Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC(O)=O)CCN[C:12]([C@:14]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:45])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])C1C=CC=CC=1.[C:56]1([NH:62][CH2:63][CH2:64][NH2:65])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[C:40]([CH2:39][N:62]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:63][CH2:64][NH:65][C:12]([C@:14]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:45])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])([OH:42])=[O:41]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)O)Cc3ccccc3)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
Reactant: NCCNc1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)O)c3ccccc3)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

Procedure:
The title compound was prepared following the method described above for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(benzyl(carboxymethyl)amino)ethylcarbamoyl)-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)benzoic acid (example 89) using N1-phenylethane-1,2-diamine as amine. The product was isolated as a white solid (0.9 mg, 9%). LCMS: m/e 735.5 (M+H)+, 1.80 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 7.26-7.19 (m, 2H), 6.86-6.70 (m, 3H), 5.37 (d, J=4.58 Hz, 1H), 4.77 (s, 1H), 4.63 (s, 1H), 4.22 (s, 2H), 3.82-3.43 (m, 4H), 3.21-3.07 (m, 1H), 2.69-2.53 (m, 1H), 2.23-2.13 (m, 2H), 1.73 (s, 3H), 2.05-1.07 (m, 19H), 1.06 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]([OH:17])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(O[N:26]1[N:34]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.ONC(=O)CCC(N)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:8]([OH:17])([C:9]([NH:26][NH2:34])=[O:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)C(O)(Cc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)CCC(=O)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)(Cc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 133 %

Procedure:
A mixture of 2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid (250 mg), HATU (479 mg), diisopropylethyl amine (149 mg) and N-hydroxysuccinamide (145 mg) in 4 mL of DMF was stirred at ambient temperature for 1.5 h. The mixture was diluted with ethyl acetate, washed with water. The organic layer was dried with magnesium sulfate and concentrated to give the desired product ethyl 2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate (352 mg), which was directly used for the next step. To ethyl 2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate (352 mg) in DCM (5 mL) was added hydrazine (anhydrous, 101 mg) at ambient temperature. Instantaneously the solution turned cloudy and after 15 min the solvent was removed in vacuo to afford the crude title compound as an amorphous solid. LC/MS 275.2 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Yield: 78.6 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL COCl2. The resulting solution concentrated under reduced pressure and the crude acyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) and pyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up and column chromatography (2-5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:12]=2)[CH2:8][CH2:9]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CCCc1ccc2c(c1)NCC2
Solvent: CC(C)O
Product: CCCc1ccc2c(c1)N(c1ncnc3cc(OC)c(OC)cc13)CC2
Yield: 43 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 43% yield from 6-propyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH.(M.P. 140°-141° C.; LC-MS: 350 (MH+); anal. RP18-HPLC RT: 5.73 min.).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=2.C[O-].[Na+]>CO>[C:1]1([C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1cc2ccc(C(=O)O)cc2[nH]1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Cyclohexanone (96 mL, 0.926 mol) was added to a stirred solution of methyl indole-6-carboxylic acid (50.0 g, 0.335 mol) in methanol (920 mL) at 22° C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl solution. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the title compound as a tan colored solid (80.9 g, 97.5% yield).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:16]([S:18]C)=S)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]2=[O:15])[CH:4]=1.C>C(O)C.C(#N)C>[CH3:1][NH:2][C:16]([C:9]1([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11][S:10]1=[O:15])=[S:18]
Reactant: CN
Reactant: CSC(=S)C1(c2cccnc2)CCCCS1=O
Solvent: CC#N
Solvent: CCO
Product: CNC(=S)C1(c2cccnc2)CCCCS1=O
Temperature: 22 °C
Reaction time: 0.58 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (10.2 cc) is added dropwise, in the course of 5 minutes, to a solution of methyl 2-(pyridin-3-yl)tetrahydrothiopyran-2-carbodithioate 1-oxide (a single stereoisomeric form; 10.2 g) in ethanol (150 cc), kept at between 25° and 30° C. The solution is then stirred for 1 hour 35 minutes at a temperature of about 22° C. and a further amount of 33% (weight/volume) solution of methylamine in ethanol (1.5 cc) is then added. After it has been stirred for 1 hour at the same temperature, the reaction mixture is concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) at 40° C. The product obtained (9.8 g) is dissolved in acetonitrile (15 cc) at a temperature of about 20° C. and the solution is kept at a temperature of about 5° C. for 1 hour. The resulting crystals are filtered off, washed twice with acetonitrile (10 cc in total) and dried under reduced pressure (25 mm Hg; 3.4 kPa) at 20° C. The product obtained (3.4. g), to which 0.8 g prepared under the same conditions has been added, is dissolved in boiling acetonitrile (80 cc); the solution is treated with decolourising charcoal (0. 1 g) and filtered hot and the filtrate is then cooled at a temperature of about 5° C. for 2 hours. The resulting crystals are filtered off, washed twice with acetonitrile (10 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. This gives the A form of N-methyl-2-(pyridin-3-yl)tetrahydrothiopyran-2-carbothioamide 1-oxide (3.3 g) melting at 228° C. [Rf=0.22 (chromatography on a thin layer of silica gel; solvent: ethyl acetate/methanol (80/20 by volume)].
Reaction SMILES: [CH:1]1[C:13]2[C:12]3([C:25]4[CH:24]=[C:23]([CH2:26][OH:27])[CH:22]=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:28][OH:29]>C1(C)C=CC=CC=1.[O-2].[Cr+6].[O-2].[O-2]>[CH:24]1[C:25]2[C:12]3([C:13]4[CH:1]=[C:2]([CH:28]=[O:29])[CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][C:23]=1[CH:26]=[O:27]
Reactant: OCc1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(CO)cc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C=O)cc21
Yield: 40.4 %

