Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[S:8]1(=[O:25])[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:10]2=[N:9]1.[Cl:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>CN(C=O)C>[Cl:26][C:27]1[CH:34]=[C:33]([O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:17]3[C:10]4=[N:9][S:8](=[O:7])(=[O:25])[CH2:13][CH2:12][N:11]4[CH2:14][CH2:15][CH2:16]3)=[CH:19][CH:20]=2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: O=S1(=O)CCN2CCCC(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Potassium carbonate (73.9 mg) was added to a mixture of 4-(2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (50 mg) and 2-chloro-4-fluorobenzonitrile (41.6 mg) in DMF (dry) (1 mL). The mixture was stirred at 60° C. under atmosphere overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated. The residue was crystallized from MeCN-THF/IPE to give the title compound (32.2 mg) as colorless crystals.
Reaction SMILES: [OH-:1].[Mg+2:2].[OH-].[C:4](=[O:6])=[O:5]>O>[C:4](=[O:1])([OH:6])[O-:5].[Mg+2:2].[C:4](=[O:1])([OH:6])[O-:5]
Reactant: O=C=O
Reactant: [OH-]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])O

Procedure:
Magnesium chloride solution (5.0 mol/L, MgO 200 g/L) is added into 30% sodium hydroxide solution by Na/Mg molar ratio of 1 for a 25 minutes reaction at 20° C., to get magnesium hydroxide slurry which is then filtered to get magnesium hydroxide cake. The magnesium hydroxide cake is mixed with water at liquid to solid ratio of 30:1 (calculated by the weight of water and magnesia), and then carbon dioxide gas is introduced into it to carbonize continuously at 25° C. Aqueous solution of magnesium bicarbonate (MgO: 30 g/L, Fe: 0.3 ppm, Al: 0.4 ppm) is obtained after filtration.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:5]([OH:17])[CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[K+]>C(Cl)Cl.C(O)C.O>[CH2:1]([N:3]1[CH2:4][C@@H:5]([OH:17])[C@H:6]([N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:7]1)[CH3:2]
Reactant: CCN1C[C@@H](O)[C@H](NCCc2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCN1C[C@@H](O)[C@H](N(CCc2ccccc2)C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirring slurry of 3.5 g (0.15 mole) of trans-1-ethyl-4-[(2-phenylethyl)amino]-3-pyrrolidinol and 5 g potassium carbonate in 75 ml of methylene chloride at ice bath temperature was added dropwise a solution of 3.2 g (0.023 mole) of benzoyl chloride in 25 ml of methylene chloride. After addition was complete, the mixture was stirred at ambient temperature overnight. The mixture was filtered through Celite and the filtrate was concentrated to give a yellow gum as residue. An NMR analysis of this gum indicated that it was a mixture of desired amide and the di-substituted amide-ester. The gum was dissolved in 50 ml ethanol and a solution of 0.5 g (0.08 mole) potassium hydroxide in 10 ml of water was added. The mixture was heated at reflux for 3 hr. The solution was concentrated and water was added to the residue. The mixture was extracted with methylene chloride and the combined extracts were dried over anhydrous sodium sulfate and concentrated to give 4.9 g (98%) of gum as residue. The gum crystallized upon standing and the solid was recrystallized from cyclohexane to yield white solid, m.p. 71°-75° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.87 min; [M+H]+=408.12.
Reaction SMILES: [S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]1.[CH3:11]SC>>[CH3:11][CH:2]1[CH:3]([C:8]([OH:10])=[O:9])[C:4](=[O:7])[CH2:5][CH2:6][S:1]1
Reactant: O=C(O)C1CSC=CC1=O
Reactant: CSC
Product: CC1SCCC(=O)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of methyl cuprate in dimethylsulfide (prepared from 1.05 g copper (I) iodide/4.0 mL dimethylsulfide and 4.0 mL methyllithium/ether at −78° C.) at −78° C. was added a solution of 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.910 g, 4.6 mmol) in dimethylsulfide (5 mL). The resulting yellow-colored solution was stirred for 30 min. at the same temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride and ammonia solution and then warmed to room temperature for and 1 h. The reaction mixture was added to ether (100 mL) and the etheral layer washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the product purified by flash column chromatography on silica gel eluted with hexane:ether (4:1) to give 2-methyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.794 g) as a 7:3 mixture of enol : keto tautomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1.[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC.C(OCC)(=O)C>CN(C=O)C>[CH:19]([C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1)=[CH2:20]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(Br)cnn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 90.8 %

