Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.[F-].[Cs+].C(O[Si](OCC)(OCC)OCC)C.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>O1CCCC1>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:37][CH2:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: C=CC(=O)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCn1ccc(OCc2ccccc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.50 g, 1.78 mmol) and cesium fluoride (0.0027 g, 0.178 mmol) were suspended in tetrahydrofuran (10 mL) followed by dropwise addition of tetraethylortho silicate (0.37 g, 1.78 mmol) at room temperature. After stirring for 10 minutes at room temperature, ethyl acrylate (0.23 g, 2.32 mmol) was added dropwise and the reaction stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated and the resulting residue subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford a white solid (0.62 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.79 Hz, 1H), 7.41-7.29 (m, 5H), 6.03 (d, J=7.65 Hz, 1H), 5.20 (s, 2H), 4.17 (t, J=5.98 Hz, 2H), 4.07 (q, J=7.16 Hz, 2H), 2.83 (t, J=5.98 Hz, 2H), 1.19 (t, J=7.18 Hz, 3H). ES-HRMS m/z 380.0523 (M+H C17H18BrNO4 requires 380.0492).
Reaction SMILES: C([O:4][C@H:5]1[C@H:21]([O:22]C(=O)C)[C@@H:20]([CH2:26][O:27]C(=O)C)[O:19][C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C@@H:6]1[N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(=O)C.C[O-].[Na+]>C(Cl)Cl>[C:32]1(=[O:41])[N:31]([C@@H:6]2[C@@H:5]([OH:4])[C@H:21]([OH:22])[C@@H:20]([CH2:26][OH:27])[O:19][C@H:7]2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CC(=O)OC[C@H]1O[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@H]1[C@H](OCc2ccc([N+](=O)[O-])cc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A solution of compound 16 (3 g, 5.25 mmol) in anhydrous DCM (30 mL) was cooled to −10° C. under a nitrogen atmosphere. Freshly prepared sodium methoxide solution [sodium (48 mg, 2.10 mmol) in dry methanol (30 mL)] was added slowly to the reaction mixture and stirred at 0° C. for 3 hours. Reaction mixture was neutralized by adding amberlyst IR 120 resin and filtered. Solvents were removed at reduced pressure to get p-nitrobenzyl 2-deoxy-2-phthalimido-β-D-glucopyranoside in 98% yield. 1H-NMR (600 MHz, CD3OD) δ 7.86-7.90 (m, 2H), 7.60-7.84 (m, 4H), 7.24-7.32 (m, 2H), 5.18 (d, 1H, J=9.0 Hz), 4.92 (d, 1H, J=13.2 Hz), 4.65 (d, 1H, J=13.2 Hz), 4.23 (dd, 1H, J=9.0, 10.8 Hz), 4.04 (dd, 1H, J=9.0, 10.8 Hz), 3.94 (dd, 1H, J=2.4, 12.0 Hz), 3.75 (dd, 1H, J=5.4, 12.0 Hz), 3.38-3.46 (m, 2H); 13C-NMR (100 MHz, CD3OD) δ 148.3, 146.2, 135.3, 132.5, 129.1, 124.1, 98.9, 78.0, 72.2, 72.0, 70.5, 62.5, 58.2; ESI-MS: m/z: calcd for C21H20N2O9Na: 467.1. found: 467.1 [M+23]+. p-Nitrobenzyl 2-deoxy-2-phthalimido-β-D-glucopyranoside (1.5 g, 0.031 mol) was azeotropically refluxed with toluene (100 mL) using a Dean-Stark apparatus for 3 hours. Then temperature was lowered down to 90° C. At this temperature, DL-camphorsulfonicacid (0.844 mmol) was added followed by benzaldehyde dimethylacetal (0.54 g, 0.035 mol). After 30 minutes, the temperature was raised to reflux temperature. The reaction was quenched by adding triethylamine. Solvents were removed under reduced pressure. Residue was extracted in ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Flash column chromatography using hexanes/ethyl acetate (2:3) gave the pure compound 17 in 82% yield. 1H NMR (400 MHz, CDCl3) δ 7.86-7.90 (m, 2H), 7.68 (m, 4H), 7.46-7.49 (m, 2H), 7.33-7.35 (m, 3H), 7.20-7.26 (m, 2H), 5.56 (s, 1H), 5.27 (d, 1H, J=8.8 Hz), 4.91 (d, 1H, J=13.6 Hz), 4.57 (m, 2H), 4.38 (dd, 1H, J=4.0, 10.4 Hz), 4.27 (dd, 1H, J=8.8, 10.4 Hz), 3.79-3.85 (m, 1H), 3.56-3.65 (m, 2H), 2.98 (d, 1H, J=4.0 Hz); 13C-NMR (100 MHz, CDCl3) δ 147.5, 144.6, 137.1, 134.6, 131.6, 129.7, 128.7, 128.1, 126.5, 123.8, 102.2, 98.7, 82.3, 70.3, 68.8, 68.7, 66.5, 56.7; ESI-MS: m/z: calcd for C28H24N2O9Na: 555.1. found: 555.2 [M+Na]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[C:5]1[O:6][C:2]([C:22]2[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=2)=[C:3]([C:15]([NH2:17])=[O:16])[N:4]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a mixture of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.060 g, 0.20 mmol), 4-hydroxyphenylboronic acid (0.055 g, 0.40 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride (0.008 g, 0.01 mmol) in MeCN (4 ml) was added 1M aqueous Na2CO3 (0.4 m, 0.4 mmol). The reaction was heated via microwave irradiation to 150° C. and held at this temperature for 15 minutes. The reaction was then diluted with EtOAc and washed with 2M HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 5-70% EtOAc in hexane as eluant to furnish 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.050 g, 0.16 mmol, 80%) as an off white powder. LCMS (1) 1.73 min; m/z (ES−) 315.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:12][CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[OH:29])=[O:11].[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:30]([O:29][C@@H:15]1[C@@H:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16]1)(=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC(=O)O[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)Cc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
A mixture of 400 mg of 5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine, 0.15 ml of butyryl chloride and 1 mg of 4-dimethylaminopyridine in 50 ml of pyridine was stored at room temperature overnight and then evaporated. The residue was subjected to flash chromatography on a column of silica gel using dichloromethane/methanol (24:1) for the elution, there being obtained 175 mg of 3'-O-butyryl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 130°-132° C.
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][C:9](=[O:42])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH:22]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[C:23](=[N:26][C:27]([O:29]CC)=O)SC)[C:15]=1[F:41])[CH3:7].[N:43]1[CH:48]=[CH:47][CH:46]=[N:45][C:44]=1[NH:49][NH2:50].N12CCCN=C1CCCCC2>CO>[CH2:6]([O:8][C:9](=[O:42])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH:22]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]#[N:40])=[CH:37][CH:38]=2)[C:23]2[NH:26][C:27](=[O:29])[N:49]([C:44]3[N:45]=[CH:46][CH:47]=[CH:48][N:43]=3)[N:50]=2)[C:15]=1[F:41])[CH3:7]
Reactant: NNc1ncccn1
Reactant: CCOC(=O)N=C(SC)C(Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCOC(=O)OCC)c1F
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)OCCOc1cc(OC)cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Reaction time: 1 h

