Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:29])[CH:10]([F:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[C:3]21[CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:16](=O)[NH:15][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[N:13]2.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:16]1[NH:15][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:13][C:3]2([C:4]3[C:9](=[CH:8][C:7]([F:12])=[CH:6][CH:5]=3)[CH:10]([F:11])[C:2]2([F:29])[F:1])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1C(=O)NC(c2ccccn2)=NC12c1ccc(F)cc1C(F)C2(F)F
Product: COC(=O)C1=C(Cl)NC(c2ccccn2)=NC12c1ccc(F)cc1C(F)C2(F)F
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Compound 165 (10.2 g, 23.1 mmol), pyridine-2-carboximidamide hydrochloride (6.37 g, 40.4 mmol), sodium bicarbonate (7.76 g, 92.4 mmol) and dioxane (200 mL) were heated and stirred at 60° C. during 6 hours and stirred further overnight at 40° C. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. The product fractions were combined and concentrated yielding methyl 2,2,3,5-tetrafluoro-6′-oxo-2′-(pyridin-2-yl)-2,3,5′,6′-tetrahydro-1′H-spiro[indene-1,4′-pyrimidine]-5′-carboxylate (6.1 g) as a light yellow amorphous powder. A solution of methyl 2′,2′,3′,5′-tetrafluoro-6-oxo-2-(2-pyridyl)spiro[1,5-dihydropyrimidine-4,1′-indane]-5-carboxylate in phosphorus oxychloride (50 g) equipped with a CaCl2 drying tube was heated at 110° C. during 210 minutes. The reaction mixture was concentrated, the residue dissolved in CH2Cl2 (200 mL), poured in saturated NaHCO3 (200 mL) solution and stirred 30 minutes. The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 till 100% EtOAc in heptane. methyl 6′-chloro-2,2,3,5-tetrafluoro-2′-(pyridin-2-yl)-2,3-dihydro-1′H-spiro[indene-1,4′-pyrimidine]-5′-carboxylate was isolated as two separate diastereoisomers: and compound 167A (1046 mg after second purification) and compound 167B (1705 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][OH:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:19](OC)([CH3:21])[CH3:20]>CC(C)=O.B(F)(F)F.CCOCC>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C@H:9]1[CH2:15][O:16][C:19]([CH3:21])([CH3:20])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (7.0 g, 30.0 mmol) in acetone (90 mL), there was added 2,2-dimethoxypropane (37 mL, 300 mmol) followed by BF3.Et2O (0.11 mL, 0.9 mmol). The resulting solution was stirred at rt overnight. Solvents were removed under vacuum, and the residue was redissolved in ether (100 mL), washed with sat'd NaHCO3 (20 mL). Upon concentrating under vacuum, the residue was purified by flash column chromatography to give (S)-tert-butyl 4-(2-methoxy-2-oxoethyl)-2,2-dimethyloxazolidine-3-carboxylate (7.51 g, 92%). MS m/z 296 (M+Na+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:18])([F:17])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>>[F:6][C:7]([F:17])([F:18])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=1)=[O:9]
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(Nc1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F

Procedure:
Chlorosulfonic acid (100 g.) was cooled to 0° C. and trifluoroacetanilide (30 g.) was added portionwise with vigorous stirring keeping the temperature below +5° C. The reaction was stirred at room temperature overnight, and cautiously poured onto ice. The white solid produced was filtered, washed copiously with water, and dried to give 4-trifluoroacetamido benzenesulfonyl chloride (39.14 gl)(m.r. 143°-146° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, off-white solid, m.p. 128° C. and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].[C:9]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25])=[S:14])(=O)[CH3:10].BrCC([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O>O>[CH3:25][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[NH:15][C:13]1[S:14][CH:10]=[C:9]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:12]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: CC(=O)NC(=S)Nc1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(-c2cccnc2)cs1
Temperature: 27.5 °C

