Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([NH:16][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:15][C:9]=3[N:8]=2)=[CH:5][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc2[nH]c(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a solution of 2-p-tolyl-1H-benzo[d]imidazol-5-amine (150 mg, 0.67 mmol) in pyridine (10 mL) at room temperature was added butyryl chloride (77 μL, 0.74 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed twice with saturated aqueous copper sulfate, followed by sodium bicarbonate and brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 56 mg (28%) of the title compound (LCMS RT=6.96 min, MH+ 294.0)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[Na+]>C(O)C>[NH2:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCC1CN(Cc2ccccc2)CCO1
Yield: 109.5 %

Procedure:
To a solution of crude 4-benzyl-2-phthalimidomethylmorpholine (64 g) in ethanol (500 ml) was added hydrazine monohydrate (18 ml, 0.57 mol) and the mixture was heated under reflux for 2 hours. After cooling, 10% aqueous sodium hydroxide (200 ml) was added to dissolve insolubles and the ethanol was distilled off under reduced pressure. The aqueous layer was extracted with chloroform (200 ml×3), the combined organic layer was dried over potassium carbonate and the solvent was distilled off to give crude 2-aminomethyl-4-benzylmorpholine (42.97 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[OH:4][C:5]1[CH:6]=[C:7]([C:24]2[CH:25]=[CH:15][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:23]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cccc(I)c1
Product: CCOC(=O)c1cccc(-c2cccc(O)c2)c1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 2 g (13.3 mmol) of 3-methoxymethoxyphenylboronic acid with 1.83 mL (11 mmol) of ethyl 3-iodobenzoate, 1.9 g (72%) of the expected ethyl ester are obtained.
Reaction SMILES: Cl.C([O:6][C:7]([N:9]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:10]1)=[O:8])(C)(C)C>O1CCOCC1>[CH:7]([OH:8])=[O:6].[NH:9]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:10]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CN(C(=O)OC(C)(C)C)C1)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CNC1)C3
Product: O=CO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 6.7 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (2.51 mL; 10.04 mmol; 5 eq.) was added to a solution of 3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (1 g; 2.01 mmol; 1 eq.) in 1,4-dioxane (15 mL) and the resulting mixture was stirred at room temperature for 3.5 hours. A 4M solution of HCl in 1,4-dioxane (1 mL; 4 mmol; 2 eq.) was added and the reaction mixture was stirred at room temperature for 2.5 hours then concentrated in vacuo. The residue was taken up in water and the pH made basic. The solution was extracted with DCM and the organic layer dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (60 mg, 7%) as a white solid. 1H NMR (CDCl3) δ 8.41 (s, 1H), 7.40-7.33 (m, 4H), 7.14-7.07 (m, 1H), 6.66-6.62 (m, 1H), 5.13-5.07 (m, 1H), 4.97 (s, 2H), 4.59 (s, 2H), 4.29-4.23 (m, 2H), 3.97-3.92 (m, 2H), 2.88 (s, 2H), 2.83 (s, 1H), 2.67 (s, 1H), 2.60 (s, 2H). HPLC (max plot) 97.3%, Rt 2.45 min. UPLC/MS: (MS+) 398.4 ([M+H]+).
Reaction SMILES: ClN1C(=O)C[CH2:4][C:3]1=O.[CH:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]2[CH:29]=[N:30][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:33]=2)[C:23]([C:38]([OH:40])=[O:39])=[CH:22]3)=[CH:15][CH:14]=1)([CH3:11])[CH3:10].C(Cl)(Cl)(Cl)[Cl:42]>CCOC(C)=O>[CH2:3]([O:39][C:38]([C:23]1[N:24]([C:28]2[CH:29]=[N:30][C:31]([O:34][CH:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=2)[C:25]2[C:21]([C:22]=1[Cl:42])=[CH:20][C:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:9]([CH3:10])[CH3:11])=[CH:18][CH:17]=1)=[CH:27][CH:26]=2)=[O:40])[CH3:4]
Reactant: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC(C)C)nc2)cc1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c2cc(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
N-Chlorosuccinimide (37 mg, 280 nmol) and 5-(4-isopropoxyphenyl)-1-(6-isopropoxypyrid-3-yl)indole-2-carboxylic acid ethyl ester (117 mg, 255 nmol; see Example 17) were mixed in CCl4 (2 mL) and stirred at 80° C. for 2 h. The mixture was diluted with EtOAc and washed with Na2S2O3 (aq., 10%) and NaHCO3 (aq., sat.). The combined extracts were washed with water, brine and dried over Na2SO4. Concentration gave the sub-title compound (116 mg, 92%).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CO.N1C=CC=CC=1>[Br:1][C:10]1[CH:11]=[C:6]2[CH2:5][CH2:4][NH:3][C:7]2=[N:8][CH:9]=1
Reactant: c1cnc2c(c1)CCN2
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2c(c1)CCN2
Yield: 84.7 %

