Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([O:12][CH3:13])[C:5]=1[NH2:14].[CH:16](OCC)(OCC)[O:17][CH2:18][CH3:19]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([O:12][CH3:13])[C:5]=1[N:14]=[CH:16][O:17][CH2:18][CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1c(Cl)cc(Cl)c(OC)c1N
Product: CCOC=Nc1c(OC)c(Cl)cc(Cl)c1C(=O)OC
Temperature: 25 °C

Procedure:
A solution of the 2-amino-4,6-dichloro-3-methoxybenzoic acid methyl ester (2-3) (6.35 g, 25.4 mmol) and triethyl orthoformate (60 mL, 361 mmol) was heated under reflux for 5 days. The solution was cooled to room temperature and evaporated under reduced pressure to afford the imidate, 4,6-dichloro-2-ethoxymethyleneamino-3-methoxybenzoic acid methyl ester (5-2), and starting material (7.80 g) as a brown oil; 5-2:2-3-9:1.
Reaction SMILES: C(OC(O[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:8]=[CH2:9])=O)C.C([Mg]Br)(C)C.[I:21]I.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.O1CCCC1.C(OCC)C>[I:21][C:8](/[CH:7]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH2:9]
Reactant: C=C=C(CCCCCC)OC(=O)OCC
Reactant: II
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(I)/C=C/CCCCC
Temperature: -50 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To an ethyl ether solution (12 ml) containing 3-[(ethoxycarbonyl)oxy]-1,2-nonadiene (424 mg, 2.0 mmol) and tetraisopropoxytitanium (0.89 ml, 3.0 mmol) was added at −78° C. an ethyl ether solution containing isopropylmagnesium bromide (6.0 mmol). The reaction liquid was heated to −50° C. over 30 minutes and stirred for 1 hour. The reaction liquid was given dropwise a tetrahydrofuran solution (4 ml) containing iodine (761 mg, 3.0 mmol). After heating to 0° C. over 1.5 hours, the reaction liquid was given 3N hydrochloric acid (4 ml) and separated into layers. The organic layer was washed with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, dried with anhydrous magnesium sulfate, and freed of solvent by vacuum distillation. The residues were purified by silica gel chromatography. There was obtained 385 mg of (E)-2-iodo-1,3-nonadiene as an iodinated compound (yield: 77%).
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[CH:9]=1>CCOCC.[Cl-].[NH4+].[Cu](I)I>[CH3:3][C:4]1([CH3:1])[CH2:9][C:8](=[O:10])[CH2:7][CH2:6][CH:5]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1CCC(=O)C=C1C
Reactant: [Li]C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C1CCC(=O)CC1(C)C
Temperature: -20 °C
Reaction time: 5 h

Procedure:
Copper iodide (121.8 g, 639.54 mmol) was suspended in Et2O (800 mL). Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at −40° C. over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 319.88 mmol) in Et2O (400 mL) was added at −40° C. over 2 minutes. The resulting solution was stirred 5 hours at −20° C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with EtOAc (3×2 L). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (1:20 EtOAc/petroleum ether). Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate was obtained as a yellow oil. MS ESI calcd. for C10H17O3 [M+H]+ 185. found 185. 1H NMR (600 MHz, CDCl3) δ 3.49 (s, 3H), 2.43-2.40 (m, 1H), 2.35-2.29 (m, 1H), 2.21-2.17 (m, 1H), 2.11-2.04 (m, 1H), 2.00-1.96 (m, 1H), 1.91-1.85 (m, 1H), 0.85 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]3[CH2:25][O:24]3)[CH:16]=2)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][NH:27]1>CCO>[CH:1]1([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][N:27]3[CH2:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:26]3)[CH:16]=2)[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(OCC2CO2)c1)C1CCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(OCC(O)CN2Cc3ccccc3C2)c1)C1CCCC1
Temperature: 110 °C
Yield: 55 %

