Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
To a solution of 4-bromobenzyl alcohol (10.0 g, 53.5 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (3.08 g, 64.2 mmol, 50% in oil) at 0° C. This mixture was stirred for 5 minutes at 0° C., and 1-bromobutane (7.47 mL, 69.3 mmol) was added thereto at 0° C. This mixture was stirred for 40 minutes at room temperature and then stirred for 25 minutes at 70° C. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the title compound (11.5 g, 89%).
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.[CH3:20][C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22]>CN1CCCC1=O>[CH:23]1([C:21](=[O:22])[CH2:20][C:8]([C:7]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:6]=2[S:5][CH3:4])=[O:10])[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1SC
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)CC(=O)C1CC1
Temperature: 30 °C
Yield: 94.7 %

Procedure:
Sodium methoxide (0.54 g, 0.01M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (1.25 g. 0.005M) and cyclopropyl methyl ketone (0.5 g, 0,006M) in anhydrous N-methylpyrrolidinone and heated at 30° C. for 3 hours. The cooled mixture was acidified, extracted (ether), washed (Water) and evaporated to give 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione (1.43 g), m.p.68° C. in a yield of 94%. The purity of the product was greater than 95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13]S(C(C)(C)C)=O)[C:9]([F:12])([F:11])[F:10])[CH:5]=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:13])[C:9]([F:10])([F:11])[F:12])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)S(=O)NC(c1cncc(Br)c1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(c1cncc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To N-(1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.18 mmol) in MeOH (8.35 ml) was added HCl 4N in dioxane (2.088 ml, 8.35 mmol) dropwise, and the mixture stirred at room temperature for 16 h. Concentrated, and then the mixture was quenched with saturated NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The title compound was isolated as a light yellow oil used as is for next step. LC-MS (M+1) 257.0, t=1.05 min
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:44])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][C:40]([O:42]C)=[O:41]>>[C:40]([CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:44])=[O:17])([OH:42])=[O:41]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1c(CCCCCCOS(C)(=O)=O)cccc1OCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-(2-methoxy-2-oxoethoxy)-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 64.4% overall yield. The product was an off-white solid, mp 127°-129° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CCOC(C)=O>[C:19]([Si:22]([CH3:24])([CH3:23])[O:12][CH2:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC/C=C/Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC/C=C/Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirred solution of (E)-5-phenylpent-3-en-1-ol (Preparation example 236, 6.3 g, 38.83 mmol) in CH2Cl2 was added imidazole (3.4 g, 50.48 mmol) and TBDMS-Cl (7.6 g, 50.48 mmol) at 0° C. then stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (10.6 g, 80˜98%)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:45])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]4[CH:40]=[CH:41][CH:42]=[CH:43][C:34]3=4)=[O:32])=[CH:27][C:26]=2[CH3:44])[CH2:13][C:12]1=[O:46])(C)(C)C.Cl.O1CCOCC1>C1(C)C=CC=CC=1>[CH3:44][C:26]1[CH:27]=[C:28]([C:31]([N:33]2[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3[CH:40]=[CH:41][CH:42]=[CH:43][C:34]2=3)=[O:32])[CH:29]=[CH:30][C:25]=1[CH2:24][NH:23][C:22]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[C:12](=[O:46])[CH2:13]1)=[O:45]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CCCNC(=O)OC(C)(C)C)c2cccc(F)c21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CCCN)c2cccc(F)c21
Reaction time: 0.5 h

Procedure:
(3-{5-Fluoro-4-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)-benzylcarbamoyl]-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl}propyl)carbamic acid tert-butyl ester from Example 15B (90 mg, 0.14 mmol) was added to a solution of 4N HCl/dioxan (10 ml) and the mixture was stirred for 0.5 h. The mixture was diluted with toluene, evaporated in vacuo and azeotroped with toluene to give a pale yellow solid; yield 82 mg, 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH3:19])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:19])[CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
(R)-tert-Butyl 4-(3-(2-chlorobenzamido)-N-methyl-2,3-dihydro-1H-indene-5-carboxamido)-piperidine-1-carboxylate (300 mg, 0.587 mmol, 1 eq) was dissolved in dichloromethane (10 ml). The solution was cooled to 0° C., and trifluoroacetic acid (2 ml) was added dropwise. The reaction mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure. The residue was taken up in dichloromethane (100 ml), washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. The desired product was in the form of a brown solid and was used in the next stage without being purified further. Yield: 95% (230 mg, 0.559 mmol)
Reaction SMILES: [C@@H:1]12[NH:8][CH2:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:23][C:19]1[N:18]=[C:17]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]3)[CH2:7]2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]32)n1
Yield: 14.9 %

