Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([NH:9][NH2:10])[CH:8]=1.[CH3:13][CH2:14][O:15][C:16]([CH:18]([C:22]([CH3:24])=O)[C:19]([CH3:21])=O)=[O:17]>>[CH2:14]([O:15][C:16]([C:18]1[C:19]([CH3:21])=[N:10][N:9]([C:7]2[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=2[O:11][CH3:12])[C:22]=1[CH3:24])=[O:17])[CH3:13]
Reactant: COc1ccc(Cl)cc1NN
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2cc(Cl)ccc2OC)c1C
Yield: 38 %

Procedure:
In analogy to the procedure described in Example 38A], (5-chloro-2-methoxy-phenyl)-hydrazine hydrochloride and ethyl diacetoacetate gave, after precipitation (CH2Cl2/n-pentane), the title compound in 38% yield as light brown solid. MS: 309.1 (MH+, 1 Cl).
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=[N:3]1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[C:7]([C:6]1[N:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=[CH:4][CH:5]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccnn1O
Product: CN(C(=O)On1nccc1C(=O)c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-5-benzoylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (30%, crystals).
Reaction SMILES: [S:1](Cl)(Cl)=O.C(OC([NH:10][N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:13])=O)C>>[C:15]1([CH3:20])[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[N:11]=[N:10][S:1][CH:13]=1
Reactant: CCOC(=O)NN=C(C)c1ccccc1C
Reactant: O=S(Cl)Cl
Product: Cc1ccccc1-c1csnn1
Temperature: 60 °C

Procedure:
To thionyl chloride (1 ml), cooled to 0° C. was added N′-(1-o-tolyl-ethylidene)-hydrazinecarboxylic acid ethyl ester. The reaction mixture was heated to 60° C. for 1 h. Solvent evaporation gave 4-o-tolyl-[1,2,3]thiadiazole; 1 H NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H), 7.65 (d, 1H, J=7.3 Hz), 7.36 (m, 3H), 2.46 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][N+:16]([O-])=O)[CH2:11][N+:12]([O-])=O)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:15][NH2:16])[CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])CC(C[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CO
Product: NCC(CN)c1ccc(N)cc1

Procedure:
A mixture of 1-nitro-4-[2-nitro-1-(nitromethyl)ethyl]benzene (742 mg, 0.45 mmol) and 148 mg platinum (IV) oxide in 40 mL MeOH was reacted under 60 PSI hydrogen on the Pan apparatus. After 24 hours the mixture was filtered and rinsed with MeOH. The MeOH solution was acidified to pH=0 using concentrated HCl and then evaporated to give a quantitative yield of the title compound. 1H NMR (D2O) δ: 7.55-7.60 (m, 2H), 7.48-7.54 (m, 2H), 3.26-3.51 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10](S(C)=O)[N:9]=1)#[N:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH2:21]>>[C:1]([C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:21][C:20]2[CH:22]=[C:23]([CH3:25])[CH:24]=[C:18]([CH3:17])[CH:19]=2)[N:9]=1)#[N:2]
Reactant: Cc1cc(C)cc(N)c1
Reactant: CS(=O)c1nccc(-c2[nH]ncc2C#N)n1
Product: Cc1cc(C)cc(Nc2nccc(-c3[nH]ncc3C#N)n2)c1

