Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH2:28][CH2:29][O:30][CH2:31][CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(COC)OC>[O:30]1[CH2:29][CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=2)[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:32][CH2:31]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccn1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(C2=CCOCC2)cc1NCc1ccccn1

Procedure:
5-bromo-2-nitro-N-(pyridin-2-ylmethyl)aniline E-1.9″ (145 mg; 0.47 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (145 mg; 0.69 mmol), cesium carbonate (300 mg; 0.90 mmol) and [1,1′-Bis[diphenylphosphino]-ferrocene]dichloropalladium (30 mg; 0.04 mmol) are suspended in 2.5 ml dimethoxyethane and 0.8 ml water and heated for 1 h at 100° C. The solvent of the reaction mixture is removed under reduced pressure and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9](=[NH:12])[O:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N[OH:15].N>CN(C)C=O>[OH:15][N:12]=[C:9]([O:10][CH3:11])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=N)Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: COC(Cc1ccccc1)=NO
Yield: 84.8 %

Procedure:
Methyl phenylacetimidate hydrochloride (30.9 grams; 0.167 mole) was stirred with solid hydroxylamine hydrochloride (12.8 grams; 0.184 mole) in dimethyl formamide (120 ml) while ammonia gas was added slowly without cooling. Ammonia addition (approximately 5 grams) was stopped when the temperature of the mixture peaked at 40° C. and dropped to 29° C. The slurry was then cooled in an ice bath and filtered. The filtrate (131 grams) was analyzed by GC and GC-mass spectroscopy and established to contain methyl N-hydroxyphenylacetimidate (23.4 grams; 84.8% yield).
Reaction SMILES: C([O:5][C:6]([CH2:8][S:9][C:10]1[N:11]=[C:12]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=3)[CH:27]=[CH:26][N:13]2[C:14](=[O:25])[C:15]=1/[CH:16]=[CH:17]/[C:18]([O:20]C(C)(C)C)=[O:19])=[O:7])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][S:9][C:10]1[N:11]=[C:12]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=3)[CH:27]=[CH:26][N:13]2[C:14](=[O:25])[C:15]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])([OH:7])=[O:5]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(SCC(=O)OC(C)(C)C)nc3c2)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(SCC(=O)O)nc3c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.2 %

Procedure:
The tert-butyl (E)-3-{2-(tert-butoxycarbonylmethylthio)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (19 mg) obtained in (B) was dissolved in methylene chloride (2 ml), added with triethylsilane (0.5 ml) and trifluoroacetic acid (0.5 ml), and then the mixture was stirred at room temperature for 5 hours. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (4 mg) as yellow powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
N-Acetylethylenediamine (10.2 g, 100 mmol) and triethylamine (15 ml, 10.9 g, 108 mmol) were dissolved in dichloromethane (300 ml) and the solution cooled to 0° C. Methanesulphonyl chloride (8 ml, 11.8 g, 103 mmol) was dissolved in dichloromethane (10 ml) and added dropwise, and stirring was continued at 0° C. for 3 hours. The dichloromethane was removed in vacuo, and the residue was suspended in a mixture of ether and acetone, removing the insoluble material by filtration. The filtrate was concentrated in vacuo to give the title compound as a pale brown gum (14.5 g, 88.3 mmol, 88%); δH [2H6]DMSO 7.93 (1H,br t), 7.05 (1H,t), 3.11 (2H,t), 2.97 (2H,t), 2.89 (3H,s), 2.09 (3H,s).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][C:9](=[O:22])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]O)=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:7][O:8][C:9](/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])=[CH:16][CH:17]=1)=[O:22]
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)/C=C/c1ccc(OCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCOc1ccc(/C=C/C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.56 g (30 mmol) of methacrylic acid in 10 ml of THF were slowly added dropwise to a solution of 6 g (27 mmol) of (E)-3-[4-[2-hydroxyethoxy]phenyl]acrylic acid methyl ester, 5.85 g (28.3 mmol) of N,N′-dicyclohexylcarbodiimide (DCC) and 0.37 g (3 mmol) of 4-dimethylamino-pyridine in 80 ml of tetrahydrofuran (THF). The batch was stirred at room temperature overnight. In order to complete the reaction there were added firstly a further 1.46 g (7.1 mmol) of DCC and, after stirring for one hour, a further 0.5 g (5.9 mmol) of methacrylic acid. The batch was stirred for a further 24 hours, filtered and the filtrate was extracted 3 times each time with 200 ml of 5% acetic acid and 200 ml of water. The ether phase was dried over Na2SO4, evaporated and the residue was recrystallized from cyclohexane. Subsequently, the still slightly impure product was filtered over a thin silica gel layer (eluent:diethyl ether/hexane=1:1). This gave 8.3 g of 2-methylacrylic acid 2-[4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]ethyl ester as a white powder with a melting point of 81-82° C. and an absorption maximum of λmax. (in CH2Cl2)=306.5 nm (ε=23675 l/mmol cm).
Reaction SMILES: [CH3:1][NH2:2].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O.[BH4-].[Na+]>C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][NH:2][CH3:1])=[CH:5][C:4]=1[OH:3]
Reactant: COc1ccc(C=O)cc1O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1ccc(OC)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Methylamine (40% aqueous solution, 2.2 mL, 25 mmol) is added to a solution of 3-hydroxy-4-methoxybenzaldehyde (3.0 g, 20 mmol) in ethanol (35 mL). The resulting slurry is stirred for 30 minutes at room temperature. Then the solvents were evaporated under reduced pressure. The resulting solid is dissolved in methanol (300 mL) and sodium borohydride (0.90 g, 24 mmol) is added. The reaction mixture is stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue is partitioned between saturated aqueous potassium carbonate solution and ethyl acetate. The aqueous phase is extracted 3× with ethyl acetate, and the combined extracted were concentrated under reduced pressure to give 2-methoxy-5-methylaminomethyl-phenol as a granular white solid (2.5 g, 75%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23]C)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[CH3:22][O:21][C:19]1[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=[C:17]([OH:23])[N:18]=1
Reactant: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(OC)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(NC2CCNCC2)nc(O)n1