Procedure:
5-Bromo-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (2.0 g, 0.0066 mole), tributylvinyltin (2.3 g, 0.00726 mole) and Pd(PhCH2)Cl(Ph3P)2 (0.1 g, 0.000132 mole) were heated at 100° C. in DMF (75 mL) for 1 hour. The mixture was then poured into ethyl acetate and extracted 2×200 mL with aqueous KF, brine, dried (MgSO4), filtered through a pad of silica gel with ethyl acetate and evaporated in vacuo. The crude oil was purified by silica gel chromatography to give 5-ethenyl-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.62 g, 91% yield) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][CH2:16][OH:17])([CH3:14])[CH2:6][CH2:5]2.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][CH2:16][OH:17])([CH3:14])[CH2:6][CH2:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCO)O2
Reactant: BrCc1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2

Procedure:
Following the procedure described in Preparation 1, 2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)ethanol was reacted with benzyl bromide and treated and purified to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][C:13](=[O:15])[CH3:14])[C:4](=[O:16])[C:3]=1[NH:17][C:18]([C:20]12[CH2:27][CH:26]3[CH2:28][CH:22]([CH2:23][CH:24]1[CH2:25]3)[CH2:21]2)=O.[OH-].[Ca+2].[OH-].C(O)C.Cl>O>[O:15]=[C:13]([CH3:14])[CH2:12][N:5]1[C:4](=[O:16])[C:3]2[NH:17][C:18]([C:20]34[CH2:27][CH:26]5[CH2:28][CH:22]([CH2:23][CH:24]3[CH2:25]5)[CH2:21]4)=[N:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11]
Reactant: CCCn1c(N)c(NC(=O)C23CC4CC(CC2C4)C3)c(=O)n(CC(C)=O)c1=O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)n(CC(C)=O)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Yield: 53.9 %

Procedure:
A suspension of Compound B (1.70 g, 4.38 mmol) and calcium hydroxide (2.27 g, 30.7 mmol) in water (30 ml) -ethanol (22 ml) was refluxed under heating for 30 minutes. After cooling, the reaction solution was adjusted to pH 2 with concentrated hydrochloric acid, and then extracted three times with chloroform. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from acetone/water to give 874 mg (yield 54%) of Compound C as white plates.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1>[OH:8][C:7]1[C:2]2[NH:1][C:10](=[O:11])[O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(O)cccc1O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(O)cccc2o1

Procedure:
A mixture of 2-amino-benzene-1,3-diol (K-68, 2.03 g, 16.2 mmole) and 1,1′-carbonyldiimidazole (2.63 g, 16.2 mmole) in THF (200 ml) was refluxed over night. After removal of THF under vacuum, residue was dissolved in ethyl acetate and washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, solid was washed with ether to give 1.9 g of compound K-72. 1H-NMR (500 MHz, DMSO-d6).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][C:10]([C:11]([NH:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)OCC
Reaction time: 3 h
Yield: 95 %