Procedure:
A solution of 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidine (4-4, 155 mg, 0.66 mmol) and 3,5-dimethylaniline(3 mL, excess) was heated at 90° C. for 20 hours. The reaction was purified by flash chromatography. Elution with CH2Cl2 to 4% EtOAc/CH2Cl2 gave 4-(4-cyano-1H-pyrazol-5-yl)-2-[(3,5-dimethylphenyl)amino]pyrimidine (4-5) as a solid. 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.63 (dd, 1H, J=5 Hz), 7.50 (dd, 1H, J=5 Hz), 7.31 (br s, 2H), 7.21 (br s, 1H), 6.74 (br s, 1H), 2.35 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>>[CH2:7]([NH:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Yield: 93.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 195(A), from phenylmethanamine (3.51 g, 32.78 mmol) and 1-fluoro-2-nitrobenzene (4.40 g, 31.22 mmol). 6.65 g of N-benzyl-2-nitrobenzenamine (Yield: 93%) was obtained as an orange crystalline solid which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10](CC2C=CC=CC=2)C(=O)OCC2C=CC=CC=2)[CH2:5]1)(=[O:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([N:4]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH2:10])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC[C@H](CN(Cc2ccccc2)C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CC[C@H](CN)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A mixture of benzyl N—((S)-1-acetylpyrrolidin-3-ylmethyl)-N-benzylcarbamate (Intermediate 165, 4.2 g) and palladium hydroxide on carbon (0.4 g) in methanol (42 mL) was stirred under an atmosphere of hydrogen at 60° C. for 48 hours. The mixture was filtered and the filtrate was evaporated to dryness to give ((R)-1-acetylpyrrolidin-3-ylmethyl)amine (1.5 g) as a light yellow oil.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:39])=[C:5]([C:30]([O:37]C)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][C:7]1[C:8]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:9]([CH:21]=[CH:22][CH:23]=1)[C:10]([NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)([O-])O.[Na+]>C(#N)C.O>[CH3:34][O:33][C:32]1[C:3](=[O:2])[C:4]([CH3:39])=[C:5]([CH2:6][C:7]2[C:8]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:9]([CH:21]=[CH:22][CH:23]=2)[C:10]([NH:12][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])=[O:11])[C:30](=[O:37])[C:31]=1[O:35][CH3:36]
Reactant: COc1c(C)c(Cc2cccc(C(=O)N[C@@H](C)c3ccccc3)c2-c2cccnc2)c(OC)c(OC)c1OC
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N[C@@H](C)c3ccccc3)c2-c2cccnc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
(S)-N-[3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]-1-phenylethylamine (69 mg, 0.1311 mmol) was dissolved in a mixed solvent of acetonitrile (9 ml) and water (3 ml), then CAN (180 mg, 0.3284 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:3) to give the title compound (48 mg, 0.0967 mmol, 74%).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[N:16]3)[CH:10]=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:24]([NH:23][C:18]1[CH:17]=[N:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[CH:14]=2)[N:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc3nc(NCc4ccccc4)cnc3c2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CNc2cnc3cc(-c4cn[nH]c4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To the ice cold solution of 4-(2-benzylamino-quinoxalin-6-yl)-pyrazole-1-carboxylic acid tert-butyl ester (157 mg, 0.39 mmol) in 1,4-dioxane (3 mL) was added 14% HCl in dioxane (2 mL). The resulting mixture was stirred at RT for 2 hrs. After completion of reaction the volatiles were evaporated off under vacuum and the HCl salt was triturated with DCM to obtain crude product. The crude was further purified by prep-HPLC to afford the title compound (32 mg, 27%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:15][CH:16](Br)[CH3:17].[H-].[Na+]>CCOCC.CS(C)=O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:17][CH2:16][CH2:15]1
Reactant: CC(Br)CBr
Reactant: N#CCc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccccc2C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.6 g of (2-trifluoromethyl-phenyl)-acetonitrile and 7.6 ml of 1,2-dibromopropane in 36 ml ether were added slowly through a dropping funnel to a suspension of 3.62 g of sodium hydride in 85 ml DMSO at 0° C. After addition, the ice-water bath was allowed to warm up to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched with isopropyl and H2O. The suspension became clear. The organic layer was separated, and the aqueous layer was extracted twice with ether. The combined organic extracts were combined, dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%) to yield 8.5 g of product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].[C:19]([O-])(=[O:21])[CH3:20].[Tl+].C(OCCCC)=C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16])(=[O:21])[CH3:20]
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: C=COCCCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nn(C)c(=O)n1Cc1cc(C(C)=O)ccc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 4.56 g (14.6 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention) in 30 ml of N,N-dimethylformamide were added 4.20 g (16 mmol) of thallium (I) acetate, 9.34 ml (72.6 mmol) of butyl vinyl ether, 604 mg (3.64 mmol) of 1,3-bis(diphenylphosphino)propane, 160 mg (0.72 mmol) of palladium (II) acetate and 2.44 ml (17.5 mmol) of triethylamine and the mixture was stirred at 90° C. under an atmosphere of nitrogen for 8 hours. After the reaction mixture was cooled to room temperature, diluted hydrochloric acid (prepared by mixing 21 ml of concentrated hydrochloric acid and 130 ml of water) was added thereto, and the mixture was stirred for 30 minutes. The reaction mixture was filtered with cotton and washed with chloroform, and the filtrate was separated. After the water layer was extracted with chloroform once again, the organic layers were combined, washed with water (twice), dried and concentrated. Then, to the semisolid residue was added a mixture of equal amounts of tert-butyl methyl ether and hexane and the mixture was stirred at room temperature for a while. The solid was collected by filtration to obtain 2.58 g of 4-(5-acetyl-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 73 of the present invention) as pale yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:26](=[O:28])[CH3:27])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Product: CC(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 87.9 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (88 mg, 88%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and acetyl chloride (0.02 mL, 0.25 mmol) following the general procedure T.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[C:19]([NH2:27])[N:18]=1>ClCCl.C(OCC)(=O)C.CCCCCC>[N:27]([C:19]1[N:18]=[CH:17][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=1)=[C:1]=[S:2]
Reactant: Nc1cc2c(cn1)CCCC2
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: S=C=Nc1cc2c(cn1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (222 mg, 0.956 mmol) in dchloromethane (5 mL) was added a solution of 5,6,7,8-tetrahydroisoquinolin-3-amine (139 mg, 0.938 mmol) in dichloromethane (1.5 mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was applied directly to a Biotage column in 20-25% ethyl acetate/hexane, collecting the first major peak. Yield 141.8 mg (79%) 3-iothiocyanato-5,6,7,8-tetrahydroisoquinoline. NMR 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.10 (1H, s), 6.84 (1H, s), 2.74 (4H, t, J=6.3 Hz), 1.81 (4H, dd, J=4.0, 2.7 Hz).
Reaction SMILES: O[C@H](C(C)(C)C)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:29]([C:51]([CH3:54])([CH3:53])[CH3:52])[C@@H:30]([N:34]([C:39]1C=CC(C2C=CC=CC=2)=CC=1)[C:35]([O:37]C)=[O:36])[C:31]([OH:33])=[O:32].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:37][C:35](=[O:36])[N:34]([CH3:39])[C@H:30]3[C:31](=[O:33])[O:32][C@@H:29]3[C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@@H](O)C(C)(C)C
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@H](O)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(-c2ccccc2)cc1)[C@H]1C(=O)O[C@@H]1C(C)(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4,4-dimethyl-2-[(4-phenyl-phenyl)-methoxy-carbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-4,4-dimethyl-2-[(4-phenyl-phenyl)-methoxy-carbonylamino]-pentanoic acid (0.203 g, 0.55 mmol) in dry CH2Cl2 (25 mL), at 0° C., Et3N (0.23 mL, 1.65 mmol) and subsequently TBTU (0.21 g, 0.66 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.063 g, 58%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 371 [M−NH4]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.95 (s, 9H), 4.37 (d, J=4.64 Hz, 1H), 4.83 (dd, J=4.65, 8.16 Hz, 1H), 5.14 (s, 2H), 7.32-7.56 (m, 5H), 7.60-7.75 (m, 4H), 8.25 (d, J=8.12 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15].[OH-].[K+]>O>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: COCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1ncnc2[nH]ccc12
Temperature: 100 °C
Yield: 90.5 %

