Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][C:14]1[CH:18]=[C:17]([NH2:19])[N:16]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[N:25]3)[N:15]=1.ClCCl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:19][C:17]2[N:16]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[N:25]4)[N:15]=[C:14]([CH3:13])[CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(S(=O)(=O)Nc2cc(C)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A mixture of 4-ethylbenzenesulfonyl chloride (0.033 g, 0.16 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.030 g, 0.13 mmol) in pyridine (1.0 mL) was heated at 80° C. for 2 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.019 g, 0.049 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ 8.86 (dd, J=2.0, 4.0 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.60 (dd, J=7.2, 8.4 Hz, 1H), 7.51-7.46 (m, 3H), 7.27-7.23 (m, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.27 (s, 1H), 2.68 (q, J=7.6 Hz, 2H), 2.34 (s, 3H), 1.27 (t, J=7.6 Hz, 3H); MS: (ES) m/z calculated for C21H21N4O2S [M+H]+ 393.2. found 393.2
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH:5]([N:13]2[CH2:18][CH2:17][CH:16](O)/[C:15](=[CH:20]/[C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)/[CH2:14]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[F:12])[CH2:3][CH2:2]1.[C:27]([OH:30])(=[S:29])[CH3:28].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:27]([S:29][CH:16]1[CH2:17][CH2:18][N:13]([CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[F:12])[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:26])[CH2:14]/[C:15]/1=[CH:20]\[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)(=[O:30])[CH3:28]
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)/C(=C/c2ccco2)C1
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-[(furan-2-yl)methylidene]piperidin-4-ol (2.30 g) in toluene (50 ml) were added thioacetic acid (0.92 ml) and N,N-dimethylformamide dineopentyl acetal (3.61 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19 to 1:9) as the eluent to afford the title compound (0.58 g, yield: 22%) as an orange-coloured oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].BrBr.C(N(CC)CC)C.[NH2:27][C:28]([NH2:30])=[S:29].C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:8]1[S:29][C:28]([NH2:30])=[N:27][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:10]
Reactant: NC(N)=S
Reactant: O=C(CC(=O)c1ccccn1)c1ccccn1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Nc1nc(-c2ccccn2)c(C(=O)c2ccccn2)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
1,3-Di(2-pyridyl)propane-1,3-dione (1.17 g, 5.15 mmol) was dissolved in acetic acid (20 mL), and bromine (856 mg, 5.35 mmol) was added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in ethanol (30 mL), and triethylamine (0.750 mL, 5.38 mmol) and thiourea (416 mg, 5.47 mmol) were added thereto, followed by stirring under heating and reflux for 30 minutes. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to afford the entitled Compound 630 (739 mg, 51%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1>O1CCOCC1.CCOCC>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1cccc(C=C2CCCNC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of HCl in dioxane (4M, 30 mL) was added to a solution of tert-butyl 3-[1-(3-fluorophenyl)methylidene]piperidine-1-carboxylate (Intermediate 227, 2.38 g) in ether (30 mL) and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was treated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 3-[1-(3-fluorophenyl)methylidene]piperidine hydrochloride (1.64 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
20 ml of freshly distilled THF was flushed for 30 min with a stream of nitrogen after which benzothiazole (1.0 g, 7.4 mmol) was added. After being flushed for another 30 min, the solution was cooled to −78° C. and placed under inert nitrogen atmosphere. 0.9 equivalents of n-BuLi (2 M solution in hexane, 2.66 ml, 6.66 mmol) was added dropwise over a period of 30 min, during which the solution turned to deep red. The solution was kept at −78° C. for 1 h and then tri-n-butyltin chloride (2.0 mi, 7.4 mmol) was added dropwise over a period of 1 h. During this addition, the solution shifted from deep red to brownish yellow, then to greenish blue and finally to light brown. After yet another hour at −78° C., the solution was allowed to reach room temperature. The THF was removed on a rotary evaporator and the product, a yellow oil, was isolated by distillation in vacuo. Yield: 2.47 g, 79%. 1H NMR (CDCl3): δ 0.90 (t, J═S, 9H, Bu3Sn), 1.29 (in, 6H, Bu3Sn), 1.35 (m, 6H, Bu3Sn), 1.63 (t, J=8, 6H, Bu3Sn), 7.37 (t, J=8, 1H, ArH), 7.46 (t, J=8, 1H, ArH, 7.96 (d, J=8, 1H, ArH), 8.17 (D, J=8, 1H, ArH).
Reaction SMILES: Cl.CN.CS([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:11]=[CH:10][N:9]=1)(=O)=O.C[CH2:31][N:32](C(C)C)C(C)C>CC(O)C>[CH3:31][NH:32][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Agent: CN
Agent: Cl
Solvent: CC(C)O
Product: CNc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of methylamine hydrochloride (0.863 g, 12.8 mmol), 2-(methylsulfonyl)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine (0.791 g, 2.13 mmol) in iPrOH was added n,n-diisopropylethylamine (2.60 ml, 14.9 mmol). The reaction was sealed and heated to 70 deg. C. overnight. The resulting clear yellow solution was judged complete by LCMS in the morning. The reaction was cooled to ambient temperature, resulting in the formation of whit crystals. Filter, rinsing with isopropanol. Concentrate filtrate, partition between EtOAc and 1N NaOH. Dry over anhyd. Na2SO4, filter, concentrate to give N-methyl-4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine as a light yellow solid. MS m/z=323 [M+1]+. Calc'd for C17H14N4O3: 322.32.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]2[O:10][CH2:14][CH2:13][O:11][C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Cl)cc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc2c1OCCO2
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
5-Chloro-2,3-dihydroxybenzaldehyde (6.0 g, 34.7 mmol) was dissolved in DMF (100 mL) and to the solution were added 1,2-dibromoethane (8.0 g, 42.5 mmol) and potassium carbonate (10.0 g, 70 mmol). The mixture was stirred at 100° C. for one hour, cooled to room temperature and then diluted with water (200 mL). After extraction twice with ethyl acetate (200 mL) the combined organic solutions were washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the solid residue treated with methanol. After filtration and drying there was obtained 6.5 g (94%) of 7-chloro-2,3-dihydro-1,4-benzodioxine-5-carbaldehyde. 1H NMR (300 MHz, CDCl3): 4.3-4.4 (m, 4H), 7.1 (d, 1H), 7.3 (d, 1H), 10.3 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1[CH2:40][O:39][CH2:38]C1.BrCOC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:38][O:39][CH3:40])[C:22]([O:24][CH3:25])=[O:23]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: COCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: COCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 77.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.351 g; 1 mmol), LHMDS 1N in THF (1.1 mL; 1.1 mmol), 1 bromomethylmethylether (0.122 mL; 1.5 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.307 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=1)[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]([C:36]1[O:40][N:39]=[C:38]([NH2:41])[CH:37]=1)([CH3:35])[CH3:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:41][C:38]2[CH:37]=[C:36]([C:33]([CH3:35])([CH3:34])[C:32]([F:42])([F:31])[F:43])[O:40][N:39]=2)=[O:29])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)on2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (55.1 g, 134 mmol) and 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (26 g, 134 mmol) in pyridine (500 mL) was added T3P® (137.5 mL, 134 mmol) dropwise and stirred at 25° C. for 1 h. After TLC analysis showed the starting material was consumed completely, the mixture was poured into stirring cold water (1 L). The mixture was stirred for 0.5 h and then let stand for 10 h. The solid was filtered, washed with H2O (200 mL×3) and TBME (200 mL×2) and dried in vacuo to give an off-white solid of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (65 g, 100 mmol, 74% yield): 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.40-7.32 (m, 3H), 7.26 (d, J=9.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 3H), 6.43 (s, 1H), 5.26 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 3.78 (s, 3H), 1.56 (s, 6H), 1.35 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 588 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[CH:18][C:17]=2[N+:32]([O-])=O)=[C:9]([CH3:35])[CH:8]=1)=[O:4].COP(OC)OC>>[CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:32][C:17]3[C:16]([CH:15]=2)=[CH:31][CH:30]=[C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:18]=3)=[C:9]([CH3:35])[CH:8]=1)=[O:4]
Reactant: COC(=O)/C=C/c1cc(C)c(/C=C/c2ccc(C(=O)OCc3ccccc3)cc2[N+](=O)[O-])c(C)c1
Agent: COP(OC)OC
Product: COC(=O)/C=C/c1cc(C)c(-c2cc3ccc(C(=O)OCc4ccccc4)cc3[nH]2)c(C)c1
Temperature: 110 °C

