Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1.CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Reactant: Cc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CCCN[C@H]2CC[C@@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Reaction time: 48 h
Yield: 9.8 %

Procedure:
A mixture of cis and trans 4-(4-benzyloxy-phenyl)-cyclohexyl-amine (preparation see under example 43a, 1.25 g, 4.44 mmol), K2CO3 (1.23 g, 8.88 mmol), 1-(3-Bromo-propyl)-4-methyl-benzene (1.18 g, 4.44 mmol) and 2-butanone was stirred at 80° for 48 h. Water was then added and the products were extracted with EtOAc. The organic layer was dried (Na2SO4), evaporated and the residue was purified by chromatography (SiO2, CH2Cl2—MeOH—aq. NH3 140:10:1) to give cis-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-p-tolyl-propyl)-amine (180 mg; 10 %) as a light yellow solid (MS: m/e=414.4 (M+H+))and trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-p-tolyl-propyl)-amine (38 mg; 2%) as a light yellow solid (MS: m/e=414.4 (M+H+)).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]=[CH2:40]>>[CH2:38]([NH:37][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:36][CH:35]=1)[CH:39]=[CH2:40]
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: C=CCN
Product: C=CCNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 96.7 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: [F:1][C:2]1([S:5]([NH:8][C:9]([C@@:11]23[CH2:26][C@H:25]2[CH:24]=[CH:23][CH2:22][CH2:21][C@@H:20]([CH3:27])[CH2:19][C@@H:18]([CH3:28])[C@H:17]([NH:29]C(=O)OC(C)(C)C)[C:16](=[O:37])[N:15]2[CH2:38][C@H:39]([O:41][C:42]4[C:51]5[C:46](=[CH:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=5)[CH:45]=[CH:44][N:43]=4)[CH2:40][C@H:14]2[C:13](=[O:54])[NH:12]3)=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1.[ClH:55]>O1CCOCC1>[ClH:55].[NH2:29][C@@H:17]1[C:16](=[O:37])[N:15]2[CH2:38][C@H:39]([O:41][C:42]3[C:51]4[C:46](=[CH:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=4)[CH:45]=[CH:44][N:43]=3)[CH2:40][C@H:14]2[C:13](=[O:54])[NH:12][C@:11]2([C:9]([NH:8][S:5]([C:2]3([F:1])[CH2:4][CH2:3]3)(=[O:6])=[O:7])=[O:10])[CH2:26][C@H:25]2[CH:24]=[CH:23][CH2:22][CH2:21][C@@H:20]([CH3:27])[CH2:19][C@H:18]1[CH3:28]
Reactant: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(F)CC6)C[C@H]5C=CCC[C@@H](C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nccc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(F)CC6)C[C@H]5/C=C\CC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N4C3)nccc2c1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(F)CC6)C[C@H]5/C=C\CC[C@@H](C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(F)CC6)C[C@H]5C=CCC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N4C3)nccc2c1

Procedure:
A solution of tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-fluorocyclopropyl)sulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (30 mg, 0.039 mmol) in 4M HCl in dioxane (5 ml 4M solution) was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure to get crude compound (23 mg, 90%) as brown solid. The crude compound was washed with diethyl ether and taken to the next step without further purification. MS: MS m/z 772.8.0(M+−36).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:23][N:22]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: NO
Reactant: Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(C(CCC(=O)O)=NO)cc2)cc1
Yield: 90.5 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid (1.052 g, 0.003922 mol) was allowed to react with hydroxylamine hydrochloride (0.3245 g, 0.00467 mol) in the presence of sodium carbonate (0.498 g, 0.00470 mol) in absolute ethanol to give 1.006 g of 4-hydroxyimino-4-(4′-methyl-biphenyl-4-yl)-butyric acid as a white solid; mp 176.5-177.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:22].[C:23]([C:31]1[CH:32]=[C:33]([CH:37]([CH3:41])[C:38]([O-:40])=[O:39])[CH:34]=[CH:35][CH:36]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:40][C:38](=[O:39])[CH:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:32]=2)[CH3:41])=[O:7])=[CH:4][C:3]=1[Br:22]
Reactant: CCN(CC)Cc1cc(C(=O)OCCCCCl)cc(Br)c1N
Reactant: CC(C(=O)[O-])c1cccc(C(=O)c2ccccc2)c1
Agent: [Na+]
Product: CCN(CC)Cc1cc(C(=O)OCCCCOC(=O)C(C)c2cccc(C(=O)c3ccccc3)c2)cc(Br)c1N

Procedure:
This compound was prepared from 4-(4-amino-3-bromo-5-diethylaminomethyl-benzoyloxy)-n-butyl chloride and sodium 3-benzoyl-α-methyl-phenylacetate analogous to Example 8.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: COC(=O)COc1ccccc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 15.16 g of methyl (2-hydroxyphenoxy)acetate, 29.23 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]nitrobenzene, 11.5 g of anhydrous potassium carbonate, and 160 ml of N,N-dimethylformamide was stirred at room temperature for 30 minutes and then at 70° C. for 3 hours. Another 5 g of methyl (2-hydroxyphenoxy)acetate was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 17.8 g of methyl [2-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]-2-nitrophenoxy}phenoxy]acetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][C:22]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])([OH:25])[CH2:21][CH2:20]2)[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([C:26]([C:22]3([OH:25])[CH2:21][CH2:20][N:19]([C:17]4[CH:16]=[CH:15][N:14]=[C:13]([CH3:12])[N:18]=4)[CH2:24][CH2:23]3)=[O:27])[CH2:29][CH2:30]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1nccc(N2CCC(O)(C(=O)N3CCNCC3)CC2)n1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCC(O)(C(=O)N3CCN(C(=O)c4ccc(Br)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromobenzoylchloride (0.53 g) in dichloromethane (3 ml) was added to a mixture of 1-(2-methylpyrimidin-4-yl)-4-(piperazin-1-ylcarbonyl)piperidine-4-ol hydrochloride (0.65 g) and triethylamine (1.7 ml) in dichloromethane (30 ml) at 5° C. The solution was stirred at ambient temperature for 18 hours. The resulting solution was evaporated to dryness. The residue was dissolved in dichloromethane and the solution was washed with water, dried (Na2SO4) and evaporated to dryness. The residue was purified by flash column chromatography on alumina (ICN alumina N32-63), using 0.1-0.4% methanol in dichloromethane as eluent. Recrystallisation from ethyl acetate/isohexane gave 1-(4-bromobenzoyl)-4-[1-(2-methylpyrimidin-4-yl)-4-hydroxy-4-piperidylcarbonyl]piperazine, as a colourless solid (0.53 g), mp114-117° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)#[N:2].[OH:34]O.[OH-].[Na+]>CS(C)=O.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)(=[O:34])[NH2:2]
Reactant: OO
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C#N)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.34 mmol) in DMSO (1.6 mL) and EtOH (6.4 mL) was added H2O2 (1.2 mL, 40%), NaOH (0.4 mL, 1M) with stirring overnight at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (15 mL), adjusted pH to 7 with AcOH. The solids were collected by filtration to give 3-(6-carbamoyl-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a solid (131 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:20][C@H:21]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)=[N:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[OH:19])=[N:9]2)=[CH:4][CH:3]=1.[OH:33][C:34]1C=CC=[CH:36][C:35]=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([OH:19])=[C:12]([C:8]2[N:7]=[C:6]([NH:20][C@H:21]3[CH2:25][CH2:24][NH:23][CH2:22]3)[C:5]3[C:10](=[CH:11][C:2]([C:36]#[C:35][CH2:34][OH:33])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(F)ccc3O)nc3cc(Br)ccc23)C1
Product: OCC#Cc1ccc2c(N[C@H]3CCNC3)nc(-c3cc(F)ccc3O)nc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 59, replacing (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with (S)-tert-butyl 3-(7-bromo-2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[C:42]([C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1)#[N:43]>O1CCCC1.O>[C:42]([C:44]1[CH:45]=[C:46]([S:50]([N:15]2[C:11]([C:10]3[C:5]([C:3]#[N:4])=[N:6][CH:7]=[CH:8][CH:9]=3)=[C:12]([F:26])[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:14]2)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1)#[N:43]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 401 mg, 81%).
Reaction SMILES: COC1C2OCCC=2C=C2C=CC(OC=12)=O.[Cl:17][C:18]1[C:19](=[O:30])[C:20]([C:28]#[N:29])=[C:21]([C:26]#[N:27])[C:22](=[O:25])[C:23]=1[Cl:24].C1(C)C=CC=CC=1>ClC1C=CC=CC=1>[Cl:17][C:18]1[C:23]([Cl:24])=[C:22]([OH:25])[C:21]([C:26]#[N:27])=[C:20]([C:28]#[N:29])[C:19]=1[OH:30]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: COc1c2c(cc3ccc(=O)oc13)CCO2
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N

