Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:15][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:10]([N:12]([CH3:13])[CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)C(=O)N(O)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CN(C)C(=O)N(OC(=O)Oc1ccccc1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3,3-dimethylurea (12.5 grams; 0.05 mol) in isopropyl alcohol (40 ml), and pyridine (6 ml) are charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl chloroformate (7.8 grams; 0.05 mol) is added to the flask, with stirring, at a temperature of about 10° to 15°C. After the addition is completed, the reaction mixture is stirred for an additional period of about one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture is poured onto ice and the precipitate is recovered by filtration and is dried. The dried precipitate is recrystallized to yield 1-(3,4-dichlorophenyl)-1-phenoxycarbonyloxy-3,3-dimethylurea.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][NH:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[C:19]=[O:20]>C(Cl)Cl>[NH:7]([C:8]1[N:9]=[CH:10][C:11]2[CH2:17][N:16]([C:19]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:15][CH2:14][C:12]=2[N:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2ncc3c(n2)CCNC3)cc1
Reactant: O=C=Nc1cccnc1
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CCc2nc(Nc3ccccc3)ncc2C1

Procedure:
A solution of N-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 6 (75 mg, 0.33 mmol), 3-isocyanatopyridine (41.8 mg, 0.35 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature for 1 hour. After 1 hour the reaction mixture was diluted with CH2Cl2 and washed with sat. aqueous NaHCO3(aq). The organic phase was collected, dried and concentrated. The residue was dissolved in CH2Cl2 and washed with 3% aqueous LiCl solution and water. The organic phase was collected, dried and concentrated to give the title compound (45.9 mg).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][S:25][CH:26]([C:30](O)=[O:31])[C:27](O)=[O:28]>>[OH:31][C:30]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:27](=[O:28])[C:26]=1[S:25][CH2:24][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(SCc1ccc2ccccc2c1)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1SCc1ccc2ccccc2c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.475 g, 2.46 mmol) and dimethyl ester of [(2-naphthalenylmethyl)thio]propanedioic acid (0.500 g, 1.64 mmol). m.p. dec>250° C.; 1H NMR (250 MHz, DMSO-d6) δ4.06 (s, 2 H), 6.47 (s, 1 H), 7.46 (m, 6 H), 7.78 (m, 6 H).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[C@@H:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C@@H:5]([OH:28])[CH2:4][CH2:3]2.C1(=O)CCCCC1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[CH3:1][C@@:2]12[CH:11]3[CH2:12][C@@H:13]([OH:27])[C@:14]4([CH3:26])[C@@H:18]([C:19]5[CH2:24][O:23][C:21](=[O:22])[CH:20]=5)[CH2:17][CH2:16][C@:15]4([OH:25])[CH:10]3[CH2:9][CH2:8][C@@H:7]1[CH2:6][C:5](=[O:28])[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: C[C@]12[C@H](O)CC3C(CC[C@@H]4CC(=O)CC[C@]34C)[C@@]1(O)CC[C@@H]2C1=CC(=O)OC1
Yield: 189.5 %

Procedure:
A mixture of 488 mg digoxigenin, 7.5 ml toluene, 3.75 ml cyclohexanone, and 550 mg aluminum isopropoxide was heated under reflux for 2.3 hours and then concentrated in vacuo to half of its original volume. Two hundred μl water was added and the mixture was evaporated in vacuo to dryness. The powdery solid was dried in vacuo over overnight. The dry residue was stirred in 25 ml methanol and the resulting mixture was filtered. The residue on the funnel was washed with 25 ml methanol. The filtrate and washing were combined and evaporated in vacuo affording 920 mg white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/[CH:11]=O)=[CH:4][CH:3]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1.CCOC(C)=O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C/C=N/Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 17.1 %

Procedure:
Crude (E)-2-(2-(4-fluorophenyl)hydrazono)acetaldehyde (0.97 g, 5.8 mmol) is dissolved in EtOH (50 mL), and diethyl malonate (0.93 g, 5.8 mmol) and piperidine (0.2 mL, 2.0 mmol) are added. The mixture is heated at reflux overnight. The reaction mixture is then cooled and concentrated. The residue is diluted with water and extracted with EtOAc twice. The combined organic extracts are dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel, eluting with PE:EtOAc (from 3:1 to 1:1), to afford title compound (0.26 g, 17% yield of two steps) MS (m/z): 263 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>CCOCC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)=[O:22]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccc(Cl)c(Cl)c3)c3ccccc23)CC1