Procedure:
A mixture of benzyl 4-{(E)-2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-vinyl}-3-nitrobenzoate (1.87 g, 3.97 mmol) and trimethylphosphite (5.0 mL, 5.26 g, 42 mmol) was heated at 110° C. for 3 h. The solvent was then removed under reduced pressure and the residue chromatographed using a 10-50% gradient of heptane/ethyl acetate to yield benzyl 2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-1H-indole-6-carboxylate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.CS(O[CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])(=O)=O>C(O)C>[N:1]([CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CCC#N)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(CCC#N)N=[N+]=[N-]
Yield: 91.2 %

Procedure:
To a stirring solution of NaN3 (15 g) in boiling water (20 ml) was added a solution of crude 4-methanesulphonyloxypentanonitrile (37.7 g, ≈0.189 mol) in ethanol (240 ml) and the mixture refluxed for 1.5 h. After cooling the mixture was partitioned between H2O and CH2Cl2. The organic phase was dried and concentrated in vacuo to give 21.4 g of the title material as a light brown oil, (91.6): 1Hmr (CDCl3) δ: 4.05 (1H, q, J=13 Hz), 2.46 (2H, t, J=13 Hz), 1.8 (2H, t, J=13 Hz) and 1.35 ppm (3H, d, J=13 Hz); ir (neat) νmax : 2242, 2100 cm-1.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=O)[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18].C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>CO.O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[N:29][OH:30])[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC(F)(F)C(=O)c1ccc2oc3ccccc3c2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CC(F)(F)C(=NO)c1ccc2oc3ccccc3c2c1