Procedure:
A solution of 380 mg of 9,9'-spirobifluorene-2,2'-dimethanol in 15 ml of toluene is admixed with 5 g of chromium(VI) oxide on graphite (Seloxcette, Alpha Inorganics) and the mixture is refluxed for 48 hours under nitrogen. It is then filtered with suction through a glass filter and the filtrate is evaporated. Chromatography over silica gel using chloroform and crystallization from methylene chloride/ether gives 152 mg of 9,9'-spirobifluorene-2,2'-dicarbaldehyde (m.p. >300° C.) and 204 mg of 2'-hydroxymethyl1-9,9'-spirobifluorene-2-carbaldehyde (m.p. from 262° to 263° C.)
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4](=[O:18])[C:3]=1[N:19]=O.[H][H]>[Pd].C(O)C>[NH2:19][C:3]1[C:4](=[O:18])[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[NH2:1]
Reactant: CCCn1c(N)c(N=O)c(=O)n(CC(=O)OCC)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(N)c(N)c(=O)n(CC(=O)OCC)c1=O

Procedure:
6-Amino-3-carboethoxymethyl-5-nitroso-1-propyluracil (2.84 g, 10 mmol) is slurried with 75 mL of absolute ethanol and 100 mg of 10% palladium-on-carbon. The mixture is hydrogenated at 25° C. and an initial pressure of 60 p.s.i. of hydrogen in a Parr apparatus. After uptake of hydrogen is completed the mixture is filtered and the filtrate concentrated to give the diaminouracil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH2:7][N:8]=[C:9]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1)(=O)[CH3:2].Cl>C(Cl)Cl>[Cl:16][C:14]1[S:13][C:11]2[N:12]3[C:1]([CH3:2])=[N:4][N:5]=[C:6]3[CH2:7][N:8]=[C:9]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:10]=2[CH:15]=1
Reactant: CC(=O)NNC1=Nc2sc(Cl)cc2C(c2c(F)cccc2F)=NC1
Agent: Cl
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(Cl)cc1C(c1c(F)cccc1F)=NC2
Temperature: 270 °C

Procedure:
0.35 g of 2-(2-acetylhydrazino)-7-chloro-5-(2,6-difluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine are distributed on a metal plate in as thin as possible a layer and maintained at 270° C. for 1 minute in a sand bath. The melt is taken up in methylene chloride and shaken three times with 0.1-N hydrochloric acid in order to remove the starting material. The methylene chloride is distilled off and the product recrystallized from ethyl acetate containing active carbon. There is obtained 2-chloro-4-(2,6-difluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 185°-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[C:15]([C:14]1[CH:23]=[CH:24][C:25]2[N:26]=[C:8]([C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])[NH:11][C:12]=2[CH:13]=1)(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C)c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
3,5-Dimethylpyrrole-2-carboxylic acid (99 mg, 0.71 mmol) was added to a pyridine (3 ml) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added, and the mixture was heated to 70° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2). The residue was dissolved in acetic acid (3 ml), and stirred for 8 hours at 100° C. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), to afford 5-benzoyl-2-(3,5-dimethylpyrrol-2-yl)-benzimidazole (34 mg, 15% in two steps) as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.[NH4+].[OH-]>ClC(Cl)C.CO>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: O=C1NCc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: O=C1NCc2ccccc2N1C1CCNCC1
Temperature: 25 °C

