Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](O)=[O:17])=[O:13])=[C:4]1[CH3:23])[CH3:2].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:38]([C:39]3[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:43][CH:44]=3)[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[CH:37][CH:36]=3)[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)cc1

Procedure:
Following a procedure similar to that described in Example 2B but employing 10.0 g of 2-(1-ethyl-2-methyl-3-indolylcarbonyl)benzoic acid and 13.0 g of 4,4'-dioctyldiphenylamine there was obtained a quantitive yield of 3-(1-ethyl-2-methyl-3-indolyl)-3-[N,N-bis-(4-octylphenyl)amino]phthalide, m.p. 106°-108° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a yellow-colored image.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][C:8]([N:11]1[C:19]2[C:18]([F:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:13](I)=[CH:12]1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:29](=[N:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([CH:54]=1)[C:48](N(OC)C)=[O:49])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[C:29](=[N:42][C:43]1[CH:54]=[C:47]([C:48]([C:13]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=3[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:23])[CH3:22])[CH:12]=2)=[O:49])[CH:46]=[N:45][CH:44]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncc(F)c21
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncc(F)c21
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a stirring solution of 1-[2-(tert-Butyl-dimethyl-silyloxy)-1,1-dimethyl-ethyl]-7-fluoro-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 73, 3 g, 6.69 mmol) in dry ether (100 mL) at −78° C., n-BuLi (3.9 mL, 1.84M, 7.17 mmol) was added and stirred for 30 minutes. Then 5-(benzhydrylidene-amino)-N-methoxy-N-methyl-nicotinamide (Preparation 52, 2.31 g, 6.69 mmol) in dry ether (10 mL) was added drop wise for 5 min. After 1 hr reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated in vacuo to afford the crude compound, purified by silica gel column chromatography eluting with Ethyl acetate: Hexane 30:70 to 35:65 to afford the title compound as a light red solid (25%, 1 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[N:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[Cl:11][C:9]1[CH:8]=[C:7]([O:12][CH3:13])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(Cl)cc(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Cl)cc(C(=O)O)n1

Procedure:
630 mg (3.13 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylic acid methyl ester was dissolved in 20 mL MeOH and treated with 2.34 mL 4 M aqueous NaOH solution at RT for 12 h. The reaction mixture was acidified with 4 M aqueous HCl. The solvent was removed by distillation and the residue taken up in water. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18](O)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:3][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([N:34]2[CH2:35][CH2:36][N:31]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:32][CH2:33]2)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:1])[CH3:4]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
The title compound of Example 24 is converted to its acid chloride and is reacted with N benzylpiperazine by the method of Example 23 to give the title compound.
Reaction SMILES: [N:1]1([CH:6]([CH3:10])[CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)([O-])=O>>[N:1]1([CH:6]([CH3:10])[CH2:7][CH2:8][O:9][C:17]2[CH:18]=[CH:19][C:14]([NH2:11])=[CH:15][CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(CCO)N1CCCC1
Product: CC(CCOc1ccc(N)cc1)N1CCCC1

Procedure:
The target compound was obtained by the method according to Example 18, using 3-pyrrolidin-1-yl-butan -1-ol (racemic mixture) manufactured by the method described in the literature (J. Org. Chem., 1949, Vol. 14, p. 862) and 4-nitrofluorobenzene as starting materials.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:9][C:10]([C:12]1[C:13](=[O:32])[C:14]2[CH:19]=[N:18][C:17](S(C)(=O)=O)=[N:16][C:15]=2[N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:25]=1)=[O:11])[CH3:8]>>[CH2:7]([O:9][C:10]([C:12]1[C:13](=[O:32])[C:14]2[CH:19]=[N:18][C:17]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:16][C:15]=2[N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:25]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COCCCN
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCOC)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3-methoxy-propylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 35 (Step E) above, 30 mg, 0.08 mmol). 8-Cyclohexyl-2-(3-methoxy-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (24 mg, 80%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (br, 1H), 8.48 (s, 1H), 6.21 (br, 1H), 5.11 (m, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.70-3.46 (m, 4H), 3.37 (s, 3H), 2.06-1.24 (m, 15H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C20H28N4O4: 389.21 (M+H). Found: 389.2.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](/[C:7](/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2OCC2C=CC=CC=2)=[CH:8]\[C:9]([O:11][CH2:12]C)=[O:10])=[N:4][CH:3]=1.[Mg].Cl.[CH3:31][OH:32]>>[CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:32][CH2:31][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:19][CH:20]=2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:3]=1
Reactant: CCOC(=O)/C=C(/Cc1ccccc1OCc1ccccc1)c1ncc(C)s1
Reactant: CO
Agent: Cl
Agent: [Mg]
Product: COC(=O)CC(Cc1ccc(OCc2ccccc2)cc1)c1ncc(C)s1