Procedure:
A solution of 4-dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid (1 equivalent, Example 1) and sodium acetate (1.2 equivalents) in methanol is treated with a solution of hydroxylamine hydrochloride (1.2 equivalents) in water. The solution is heated to reflux for 3 hours, then cooled, concentrated, and filtered. The filter cake is washed with water and dried in vacuo. The crude product is recrystallized from an organic solvent, such as ethyl acetate, to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>O.C(Cl)Cl>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Reaction time: 2 h

Procedure:
Piperidine-4-carboxylic acid (25.8 g, 200 mmol) and potassium carbonate (82.9 g, 600 mmol) are combined in water (500 mL) and methylene chloride (1 L) at 0° C. 4-Fluorobenzoyl chloride (31.7 g, 200 mmol) is dissolved in methylene chloride (200 mL) and added to the first mixture dropwise over 45 min. The mixture is stirred for 2 hr, after which the aqueous layer is separated and acidified to pH 1.5 with concentrated HCl. The aqueous mixture is extracted three times with methylene chloride, and the organic extracts are dried over magnesium sulfate and evaporated to give the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: O=C(Cl)OCc1ccccc1
Product: CSc1nc(-c2cccc(OC(=O)OCc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with benzyl chloroformate (368 μl) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]#[N:9])[CH:4]=[CH:3]1.[CH2:10]([O:12][C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]O)[CH:16]=1)[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:10]([O:12][C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6]2)[CH:16]=1)[CH3:11]
Reactant: N#Cc1ccc(=O)[nH]n1
Reactant: CCOC(=O)Nc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(C#N)ccc2=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, 1 g (8.3 mmol) of 6-oxo-1,6-dihydropyridazine-3-carbonitrile (prepared in accordance with WO 2002/079200) is suspended in 50 ml of THF, and 2.4 g (12.4 mmol) of ethyl(3-hydroxymethylphenyl)carbamate and 5 g (12.4 mmol) of triphenyphosphine are added. 1.95 ml (12.4 mmol) of diethyl azodicarboxylate is added dropwise to this suspension at 2-10° C. with ice-cooling. The suspension is stirred at room temperature for 15 h. The suspension is filtered, and the filter residue is washed with dichloromethane, the filtrate is evaporated to dryness, taken up in ethyl acetate, and the organic phase is extracted with 1N HCl and saturated sodium hydrogencarbonate solution. The organic phase is subsequently dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[C:14]([SiH2:18][O:19][C:20]([CH3:31])([CH3:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([SiH2:18][O:19][C:20]([CH3:31])([CH3:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH:25][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Cyclopropylcarbonyl chloride (2.88 mL, 31.0 mmol) and Et3N (4.38 mL, 31.0 mmol) were added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) in CH2Cl2 (125 mL). The mixture was stirred for 30 min at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl (2×), with aq. 1M NaOH (2×) and with brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:19) yielded the title compound (6.10 g, 82%). LC-MS: tR=1.09 min; ES+: 395.42.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=N[C:20]([C:23](=O)N(C)C)=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].BrC1C=CC([C:33]#[N:34])=CC=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:23][C:20]([C:33]#[N:34])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: N#Cc1ccc(Br)cc1
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C#N)cc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo benzonitrile (246 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (257 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ 7.58-7.71 (m, 2 H) 7.20-7.30 (m, 2 H) 6.95-7.06 (m, 2 H) 3.88 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C19H17NO4 m/z 324.00 (M+H+).
Reaction SMILES: Br.Br[CH:3]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:4]1[CH:17]=[CH:16][C:7]2[NH:8][C:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:10][C:6]=2[CH:5]=1.[CH3:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.CN(C)C=O>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:3]([N:27]2[CH:28]=[CH:29][N:30]=[C:26]2[CH3:25])[C:4]2[CH:17]=[CH:16][C:7]3[NH:8][C:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:10][C:6]=3[CH:5]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)Nc1nc2cc(C(Br)c3ccc(F)cc3)ccc2[nH]1
Reactant: Cc1ncc[nH]1
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2cc(C(c3ccc(F)cc3)n3ccnc3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.2 %

Procedure:
A mixture of 9.18 parts of methyl [5-[bromo(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbamate monohydrobromide, 12.3 parts of 2-methyl-1H-imidazole and 56.4 parts of N,N-dimethylformamide was stirred for 17 hours at room temperature. The reaction mixture was diluted with 300 parts of water. The precipitated product was filtered off and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 27 parts of ethyl acetate. The product was filtered off, washed with 1,1'-oxybisethane and dried, yielding 2.6 parts (34.2%) of methyl [5-[(4-fluorophenyl)(2-methyl-1H-imidazol-1-yl)methyl]-1H-benzimidazol-2-yl]carbamate; mp. >300° C. (compound 6).