Procedure:
In a reactor, introduce methanol (1120 L), potassium carbonate (287 kg, 2076.70 mol) and 1-acetyl-3-(2-methyl-5-nitro-phenyl)-thiourea (67 kg, 264.53 mol). 2-bromo-1-pyridin-3-yl-ethanone (Int4) (52 kg, 259.96 mol) was then added and temperature maintained at 25-30° C. for 4 hours. Water (692 L) was added to the reaction mixture and precipitate filtered, washed with water and diisopropylether. The product was then dried in a tray drier at 45-50° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23])[CH3:20].C(OCC)(=O)C>CCCCCC>[CH2:19]([O:21][C:22](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([N:14]2[C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[CH3:18])=[CH:17][N:16]=[CH:15]2)[CH:29]=1)[CH3:20]
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-n2cncc2-c2c(-c3cccc(F)c3)noc2C)c1
Yield: 32 %

Procedure:
As described for Example 3, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (2.43 g, 10 mmol) was converted, using of 3-ethoxycarbonylphenylboronic acid instead of 4-fluorophenylboronic acid, through chromatography (SiO2, ethyl acetate: hexane=20:10) to the title compound (1.26 mg, 32%) which was obtained as a light yellow solid. MS: m/e=392.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:6]([CH2:14][OH:15])[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:6]([CH2:14][OH:15])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)O)cc1
Yield: 53.5 %

Procedure:
A solution of 0.75 g (1.72 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionic acid, tert-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of CH2Cl2 was stirred at room temperature for 3 hours and then concentrated to dryness under vacuum. To the residue was added H2O, CH2Cl2 and 1N NaOH until the aqueous layer reached pH 8. The aqueous layer was then separated, acidified with 2 N citric acid and extracted with ethyl acetate. The extract was washed with H2O, brine and dried Na2SO4. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Anal. for C17H20N2O6S: Calc'd: C, 53.7; H, 5.3; N, 7.4; Found: C, 53.0; H, 5.3; N, 6.9.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[N:13]3[CH:28]=[CH:29][N:30]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].C(#N)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)Cl>[CH:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:22][N:23]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:24]4)[CH:20]=3)[N:13]3[CH:28]=[CH:29][N:30]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Yield: 47 %

Procedure:
To a flask charged with 2-(3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.050 g, 0.10 mmol) was added 1 mL of acetonitrile, potassium carbonate (0.10 g, 0.75 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.040 g, 0.17 mmol) at ambient temperature with stirring. The reaction flask was then sealed and allowed to proceed at ambient temperature over the weekend. The reaction was diluted with DCM and the suspension was loaded directly onto a silica gel column pre-wetted and eluted with 75% ethyl acetate in Hexanes with 1% ammonium hydroxide to afford the title compound (0.022 g, 0.047 mmol, 47% yield). MS (apci) m/z=470.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:38]=3[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Cn1ccc2cccc(N)c2c1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4ccn(C)c(=O)c34)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (203.1 mg, 0.4793 mmol) and 8-amino-2-methylisoquinolin-1(2H)-one (Compound 131A, 100.0 mg, 0.5740 mmol). The crude product was purified using the Teledyne/ISCO Combiflash system, eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo, yielding the title material as a yellow solid, 225.9 mg (82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 9.88 (s, 1H), 8.87 (br s, 1H), 8.48 (s, 1H), 7.55-7.68 (m, 3H), 7.53 (d, J=7.1 Hz, 1H), 7.31 (d, J=7.1 Hz, 1H), 7.24 (dd, J=8.6, 2.3 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 3.91-4.01 (m, 4H), 3.53 (s, 3H), 3.20 (d, J=21.2 Hz, 2H), 1.18 (t, J=6.9 Hz, 6H). MS (ES+): m/z 562.11 (100) [MH+]. HPLC: tR=3.58 min (ZQ3, polar—5 min).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[SH:39])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[S:39][CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1)[CH3:33]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CSc2nccn2CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.0 g), 1-ethyl-2-mercaptoimidazole (1.0 g), potassium carbonate (1.1 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (=3/2, v/v) gave ethyl 2-[(1-ethylimidazol-2-yl)thiomethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (2.8 g, 78%) which was then recrystallized from ethyl acetate-hexane.
Reaction SMILES: C[Mg]Cl.O1CCCC1.[CH:9](=O)/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH3:17].BrCBr.C([Mg]Cl)(C)(C)C.C([O:30][CH2:31][CH3:32])C>>[CH:14](/[CH:15]1[CH2:17][CH:16]1[CH:31]([OH:30])[CH3:32])=[CH:13]\[CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCC/C=C/C=C/C=O
Reactant: CCOCC
Agent: CC(C)(C)[Mg]Cl
Agent: C[Mg]Cl
Solvent: BrCBr
Solvent: C1CCOC1
Product: CCCC/C=C/C1CC1C(C)O
Reaction time: 18 h
Yield: 87.7 %