Procedure:
Ethyl (±)-3-(5-methylthiazol-2-yl)-4-(benzyloxyphenyl)crotonate (0.99 mmole, crude) was dissolved in MeOH (5 mL), and magnesium turnings (120 mg, 4.95 mmole) were added at RT. After 72 hr the mixture was poured into 10% HCl (75 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the crude title compound. This was used without purification: MS (ES) m/e 382 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]2)[CH:3]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29]>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]1)[CH:3]=[C:2]2[NH:29][CH2:28][CH2:27][NH2:30]
Reactant: NCCN
Reactant: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(NCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 30 by using 4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and ethane 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J=7.83 Hz, 1 H), 7.85 (brs, 1 H), 7.70-7.60 (m, 2 H), 7.52-7.40 (m, 2 H), 7.30 (dd, J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.13 (brs, 2 H), 3.67-3.57 (m, 1 H), 3.56-3.48 (m, 2 H), 3.31-3.30 (m, 3 H), 3.15-3.04 (m, 2 H), 2.42 (s, 3 H), 1.51 (brs, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([CH2:16][C:17](OCC)=[O:18])#[N:15]>C1(C)C=CC=CC=1>[C:14]([CH2:16][C:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:18])#[N:15]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC#N)CC1
Yield: 36.3 %

Procedure:
A mixture of 1-tert-butoxycarbonylpiperazine (7.44 g, 40 mmol) and ethyl cyanoacetate (8.53 mL, 80 mmol) was gently stirred in 20 mL of toluene at 90° C. for 2 days. The mixture was concentrated and purified by silica gel column chromatography, eluting with 30% ethyl acetate in n-hexane to provide the title compound (3.68 g). MS (ESI(−)) m/e 252 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 3.41 (m, 4H), 3.27-3.35 (m, 4H), 2.72 (m, 2H), 2.38 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2.[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[C:24]([CH:36]=O)[NH:23][C:22]=1[CH3:38])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[C:24]([CH:36]=[C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[NH:10][C:9]2=[O:15])[NH:23][C:22]=1[CH3:38])=[O:20])[CH3:17]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2nccs2)N1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4nccs4)c32)c1CCCN1CCN(C)CC1

Procedure:
4-Thiazol-2-yl-1,3-dihydroindol-2-one (54 mg, 0.25 mmol) was condensed with 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (88 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[C:32](N)[N:31]=[C:23]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]=2[N:21]=[CH:20]1)(=O)C.[F:36][B-](F)(F)F.[H+].N([O-])=O.[Na+]>C1COCC1>[F:36][C:32]1[N:31]=[C:23]([NH:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:22]2[N:21]=[CH:20][N:19]([C:34]=2[N:33]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: F[B-](F)(F)F
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(F)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
The above 2',3',5'-tri-O-acetyl-N-(1-piperidinyl)adenosine (1.33 g, 2.7 mmol) was dissolved in THF (50 ml) and the temperature of the solution was held between -10° C. and -20° C. Fluoroboric acid (48%, 100 ml) was added followed by an aqueous solution of sodium nitrite (0.75 g/ml, 1.5 ml). Addition of three identical amounts of sodium nitrite was continued at 0.3 hour intervals, after which TLC investigation (on a neutralised sample) indicated that the starting material was consumed [rf 0.47 (SiO2, ethyl acetate/methanol (90/10))]. The pH of the reaction mixture was adjusted to ca. 6 with 50% sodium hydroxide solution with cooling to below 0° C. and the now red reaction mixture was diluted with water (250 ml). The solution was extracted with chloroform (2×100 ml) and the combined extracts were dried (MgSO4). The residue on evaporation (containing 2',3',5'-tri-O-acetyl-2-fluoro-N-(1-piperidinyl)adenosine was treated with methanolic ammonia (150 ml) (previously saturated at -10° C.) and stirred at room temperature for 72 hours. The reaction mixture was evaporated and the resultant residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (0-10%) to provide the title compound (0.093 g) as a white solid, after washing with ethyl acetate. M.p. 197°-199° C.; 1H NMR (400 MHz, Me2SO-d6) δ 3.57, 3.65 (2H, ABX, H-5'a and H-5'b), 3.92 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.50 (1H, q, H-2'), 5.80 (1H, d, H-1'), 8.35 (1H, s, H-8). HPLC retention time 10.12 (gradient elution, 5-25% acetonitrile/0.1M pH 3.3 ammonium sulphate buffer: 214 nm detector): 100% purity.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Cl[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1>CS(C)=O>[CH3:32][C:31]1[C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=[C:29]([N+:33]([O-:35])=[O:34])[CH:30]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
To the solution of benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 10, 1.84 g, 6.06 mmol) in 15 ml of DMSO was added NaH and the resulting solution was stirred at 45° C. for 15 min. The mixture was then cooled to 0° C. via an ice/water bath and 2-chloro-3-methyl-5-nitropyridine (1.05 g, 6.06 mmol) was added in portions. The reaction mixture turned dark and became a slurry. After 10 minutes, the ice/water bath was removed and 20 ml of DMSO was added. The resulting mixture was stirred for 40 minutes allowing to warm to room temperature. The reaction was quenched by water and extracted with ethyl acetate (3×100 mL). The organics were combined and washed with brine, dried on sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified via Biotage column (65M silica gel) using ethyl acetate in hexane (0-60%, 1000 ml) to afford the title compound. MS (ESI) m/z 440 [M+H]+.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C:13](=[O:35])[C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C:28](=[CH:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]3)[CH2:20][CH2:19]4)[CH2:16][C@H:15]2[CH3:34])(=O)=O)=CC=1.[CH:36]1([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:45]=[C:44]([N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[N:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53]3)[CH:45]=[C:44]([N:54]3[CH2:59][CH2:58][N:57]([CH2:12][C:13](=[O:35])[C@@H:14]4[C@:31]5([CH3:32])[C@H:17]([C@H:18]6[C:28](=[CH:29][CH2:30]5)[C@:26]5([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]5)[CH2:20][CH2:19]6)[CH2:16][C@H:15]4[CH3:34])[CH2:56][CH2:55]3)[N:43]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Reactant: c1c(NC2CCCC2)nc(NC2CCCC2)nc1N1CCNCC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(NC3CCCC3)nc(NC3CCCC3)n2)CC1
Yield: 73.1 %