Procedure:
After the atmosphere in the reaction vessel had been replaced with nitrogen, the tetrahydrofuran solution containing Carbonic acid 2-(3-{1-(4-cyanophenylamino)-2-[ethoxycarbonylimino]-2-methylsulfanylethyl]-2-fluoro-5-methoxyphenoxy)ethyl ester ethyl ester obtained in Example 64 was added, rinsing in with tetrahydrofuran (1250 mL) and stirred. Thereafter, pyrimidin-2-yl-hydrazine (275 g, 2.497 mol) was added portionwise at a bath temperature of 15° C., rinsing in with tetrahydrofuran (1000 mL), and the mixture was stirred at a bath temperature of 22° C. for 14 hours. Pyrimidin-2-yl-hydrazine (8.2 g, 0.074 mol) was additionally added, rinsing in with tetrahydrofuran (30 mL), and stirring was continued for one hour. Thereafter, the bath temperature was set at 15° C., 1,8-diazabicyclo[5.4.0]undec-7-ene (304 g, 1.999 mol) was added dropwise to the mixture, rinsing in with tetrahydrofuran (50 mL), and then the bath temperature was set at 22° C. and the mixture was stirred for 2.5 hours. Thereafter, the bath temperature was set at 15° C., and ethyl acetate (7504 mL) and 1 N hydrochloric acid (7504 mL) were added to the reaction solution. Then, the bath temperature was set at 22° C., the organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (3752 mL). All the organic layers were combined, the organic layer was washed with 10% aqueous sodium chloride solution (7504 g) twice, and concentrated under reduced pressure. The residue obtained was subjected to azeotropic distillation three times with methanol (1250 mL of methanol was used, each time). To the residue obtained, tetrahydrofuran (375 mL) and methanol (475 mL) were added to obtain the suspension of the captioned compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:29])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:30])[C:6]([C:31]([O:33]CC)=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>>[CH2:22]([N:20]([CH:17]1[CH2:18][CH2:19][N:15]([C:11]2[C:12]([CH3:14])=[C:13]3[C:8]([C:7](=[O:30])[C:6]([C:31]([OH:33])=[O:32])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:29])[CH2:16]1)[CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(N3CCC(N(C)Cc4ccccc4)C3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(N2CCC(N(C)Cc3ccccc3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 39.5 %