Procedure:
To a microwave safe vial was added Intermediate 39 (375 mg, 1.77 mmol), 2-chloro-6-methylpyridine (0.39 mL, 3.53 mmol), CH3CN (10 mL) and DIPEA (0.61 mL, 3.53 mmol). The resulting mixture was heated to 180 C in a microwave reactor. After 3 h the crude mixture was concentrated and purified directly by FCC (SiO2, ethyl acetate/hexanes, 0-40%) to yield (1R,6S)-tert-butyl 8-(6-methylpyridin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (80 mg, 15%). MS (ESI) mass calcd. for C17H25N3O2, 303.2; m/z found, 304.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.31 (t, J=7.7 Hz, 1H), 6.50-6.40 (m, 1H), 6.09 (dd, J=45.4, 8.1 Hz, 1H), 4.44-4.27 (m, Hz, 2H), 4.04-3.89 (m, 1H), 3.84-3.66 (m, 2H), 3.60-3.22 (m, 2H), 2.86-2.72 (m, 1H), 2.37 (s, 3H), 2.07-1.96 (m, 1H), 1.92-1.80 (m, 1H), 1.44-1.28 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:20])([F:22])[F:21])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[C:3]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1
Reactant: Cc1sc2nc(Cn3cc(C=O)c(C(F)(F)F)n3)[nH]c(=O)c2c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1sc2nc(Cn3cc(CO)c(C(F)(F)F)n3)[nH]c(=O)c2c1-c1ccccc1
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a stirred solution of 1-((6-methyl-4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (97 mg, 0.232 mmol) in DCM (2 mL) and MeOH (2 mL) was added sodium borohydride (26 mg, 0.696 mmol) and the mixture was stirred overnight. Sodium borohydride (53 mg, 1.39 mmol) was added and the mixture was stirred for a further 20 h. The reaction mixture was quenched with water and concentrated in vacuo. The residue was taken up in 1:1 DMSO:MeCN, filtered and purified by preparative LCMS to give the title product as a white solid (10 mg, 0.024 mmol, 10%).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([N:27]4[CH:31]=[CH:30][CH:29]=[CH:28]4)=[CH:33][CH:34]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, off-white solid (77 mg, 62%), MS (ISP) m/z=496.4 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:8]2[C:14]([CH2:15][CH:16]=[CH2:17])=[C:13]([CH2:18][CH:19]=[CH2:20])[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])=[C:8]2[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: C=CCc1c(CC=C)n(Cc2ccccc2)c2cnc(C(=O)OCC)c(OC(=O)C(C)(C)C)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(CCC)n(Cc2ccccc2)c2cnc(C(=O)OCC)c(OC(=O)C(C)(C)C)c12