Procedure:
21-(4-Bromobenzenesulfonyloxy)-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione is reacted with 2,4-bis(cyclopentylamino)-6-(1-piperazinyl)pyrimidine according to the method of Example 6 to obtain the title compound in a yield of 73.1%, m.p.:180°-185° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+].O>C(O)C>[CH2:22]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution (150 ml) of 5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (5.0 g) and benzaldehyde (2.0 g) in ethanol was stirred at 70° C. for 3 hr. After cooling, sodium borohydride (1.40 g) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3.7 g of N-benzyl-5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C)C=O>[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)[CH:20]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1cccc(OCc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
2.87 g (19.8 mmol) of 1-chloromethyl-3-fluoro-benzene in 5 ml of dry dimethylformamide were added to a suspension of 4.66 g (19.6 mmol) of [2-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester, 4 g of K2CO3 and 0.3 g of potassium iodide in 50 ml of dry dimethylformamide. The reaction was first stirred at room temperature overnight, then was heated up to 50° C. for 6 hours. After evaporation of the solvent, water was added to the residue and the product was extracted with ethyl acetate. 7 g of crude oil were obtained. Purification by flash chromatography using a mixture of ethyl acetate/hexane (1:9→2:8 gradient) gave 5.9 g (86% yield) of the title product as a colourless oil.
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C@H:6]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[C:44]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture of 30 ml chloroform and 30 ml water containing 1.0 g of phenylalanyl-valyl-tryptophan and 0.6 g of sodium carbonate is cooled to 0° and treated with 0.20 ml of benzoyl chloride. The reaction mixture was allowed to warm to room temperature and stirred overnight. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to give 0.47 g (53 percent) of the title compound. Analysis calculated for C32H34N4O5.H2O: C, 67.11; H, 6.34; N, 9.79. Found: C, 67.00; H, 6.23; N, 9.13.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[C:13](OC)[CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].NC1C=[C:28]([O:30]C)C=CC=1C#N>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([O:30][CH3:28])[C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cc(OC)ccc3c2n1
Reactant: COc1ccc(C#N)c(N)c1
Product: CCOC(=O)c1ncc2[nH]c3cccc(OC)c3c2n1

Procedure:
The 7-methoxy-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester is produced analogously, but starting with 2-amino-4-methoxybenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][CH2:44][N:45]1[CH2:51][CH:50]([OH:52])[C:47]2([CH2:49][CH2:48]2)[CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:52][CH:50]1[C:47]2([CH2:49][CH2:48]2)[CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:22]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:23]([C:25]5([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]5)=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:51]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.2 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (260 mg, 0.534 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (266 mg, 1.068 mmol) and Cs2CO3 (520 mg, 1.602 mmol). The reaction was then stirred at rt for 2 days. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (264 mg, 77%).