Procedure:
To ethyl 1-cyclopropyl-7-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.86 g) is added 10% aqueous sodium hydroxide (7 ml), and the mixture is refluxed for 5 hours. After cooling, the mixture is acidified with diluted hydrochloric acid and is extracted with dichloromethane. The aqueous layer is adjusted to about pH 7.5 with sodium hydrogen carbonate, and the resulting precipitates are recrystallized from ethanol-diethyl ether to give 7-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.32 g), as pale yellow powder, m.p. 160.8°-161.3° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]([CH3:23])([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][C:7]([CH3:23])([C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccccc1)C(C)(C)C(=O)OC(C)(C)C

Procedure:
After methyltriphenylphosphonium bromide and n-butyllithium were reacted in THF, a THF solution of tert-butyl 2,2-dimethyl-3-oxo-3-phenylpropanoate was added thereto and the whole was reacted under heating to obtain tert-butyl 2,2-dimethyl-3-phenylbut-3-enoate.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:24].CCOC(C)=O>C1COCC1>[ClH:24].[ClH:24].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)Oc2cccnc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC1CCN(C(=O)Oc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyridin-3-yl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (0.249 g) was dissolved in THF (5.0 ml), and under ice cooling, 4 M hydrogen chloride/EtOAc solution (2.10 ml) was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was concentrated to dryness to obtain pyridin-3-yl 4-aminopiperidine-1-carboxylate dihydrochloride (0.280 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:11]1[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:39]([C:36]1[CH:35]=[CH:34][C:33]([S:32][CH3:31])=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: COC(=O)c1cc(N)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(SC)cc2)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1

Procedure:
Analogously to Example 86, by condensing methyl 3-amino-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate with 4-methylsulphanylbenzenesulphonyl chloride there was obtained methyl 4-(3-methoxy-phenoxy)-3-(4-methylsulphanyl-benzenesulphonylamino)-5-[2-(tetrahydro-pyran-2-yl-oxy)-ethoxy]-benzoate and therefrom by treatment with 5.5M HCl there was obtained methyl 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:41])[F:40])[CH:36]=4)[NH:31][N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:40])[F:41])[CH:36]=4)[N:31]([CH2:2][C:3]([NH:5][CH3:6])=[O:4])[N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 2-chloro-N-methylacetamide (80 mg, 744 μmol) in DMF (28.0 mL) under Ar, potassium carbonate (280 mg, 2.03 mmol) was added at 25° C. After 1 h, N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 132 μmol) in DMF (7.00 mL) was added and the reaction was stirred at 70° C. After 6 h, the reaction was cooled to 25° C. and quenched with water (350 mL). The product was extracted with ethyl acetate (2×250 mL). The organic layer was dried over sodium sulfate, filtered through Celite, and the solvent removed in vacuo to give a beige solid. The solid was triturated in hexanes (20 mL), filtered and dried in vacuo (200 mTorr, 25° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62.2 mg, 103 μmol, 78%) as a light brown solid. MS (M)'=602; 1H NMR (DMSO-d6) δ: 9.10 (s, 1H), 8.60 (s, 1H), 8.22 (m, 2H), 7.88 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.41 (dd, J=2.3, 9.0 Hz, 1H), 7.21 (t, J=74.5 Hz, 1H), 5.73 (s, 2H), 5.27 (s 2H), 3.58 (t, J=8.0 Hz, 2H), 2.65 (d, J=4.5 Hz, 3H), 1.51 (s, 9H), 0.86 (t, J=7.8 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:17]([NH:24][CH:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:29]([O:28][C:26](=[O:27])[C@H:25]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:30]
Reactant: C(=Cc1ccccc1)COc1ccccc1
Reactant: CCOC(=O)C(Cc1ccccc1)NCc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccccc1)N(C/C=C/c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
Following the general procedure using cinnamyloxybenzene (105 mg, 0.50 mmol) and ethyl 2-(benzylamino)-3-phenylpropanoate (212 mg, 0.75 mmol), the reaction was stirred for 2.5 h at rt. Column chromatography on silica gel (eluting with 10% EtOAc/hexanes) afforded the product as a pale yellow liquid (190 mg, 95%).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:22])[CH:20]=[CH2:21]>>[CH2:19]([O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:20]=[CH2:21]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: C=CCO
Product: C=CCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 118-120° C. and MS: m/e=295 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and allyl alcohol.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[C:5]([Cl:11])[C:4]=1[OH:12].C(N(CC)C1C=CC=CC=1)C.[CH3:24][C:25](C)=[O:26].C(Cl)(=O)C>O>[C:25]([NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[C:5]([Cl:11])[C:4]=1[OH:12])(=[O:26])[CH3:24]
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Reactant: CC(C)=O
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1cc(Cl)c(C)c(Cl)c1O