Procedure:
To 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.00 g, 32.6 mmol) in 12.5 mL of 2-methoxy-ethanol (23, 158 mmol), potassium hydroxide (3.3 g, 59 mmol) is added. The reaction is heated at 100° C. overnight, then poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (24, 5.70 g).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]1(=[O:27])[O:26][CH2:25][CH2:24][CH2:23]1>>[NH2:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][OH:27])[CH2:3][CH2:2]2)[N:16]=1
Reactant: O=C1CCCO1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)CCCO)CC3)nc(N)c2cc1OC

Procedure:
5 g of 2-piperazinyl-4-amino-6,7-dimethoxy quinazoline were heated in 15 g of γ-butyrolactone to 100° C. until a sample on thin layer chromatography (as described in Examples 1 and 3) indicated the reaction was complete. The precipitate formed overnight with cooling was removed and recrystallized from ethanol. The 1-(4-amino-6,7-dimethoxy quinazolin-2-yl)-4-(4-hydroxy-butyryl)-piperazine obtained showed a crystal transformation at 135°-140° C. and melted at 241°-243° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][NH:6]2.[H-].[Na+].[CH3:16]I>C1COCC1>[CH3:16][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:11][C:12]#[N:13])=[CH:5]1
Reactant: Cc1cccc2[nH]cc(CC#N)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1c(CC#N)cn2C
Reaction time: 0.33 h

