Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][C:8]1(CO)[CH:14]=[CH:13][C:12]2[CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1>O1CCOCC1.O>[O:7]=[C:8]1[CH:14]=[CH:13][C:12]2[CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C=CC(O)(CO)CO2
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)C=CC(=O)CO2
Yield: 45 %

Procedure:
116 mg (0.54 mmol) of sodium periodate are added at ambient temperature in 4 equal portions, every quarter of an hour, to 135 mg (0.54 mmol) of methyl 3-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 45, in solution in 16 ml of a 3/1 dioxane/water mixture. After the usual treatments, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 25/75) to give 53 mg (45%) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate in the form of a white solid; M.p.=98° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25])(=[O:36])=[O:35]
Reactant: CCCc1c(O[C@@H]2CCCC[C@@H]2CO)ccc2c(C(F)(F)F)noc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(O[C@H]2CCCC[C@H]2COS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reaction time: 4 h

Procedure:
To a solution of 6-{[cis-2-(hydroxymethyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (388 mg, 1.09 mmol), from this Example step 3, in CH2Cl2 (11 mL) was added Et3N (0.230 ml, 1.635 mmol) at 0° C., followed by methanesulfonyl chloride (0.093 mL, 1.2 mmol). The reaction mixture was stirred from 0° C. to room temperature for four hours. The mixture was diluted with CH2Cl2, washed with 5% HCl, followed by H2O then NaHCO3. Organic extracts were dried over NaSO4 and filtered. The solvent was evaporated in vacuo to give title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:15][CH3:16])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].N1C=CC=CC=1>>[CH3:1][S:2]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([O:15][CH3:16])=[O:14])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
Methanesulfonyl chloride (3.4 mL, 44 mmol) was added to a solution of methyl anthranilate (5.0 mL, 39 mmol) in pyridine (10 mL, 124 mmol). Mixture stirred at room temperature for 16 hours. Reaction was quenched with 1N hydrochloric acid (150 mL). Mixture was extracted with ethyl acetate (2×200 mL). Organic layers were washed successively with 1N hydrochloric acid (2×100 mL) and brine (50 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was crystallized from 50 mL isopropyl alcohol. Solids were filtered, washed with isopropyl alcohol and dried in vacuo. Title compound was obtained as pink crystals in 75% yield. MS m/e (M−H)−=228.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.Cl>CO.[Zn]>[NH2:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: COC(=O)Cc1ccc(Cl)c(N)c1
Yield: 88.1 %

Procedure:
13.07 mmol (3.0 g) of methyl 4-chloro-3-nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust are refluxed in 500 ml of MeOH for 10 minutes. Then, 13 ml of concentrated HCl is added in drops under reflux and refluxed for another 30 minutes. The suspension is hot-filtered, the methanol is distilled off, and the residue is set at pH 14 with NaHCO3 solution. Extraction with ethyl acetate, drying with Na2SO4 and distillation of the solution yields 2.3 g of methyl 3-amino-4-chlorobenzeneacetate as a beige solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].[OH-].[NH4+]>S(=O)(=O)(O)O>[N+:13]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[NH2:8])([O-:15])=[O:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
20 g (112.9 mmol) 4-(trifluormethoxy)-aniline were dissolved in to 50ml conc. sulfuric acid and treated at −5° C. with a mixture of 24 ml conc. sulfuric acid and 6 ml nitric acid. After stirring the mixture at 0° C. for 3 h, the reaction mixture was poured on 1 L ice water and made alkaline with 200 ml conc. aqueous ammonium hydroxide. The resulting solution was extracted with ethyl acetate, the combined organic phases were dried and evaporated to dryness. The residue was purified by flash chromoatography (Silica gel, methylene chloride:methanol=98: 2) and subsequent recrystallization from methylenchoride/heptane. Yield: 14.8 g
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1.N1C=CC=CC=1.[O:20]=[O+][O-].NC(N)=S>C(Cl)Cl.CO>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][C:2](=[O:20])[CH3:1])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: C=C(C)Cc1ccc2c(c1)CCO2
Reactant: O=[O+][O-]
Agent: NC(N)=S
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 5-(2-methylallyl)-2,3-dihydrobenzofuran (58 grams, 0.333 mole) and pyridine (27 ml) in methylene chloride (450 ml) and methanol (150 ml) was cooled in a dry ice/acetone bath and a stream of ozone passed through for 1.0 hour. Thiourea (18 grams, 0.24 mole) was added and the mixture was warmed to room temperature. The resultant precipitate was filtered and the mother liquor evaporated to give an oil which was distilled under reduced pressure to give 1-(2,3-dihydrobenzofuran-5-yl)propan-2-one (32 grams, 54%), bp. 110° C. @ 120 mT.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.[CH2:27]([O:34][NH:35][C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[C:38](Cl)[N:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O1C2C=CC(N)=CC=2OCC1>>[CH2:27]([O:34][NH:35][C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[C:38]([NH:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)[N:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: CCOC(=O)c1cnc(Cl)nc1NOCc1ccccc1