Procedure:
A solution of Br2 (18.1 mL, 56.2 g, 0.351 mol) in dry CH2Cl2 (250 mL) was added dropwise over a period of 1 h 45 min to a stirred and cooled (−5° C.) solution of 2 (42.22 g, 0.351 mol) in dry CH2Cl2 (410 mL)-pyridine (40 mL). The yellow suspension was stirred at 0° C. for 45 min and poured into a mixture of saturated aqueous NaHCO3 (800 mL) and saturated aqueous Na2S2O3 (100 mL). Methanol (10 mL) was added and the lower organic layer was separated and dried over MgSO4. The aqueous layer was extracted with AcOEt:MeOH=99:1 (7×1000 mL). These extracts were also dried with MgSO4. The organic solutions were combined and concentrated to afford 5 (59.17 g, 85%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.07 (tt, J=8.4, 1.1 Hz, 2H), 3.64 (t, J=8.4 Hz, 2H), 4.47 (bs, 1H), 7.31 (m, 1H), 7.85 (dt, J=2.1, 0.9 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1.Cl.[NH2:22][CH2:23][C@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:23][NH:22][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]=[CH:10][C:2]2[NH:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)=[CH:20][CH:19]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1ccc(C=Cc2nc3ncccc3[nH]2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(C=Cc2nc3ncccc3[nH]2)cc1)NS(=O)(=O)c1ccccc1
Reaction time: 18 h

Procedure:
A DMF solution (10 mL) containing 31-3 (301 mg, 1.0 mmol) 2-1 (336 mg, 1.0 mmol), HOBT (206 mg, 1.35 mmol), EDC (258 mg, 1.35 mmol) and NMM (440 μl, 4.0 mmol) was stirred under ambient conditions for 18 h. The DMF was evaporated and the residue partitioned between CH2Cl2 and H2O. The organic layer was dried (MgSO4) and concentrated to a yellow gum which was purified by flash chromatography (silica, 4:1, CHCl3 ·NH3 /IPA) to provide impure 31-4 which was rechromatographed (silica, 9:1 EtOAc/IPA) to give 31-4 as a colorless foam.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH:37]([NH2:43])[C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH:37]([NH:43][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccsc1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccsc1

Procedure:
(2-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and (2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester (from Example 6 supra) by following the method in Example 61.
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]([O:28]C(C)(C)C)=[O:27])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].Cl>C1COCC1.O1CCOCC1>[CH2:1]([C:4]1([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]([OH:28])=[O:27])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(CCN2CCCC2C(=O)OC(C)(C)C)c2ccccc2CCc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C=CCC1(CCN2CCCC2C(=O)O)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 38.3 %

Procedure:
Dissolved 1,1-dimethylethyl 1-[2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-2-pyrrolidinecarboxylate (2.40 g, 5.56 mmol) in 30 mL of dry THF. Added 25 mL of 4.0M HCl in dioxane, and refluxed for 16 hours on steam bath. Cooled to room temperature, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% MeOH-CH2Cl2. Combined appropriate fractions and evaporated to give 0.80 g (40% yield) of 1-[2-[10,11-dihydro-5-(2propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-2-pyrrolidinecarboxylic acid. Dissolved free base in dichloromethane, and added 3.4M HCl in ether to pH=2. Evaporated, and added ether to precipitate hydrochloride salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([NH:25][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nccc(N2CCC3(CC2)OCCO3)n1
Reactant: NCc1ccccc1
Solvent: O
Product: c1ccc(CNc2nccc(N3CCC4(CC3)OCCO4)n2)cc1
Temperature: 150 °C

Procedure:
A mixture of 8 g 8-(2-chloro-pyrimidin-4-yl)-1,4-dioxa-8-aza-spiro[4.5]decane 8a) and 7.2 ml benzylamine is heated for 2 hours at 150° C., then cooled, admixed with 20 ml water and the aqueous solution is extracted three times with 20 ml methylene chloride each time. After drying the combined organic phases over sodium sulfate and removing the solvent, the residue is washed with cold isohexane. In this way 9.6 g benzyl-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-pyrimidin-2-yl]amine is obtained as a yellow powder. 1H-NMR (d6 -DMSO): δ=7.85 ppm (d, 1H); 7.40-7.18 (m, 5H) 7.15 (broad s, 1H, NH); 6.12 (d, 1H); 4.45 (d, 2H); 3.96 (s, 4H); 3.65 (m, 4H); 1.61 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4](=O)[CH2:5][Br:6].[NH2:9][C:10]1[C:19]([NH2:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>>[Br:1][CH2:2][C:3]1[C:4]([CH2:5][Br:6])=[N:9][C:10]2[CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]3=[CH:18][C:19]=2[N:20]=1
Reactant: O=C(CBr)C(=O)CBr
Reactant: Nc1cc2ccccc2cc1N
Product: BrCc1nc2cc3ccccc3cc2nc1CBr