Procedure:
The 2,3-dihydroxanthotoxin thus obtained is then dehydrogenated. This advantageously is effected by heating the 2,3-dihydroxanthotoxin with 2,3-dichloro5,6-dicyano-1,4-benzoquinone in a substantially inert solvent, for example, toluene or chlorobenzene, advantageously at reflux, until substantial dehydrogenation is obtained. The 2,3-dichloro-5,6-dicyano-hydroquinone formed and any residual 2,3-dichloro-5,6-dicyano-1,4benzoquinone are removed and the product taken up in chloroform and recovered therefrom. If substantial amounts of the residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are present, it is desirable to convert this to the corresponding hydroquinone with sodium dithionite, dissolve the hydroquinone in aqueous sodium bicarbonate, and extract the sodium bicarbonate solution with chloroform to recover the 8-methoxypsoralen which can be recovered by drying over sodium sulphate and concentrating to dryness. The resulting product can then be recrystallized from benzene or any suitable inert solvent in which 8-methoxypsoralen has limited solubility. If there is little residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, the reaction mixture can be cooled and the precipitated hydroquinone filtered off and the reaction mixture, i.e., the filtrate, then extracted with chloroform. If desired, the filter cake can be extracted with benzene or like solvents such as chlorobenzene, toluene, and the like, for example, by refluxing the filter cake in the solvent and then adding the extract to the reaction mixture filtrate prior to the chloroform extraction. The chloroform solution is then washed successively with dilute sodium bisulfite solution, dilute sodium bicarbonate solution, and water and dried over sodium sulfate. The resulting chloroform solution is then concentrated by distillation until the product precipitates and an inert non-solvent such as hexane or like aliphatic or cycloaliphatic hydrocarbon is added to cause further precipitation of the product and the product is filtered. If desired, the product can be further purified by redissolving it in chloroform, or chloroform containing a minor amount of ethyl acetate, passing the solution over an alumina column concentrating the effluent until crystallization takes place, adding hexane or like solvent further to cause precipitation of the product, and filtering the solution.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)C(O)=O)([CH3:3])[CH3:2].NC1C=C(C=CN=1)[C:21]([O:23]CC)=[O:22].NC1C=CC(C(OC)=O)=CN=1>>[CH:1]([NH:4][C:5](=[O:16])[NH:6][C:7]1[CH:8]=[CH:9][C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]=1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: CC(C)NC(=O)Nc1cc(C(=O)O)ccn1
Agent: COC(=O)c1ccc(N)nc1
Product: CC(C)NC(=O)Nc1ccc(C(=O)O)cn1

Procedure:
This compound is prepared analogously to Intermediate Y by replacing ethyl 2-aminoisonicotinate in step 1 with methyl 6-aminonicotinate; [M+H]+ 224.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:33][CH3:34])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:33][CH3:34])=[N:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: COc1nc(C(F)(F)F)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.25 h
Yield: 101 %

