Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28](=[O:31])[N:27]([CH3:32])[N:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28](=[O:31])[N:27]([CH3:32])[N:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cn1nc(O)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)ccc1=O
Temperature: 160 °C
Yield: 39 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 3-hydroxy-1-methylpyridazin-6(1H)-one (Oakwood Products, Inc., West Columbia, S.C., USA; 24 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (25 mg, 39%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.04 (m, 2H), 2.20-2.36 (m, 2H), 2.92-3.05 (m, 2H), 3.76 (s, 3H), 4.26-4.40 (m, 2H), 4.90-5.02 (m, 1H), 7.07 (d, 1H, J=9.7 Hz), 7.24 (d, 1H, J=9.7 Hz), 8.17 (s, 1H), 8.51 (s, 1H). Mass spectrum (ES) MH+=428. HRMS Calcd. for C20H26N7O4 (MH+): 428.2041. Found: 428.2040.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([C:17](OC)=[O:18])=[CH:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:11]1.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([CH2:17][OH:18])=[CH:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:11]1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CCc2ccccc2Cl)c1=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2cc(CO)c(=O)n(CCc3ccccc3Cl)n2)ccc1F
Reaction time: 0.17 h
Yield: 11 %

Procedure:
To a solution of 2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one (480 mg, 1.20 mmol) in THF/methanol (2 mL/1 mL), cerium(III) chloride hexahydrate (425 mg, 1.20 mmol) was added at −15° C., followed by the addition of sodium borohydride (45 mg, 1.20 mmol). After stirred for 10 minutes, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. Further, the concentrate was purified by column chromatography on silica gel [hexane/ethyl acetate (2/1)] to yield the title compound as a pale yellow syrupy substance (yield: 11.0%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29]C(=O)OC(C)(C)C.CO[Si](C)(C)C>CN1C(=O)CCC1>[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[NH:29][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1OC
Agent: CO[Si](C)(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1OC
Temperature: 150 °C
Yield: 35.5 %

Procedure:
To 6-chloro-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (500 mg, 1.6 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (692 mg, 3.2 mmol) in NMP (1.5 mL), methoxy trimethylsilane (0.5 mL, 3.6 mmol) was added and the mixture heated to 150° C. for 65 h. The mixture was concentrated under high vacuum to obtain a sticky crude mass that was purified by chromatography (silica, 100-200 mesh, 1-10% methanol in dichloromethane) to give 6-((1R,2S)-2-amino-cyclohexylamino)-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (220 mg 35%) as a yellow solid. LC-MS 388 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([C:18](=[O:21])[CH2:19]Cl)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:10]2[C:15](=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[CH2:19][C:18]1=[O:21]
Reactant: CCc1ccc(N(C(=O)CCl)c2c(C)cccc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc2c(c1)CC(=O)N2c1c(C)cccc1Cl
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
In a flask are mixed N-(2′-chloro-6′-methylphenyl)-N-chloroacetyl-4-ethylaniline (2.08 g) are mixed with aluminum trichloride (1.16 g) and the mixture is flushed with nitrogen. The flask is introduced into an oil bath (155-160° C.) and the mixture is stirred under a stream of nitrogen for 4.5 hours. The mixture is slightly cooled to about 100° C., treated with toluene (30 ml) and 1N HCl (20 ml) and stirred for 30 minutes while the temperature decreases gradually. After phase separation, the organic phase is washed with 1N HCl and water, dried (magnesium sulfate) and evaporated. The residue is chromatographed on silica (86 g) using toluene containing 5-20% isopropyl acetate as eluent affording the title product.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:30])[F:31]
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 4-chloro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.077 g) as a light yellow gum (0.084 g). MS (ESI−): 472.8 ([M−H]−)
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH2:32]([NH2:34])[CH3:33]>CO>[CH2:32]([NH:34][CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[CH3:33]
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CCN
Solvent: CO
Product: CCNCCN1C(=O)N2C(c3cccc(O)c3)c3[nH]c4ccc(OC)cc4c3CC2(C)C1=O

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and a 2 M solution of ethyl amine in methanol as starting materials.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:27][C:28]([F:31])([F:30])[F:29]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][C:28]([F:31])([F:30])[F:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCC(F)(F)F)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.7 mmol) and 2-iodo-1,1,1-trifluoroethane (0.07 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (20 mg, yield 12%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=O.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([NH:20][C:19]1[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=1)=[O:14]
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(O)ccc2ccccc12
Yield: 30.2 %