Procedure:
To a solution of tert-butyl cyclopentyl(3-(oxiran-2-ylmethoxy)benzyl)carbamate (300 mg, 0.86 mmol) in EtOH (5 mL) was added isoindoline (113 mg, 0.95 mmol). The reaction mixture was heated under microwave conditions at 110° C. for 0.8 h. The mixture was concentrated and the crude product was used in the next step without further purification. (220 mg, yield 55%) MS (ESI+) e/z: 467.3 [M+1]+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:3]1[OH:19].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[Si:25]([O:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH:3]1[OH:19])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O)C1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O[Si](C)(C)C(C)(C)C)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
4,5-Dihydroxy-6-(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (287 mg) was dissolved in 10 ml of methylene chloride, and 200 mg of imidazole and 226 mg of tert-butyldimethylsilyl chloride were added under ice cooling, followed by stirring the mixture overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 265 mg of 4,6-bis(tert-butyldimethylsilyloxy)-5-hydroxy-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 66%).
Reaction SMILES: [N-]=[C:2]=[O:3].[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:7])[CH:5]=[CH2:6]>C1(C)C=CC=CC=1>[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:7])[CH:5]=[CH2:6].[C:4]([O:8][CH2:9][CH2:2][OH:3])(=[O:7])[CH:5]=[CH2:6]
Reactant: [N-]=C=O
Agent: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCO

Procedure:
An isocyanate derived cross-linking agent (Collonate L manufactured by NIPPON POLYURETHANE INDUSTRY CO., LTD.) 1 part was added to a polymer 100 parts (converted from a solid content 40% of toluene solution) that comprises a copolymer obtained by copolymerizing butyl acrylate 100 parts, acrylonitrile 5 parts, and acrylic acid 5 parts, and mixed to prepare an adhesive. The adhesive was applied using an applicator on a polyester film (50 micrometers) so that a thickness of the adhesive layer after dried is 10 micrometers, and then dried for 3 minutes by the hot-air dryer at 130 degrees C. to obtain a desired carrier sheet.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([N:8]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)=O)[CH3:2].C([O-])(=O)C.[NH4+:31]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:31]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)N(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Yield: 8.8 %

Procedure:
1.2 g N-(4-fluoro-phenyl)-N-(2-(4-fluoro-phenyl)-2-oxo-ethyl)-malonamic acid ethyl ester and 1.8 g ammonium acetate in 20 mL concentrated acetic acid were refluxed 4 h. The reaction was evaporated. Water was added to the residue and the mixture was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by chromatography on silica (100% dichlormethane) to yield 100 mg of the desired compound. Rt: 1.39 min (method B), (M+H)+: 343
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:9]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:35][N:33]([CH3:34])[C:32]([C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:37])=[O:3])[CH:12]=[CH:11][C:10]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:36]
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)c1cc(CCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
3-{3-Dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}propionic acid ethyl ester (0.843 g) was dissolved in ethanol (4 mL), and 4N aqueous sodium hydroxide (1 mL) was added thereto. The mixture was stirred at room temperature for 2 hours, concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and concentrated to give the title compound (0.740 g) as a colorless solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:10])([C:7](=[O:9])[CH3:8])[CH2:5][OH:6].S(OC)(O[CH3:15])(=O)=O>O>[CH3:3][C:4]([CH3:10])([C:7](=[O:9])[CH3:8])[CH2:5][O:6][CH3:15]
Reactant: CC(=O)C(C)(C)CO
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(C)(C)C(C)=O
Temperature: 40 °C
Reaction time: 15 h