Procedure:
4-Phenylbenzoyl chloride (4.3 g) was added little by little to a chloroform (80 mL) solution of diethyl aminopropanedioate hydrochloride (4.3 g) and TEA (8.4 mL) under ice cooling, and the mixture was stirred for 3 hours at the same temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by OH type silica gel column chromatography (chloroform/methanol=20/1) to obtain diethyl [(biphenyl-4-ylcarbonyl)amino]propanedioate (white solid) (6.7 g, 95%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[N+:58]([C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1)([O-:60])=[O:59]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:65](=[O:66])[C:64]3[CH:63]=[CH:62][C:61]([N+:58]([O-:60])=[O:59])=[CH:69][CH:68]=3)[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)c4ccc([N+](=O)[O-])cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the FR-900506 substance (30.5 mg) in pyridine (1 ml) was added p-nitrobenzoyl chloride (ca. 100 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate, water, 1N-hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride, successively, and then dried. The resulting solution was concentrated under reduced pressure, and the residue was purified on silica gel column chromatography to give 17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-12-[2-[4-(p-nitrobenzoyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (37.7 mg).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1)([F:4])[F:3].C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([NH2:23])=[O:16])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: O=C(O)C=Cc1ccc(SC(F)(F)F)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(SC(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.24 g (21.1 mmol) 3-(4-trifluoromethylsulfanyl-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethylformamide a solution of 2.70 ml (32.0 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 20 min. Stirring was continued at 0-5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 100 ml of a 25% aqueous ammonia solution. After evaporation of the organic solvent, 200 ml water were added and the solution cooled. The precipitated amide was collected, washed with water and dried at 40° C. in vacuo. Yield 4.62 g (89%) 3-(4-Trifluoromethylsulfanyl-phenyl)-acrylamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (1RS,2RS,3SR)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (60 mg, 0.15 mmol) in EtOH (0.5 ml) was added 6M KOH (0.14 ml, 0.84 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from EtOAc/hexanes. The title compound was obtained as an off-white crystalline solid (22 mg, 39%); m.p. 146°-149° C.
Reaction SMILES: O.Cl.C(N1CC(C2C=CC([Cl:37])=C(Cl)C=2)(CCN2CCC(O)(C3C=CC=CC=3)CC2)[O:13]CC1=O)C1C=CC=CC=1.[CH2:40]([N:47]1[CH2:52][C:51]([CH2:61][CH2:62]N2CCC(C3C=CC=CC=3)(O)CC2)([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=2)[O:50][CH2:49][C:48]1=[O:76])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.[C:78]1([C:84]2([C:90]([N:92]3[CH2:96][CH2:95][CH2:94][CH2:93]3)=[O:91])[CH2:89][CH2:88][NH:87][CH2:86][CH2:85]2)[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:13].[ClH:37].[CH2:40]([N:47]1[CH2:52][C:51]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=2)([CH2:61][CH2:62][N:87]2[CH2:88][CH2:89][C:84]([C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([C:90]([N:92]3[CH2:96][CH2:95][CH2:94][CH2:93]3)=[O:91])[CH2:85][CH2:86]2)[O:50][CH2:49][C:48]1=[O:76])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C1COC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Reactant: O=C(N1CCCC1)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1COC(CCN2CCC(C(=O)N3CCCC3)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of 0.98 g of the compound obtained in step B of EXAMPLE 14, 0.645 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine and 0.69 g of K2CO3 in 3 ml of DMF is heated at 80° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and extracted with an AcOEt/ether mixture, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/2; v/v) as the eluent. The product obtained is dissolved in the minimum amount of DCM and acidified to pH 1 by the addition of a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.42 g of the expected product. M.p.=155-178° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].C([O:46][C:47](=[O:55])[CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(C)(C)C>>[CH2:35]([O:34][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:52]4[CH2:51][CH2:50][N:49]([CH2:48][C:47]([OH:46])=[O:55])[CH2:54][CH2:53]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:31][CH2:32][CH3:33])=[O:37])[CH3:36]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 251 using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester. MS (ES+): m/z 722.28 (100) [MH+]; HPLC: tR=0.80 min (UPLC, purity).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:34])[N:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:26])=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:26])=[O:34])=[CH:11][N:10]=1
Reactant: COc1cc2c(CC(=O)N(C)Cc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(CC(=O)N(C)Cc3ccccc3)cnc(CN)c2cc1OC
Yield: 66 %

Procedure:
As described in Example 1, 60 mg of {4-[(benzyl-methyl-carbamoyl)-methyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 31 mg (66%) of 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-N-benzyl-N-methyl-acetamide hydrochloride. MS: APCI (M+H) calc'd for C22H25N3O3+H 380.5; found 380.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:25]1[C:26]([OH:34])=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:25]1[C:26]([OH:34])=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)OCC3)c2c(Cl)cccc2N1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (9.25 g, 19.1 mmol) in dichloromethane (25 mL) was added triethylsilane (10 mL). The mixture was cooled to 0° C. followed by the addition of trifluoroacetic acid (10 mL) slowly over 5 min. The resultant mixture was stirred at ambient temperature for 5 h and concentrated in vacuo to dryness. The residue was triturated in diethyl ether (25 mL) in a Branson ultrasonic bench top water bath to afford 4-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (8.90 g, quantitative) as a beige solid: MS (ES+) m/z 468.0 (M+1), 470.0 (M+1).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].C(OOC(C)(C)C)(C)(C)C>>[C:12]1([CH:10]([CH3:11])[O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1ccccc1
Reactant: CCCCCCCCO
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCCCCOC(C)c1ccccc1
Temperature: 90 °C
Yield: 52 %

Procedure:
Into a pressure vessel 1-octanol (160 μL, 1 mmol, 1 eq) was added and diluted with ethylbenzene (1.225 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing ethylbenzene under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials. 1H NMR Yield: 52%.