Procedure:
Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[C:33]2[C:28](=[CH:29][C:30](O)=[CH:31][CH:32]=2)[CH:27]=[C:26]([NH:35][C:36]2[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=2)[N:25]=1.C(N(CC)CC)C>ClCCl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[C:24]([C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[F:16])=[N:25][C:26]([NH:35][C:36]1[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=1)=[CH:27]2)(=[O:8])=[O:9]
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (204.4 mg) in 5 mL of dichloromethane was added to the mixture of 1-(2,4-difluoro-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (170 mg, 0.48 mmol) and triethylamine (145.4 mg) in 20 mL of dichloromethane by syringe at 0° C. The solution was stirred at room temperature overnight, and was diluted with dichloromethane (20 mL). The organic layer was washed with 10% hydrochloric acid, sodium bicarbonate, saturated sodium chloride, and evaporated to give an oil which was used for the next reaction without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]([C:30]4([CH:57]([OH:59])[CH3:58])[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:38]5[CH2:43][CH2:42][N:41]([C:44]6[CH:49]=[CH:48][C:47]([C:50]7[N:55]=[CH:54][CH:53]=[CH:52][N:51]=7)=[CH:46][N:45]=6)[CH2:40][CH:39]5[CH3:56])=[O:37])[CH2:31]4)=[O:29])[CH:25]=3)[N:20]([C:60]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]([C:30]4([C:57](=[O:59])[CH3:58])[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:38]5[CH2:43][CH2:42][N:41]([C:44]6[CH:49]=[CH:48][C:47]([C:50]7[N:51]=[CH:52][CH:53]=[CH:54][N:55]=7)=[CH:46][N:45]=6)[CH2:40][CH:39]5[CH3:56])=[O:37])[CH2:31]4)=[O:29])[CH:25]=3)[N:20]([C:60]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)[N:19]=2)=[CH:14][CH:13]=1
Reactant: CC1CN(c2ccc(-c3ncccn3)cn2)CCN1C(=O)CN1CCC(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)(C(C)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Added DMSO (200 mg, 2.56 mmol) to a solution of oxalyl chloride (180 mg, 1.40 mmol) in MeCl2 (10 ml) at −78° C., then stirred at −78° C. for 1 hour. Added 3-(1-Hydroxy-ethyl)-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (9N) in MeCl2 (5 ml) at −78° C. then stirred at −78° C. for 2 hours. Triethylamine (200 mg, 1.96 mmol) was added, the solution allowed warm to room temperature then stirred overnight. Added water (50 ml) and MeCl2 (150 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding 10N as a solid (600 mg, 66%) ESMS (MH, 904)
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([NH:22][NH2:23])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: NN
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 25 °C

Procedure:
Alternatively, to a suspension of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (4.55 g) in ethanol (50 mL) was added hydrazine monohydrate (5 mL) and the reaction heated at reflux for 16 h. After cooling to room temperature, the solid was filtered, washed with diethyl ether and air-dried to give 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid hydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][C:7]=2[CH:6]=[C:5]2[CH:12]=[CH:13][C:14]([O:16][C:4]=12)=[O:15].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:16][C:14]([CH:13]=[CH:12][C:5]=2[CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12)=[O:15]
Reactant: COc1c2c(cc3ccc(=O)oc13)CCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1c2occc2cc2ccc(=O)oc12
Yield: 70 %

Procedure:
A reaction mixture of 218 g of 2,3-dihydroxanthotoxin of Part E, 281 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and 3 liters of toluene was stirred and heated at reflux for 20 hours. The mixture was cooled and poured into 10 liters of 10 percent sodium hydroxide solution containing 5 percent sodium dithionite. The solution was then extracted twice with about 2 liters of chloroform. The combined chloroform extracts were washed with water and dried over sodium sulphate and concentrated to dryness. There was obtained 150 g (70 percent yield), of crude 8-methoxypsoralen which on crystallization from benzene was obtained as white crystals melting at 138°-140° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(CCN1CCCCC1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNCCN1CCCCC1

Procedure:
A solution of the title compound of Step 11 (1 85 g, 7.96 mmol) and 20% Pd(OH)2 on carbon in EtOH (50 mL) was placed under a hydrogen atmosphere (60 psi) at room temperature for 17 hours. The mixture was filtered and concentrated to give the title compound as a clear, yellow liquid (1.02 g, 90% crude yield). The proton spectral data were consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH:10]([NH2:30])[C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2[C:13](=[CH:14][C:15]([Cl:29])=[CH:16][CH:17]=2)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:41]1([CH3:49])[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH:10]([C:11]1[N:20]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:19](=[O:28])[C:18]2[C:13](=[CH:14][C:15]([Cl:29])=[CH:16][CH:17]=2)[N:12]=1)[NH:30][CH2:49][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(CCNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Formula 107 where R1, R2, R4, R6, R7, R8 and R9 are H: R3 is Chloro; R5 is Benzyl; and R10 is p-Methyl-benzyl: To a solution of [3-amino-3-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamic acid tert-butyl ester (700 mg, 1.58 mmol) and DIEA (275 μL, 2.37 mmol) in 50 mL of DCM was added p-tolualdehyde (188 μL, 1.58 mmol). The mixture was stirred for 1 hour, after which sodium triacetoxyborohydride (500 mg, 2.37 mmol) was added. After stirring an additional 3 hours, the mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate. The solvents were evaporated to dryness and the residue was purified by flash silica gel chromatography (stepwise gradient 1:4, 1:2, 1:1, 2:1, 4:1 with ethyl acetate:hexanes as eluent) to give the corresponding, pure compound of Formula 107, [3-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-3-(4-methyl-benzylamino)-propyl]-carbamic acid tert-butyl ester (760 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[ClH:12].N([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]3[N:32]=[CH:31][NH:30][C:28]3=2)[N:23]=[C:22]([CH3:33])[CH:21]=1)C1C=CC=CC=1>C(O)C>[ClH:12].[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]4[N:32]=[CH:31][NH:30][C:28]4=3)[N:23]=[C:22]([CH3:33])[CH:21]=2)=[CH:7][CH:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccc(N)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: CCC(=O)c1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1
Reaction time: 8 h