Procedure:
A solution of 4-(2,6-dimethoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.71 g, 2.10 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 225.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:48]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 200 mg (1 mmole) of lauric acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 202 mg (Yield: 43%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([O:13][S:14](C1CC1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[CH3:2][C:3]1([S:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:15])=[O:16])[CH2:5][CH2:4]1
Reactant: O=S(=O)(OCc1ccccc1)C1CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(S(=O)(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (0.78 g, 12.25 mmol) was added drop-wise at −78° C. to a solution of Benzylcyclopropane sulfonate (2.0 g, 11.2 mmol) in THF (20 mL) and continued stirring at the same temperature for 10 min. CH3I (3.98 g, 28.0 mmol) was added at −78° C., allowed the reaction to warm to 0° C. with stirring for 30 min. The reaction mixture was quenched with ice cold water, diluted with ethylacetate (100 mL), organic layer collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (using silica gel and 4% ethyl acetate in Hexane as eluent) to afford benzyl 1-methylcyclopropane-1-sulfonate (Int-25). 1H NMR (300 MHz, CD3OD) δ ppm 4.2-4.1 (2H, t), 1.7-1.6 (2H, m), 1.4 (3H, s), 1.5-1.3 (2H, m), 1.3-1.2 (2H, m), 1.0-0.9 (2H, m), 0.9 (3H, t).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)CCN2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the indoline product of Example 42 (110 mg, 0.420 mmol) and acetic acid (0.1 mL) in methanol (4 mL), 37% aqueous formaldehyde (0.04 mL, 0.5 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 1 h, and then sodium cyanoborohydride (66 mg, 1.05 mmol) was added in portions at room temperature. The mixture was stirred at room temperature under nitrogen for 3 h and then quenched with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/methanol, 10:1) to afford the N-methyl indoline product, Example 41, as a white solid (92 mg, 80%): mp 88-90° C.; 1H NMR (500 MHz, CDCl3) δ7.17-7.28 (m, 5H), 6.59 (d, J=8.0 Hz, 1H), 6.26 (d, J=8.0 Hz, 1H), 4.17 (dd, J=8.5, 5.4 Hz, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.43 (d, J=15.0 Hz, 1H), 3.31 (m, 2H), 2.96 (dd, J=11.3, 5.4 Hz, 1H), 2.82 (m, 2H), 2.70 (s, 3H), 2.54 (dd, J=11.3, 8.5 Hz, 1H), 2.42 (s, 3H); CI MS m/z=279 [C19H22N2+H]+; IR (KBr) 3020, 2940, 2773, 1610, 1487 cm−1; Anal. Calcd for C19H22N2-0.1 H2O: C, 81.45; H, 7.99; N, 10.00. Found: C, 81.21; H, 8.00; N, 9.74.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[N:13][C:12]=23)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[CH:7][CH:6]=2)=[C:12]2[N:13]=[C:14]([CH3:23])[N:15]([CH2:18][C:19]([F:20])([F:22])[F:21])[C:16](=[O:17])[C:11]2=[N:10]1
Reactant: Cc1nc2c(-c3ccc(Br)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc2c(-c3ccc(C#N)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 200 °C