Procedure:
To a solution of 1-(1-benzyl-4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one (947 g, 295 mmol) from Step 4 in dry dichloroethane (20 mL) was added 1-chloroethyl chloroformate (0.35 mL, 3.2 mmol). The reaction was refluxed for 3 h. The solvent was rmoved under reduced pressure and the residue was dissolved in MeOH (50 mL) and the solution was refluxed for 1 h. The reaction was cooled to ambient temperature, conc. NH4OH (1 mL) was added, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 90:10:1 CHCl3 :MeOH:NH4OH as eluant. 1-(4-Piperidinyl)-3,4-dihydroquinazolin-2(1H)-one was obtained as an oil (48% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]([C:14](Cl)=[O:15])[CH:8]2[C:17](Cl)=[O:18]>C1COCC1>[C:2]([O:4][C:17]([CH:8]1[CH:9]([C:14]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:15])[CH:10]2[CH2:13][CH:7]1[CH:12]=[CH:11]2)=[O:18])([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)C1C2C=CC(C2)C1C(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C2C=CC(C2)C1C(=O)OC(C)(C)C

Procedure:
34 g (0.3 mol) of potassium t-butoxide was dissolved in 250 mL of THF in a round-bottom flask and then 22 g (0.1 mol) of 5-norbornene-2,3-dicarbonyl chloride was slowly added thereto at room temperature to be reacted at 45° C. for about 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: OC1CCc2cc(Cl)ccc21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a precooled (5–10° C.) solution of 5-chloro-indan-1-one (2.0 g, 12 mmoles) in 33 mL of anhydrous methanol was added sodium borohydride (0.43 g, 11 mmoles). The reaction mixture was stirred at 10° C. for 2 hrs and then at room temperature for 18 hrs. The reaction mixture was evaporated to afford a yellow residue. The residue was dissolved in 200 mL of diethyl ether and then washed with water (2×100 mL), with 0.10 N hydrochloric acid (2×100 mL), and then with brine (100 mL). The organic layer was separated, dried (sodium sulfate), filtered, and the filtrate was evaporated to provide the title compound in good purity. MS m/z 167 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18]>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:17][CH3:18]
Reactant: CCCOCCCCCCCl
Reactant: O=C1CCNCC1
Product: CCCOCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Propoxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-propoxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH:1]1([C:13]2[C:14](=[O:29])[NH:15][C:16](=[O:28])[C:17]=2[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][N:4]3[CH:3]=[N:2]1)[CH:7]=[CH:8][CH:9]=2.[CH2:30]=O.[OH-].[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:30][CH:12]1[N:4]2[C:5]3[C:10]([CH:1]([C:13]4[C:14](=[O:29])[NH:15][C:16](=[O:28])[C:17]=4[C:18]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:19]=4[CH:20]=[CH:21][N:22]=[CH:23]5)[N:2]=[CH:3]2)=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:11]1
Reactant: C=O
Reactant: O=C1NC(=O)C(C2N=CN3CCc4cccc2c43)=C1c1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1Cc2cccc3c2N1C=NC3C1=C(c2cccc3cnccc23)C(=O)NC1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Add a solution of 3-(5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-yl)-4-(isoquinolin-5-yl)-2,5-dioxopyrrole (0.300 g, 0.7853 mmol) in anhydrous dimethylformamide (1.5 mL) to formalin (37% solution in water, 0.750 ml) in 2 ml glacial acetic acid and stir at 65° C. for 2 hours. Pour into ice water and neutralize with 5.0N sodium hydroxide. Extract with 200 mL ethyl acetate, wash sequentially with water (1×75 mL), and saturated aqueous sodium chloride (1×75 mL), dry over anhydrous magnesium sulfate, and concentration under reduced pressure. Dissolve the residue in 150 ml 2.0 M ammonia in methanol stir at room temperature for 2 hours, concentrate and purify by column chromatography to give the title compound as an orange solid.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]([CH3:25])([CH3:17])[CH2:19][CH2:20]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)CCC(=O)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
In a 250 mL round-bottomed flask was placed magnesium turnings (1.85 g, 76.1 mmol), which were stirred under vacuum without solvent overnight. To the turnings was added anhydrous THF (10 mL) and 4-benzyloxybromobenzene (10.0 g, 38.0 mmol) in anhydrous THF (40 ml) over 15 min. After the reaction was complete, the resulting gray slurry was stirred for 2 h at 60° C. To the slurry, cooled in an ice-water bath, was added 4,4-dimethyl-cyclohexanone (3.36 g, 26.6 mmol) in THF (15 mL). The reaction mixture was stirred for 1 hour at room temperature after which the solvent was removed under reduced pressure. The residue was partitioned between EtOAc/saturated NH4Cl. The mixture was extracted twice with EtOAc. The organic phases were combined, dried (Na2SO4) and concentrated. The residue was purified via column chromatography on silica gel (eluting with 10-40% ethyl acetate/hexanes) to give 4.14 g (50%) of 1-(4-benzyloxy-phenyl)-4,4-dimethylcyclohexanol.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.CS(C)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (50 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (84.83 g), dimethyl sulfoxide (500 mL) and triethyl amine (127.5 g). The mixture was heated to about 95-105° C. and maintained at the same temperature for about 10-12 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 25-30° C. followed by addition of water (1000 mL) and toluene (600 mL). The mixture was stirred for about 10 minutes and layers were separated. The organic layer was sequentially washed with 20% aqueous sodium carbonate solution (1000 mL), 20% aqueous acetic acid solution (1000 mL) and water (700 mL). The organic layer was separated and subjected to complete distillation under vacuum at 60-65° C. followed by cooling to room temperature and subsequent addition of n-hexane (800 mL). The mixture was stirred for about 9 hours at room temperature followed by isolation of solid by filtration and washing with n-hexane (100 mL). The solid isolated was subjected to drying under vacuum at 55-60° C. for about 5 hours to afford the title compound in about 84% yield having HPLC purity of about 98%.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[CH:27][C:26]=2[CH3:34])=[O:24])=[CH:19][CH:18]=1.C(OC(C)C)(C)C>C1(C)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:34][C:26]1[CH:27]=[C:28]2[N:33]([C:25]=1[C:23]([C:20]1[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=1)[NH:16][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]3=[O:13])=[O:24])[CH:32]=[CH:31][CH:30]=[CH:29]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc2ccccn2c1C(=O)c1ccc(N)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c[nH]c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Temperature: 110 °C