Agent: Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)c1cnc(Nc2ccc3c(c2)OCCO3)nc1NOCc1ccccc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-benzyloxy-2-chloro-5-ethoxycarbonyl-4-pyrimidineamine and 1,4-benzodioxan-6-amine were reacted to yield N4-benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.49-7.44 (m, 3H), 7.39-7.34 (m, 4H), 7.30-7.22 (m, 1H), 6.67 (d, 1H, J=8.4 Hz), 4.98 (s, 2H), 4.23-4.17 (m, 6H), 1.26 (t, 3H, J=7.2 Hz); LCMS: ret. time: 26.14 min.; purity: 95%; MS (m/e): 423 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.072 g, 0.12 mmol) in dichloromethane (1.5 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the product as a white solid (0.007 g, 0.014 mmol, 12%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1 H), 7.66 (d, J=8.8 Hz, 1 H), 7.45 (d, J=1.6 Hz, 1 H), 7.14 (dd, J=1.6, 8.4 Hz, 1 H), 6.93 (d, J=8.4 Hz, 1 H), 6.85 (d, J=8.4 Hz, 1 H), 6.50 (d, J=2.0 Hz, 1 H), 5.89 (q, J=6.8 Hz, 1 H), 4.86-4.80 (m, 1 H), 4.56-4.85 (m, 1 H), 4.28-4.25 (m, 1 H), 3.99-3.94 (m, 1 H), 3.86-3.82 (m, 1 H), 3.73-3.70 (m, 1 H), 3.56-3.50 (m, 1 H), 3.44-3.31 (m, 2 H), 3.20-3.17 (m, 1H), 2.86-2.81 (m, 2 H), 2.71-2.66 (m, 1 H), 2.16-2.06 (m, 1 H), 1.96 (d, J=6.8 Hz, 3 H), 1.48-1.25 (m, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+486.2, found 486.4
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].B(F)(F)F.CCOCC.[OH-].[K+]>CCCCC.C(OCC)C.O.C(O)(=O)C>[C:1]12([CH:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)CC(C)=O
Agent: FB(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(C(C)=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
A stirred solution of 5.0 grams (0.033 mole) of adamantan-1-ol and 4.7 grams (0.036 mole) of ethyl acetoacetate in 60 mL of pentane was cooled to 7° C., and 5.1 grams (0.036 mole) of boron trifluoride etherate was added during a 2 minute period. An additional 3.8 mL of boron trifluoride etherate was then added, also during a 2 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for about 16 hours. After this time, the reaction mixture was again cooled to 7° C., and 24 grams of aqueous 50% potassium hydroxide was added. The reaction mixture was then made acidic with 12 mL of acetic acid. The reaction mixture was poured into a separatory funnel with 50 mL of water and 130 mL of diethyl ether. The mixture was shaken and the layers were separated. The water layer was washed with two portions of 30 mL each of toluene. The toluene washes were combined with the diethyl ether layer, and 100 mL of water was added to the combination. The mixture was filtered and the layers were separated. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 6.4 grams of ethyl 2-(adamant-1-yl)-3-oxobutanoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11]CC1C=CC([N+]([O-])=O)=CC=1)=[O:10])=[N+]=[N-].O1CCCC1.C(O)C.C(=O)(O)[O-].[Na+:40]>[Pd].O>[NH2:1][C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+:40]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=[N+]=[N-])C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(N)C[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of p-nitrobenzyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (75 mg, 0.2 mmol), tetrahydrofuran (14 ml), ethanol (14 ml), deionized water (11 ml) containing sodium bicarbonate (16.8 mg, 0.2 mmol), and 10% palladium on carbon (75 mg) is shaken under hydrogen (45 psi) at ambient temperature for 2 hours. The mixture is filtered through a celite pad to remove the catalyst which is washed with water. The combined filtrate and wash is extracted with three portions of diethyl ether, concentrated under vacuum to about 10 ml volume, and lyophilized to afford sodium (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=[O:10])[O:9][CH2:8][CH2:7][CH2:6]1>CO>[OH:2][CH2:1][CH2:3][NH:4][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][OH:10]
Reactant: O=C1CCCO1
Reactant: NCCO
Solvent: CO
Product: O=C(CCCO)NCCO

Procedure:
A solution of 24.4 gm (0.4 mole) of ethanolamine in 30 ml of methanol were slowly added dropwise with stirring to a solution of 34.4 gm (0.4 mole) of γ - butyrolactone in 50 ml of methanol. The temperature rose to 50° C. The mixture was subsequently heated for 3 hours at boiling and the methanol was distilled off under reduced pressure. A quantitative yield of N-(2-hydroxyethyl)-γ-hydroxybutyramide was obtained in the form of a colorless viscous liquid. The compound became crystalline after standing for a long period of time and melts at 54° to 56° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CCCCCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (1.08 g, 4.37 mmol) in 1,2,4-trichlorobenzene (20 ml) was stirred at 220° C. for 4 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 4 M hydrochloric acid (8 ml×3). The aqueous layer was neutralized with a 10 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (10 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1→1:2) to give 2-bromoimidazo[5,1-b]thiazole (744.8 mg, 84%) as a white solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH3:26])[C@@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[N+:2]=[N-:3].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOCC.C(OCC)(=O)C>[CH3:27][S:28]([O:9][CH2:8][C@@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:17])[C@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[C@@H:5]([CH3:26])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of tert-butyl (2R,3R,4S)-5-azido-3-(tert-butyldimethylsilyloxy)-1-hydroxy-4-methylpentan-2-ylcarbamate (1.0 equiv.) in pyridine (0.2 M) was added MsCl (1.3 equiv.) followed by DMAP (catalytic amount) at 0° C. The mixture was stirred at that temperature for 1 hour. The solution was diluted with ether and ethyl acetate (4:1), washed with aq. NaHSO4, sat. NaHCO3, brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:3) to give (2R,3R,4S)-5-azido-2-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsilyloxy)-4-methylpentyl methanesulfonate as the major isomer (5:2) in 90% yield. LC/MS=367.3 (M+H-Boc), Rt=0.81 min (Frac 65%-95% method).