Procedure:
A mixture of 3-(4-bromophenyl)-2-(2-chlorophenyl)-5-methyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (4A-9, 109 mg, 0.23 mmol), Zn(CN)2 (29 mg, 0.25 mmol), Pd(PPh3)4 (6.8 mg, 5.9 μmol) in DMF (2.5 ml) was heated in a microwave apparatus (Emrys Optimizer, Personal Chemistry) at 200° C. for 10 minutes. The reaction mixture was quenched with saturated aqueous NaCl, filtered, and extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated under vacuum. The crude residue was purified on a Chromatotron using 1 mm plates and a solvent gradient of 33% EtOAc/hexanes to 50% EtOAc/hexanes to give the desired product, 4-[2-(2-chlorophenyl)-5-methyl-7-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-3-yl]-benzonitrile (5A-1), as an amorphous solid (145 mg): MS (m/z) 444.4 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.63–7.53 (m, 5H), 7.52–7.42 (m, 3H), 5.00–4.80 (br m, 2H), 2.66 (s, 3H).
Reaction SMILES: [C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([O:17]C)=O)[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH3:19].ClCCl.CO>CO>[C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([NH2:19])=[O:17])[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: N
Reactant: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 8 h

Procedure:
A solution of 168 g (521 mmol) of the methyl ester, VI, in 2.0 l of methanol was cooled to approximately 10° and treated with anhydrous ammonia gas for eight hours. The solution was allowed to stand at room temperature overnight. The TLC (SiO2, dichloromethane-methanol, 5:1) indicated complete conversion to the desired product. A very small amount of a red solid was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was recrystallized from 2-propanol and dried at 40° under 0.5 atmospheres to give 136 g (84.9%) of the product, mp 128-130 (lit. (see below) mp 131°-133°).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1.C[O:18][B:19](OC)[O:20]C.Cl>C1COCC1>[O:15]=[C:13]1[NH:12][C:11]2[CH:16]=[C:7]([B:19]([OH:20])[OH:18])[CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(B(O)O)ccc2o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Add n-BuLi (1.6M in hexanes, 8.76 mL, 14.02 mmol) portionwise (exotherm) to a solution of 5-bromo-3H-benzooxazol-2-one (1.00 g, 4.67 mmol) in dry THF (28 mL) at −78° C. under N2. Stir at −40° C. for 1 h and add trimethylborate (1.94 g, 18.68 mmol) at once. Warm up to room temperature overnight. Add 1N aqueous HCl (50 mL) and stir for 3 h at room temperature. Extract into ethyl acetate, dry (MgSO4) and concentrate organics to a brown solid. Triturate with hexanes/toluene and collect 766 mg (92%) of the title compound as a brown powder. MS (ES) 179 (M+H), 177 (M−H); HPLC shows 80% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:32][C:33](=[O:35])[CH3:34])=[CH:24][CH:23]=1.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[C:16]([O:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([NH:32][C:33](=[O:35])[CH3:34])=[CH:24][CH:23]=3)[CH:17]=[N:18][CH:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(=O)Nc1ccc(O)c2ccccc12
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(Nc2cncc(Oc3ccc(NC(C)=O)c4ccccc34)n2)cc(OC)c1OC
Yield: 6.7 %

Procedure:
Using Method X, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and N-(4-hydroxynaphthalen-1-yl)acetamide (CJS 704), using an identical workup and chromatography using a mixture of ethyl acetate and dichloromethane (7:3) furnished 31 mg of the title compound. Yield: 6.7%. 1H NMR (250 MHz, DMSO-d6) δ 2.21 (s, 3H), 3.20 (s, 9H), 3.48 (s, 3H), 6.61 (s, 2H), 7.31 (d, 1H, J=8.2 Hz), 7.59 (t, 2H, J=7.6 Hz), 7.70 (d, 1H, J=8.3 Hz), 7.91 (s, 1H), 7.96-7.99 (m, 2H), 8.13 (d, 1H, J=7.8 Hz), 9.49 (s, 1H), 9.93 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ 23.44, 55.10, 59.95, 95.38, 116.77, 120.89, 121.48, 121.61, 123.18, 126.38, 126.53, 127.11, 128.23, 128.71, 130.90, 131.98, 136.18, 146.44, 150.64, 152.59, 158.26, 168.93. m/z [(M+H)+ calcd for C25H24N4O5 460.2].
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[CH:22]3)[C:16]([CH2:29][CH3:30])=[C:15]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:43]=[C:44]=O)(=O)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:44]#[N:43])[C:16]([CH2:29][CH3:30])=[C:15]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCc1c(-c2ccc3c(ccn3C)c2)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Solvent: CN(C)C=O
Product: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Yield: 79.1 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-5-ethyl-6-(1-methyl-1H-indol-5-yl)nicotinate (880 mg, 1.74 mmol) in DMF (10 mL) was added chlorosulfonyl isocyanate (0.18 mL, 2.07 mmol, 1.2 eq) at 0° C. The reaction was monitored by LC-MS and starting material was completely consumed within 5 min. The reaction was quenched with water then extracted by CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4 and then concentrated to give a crude product which was purified by trituration with hexanes and CH2Cl2 to afford the title compound (732 mg, 79%).
Reaction SMILES: [C:1]([O:4][CH:5]([O:16][C:17](=[O:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9](S(Cl)(=O)=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C1(C)C=CC=C([S:26]([Cl:29])(=[O:28])=[O:27])C=1>>[C:17]([O:16][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([S:26]([Cl:29])(=[O:28])=[O:27])[CH:11]=1)(=[O:19])[CH3:18]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(=O)OC(OC(C)=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)OC(OC(C)=O)c1cccc(S(=O)(=O)Cl)c1