Temperature: 100 °C
Yield: 57 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of 3,4-dichlorobenzoyl chloride was heated at 100° C. in a steam bath for 4 hrs. After the reaction mixture cooled to ambient temperature, ether was added and the salt was collected. The salt was mixed with water and ammonium hydroxide solution was added until the mixture was basic. The mixture was warmed on the steam bath for about 5 mins, cooled and extracted with dichloromethane. Evaporation of the dichloromethane in vacuo provided the free base. The base was recrystallized from methanol-trichloromethane (with concentration of the mother liquor) to yield 3.0 g (57%) of product, mp 187-189° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([NH2:9])[O:6][N:5]=2)[CH2:3][CH2:2]1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH:1]1([C:4]2[N:8]=[C:7]([NH:9][C:24]([CH:22]3[C:23]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[O:15][C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:25])[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Nc1nc(C2CC2)no1
Product: O=C(Nc1nc(C2CC2)no1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 275° C. and MS: m/e=333 (M+) was prepared in accordance with the general method of example 44a from 3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine and 9H-xanthene-carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:18][C:19]1[N:20]=[C:21]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[C:6]4[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:9][N:8]=3)[CH2:15][CH2:14]2)[N:22]=[CH:23][CH:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc2c(N3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(N3CCN(c4nccc(Cl)n4)CC3)noc2c1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole (1.0 g), 4,6-dichloropyrimidine (0.64 g) and sodium bicarbonate (1.08 g) were refluxed in absolute ethanol under N2 for 90 minutes. TLC (silica gel 2/1 acetone/heptane) showed no presence of starting material. The reaction was allowed to cool to room temperature, partitioned between CH2Cl2 and water, extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo to afford 1.44 g of material. The material was further purified through recrystallization from CH2Cl2 /pet. ether to yield the product 1.1 g, m.p. 203°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:21]#[N:22].ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[NH2:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[C:45]#[N:46]>ClCCl.O>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][O:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:27]([NH:41][C:42]3[CH:49]=[CH:48][CH:47]=[C:44]([C:45]#[N:46])[CH:43]=3)=[O:33])=[C:3]([C:21]#[N:22])[CH:4]=2)[CH2:9]1)=[O:15])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(C#N)c2)C1
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3cccc(C#N)c3)c(C#N)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-amino-3-cyanophenyl)morpholine-4-carboxylate (70 mg, example 28b) in dichloromethane (2 ml) was added triphosgene (25 mg). A solution of sodium carbonate (49 mg) in water (2 ml) was then added. The reaction mixture was stirred at room temperature for 3 hours. TLC showed all the starting material had reacted. 3-Aminobenzonitrile (28 mg, CAS 2237-30-1) was then added and the reaction mixture was stirred at room temperature for a further 40 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: 0% to 100% EtOAc in hexanes) to give (RS)-2-{3-cyano-4-[3-(3-cyano-phenyl)-ureido]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (16 mg, 16%) as a white solid. MS (ISP): 392.2 ([M+H—C4H8]+), 348.2 ([M+H—C4H8—CO2]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[N:12][N:13](C(OC(C)(C)C)=O)[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[N:12][NH:13][C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc(CSc2ccc(Cl)cc2)cc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(CSc2ccc(Cl)cc2)cn[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of tert-butyl 4-((4-chlorophenylthio)methyl)-6-oxopyridazine-1(6H)-carboxylate Part C (137 mg, 0.34 mmol) in CH2Cl2 (5 mL) was added TFA (1.50 mL, 19.41 mmol). The mixture was stirred at RT for 15 min before being concentrated. The crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product) to afford 5-((4-chlorophenylthio)methyl)pyridazin-3(2H)-one 7D (81 mg, 81% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 7.76 (1H, d, J=2.01 Hz), 7.27 (4H, s), 6.56 (1H, s), 3.82 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(CN3CCNCC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (1.00 g, 2.59 mmol, 1.00 equiv) and dichloromethane (20 mL). Trifluoroacetic acid (2.5 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.300 g (41% yield) of 1-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 286 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9](C)([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21].[CH2:22]=O>C(OCC)C>[CH3:19][N:20]([CH2:22][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1)[CH3:21]