Procedure:
Following the procedure of Example 1, 1,4-dibromo-2,3-butanedione is condensed with 2,3-diaminonaphthalene to obtain 2,3-bis(bromomethyl)benzo[g]quinoxaline, m.p. 190°-191° C.; 1H NMR (DMSO-d6, 400 MHz): δ5.07 (s, 4H, CH2), 7.68 and 8.26 (double doublets, 4H, H-7 and H-8, H-6 and H-9, resp.), 8.78 (s, 2H, H-5 and H-10).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([C:32]1([NH2:35])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C([O-])=O>>[CH2:25]([C:32]1([NH:35][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NC1(Cc2ccccc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccccc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 147 mg (1 mmol) 1-benzyl-cyclopropylamine. Yield: 56 mg (12%, trifluoroacetate); mass spectroscopy: [M+H]+=355.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2>C1C=CC=CC=1.CCO.O.[OH-].[K+]>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
Ethyl 5-(9-oxoxanthen-2-oxy)valerate (8.0 g, 24 mmol) prepared as described above was dissolved in a mixture of benzene (10 mL), 95% EtOH (40 mL), and water (5 mL), and 4N aqueous KOH (8 mL) was added. The mixture was refluxed for 6 hours (reaction complete by TLC), and partially concentrated (final volume ~10 mL). Absolute EtOH (10 mL) was added, and the resulting white precipitate was collected and washed with EtOH (2×10 mL). Yield: 1.7 g (21%), of potassium salt. The filtrate was evaporated, and the residue was dissolved in water (100 mL). The aqueous solution was extracted with EtOAc (3×20 mL), and the aqueous phase was added dropwise to a mixture of ice-water (100 mL) and 12N aqueous HCl (15 mL). A light-gray precipitate formed, which was collected, washed with water (3×10 mL), and dried. Yield: 5.45 g (74%) of free acid. A small amount of the product was recrystallized from n-hexane-EtOH (10:1) for elemental analysis. Fine white needles.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH:10]1[CH2:12][CH2:11]1>>[CH:10]1([CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: O=C1CCNCC1
Reactant: ClCC1CC1
Product: O=C1CCN(CC2CC2)CC1

Procedure:
1-(Cyclopropylmethyl)-4-piperidone is prepared from 4-piperidone and (chloromethyl)cyclopropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1ccc(C(=O)Cn2c(=O)c3cc(CC)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(=O)Cn2c(=O)c3cc(CC)sc3n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2=O)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.13 g), sodium hydrogencarbonate (1.65 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-(2-(4-ethylphenyl)-2-oxoethyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.87 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (50 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 ml) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless amorphous solid (0.59 g, 61%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl-].[NH4+]>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:2]([NH:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:3]([NH:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:7]=2)=[O:4])=[CH:24][CH:23]=1
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
103.1.B (905 mg, 2.65 mmole), 5 ml of DMF and 0.69 ml of DIEA. The reaction mixture was cooled to 0° C., and then ethyl bromoacetate (0.49 g, 2.92 mmole) was added to the mixture. The reaction was stirred at room temperature overnight. After then, the solution was poured into saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 103.1.C (552 mg, 49% yield) as orange syrup.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:27][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Reactant: NC1CCCCC1
Product: c1cc(N2CCC(CN3CCCC3)CC2)ccc1CNC1CCCCC1

Procedure:
Prepared from the product of Example 9 and cyclohexylamine.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([OH:27])=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([O:27][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(OCc3ccccc3)cc12
Reaction time: 24 h
Yield: 51.2 %

Procedure:
A solution of benzyl bromide (230 μl, 1.9 mMol) in acetone (6 ml) is added at room temperature, over 15 minutes, to a mixture containing 1-chloro-9-hydroxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 10) (490 mg, 1.73 mMol), acetone (7 ml), DMF (2 ml) and K2CO3 (400 mg). The assembly is left stirring for 24 h, then the solvents are subsequently evaporated under vacuum. Water is then added (30 ml). The assembly is again left stirring for 24 h. The solid form is recovered by filtration, washed with water, then dried at room temperature for 18 h. An inter-mediate, 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole (330 mg, 51% yield) is obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99%/1% to 95%/5%) as eluent. The product obtained is identical to that obtained according to the method described in J. Chem. Soc. Perkin Trans. 1, 1979, 1706. The mixture of 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole obtained above (320 mg, 0.86 mMol), DMF (7 ml) and sodium methoxide (30% solution in methanol, 10 ml) is heated under reflux for 20 h. The reaction mixture is poured into 60 ml of water, then left stirring for 2 h. The solid formed, recovered by filtration, is washed with water then dried. 280 mg (88% yield) of the expected compound 9-benzyloxy-1-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 7) are then obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99.5%/0.5% to 99%/1%) as eluent. The proton NMR spectrum of Compound 7 is the following: