, DMSO-d6) δ 8.49-8.39 (m, 1H), 8.10-8.01 (m, 1H), 7.96 (s, 1H), 7.93-7.85 (m, 1H), 7.50 (t, J=8.9 Hz, 1H), 6.69-6.61 (m, 2H), 4.30 (q, J=5.4, 4.7 Hz, 2H), 2.71-2.62 (m, 2H), 3.93 (d, J=12.5 Hz, 2H), 3.54 (q, J=6.3, 5.8 Hz, 4H), 3.33 (t, J=12.5 Hz, 3H), 3.11 (q, J=5.3, 4.0 Hz, 2H), 2.33 (dd, J=28.0, 11.5 Hz, 6H), 1.54 (q, J=6.7, 6.0 Hz, 3H).