Reactant: CC(C)(C(=O)c1ccc(S)cc1)N1CCOCC1
Reactant: CNC
Reactant: C=O
Solvent: CCOCC
Product: CC(C(=O)c1ccc(SCN(C)C)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.7 g (0.03 mol) of 1-(4-mercaptophenyl)-2-methyl-2-morpholinopropan-1-one are treated, while being cooled in ice, with 10 ml of a 40% aqueous solution of dimethylamine. After 30 minutes at room temperature the mixture is again cooled in an ice bath, and 3 ml of a 35% aqueous solution of formaldehyde are added dropwise (≈0.038 mol of formaldehyde). The mixture is then stirred at room temperature for 60 minutes and is heated at 50° C. for a further 2 hours. After cooling, 25 ml of diethyl ether are added to the reaction mixture, the phases are separated and the aqueous phase is extracted three times with ether. After the ether solution has been washed with water it is dried over MgSO4 and evaporated in vacuo, whereupon the crude product is left as an oil (compound No. 34).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:7]=3[C:6]=2[C:5]([Cl:17])=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:8]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:7]=3[C:6]=2[C:5]([Cl:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: CN1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(Cl)c42)CCN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (200 mg, 0.746 mmol) in DMF (2 mL), sodium hydride (90 mg, 2.25 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (543 mg, 1.86 mmol) was added to the reaction mixture and the reaction mixture was stirred at the same temperature for 40 min. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the residue that was purified by reverse phase HPLC to obtain 7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(6-methylpyridin-3-yl)ethyl)azepino [4,5-b]indole. 1H NMR TFA:—CD3OD: 8.4 (s, 1H), 8.1 (d, 1H), 7.75 (d, 1H), 7.0 (q, 2H), 4.8 (m, 1H), 4.0 (m, 1H), 3.8 (m, 2H), 3.4 (m, 3H), 3.3 (m, 2H),3.2 (t, 3H),3.0 (s, 3H), 2.7 (s, 3H).
Reaction SMILES: ClC1C(C(O)=O)=CC=C2C=1NC=C2.CO.[Cl:16][C:17]1[C:18]([C:32]([OH:34])=[O:33])=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[C:22]2[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[Cl:16][C:17]1[C:18]([C:32]([OH:34])=[O:33])=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[C:22]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Agent: [Pd+2]
Agent: O=C(O)c1ccc2cc[nH]c2c1Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1Cl
Yield: 94.4 %

Procedure:
To a mixture of 7-chloro-1H-indole-6-carboxylic acid (3.8 g, about 19.4 mmol) in MeOH (50 ml) at r.t. under N2 was added cyclohexanone (6.13 ml, 59.1 mmol), followed by a solution of NaOMe in MeOH (17.5 ml, 76.6 mmol, 25% wt). The reaction mixture was stirred at reflux for 16 hr. After cooling to r.t., the mixture was added another bath of cyclohexanone (6.13 ml, 59.1 mmol), followed by another solution of NaOMe in MeOH (17.5 ml, 76.5 mmol, 25% wt), and then re-stirred at reflux for another 7 hr. After cooling to r.t., the mixture was evaporated, added with water (100 ml), acidified with hydrochloric acid (5N) and left standing at r.t. overnight. The aqueous mixture was decanted, and the residue washed twice with hydrochloric acid (30 ml, 1N) and twice with water (30 ml). The residue was further washed three times with hexane, and then dried to give 5.5 g of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid. Another 2.6 g of the product was obtained from another reaction using 2.27 g of 7-chloro-1H-indole-6-carboxylic acid. Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=275.94, 277.94, HPLC Rt=1.750 min. To a mixture of the 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid (8.1 g) obtained from above in a mixture of THF/MeOH (25 ml/25 ml) at r.t. under N2 was added Pd(OH)2/C (764 mg, 20%). The mixture was then flushed with a stream of hydrogen gas using a balloon, and then stirred under hydrogen (using a balloon) for 27 hr. After removing the hydrogen balloon, the mixture was then flushed with a stream of N2, and then filtered through a cake of celite. The filtrate was evaporated to give 7-chloro-3-cyclohexyl-1H-indole-6-carboxylic acid (7.7 g). Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=278.01, 280.00, HPLC Rt=1.773 min.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.[I:30]I>CCCCCC.C1COCC1>[I:30][C:23]1[CH:22]=[C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:20]=[N:19][C:18]=1[O:17][CH3:16]