Procedure:
Prepared as described in Example 1 (System B) from methyl magnesium chloride 3M in tetrahydrofuran (7.3 ml, 21 mmol), (2E,4E)-nona-2,4-dienal (3 g, 21 mmol), dibromomethane (15 g, 87 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (43 ml, 87 mmol) at 0°-10° C. Work-up after 18 h and bulb-to-bulb distillation at 80° C./0.05 mbar gave 3.1 g (77%) of a colorless oil (syn/anti=83:17). Odour: fruity, pear, green. 1H NMR (CDCl3): δ 1H NMR (CDCl3): δ 0.5 (m, 1H), 0.7 (m, 1H), 0.8-1 (2H), 0.9 (t, 3H), 1.2-1.4 (6H), 1.8-2.0 (3H), 3.2 (m, 1H), 5.0 (m, 1H), 5.5 (m, 1H) ppm. 13C-NMR (CDCl3) syn-isomer: δ 11.5 (t), 13.9 (q), 18.8 (d), 22.2 (d), 22.5 (q), 28.1 (d), 31.7 (t), 32.1 (t), 71.5 (d), 128.9 (d), 131.7 (d). 13C-NMR (CDCl3) anti-isomer: δ 10.8 (t), 14.0 (q), 19.6 (d), 22.2 (d), 22.5 (q), 28.3 (d), 31.7 (t), 32.1 (t), 72.0 (d), 128.7 (d), 132.0 (d). syn-configuration assigned by GC retention time. MS (EI): m/z (%) 168 ([M]+, 1), 150 ([M-H2O]+, 7), 113 (48), 95 (47), 82 (33), 81 (80), 68 (72), 67 (100), 57 (43), 55 (45), 54 (80), 45 (75), 43 (56), 41 (64). IR (film): 3340 (br, OH), 2958 (m), 2925 (m), 2871 (m), 2858 (m), 1455 (m), 1414 (w), 1366 (m), 1290 (w), 1180 (w), 1103 (m), 1076 (m), 1029 (m), 959 (s), 897 (m).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7]C1C=C2C(C=CN2)=CC=1)(C)(C)C.[C:18]([O:22][C:23](=[O:40])[CH2:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29](N=C=O)=[CH:30][N:31]2[C:34](=[O:36])[NH2:35])=[CH:27][CH:26]=1)([CH3:21])([CH3:20])[CH3:19].C(N1C2C(=CC(OCCO)=CC=2)C(CC(O)=O)=C1)(=O)N>>[C:18]([O:22][C:23]([CH2:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH2:7][C:6]([OH:17])=[O:5])=[CH:30][N:31]2[C:34](=[O:36])[NH2:35])=[CH:27][CH:26]=1)=[O:40])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1
Reactant: CC(C)(C)OC(=O)Cc1ccc2cc[nH]c2c1
Agent: NC(=O)n1cc(CC(=O)O)c2cc(OCCO)ccc21
Product: CC(C)(C)OC(=O)Cc1ccc2c(CC(=O)O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yl)-acetic acid tert-butyl ester (described for the preparation of (1-carbamoyl-3-isocyanato-1H-indol-6-yl)-acetic acid tert-butyl ester) according to the protocol described scheme A9 steps A, B, D, E for the preparation of [1-carbamoyl-5-(2-hydroxy-ethoxy)-1H-indol-3-yl]-acetic acid. MS (LC/MS): 350.2/352.2 [M+NH4]+, 687.2/689.2 [2M+Na]+, 277.0/279.0 [MH−tBu]+, 288.0/290.0 [M−CONH2]−, 376.9/378.8 [M+HCOO]−, 662.8/664.7 [2M−H]−; tR (HPLC conditions f): 1.79 min.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH2:9])[CH3:5]>CCOCC>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH:9][C:2]#[N:1])[CH3:5]
Reactant: CCOC(CN)OCC
Reactant: N#CBr
Solvent: CCOCC
Product: CCOC(CNC#N)OCC
Temperature: 0 °C
Yield: 109.6 %