Procedure:
(4-Methyl-1H-indol-3-yl)-acetonitrile (540 mg, 3.2 mmol), is taken up in dry THF (10.3 mL), cooled to zero, and sodium hydride (228 mg, 60% in mineral oil, 6 mmol) is added to the stirring solution. The reaction is stirred for 15 minutes at zero and methyl iodide (0.26 mL, 4 mmol) is added. The solution is stirred for 20 minutes at zero, and quenched by the slow addition of saturated aqueous ammonium chloride. The compound is extracted with ethyl acetate, dried (Na2SO4), filtered, and evaporated in vacuo to give a solid that is purified on silica gel with hexanes/ethylacetate as the eluent (1.0 g, 5 mmol, 71%) LC/MS (M++1): 185.5.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([NH:18][C@:19]23[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:51])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:40])([CH3:39])[C:28]([C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47]C)=[O:46])=[CH:43][CH:42]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)=[O:17])[C:13]1([CH3:59])[CH3:58])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([NH:18][C@:19]23[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:51])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:40])([CH3:39])[C:28]([C:41]3[CH:50]=[CH:49][C:44]([C:45]([OH:47])=[O:46])=[CH:43][CH:42]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)=[O:17])[C:13]1([CH3:59])[CH3:58])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)[C@@H]3C[C@H](NC(=O)OCc4ccccc4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)[C@@H]3C[C@H](NC(=O)OCc4ccccc4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1R,3S)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (135 mg, 0.168 mmol) in THF (5 mL), MeOH (2 mL) was added a solution of lithium hydroxide monohydrate (0.014 mL, 0.504 mmol) in water (1 mL). The reaction mixture was stirred at 75° C. After 4 h, the mixture was concentrated to a white paste. The crude material was dissolved in THF (1.75 mL), MeOH (1 mL) and 1N HCl (0.25 mL) and injected into a reverse phase prep-HPLC using HPLC method 11 and dried in a vacuum oven to give the title compound (30.4 mg, 0.035 mmol, 21.09% yield) as white solid. LCMS: m/e 789.4 (M+H)+, 3.14 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (d, J=8.3 Hz, 2H), 7.41-7.37 (m, 4H), 7.36 (d, J=3.4 Hz, 1H), 7.25 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.6 Hz, 1H), 5.19-5.07 (m, 3H), 4.99 (br. s., 1H), 4.77 (s, 1H), 4.66 (s, 1H), 3.98-3.88 (m, 1H), 2.70-2.55 (m, 3H), 2.47-2.28 (m, 3H), 2.19-2.09 (m, 2H), 1.99-1.87 (m, 1H), 1.76 (d, J=7.8 Hz, 1H), 1.72 (s, 3H), 1.71-1.63 (m, 2H), 1.58 (d, J=8.1 Hz, 3H), 1.50 (br. s., 3H), 1.43 (br. s., 1H), 1.37 (br. s., 3H), 1.33 (d, J=12.2 Hz, 2H), 1.28 (s, 3H), 1.24 (d, J=7.1 Hz, 1H), 1.16 (d, J=12.2 Hz, 2H), 1.09 (s, 3H), 1.02 (s, 6H), 1.01 (br. s., 3H), 0.96 (s, 6H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[N+:6]([C:9]1[C:10]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)([O-])=O>Cl.C(O)(=O)C>[CH:21]1[C:22]2[C:17](=[CH:16][C:15]3[C:10]([C:9]=2[NH2:6])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1c2ccccc2cc2ccccc12
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Nc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of tin chloride (25.4 g, 134 mmol) in concentrated hydrochloric acid (HCl, 210 mL) was added dropwise a solution of 9-nitroanthracene (10.0 g, 44.8 mmol) in acetic acid (420 mL), and the mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature and filtered. The residue was treated with an aqueous solution of sodium hydroxide (NaOH, 1 N, 300 mL) and extracted with dichloromethane (CH2Cl2). The organic layer was dried over magnesium sulfate (MgSO4) and concentrated to give anthracen-9-yl-amine as brown crystals (6.41 g, 74% yield). 1H NMR (CDCl3) δ 8.00-7.95 (4H, m), 7.91 (1H, s), 7.47-7.42 (4H, m), 4.89 (2H, br-s).