Reactant: COc1ccc(-c2ccncc2)nn1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
45 ml 1.6M solution of n-Butyllithium in hexane are added at −30° C. to a 10.2 g 2,2,6,6-tetramethylpiperidine in 100 ml THF, and the mixture is stirred at 0° C. for 30 min. After cooling to −75° C., 11.2 g 3-Methoxy-6-pyridin-4-yl-pyridazine dissolved 300 ml THF are added, and the solution is stirred at −75° C. for 35 min. The cold (−75° C.) reaction mixture is subsequently added to a cold (−75° C.) solution of 18.3 g iodine in 400 ml THF and stirred at −75° C. for 1.5 h. The reaction is quenched by adding 80 ml methanol/THF (1:1) at −75° C. and 300 ml saturated aqueous NaHCO3 at room temperature and extracted with dichloromethane. The organic layer is washed with 5% aqueous Na2S2O3 and saturated sodium chloride solution, dried (MgSO4) and the solvent removed. The crude product is purified by chromatography on silica gel to yield 14.4 g of 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]2[C:3]=1[C:4](=O)[C:5]1[CH:6]=[C:7]([C:25]([OH:27])=[O:26])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][C:10]=1[C:11]2=[O:21].[CH:29]([C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:33]=1[NH2:34])([CH3:31])[CH3:30].ClC1C=CC=CC=1Cl>O>[CH:39]([C:35]1[CH:36]=[CH:37][CH:38]=[C:32]([CH:29]([CH3:31])[CH3:30])[C:33]=1[N:34]=[C:4]1[C:3]2[C:12](=[C:13]([OH:20])[C:14]3[C:19]([C:2]=2[OH:1])=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:21])[C:10]2[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]([C:25]([OH:27])=[O:26])=[CH:6][C:5]1=2)([CH3:41])[CH3:40]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)c1cc2c(cc1C(=O)O)C(=O)c1c(c(O)c3ccccc3c1O)C2=O
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1N=C1c2cc(C(=O)O)c(C(=O)O)cc2C(=O)c2c1c(O)c1ccccc1c2O
Reaction time: 18 h
Yield: 49.3 %

Procedure:
0.5 g (1.32 mmoles) of 6,11-Dihydroxy-naphthacene-5,12-dione-2,3-dicarboxylic acid (product of Example 8), 0.28 g (1.58 mmoles) of 2,6-diisopropylaniline, and 25 ml of o-dichlorobenzene are refluxed for 4 h with azeotropic removal of the reaction water. The mixture is filtered while hot, and the filtrate is kept at 25° for 18 h. The precipitate is washed with hot hexane and dried to give 0.35 g (51%) of red crystals, m.p. 328-330°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:13][N:7]3[C:6]=2[CH:26]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]1(C)[CH:42]=CC=C[CH:38]=1.C(Br)C=C>C1COCC1>[CH2:42]([C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][C:6]=3[N:7]2[N:13]=[C:12]1[C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[CH:37]=[CH2:38]
Reactant: Cc1ccccc1
Reactant: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(Cl)ccc3OCC21
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
8-Chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-1; a racemic mixture, 0.43 g, 1.1 mmol) was dissolved in anhydrous THF (10 mL) and cooled to −78° C. in an acetone/dry ice bath under an N2 atmosphere. The resulting solution was treated with LHMDS (1.39 mL of a 1M toluene solution, 1.39 mmol) and stirred 2 minutes to produce a deep red color. Allyl bromide (0.20 mL, 2.2 mmol) was added neat and the solution was allowed to stir 10 minutes at −78° C. and then removed from the ice bath. Upon reaching ambient temperature, the reaction was judged complete by TLC and quenched by at addition of sat. aqueous NH4Cl (10 mL). The mixture was extracted with Et2O (3×10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified using flash column chromatography (ISCO Redisep 40 g SiO2 column, 0-40% EtOAc/hexanes gradient) to provide pure 3-allyl-8-chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-2; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.42-7.15 (m, 6H), 6.77 (m, 2H), 5.83 (m, 1H), 5.27 (dd, J=16.9, 1.1 Hz, 1H), 5.21 (d, J=10.0 Hz, 1H), 4.10 (dd, J=10.3, 3.7 Hz, 1H), 3.90 (s, 3H), 3.63 (dd, J=11.0, 3.6 Hz, 1H), 3.35 (dd, J=13.4, 6.0 Hz, 1H), 3.32 (s, 3H), 2.96 (m, 2H); MS (M+H+, C22H22ClN3O3) 412.3 found 412.9 required.