Procedure:
80 g (2 moles) of sodium hydroxide, dissolved in 100 ml of water, were added dropwise to 174 g (1.5 moles) of 2,2-dimethyl-1-hydroxy-butan-3-one (for the preparation, see Example 2a) and 150 ml (2 moles) of dimethyl sulphate at 40° C. (exothermic, slight cooling). After the addition, the mixture was subsequently stirred at 40° C. for 15 hours and the 2,2-dimethyl-1-methoxy-butan-3-one formed was distilled by means of steam. The aqueous phase was saturated with sodium chloride and the oily constituent was separated off and rectified under reduced pressure. 123.8 g (63% of theory) of 2,2-dimethyl-1-methoxy-butan-3-one of boiling point 48°-62° C./5-8 mm Hg were obtained.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][S:7]([C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([C:23]3[CH:24]=[C:25]([CH2:29][CH:30]([C:37]4[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=4)[C:31](N(OC)C)=[O:32])[CH:26]=[CH:27][CH:28]=3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)([CH3:12])[CH3:11])(=[O:9])=[O:8]>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:31](=[O:32])[CH:30]([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]3[CH:22]=[C:13]([C:10]([S:7]([CH3:6])(=[O:9])=[O:8])([CH3:12])[CH3:11])[CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(CC(C(=O)C3CC3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous CeCl3 (266 mg, 1.26 mmol) was heated 2 h at 130° C. under high vacuum, refluxed in THF (10 mL) for 1 h then cooled to 0° C. To the resulting white suspension at 0° C. was added freshly prepared cyclopropylmagnesium bromide (0.6M, THF, 2.11 mL, 1.25 mmol) and the resulting mixture stirred at 0° C. for 1 h then cooled to −78° C. The 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-N-methoxy-N-methyl-propionamide from Step 1 (in THF, 150 mg, 0.25 mmol) was added and the mixture warmed to 0° C. for 1 h, diluted with ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:4) provided the 1-cyclopropyl-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one compound as a white foam.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[OH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:43]3[CH:44]=[CH:45][C:40]([CH2:39][OH:38])=[CH:41][CH:42]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1)([CH3:34])([CH3:36])[CH3:35]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(CO)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Yield: 26.4 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.097 mmol), [4-(hydroxymethyl)phenyl]boronic acid (30 mg, 0.20 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg, 0.01 mmol), and 2M Na2CO3 aq. (0.097 mL, 0.20 mmol) in DMF (1.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water (×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:2) to afford the desired product (15 mg, 26%) as a pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.17 (dd, J=8.0 Hz and 1.1 Hz, 1H), 8.01 (d, J=4.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.31 (td, J=7.4 Hz and 1.7 Hz, 1H), 7.28-7.24 (m, 2H), 7.16-7.13 (m, 3H), 6.95 (d, J=7.4 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 6.60 (dd, J=8.0 Hz and 5.2 Hz, 1H), 6.24 (s, 1H), 5.11 (br s, 1H), 4.68 (d, J=5.7 Hz, 2H), 3.49 (d, J=5.7 Hz, 1H), 2.57-2.51 (m, 4H), 2.19-2.10 (m, 1H), 1.94-1.85 (m, 1H), 1.39 (br s, 9H). LCMS: 586 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][C:19]=4[NH:24][C:25](=[O:27])[CH3:26])[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)Nc1cccc2c1CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC(=O)Nc1cccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][C@@H:14]1[CH2:13][CH:12]=[CH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.C(=O)=O.CO.[Na]>O1CCCC1.[Cl-].[NH4+]>[C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:17][NH:16][CH2:15][C@@H:14]1[CH2:13][CH:12]=[CH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@]12CC=CC[C@H]1CN(C(=O)OCc1ccccc1)C2
Agent: N
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@]12CC=CC[C@H]1CNC2
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
A solution of (1S,6S)-1-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azabicyclo[4.3.0]non-3-ene (400 mg, 1.07 mmol) in tetrahydrofuran (5.35 mL) was bubbled with ammonia gas under cooling with dry ice-methanol for 10 minutes to add 30 to 40 mL of liquid ammonia to the solution. Sodium (128 mg, 5.34 mmol) was added, and the mixture was stirred for 10 minutes. A saturated ammonium chloride solution (15 drops) was added at room temperature, and the mixture was stirred at room temperature to evaporate ammonia. A 1 mol/L sodium hydroxide solution (15.0 mL) was added, followed by extraction with chloroform (30 mL×2). The aqueous layer was concentrated under reduced pressure. A 1 mol/L sodium hydroxide solution (5.0 mL) was added, followed by extraction with the lower layer of chloroform/methanol/water=7/3/1 (35 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure to give 136 mg of the title compound as a white amorphous.
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccc(C#N)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2ccc(C#N)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution (10 mL) of 2-[cyclohexyl(hydroxy)methyl]-3-methyl-1-benzofuran-5-carbonitrile (922 mg) synthesized above in toluene was added thionyl chloride (374 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (868 mg, 88%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[Cl:11]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.CCCCCCC>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[Cl:11]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COc1cc(Cl)cc(Br)c1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: COc1cc(Cl)c(Cl)c(Br)c1
Yield: 197.3 %