Procedure:
1.69 ml of diethyl ethoxymethylene malonate are added, under an inert atmosphere at ambient temperature, to 1.83 g (6.8 mmol) of (4-aminophenyl)(2-methylindolizin-3-yl)methanone in 23 ml of toluene. The reaction medium is heated at 110° C. for 1 h 45 and then concentrated under reduced pressure. The residue obtained is dissolved in 45 ml of diphenyl ether and then heated at 230° C. for 30 minutes. After the addition of diisopropyl ether at ambient temperature, the precipitate formed is filtered off, rinsed with diisopropyl ether, with methanol and then with dichloromethane, and dried under reduced pressure at 50° C. overnight 1.2 g of a yellow powder are obtained.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]([CH2:26][CH2:27][Cl:28])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=O)C.Cl>>[ClH:28].[Cl:28][CH2:27][CH2:26][N:16]1[C:14]2[N:15]=[C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[N:11]=[CH:12][C:13]=2[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17]1
Reactant: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Agent: Cl
Product: O=C(O)c1cn(CCCl)c2nc(N3CCNCC3)ncc2c1=O
Yield: 196.2 %

Procedure:
A mixture containing 1.0 g of ethyl 2-(4-acetyl-1-piperazinyl)-8-(2-chloroethyl)-5,8-dihydro-5-oxopyrido[2,3-d]-pyrimidine-6-carboxylate and 12 ml of 20% aqueous hydrochloric acid was heated on a steam bath for 2 hours, during which period crystals separated out. The crystals were collected, after cooling, and recrystallized from diluted aqueous ethanol containing a small amount of concentrated hydrochloric acid to yield 0.9 g of the product, m.p. 280°C with decomposition.