Procedure:
The same procedure was followed as for the preparation of compound 35 starting with m-toluenesulfonyl chloride (36). 1H NMR (CDCl3, 200 MHz): δ 8.19 (m, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.65 (m, 1H), 2.16 (s, 6H)
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[SH:14])[C:7]([O:9][CH3:10])=[O:8].Br[CH2:16][C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]2([CH3:32])[CH3:31])=[CH2:18].Cl>CN(C=O)C.C(OCC)C>[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[S:14][CH2:18][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1)=[CH2:16])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(S)c(I)c1
Reactant: C=C(CBr)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(CSc1ccc(C(=O)OC)cc1I)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.33 h

Procedure:
75% NaH (115 mg, 3.58 mmol) is added to a solution of methyl 3-Iodo-4-mercaptobenzoate (531 mg, 3.25 mmol) in DMF (20 ml) at 0° C. Stirring is continued for 20 min at ambient temperature, then a solution of 6-(1-bromomethylvinyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (1 g, 3.25 mmol) in DMF (5 ml) is added dropwise. The mixture is stirred for 2 h at ambient temperature, and treated with an aqueous hydrochloric acid solution and ethyl ether. The organic phase is washed twice with water, dried over magnesium sulphate, and concentrated in vacuo at 40° C. in a rotary evaporator. The product is purified by flash chromatography on a silica column (CH2Cl2 50% heptane 50%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30]([C:33]1[CH:34]=[C:35]([CH:39]([CH3:43])[CH2:40][CH:41]=O)[CH:36]=[CH:37][CH:38]=1)([CH3:32])[CH3:31].CC(O)=O>C1COCC1>[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH2:40][CH:41]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)[CH3:43])[CH:34]=1)([CH3:32])[CH3:31]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C=CCC(C)c2cccc(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Potassium t-butylat (17.1 mL, 17.1 mmol, 1.0 equiv., 1M in THF) was added to a solution of (4-methoxyphenyl)methyltriphenylphosphonium bromide (7.90 g, 17.1 mmol, 1.0 equiv.) in THF (17 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 10 min, 3-(3-isopropylphenyl)butanal (3.24 g, 17.1 mmol, 1.0 equiv.) in THF (8.5 mL) was added, and the mixture was stirred at 25° C. 12 h. After addition of 20% aq. AcOH-solution at 25° C., the aqueous layer was extracted with hexane. The combined organic phases were washed with MeOH/H2O (4:1; 2-3x), dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5→99:1) to yield 4.03 g (80%) of the title compound as a light yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:8]=2[N:9]([CH3:11])[N:10]=1)=[O:5].[OH-:19].[Na+]>CCO>[CH3:11][N:9]1[C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:7]=2[C:6]([C:4]([OH:5])=[O:19])=[N:10]1
Reactant: CON(C)C(=O)c1nn(C)c2c1CCCCC2=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cn1nc(C(=O)O)c2c1C(=O)CCCC2

Procedure:
To a solution of N-methoxy-N,1-dimethyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide (14 mg, 0.055 mmol) in EtOH (1 mL), a solution of NaOH (2M, 55 μL) was added. The reaction was stirred under reflux for 1 h, the solvent was removed under vacuum, then DCM (5 mL) was added and the organic phase was washed with HCl 25% (3×5 mL). The aqueous phase was back-extracted with DCM (5 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated under vacuum to give 11 mg of a white solid (quantitative yield).