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[C:14]([CH3:20])[CH:13]=1.CN(/[CH:24]=[C:25](/[C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33])\[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>C(O)C>[C:32]([C:31]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:20])[N:19]=[CH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(C)(C)C
Reactant: Cc1cc(Cl)ccc1NN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C)c1C(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
N-Ethyldiisopropylamine (1.553 mL, 8.97 mmol) was added to (4-chloro-2-methylphenyl)hydrazine hydrochloride (1.733 g, 8.97 mmol) and (Z)-ethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate (Intermediate#83) (2.04 g, 8.97 mmol) in ethanol (30 mL). The resulting solution was stirred at 90° C. for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with water (2×10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate (0.891 g, 30.9%) as a orange oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].Cl.CN.[CH2:35]([N:37](CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][NH:37][CH3:35])=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: CNCc1ccc2c(c1)cc(-c1cc(OC)c(O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 31.1 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.494 g, 1.17 mmol) was dissolved in acetonitrile (16.0 mL), and the solution was treated with methylamine hydrochloride (1.60 mL, 23.4 mmol), triethylamine (3.30 mL, 23.4 mmol), acetic acid (1.30 mL, 23.4 mmol) and sodium triacetoxyborohydride (0.744 g, 3.51 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(methylaminomethyl)indol-2-yl]isoindolinone (0.159 g, 31%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2.Cl.Cl.[CH3:16][N:17]1[CH2:23][C:22]2[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:26]=[N:27][C:21]=2[NH:20][C:19](=[O:33])[CH2:18]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)C.O>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[CH:7]2)[C:30](=[O:31])/[CH:29]=[CH:28]/[C:25]1[CH:26]=[N:27][C:21]2[NH:20][C:19](=[O:33])[CH2:18][N:17]([CH3:16])[CH2:23][C:22]=2[CH:24]=1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1ccc2c(ccn2C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3ccc4c(ccn4C)c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of (methyl-(1-methyl-1H-indol-5-ylmethyl)amine (103 mg, 0.6 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (160 mg, 0.5 mmol), HOBt (81 mg, 0.5 mmol) and diisopropylethylamine (0.41 mL, 2 mmol) in DMF (12 mL) was added EDC hydrochloride (114 mg, 0.6 mmol). The mixture was stirred overnight at room temperature. Water (75 mL) was added and the solution stirred for 1 hr. The precipitate was collected by filtration. The yellow solid was preabsorded onto silica gel and purified by column chromatography (95:5 CH2Cl2/MeOH) to give a yellow oil. Diethyl ether (100 mL) was added and the mixture was sonicated. The ether layer was decanted to afford (E)-N-methyl-N-(1-methylindol-5-ylmethyl)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (158 mg, 78%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (d, J=4.3 Hz, 1H), 8.51 (d, J=6.1 Hz, 1H), 8.13 (s, 1H), 7.59-7.25 (m, 5H), 7.09-7.02 (m, 1H), 6.37 (s 1H), 4.67-4.86 (2×s, 2H), 3.72-3.79 (m, 5H), 3.42-3.38 (m, 2H), 3.06-2.87 (2×s, 3H), 2.37-2.33 (2×s, 3H); ESI MS m/z 404 [C23H25N5O2+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:20])[C:8]2[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])[CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:20][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=1[O:18][CH3:19])(=[O:23])[CH3:22]
Reactant: COc1cc(C)c(OC)c(C)c1C(O)c1cccnc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C)c(OC)c(C)c1C(OC(C)=O)c1cccnc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture comprising 3.2 g of α-(3-pyridyl)-2,5-dimethoxy-4,6-dimethylbenzyl alcohol obtained by the method described in any of the Production Examples 1, 2 and 3, 5 ml of pyridine and 5 ml of acetic anhydride was heated and stirred at 80° C. for 1 hour. Then the pyridine and acetic anhydride were distilled off and the residue was purified by silica gel column chromatography. Thus 2.9 g of the title compound was obtained.