Procedure:
1-Bromo-3-chloro-5-methoxybenzene (Preparation 16, 6.0 g, 27 mmol) and trichloroisocyanuric acid (2.3 g, 9.9 mmol) were stirred in dimethylformamide (100 ml) at 50° C. for 3 hours. n-Heptane was added and the mixture filtered to remove insoluble impurities. The mixture was then concentrated in vacuo and the residue purified by silica gel column chromatography, eluting with n-heptane:ethyl acetate 9:1, to afford the title product as a white solid (5.0 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1cc(S(=O)(=O)NCCCCO)ccc1Br
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1cc(S(=O)(=O)NCCCCO)ccc1-c1ccc(F)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-3-methylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-fluorophenyl boronic acid were reacted to give the title compound as a thick oil. δC (CDCl3, 62.9 MHz): 20.6, 26.4, 29.6, 43.1, 62.2, 115.4 (d, J 21.5), 124.5, 128.8, 130.5, 130.6, 136.1 (d, J 2.9), 136.9, 138.6, 145.3 and 162.4 (d, J 247.1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5[N:34]=[C:35]([CH3:38])[N:36]([OH:37])[C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5[N:34]=[C:35]([CH3:38])[N:36]([OH:37])[C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1nc2c(n1O)CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(n1O)CCc1nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc1-2
Reaction time: 0.01 h
Yield: 124.6 %

Procedure:
tert-butyl(1-(4-(3-hydroxy-2-methyl-8-phenyl-4,5-dihydro-3H-imidazo[4,5-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (10 mg, 0.019 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried to give the desired product as a pale brown solid (10 mg, 80% yield). 1H-NMR (500 MHz, CD3OD) δ 7.92 (1H, s), 7.48 (2H, d), 7.43 (2H, d), 7.30-7.34 (3H, m), 7.22-7.26 (2H, m), 3.42 (2H, t), 3.18 (2H, t), 2.72-2.81 (2H, m), 2.63 (3H, s), 2.54-2.64 (2H, m), 2.18-2.29 (1H, m), 1.91-2.02 (1H, m). LCMS (Method A) RT=3.14 min, M+H+=423.12.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-])=O.C([O-])=O.[NH4+].CN(C)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>CO.O1CCCC1.[Pd].O>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([NH:1][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: CN(C)C
Agent: O=C[O-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
5-nitroindoline (100 mg, 0.61 mmol) was dissolved in methanol (2 ml) and tetrahydrofuran (2 ml). Ammonium formate (192mg, 3.05 mmol, 5 equivalent) and palladium/carbon (10%) in a catalytic amount were added at room temperature and refluxed at 40° C. for ten minutes. After completing the reaction, the reacting solution was filtrated through celite and concentrated under reduced pressure. Afterward, water (5 ml) was added to the residue, extracted consecutively 4 times with ethyl acetate (10 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then dried completely under a high-degree vacuum. The obtained compound, namely (2,3-dihydro-1H-indole-5-yl)-amine, was dissolved in dichloromethane (5 ml). Then, trimethylamine (0.063 ml, 0.45 mmol) was added to be cooled to −20° C. and mesyl chloride (0.035 ml, 0.45 mmol) was added to be stirred for 30 minutes at the same temperature. Water (5 ml) was added to separate dichloromethane solution, dried over anhydrous magnesium sulfate, purified through a flash column chromatography (an eluent: ethyl acetate/n-hexane=2/1, v/v) and then triturated with isooctane. As a result, the present compound (60 mg, productive yield 47%) was obtained as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 2.00 (s, 3H), 3.15 (t, J=8 Hz, 2H), 3.95 (t, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 1H), 7.45-7.60 (m, 4H), 7.80 (s, 1H), 7.95 (d, J=8 Hz, 1H).