Procedure:
A mixture containing 14.9 g. (0.1 m) of p-aminopropiophenone 21.7 g. (0.1 m.) of the compound of Example I, C. and 500 ml. of ethanol was refluxed with stirring overnight. It was then concentrated in vacuo to give 34 g. m.p. 287°-289°, complete 320°C. The crude product was recrystallized from 1000 ml. of MeOH to yield 27 g.m.p. softens 318°, melts 328°-330°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17](F)[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH2:27])[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
To the crude 2-(3,5-Difluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester (62 g, 0.42 mol) was added 700 mL of 2M ammonia in methanol in a pressure bottle. The vessel was sealed and heated to 85° C. for 18 hours. The reaction mixture was cooled and the vessel opened carefully and the methanol solution concentrated to provide 140 g of crude material. LCMS [M+Na]-393; 1H NMR (500 MHz, DMSO) δ 6.76 (dd, J=10.8 2.8 Hz, 1H), 6.29 (dd, J=10.8, 2.8 Hz, 1H), 4.99 (brs, 2H), 4.80 (s, 1H), 1.40 (m, 18H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:6]([NH:8][CH:9]1[CH2:12][N:11]([CH3:13])[CH2:10]1)=[O:7]>[Pd].CO.C1COCC1>[NH2:17][C:16]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH:9]2[CH2:10][N:11]([CH3:13])[CH2:12]2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)NC2CN(C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 3-methoxy-N-(1-methylazetidin-3-yl)-4-nitrobenzamide (1 equiv) and 10% palladium on carbon was stirred in a mixture of MeOH/THF under a hydrogen atmosphere. The mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the desired product (99% yield) as a white solid. MS (ESI) m/z 236.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1)[CH3:2].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH2:22]([N:14]1[C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][S:17][C:13]1=[N:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:1][CH3:2])[CH:23]([CH3:25])[CH3:24]
Reactant: CCc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: CC(C)CBr
Product: CCc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC(C)C

Procedure:
2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[OH:27][C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:6]=1[O:5][CH2:4][C@@H:2]1[CH2:3][O:1]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 20.6 %

Procedure:
A solution of 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.183 g, 0.76 mmol) in 20 mL dry methylene chloride was treated with 0.258 g of 56-86% m-chloroperbenzoic acid. The reaction was stirred at ambient temperature for 45 minutes. The reaction mixture was partitioned with saturated sodium bicarbonate (sat'd NaHCO3) The organic phase was dried (Na2SO4) and concentrated to a dark red oil. Purification by flash chromatography eluting with methylene chloride (CH2Cl2), afforded 0.040 g of the title compound.
Reaction SMILES: B(C1C=CC(CCCC(O)=O)=CC=1)(O)O.CC1(C)C[O:21][B:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][O:31][C:32](=[O:42])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=3)=[CH:25][CH:24]=2)[O:19]C1.[OH-].[Na+]>>[C:40]([C:36]1[CH:35]=[C:34]([NH:33][C:32]([O:31][CH2:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([B:20]([OH:19])[OH:21])=[CH:28][CH:27]=2)=[O:42])[CH:39]=[CH:38][CH:37]=1)#[N:41]
Reactant: CC1(C)COB(c2ccc(CCOC(=O)Nc3cccc(C#N)c3)cc2)OC1
Agent: O=C(O)CCCc1ccc(B(O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cccc(NC(=O)OCCc2ccc(B(O)O)cc2)c1
Yield: 47.7 %

Procedure:
Using a procedure analogous to that used to prepare 2B, 11B (434 mg, 1.15 mmol) was reacted with NaOH to give 11C (170 mg, 48%) as a solid. 1H NMR (400 MHz, THF-d8) δ 2.98 (t, J=7.03 Hz, 2 H), 4.38 (t, J=6.81 Hz, 2 H), 7.10 (s, 2 H), 7.22 (d, J=7.91 Hz, 1 H), 7.30 (d, J=7.47 Hz, 1 H), 7.39 (t, J=7.91 Hz, 1 H), 7.68 (d, J=8.35 Hz, 1 H), 7.73 (d, J=8.35 Hz, 2 H), 7.87 (s, 1 H), 9.11 (s, 1 H).