Procedure:
6-Chloro-7-(4-(2-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (255 mg, 0.463 mmol) in 2:1 THF-MeOH (2 ml) was treated with 0.5 N sodium methoxide in methanol (926 μl, 0.463 mmol) at ambient temperature. After 15 minutes, the reaction was concentrated in vacuo. The material was suspended in ethyl acetate and concentrated to a solid. The solid was suspended in ethyl acetate, hexanes were added, and the mixture was concentrated in vacuo to a solid. The material was suspended in dichloromethane, hexanes were added, and the suspension concentrated to provide the desired compound (268 mg, 0.468 mmol, 101% yield) as a solid. MS (apci) m/z=551.0 (M-Na+2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[CH:5][CH:4]=[N:3]1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@H:30]([NH2:41])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C@H:30]([NH:41][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[N:9][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:17]3)=[O:20])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cn1nccc1Nc1cc2cc(C(=O)O)ccc2cn1
Reactant: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2NC(=O)c2ccc3cnc(Nc4ccnn4C)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.1 %

Procedure:
A 2-5 mL microwave vial equipped with a stirring bar was charged with 92 (94 mg, 0.3506 mmol, 1.1 equiv), (3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-amine (90 mg, 0.3187 mmol, 1.0 mmol, CASRN 114616-86-5), DMF (2.0 mL) and HATU (187.4 mg, 0.4780 mmol, 1.5 equiv). The reaction mixture was stirred 20 min at RT and treated with TEA (0.1347 mL, 0.956 mmol, 3.0 equiv). The microwave vial was capped, and the reaction was stirred for 2 h at RT. The DMF solution was partitioned between EtOAc and water (120 mL/40 mL). The EtOAc layer was washed twice with brine, dried, filtered, and concentrated to give a crude oil. A portion of the crude (20%) was purified by RP HPLC to give 3.5 mg of N-((3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-((1-methyl-1H-pyrazol-5-yl)amino)isoquinoline-6-carboxamide (purity=100%, 254 nM). The remainder of the crude (80%) was purified on a SiO2 column (ISCO) eluting with a MeOH/DCM gradient (2 to 8% MeOH) to afford an additional 48 mg (total 51.5 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (q, J=7.7 Hz, 4H), 7.26 (d, J=8.1 Hz, 3H), 6.92 (s, 1H), 6.86 (d, J=8.4, 2H), 6.23 (s, 1H), 4.49-4.43 (m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.62 (d, J=10.4 Hz, 1H), 3.43 (q, J=7.5 Hz, 1H), 3.04 (m, 2H), 2.60 (m, 2H). LCMS M+H+=534.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)COc1cccc(CCCO)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl [3-(3-hydroxypropyl)phenoxy]acetate (107.4 g) in DCM (1.07 L) was added TEA (113 mL) at ambient temperature. Methanesulfonyl chloride (45.4 mL) was added dropwise to the mixture at 0° C. The mixture was stirred for 1 hour at ambient temperature and water (1 L) was added to the mixture at the same temperature. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford ethyl (3-{3-[(methylsulfonyl)oxy]propyl}phenoxy)acetate (155.5 g) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].Cl(OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=O)(=O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Temperature: 100 °C

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, 1.56 parts of triphenylmethyl perchlorate and 30 parts of acetic anhydride was heated at 100° C for 30 minutes. After cooling, the reaction mixture was poured into sodium bicarbonate solution and the resulting mixture was washed with water, dried and the ether was evaporated to give an oil which was chromatographed on silica gel using a 1:1 mixture of chloroform and light petroleum (b.p. 40°-60° C) for elution. This yielded 0.14 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5° C (after crystallisation from light petroleum (b.p. 40°-60° C). This product was shown by spectral means to be the same as that prepared in Example 13.