Procedure:
A mixture of 2,3-diallyl-1-benzyl-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (710 mg, 1.54 mmol), 10% Pd—C (100 mg) in EtOAc (20 mL) was stirred at 1 atm hydrogen atmosphere for two days at room temperature. Then the catalysts were filtered off through celite, the filtrate was concentrated to give an oil, the crude product (628 mg), which is pure and used directly in the next step. The title compound: ESI MS (m/z): 465 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:29]3[C:28]4[CH2:27][CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].[ClH:30]>CCOCC>[ClH:30].[CH2:1]([NH:3][CH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:29]3[C:28]4[CH2:27][CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Agent: Cl
Solvent: CCOCC
Product: CCNC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
To a 100-mL round-bottom flask was added tert-butyl N-ethyl-N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)carbamate (300 mg, 0.72 mmol, 1.00 equiv) and ether (20 mL). Hydrogen chloride (g) was introduced at 0-5° C. The resulting solution was stirred for 5 h at 0-5° C. in a water/ice bath. The resulting mixture was concentrated under vacuum. This resulted in 240 mg (94%) of N-ethyl-4-[7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexan-1-amine hydrochloride as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Reactant: OC1Cc2ccccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 170 mg quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17 was dissolved in 10 ml of tetrahydrofuran. To the obtained solution were added 134 mg of 2-hydroxyindane, 0.5 ml of diisopropyl azodicarboxylate (40% toluene solution) and 202 mg of tri(n-butyl)phosphine, and the mixture was stirred at room temperature overnight, and at 50° C. for 2.5 hours. To the reaction mixture were added 100 mg of 2-hydroxyindane, 0.5 ml of diisopropyl azodicarboxylate (40% toluene solution) and 200 mg of tri(n-butyl)phosphine, and the mixture was stirred at 50° C. for 5 hours, and at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:methylene chloride=1:1:1) to give 92 mg of N-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-3-methylpicolinamide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[N:15][C:14]=3[CH:31]=2)=[CH:6][C:5]=1[F:32])(=[O:3])[NH2:2].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:32][C:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[CH:31]=2)[CH:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (140 mg, 0.32 mmol) dissolved in DCM (25 ml) and added trifluoroacetic acid (1 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg). 2-Fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (140 mg, 0.31 mmol) was dissolved in DMF (5 ml) and added isovaleric acid (34.6 mg, 0.34 mmol), EDC.HCl (147 mg, 0.77 mmol), HOBt (50 mg, 0.37 mmol) and TEA (0.4 ml, 2.47 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (20 mg) as a brown solid. M.P.: 186-190° C. MS (m/z): 424.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:49]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[CH2:50]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:49]3[CH2:53][CH2:52][CH:51]([C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)[CH2:50]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1Cl
Yield: 65.1 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyrrolidin-3-ylpyridine (6 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z 384 (M+1); HRMS, calcd for C20H18ClN3O3: 383.1037, found 383.1033.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])[CH:29]=3)[CH:25]=1)[N:13]=2>N1C=CC=CC=1>[C:37]([C:34]([C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[C:27]([NH:26][C:24]1[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:40])[O:19][C:14]1[N:13]=[C:12]2[S:11][C:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:7])=[N:18][C:17]2=[CH:16][CH:15]=1)=[O:39])([CH3:36])[CH3:35])#[N:38]
Reactant: O=C(Cl)c1cocn1
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
1,3-Oxazole-4-carbonyl chloride synthesized above was suspended in pyridine (4.0 mL) at 0° C., N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.451 mmol) produced in Example C33(iv) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. 5% Aqueous sodium hydrogen carbonate solution (20 mL), ethyl acetate (20 mL) and hexane (20 mL) were added to the residue, and the yielded pale-yellow precipitate was collected by filtration. The obtained precipitate was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (108 mg, 45%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O:22]1[CH:26]=[CH:25][CH2:24][CH2:23]1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[CH:11][N:10]([CH:23]3[CH2:24][CH2:25][CH2:26][O:22]3)[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: C1=COCC1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(-c2ncn(C3CCCO3)c2-c2ccc(OC)cc2)cc1
Yield: 76.9 %

Procedure:
5.61 g of 4,5-bis(4-methoxyphenyl)imidazole is suspended in 150 ml of absolute 1,2-dichloroethane and combined with 2.8 g of 2,3-dihydrofuran as well as 0.2 ml of tin tetrachloride. The mixture is heated under agitation for 12 hours to 70°, allowed to cool, and poured into 200 ml of cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate, and concentrated under vacuum. The residue is dissolved in dichloromethane and subjected to a hexane precipitation. The precipitate is subjected to column chromatography on 250 g of aluminum oxide, neutral, activity stage II. Elution with ethyl acetate/hexane 2:3 yields 5.39 g of 4,5-bis(4-methoxyphenyl)-1-(tetrahydrofuran-2-yl)imidazole, which is obtained in the form of a foam after removal of the solvent.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH:15]([CH2:16][CH3:17])[CH2:14]1>CC(O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:14][CH:15]([OH:13])[CH2:16][CH3:17])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCC1CO1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Solvent: CC(C)O
Product: CCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Yield: 43.3 %

Procedure:
A solution (6 ml) of 4-methanesulfonylbenzylamine (3.0 g) and 1,2-epoxybutane (1.1 g) in 2-propanol was heated under reflux for 12 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (1.7 g).