Procedure:
To a mixture of 68.4 g. of 2-amino-5-methyl-4,6-dichloro-phenol hydrochloride and 96 ml. of N,N-diethylaniline in 750 ml. of acetone, 23.4 ml. of acetyl chloride were added slowly by keeping the temperature under 20° C. At the end, the reaction mixture was heated to reflux for an hour. After cooling, the solution was poured into water; the solid product, thus obtained, was collected on a buckner, washed with water until the washings were neutral and dried in a desicator at 50° C. The raw product obtained was purified by crystallization from ethyl alcohol, yielding 44 g. of a pure product with M.P. = 175°-176.5° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:30][CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:23][CH:24]=2)[CH2:33][CH2:32]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CS(=O)(=O)c1ccc(C2=CCNCC2)cc1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC=C(c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized 2-isopropoxy-5-methanesulfonyl-benzoic acid and 4-(4-Methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 495.4 (M+NH4+, 100%)
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:19]1[N:20]=[N:21][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:23][CH:24]=1>CN(C=O)C>[N:25]1([C:22]2[N:21]=[N:20][C:19]([O:17][CH:13]3[CH2:14][CH2:15][CH2:16][N:11]([CH2:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:12]3)=[CH:24][CH:23]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Clc1ccc(-n2ccnc2)nn1
Reactant: OC1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCCC(Oc3ccc(-n4ccnc4)nn3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a suspension of NaH (0.21 g, 8.31 mmol) in DMF (5 mL) was added 1-benzyl-3-hydroxypiperidine hydrochloride (0.78 g, 3.3 mmol) in DMF (5 mL), and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. 3-chloro-6-(imidazol-1-yl)pyridazine (0.6 g, 3.3 mmol) in DMF (5 mL) was then added dropwise. The reaction mixture was stirred at ambient temperature for 30 minutes. After removal of DMF in vacuo, the black oil was dissolved in CH2Cl2 (50 mL), washed with water and brine. Purification using column chromatography afforded 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-benzylpiperidine (400 mg) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([F:11])[CH:5]=1.O.[NH2:14][NH2:15]>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:14][NH2:15])=[O:2])=[CH:5][C:6]=1[F:11]
Reactant: NN
Reactant: COC(=O)c1ccc(Br)c(F)c1
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(Br)c(F)c1
Temperature: 70 °C

Procedure:
A mixture of compound 4-bromo-3-fluoro-benzoic acid methyl ester (1 g, 4.29 mmol), hydrazine hydrate (2.2 mL, 42.9 mmol) and MeOH (20 mL) was heated at 70° C. for overnight. Concentrated, diluted with EtOAc (300 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated give the desired product 2AR (0.9 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[NH:10][C:11]1[N:15]([CH3:16])[C:14]2[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:20][C:13]=2[N:12]=1.N>[Ni].CCO>[NH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:22])=[CH:20][C:13]=3[N:12]=2)[CH:4]=1
Reactant: Cn1c(Nc2cc(C#N)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21
Agent: [Ni]
Agent: N
Solvent: CCO
Product: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21

Procedure:
A mixture of 2-(2-chloro-5-cyanophenylamino)-N-cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide (500 mg, 1.19 mmol, prepared in analogy to the experimental procedures described above) and EtOH (20 mL) was saturated with ammonia. Freshly prepared Raney-Nickel (7 mg, 0.12 mmol) was added and the mixture was hydrogenated (rt, 70 atm) for 48 h. The mixture was filtered through Celite and the filter cake washed with EtOAc. The combined filtrates were concentrated and the residue treated with a mixture of petroleum ether and diethyl ether to give the sub-title compound. Yield: 500 mg (98%).