Procedure:
A solution of cyanogen bromide (2.12 g.), in ether (20 ml.) was added dropwise over 35 minutes to a stirred ice-cooled solution of 2,2-diethoxyethylamine (5.32 g.) in ether (20 ml.). During this addition a white precipitate was formed. The resulting suspension was stirred at 0° for a further hour, filtered and the filtrate evaporated to dryness under reduced pressure to give 2,2-diethoxyethylcyanamide (3.47 g.) as a colourless oily liquid having the following n.m.r. spectrum in CDC13: 1.24 (t, 6H); 3.1 (d, 2H); 3.65 (m, 4H); 4.0 (br s, 1H); 4.57 (t, 1H).
Reaction SMILES: [H][H].[C:3]1([CH:9]=[CH:10][CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C(C=Cc1ccccc1)=Cc1ccccc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: c1ccc(CCCCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In Example 4, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 1,4-diphenyl-1,3-butadiene as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 1,4-diphenyl-1,3-butadiene, and 1,4-diphenylbutane was obtained at about 100% yield (See FIG. 6.).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:25][CH2:26]Cl)[S:21]([CH3:24])(=[O:23])=[O:22].O>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:26][CH2:25][N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)N(CCCl)CCCl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 45.2 %

Procedure:
In a Schlenk tube, a solution of 5 g (20 mmol) of methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.3 g (20 mmol) of N,N-bis(2-chloroethyl)methanesulfonamide in 65 ml of N,N-diisopropylethylamine is heated at 127° C. with vigorous stirring for 18 h. After the addition of water, the product is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 3.3 g (46%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.Cl.O1CCOCC1.O>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)OCCNC2=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)OCCNC3=O)ncc1Cl
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of 8-amino-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.092 g, 0.0003 mol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (0.05 g, 0.00028 mol), 4 N HCl in dioxane/water (0.07 mL, 0.00028 mol) was heated at 100° C. for 4 hrs. The slurry was evaporated and the residue treated with ethyl acetate and a 10% sodium carbonate solution. The insoluble solid was collected, washed, dried to give 2-[5-chloro-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (0.09 g, 74%) as a yellow solid. MP: 293-5° C.; 1H-NMR (DMSO-d6) δ 11.62 (s, 1H), 9.74 (s, 1H), 8.72-6 (d, 1H), 8.70 (d, 1H) 8.29 (s, 1H) 8.11 (s, 1H), 7.77 (m, 2H), 7.51-3 (d, 2H), 7.33-5 (d, 1H), 7.15-9 (t, 1H), 4.27 (s, 1H); LC/MS (ESI+): 439 (M+H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CC(C)C>[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][N:19]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:18][CH2:17]1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: FC(F)(F)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCC(C(F)(F)F)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), 4-trifluoromethylpiperidine * HCl (97 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up. The crude product obtained in this way is purified by column chromatography; yield: 43 mg (28%), crystals;
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22]C)[C:14]([C:24]3[CH:28]=[CH:27]NN=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C([C:45](OC)=[O:46])=C(O)C(Br)=CC=2)(=O)=O)C=CC=CC=1.O1C=CC(B(O)O)=C1>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:22])[C:14]([C:24]3[CH:28]=[CH:27][O:46][CH:45]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cc[nH]n2)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 45, starting from methyl 6-(benzenesulphonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 115) and furan-3-yl boronic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:16]2[CH:17]=[C:12]([Cl:11])[N:13]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:15]=2)=[C:4]([F:10])[CH:3]=1
Reactant: CC(=O)Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(Cl)cc(Oc2cc(F)c(N)cc2F)n1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 4-amino-2,5-difluoro-phenol (3.5 g, 24 mmol), N-(4,6-dichloro-pyrimidin-2-yl)-acetamide (5.30 g, 24 mmol) and potassium carbonate (3.4 g, 24 mmol) in DMF (100 mL) was stirred at 50° C. under nitrogen overnight. After cooling to room temperature the reaction mixture was suspended in water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (15%-20% ethyl acetate in petroleum ether) to give N-[4-(4-amino-2,5-difluoro-phenoxy)-6-chloro-pyrimidin-2-yl]-acetamide (3.3 g, 44% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.20-7.24 (dd, J=11.2 Hz, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.64 (dd, J=12.0 Hz, J=8.4 Hz, 1H), 5.48 (s, 2H), 2.03 (s, 3H).