Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH2:5].C(#N)C.[CH3:20][N:21]([CH3:76])[C@H:22]1[CH2:73][C@@H:72]([CH3:74])[O:71][CH:24]([O:25][C@@H:26]2[C@@H:42]([CH3:43])[C:41](=[O:44])[C@@H:40]([CH3:45])[C:39](=[O:46])[O:38][C@H:37]([CH2:47][CH3:48])[C@:36]3([CH2:49][CH3:50])[C@H:32](N(CCCCN4C5C(=NC=CC=5)N=C4)[C:34](=[O:51])[O:35]3)[C@@H:31]([CH3:65])[C:30](=[O:66])[C@H:29]([CH3:67])[CH2:28][C@@:27]2([O:69][CH3:70])[CH3:68])[C@@H:23]1[OH:75]>O>[CH3:76][N:21]([CH3:20])[C@H:22]1[CH2:73][C@@H:72]([CH3:74])[O:71][CH:24]([O:25][C@@H:26]2[C@@H:42]([CH3:43])[C:41](=[O:44])[C@@H:40]([CH3:45])[C:39](=[O:46])[O:38][C@H:37]([CH2:47][CH3:48])[C@:36]3([CH2:49][CH3:50])[C@H:32]([N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH2:6][C:7]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=[CH:9][CH:8]=4)[C:34](=[O:51])[O:35]3)[C@@H:31]([CH3:65])[C:30](=[O:66])[C@H:29]([CH3:67])[CH2:28][C@@:27]2([O:69][CH3:70])[CH3:68])[C@@H:23]1[OH:75]
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc4ncccc43)C(=O)O[C@]12CC
Reactant: CN(CCN)Cc1ccnc2ccccc12
Solvent: CC#N
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCN(C)Cc3ccnc4ccccc34)C(=O)O[C@]12CC
Yield: 18 %

Procedure:
C12 ethyl, C9, C10, C11 enone, 3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-Methyl-N1-quinolin-4-ylmethyl-ethane-1,2-diamine (6 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetra-oxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{2-[methyl-(quinolin-4-ylmethyl)amino]ethyl}-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (18% yield) as an off white solid. MH+(825.50).
Reaction SMILES: Cl.[C:2]1([CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[N:14]=[C:13]([C:15]([NH2:17])=[NH:16])[CH:12]=[CH:11][CH:10]=1.C[O-].[Na+].[CH3:22][CH2:23][CH2:24][CH2:25]CC.C(OCC)(=O)C>CO.COC(OC)C(=O)CC>[CH3:25][C:24]1[CH:23]=[CH:22][N:17]=[C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:18])[N:14]=2)[N:16]=1
Reactant: Cc1ccccc1Oc1cccc(C(=N)N)n1
Reactant: CCCCCC
Agent: CCC(=O)C(OC)OC
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2cccc(Oc3ccccc3C)n2)n1
Yield: 76 %

Procedure:
To a mixture of 6-o-tolyloxy-2-picoline amidine hydrochloride (3 g) and methanol (100 ml) were added 28% sodium methoxide solution in methanol (3.3 g) and 1,1-dimethoxybutanone (1.9 g). The mixture was heated under refluxing for an hour, and was left to stand at room temperature. The reaction solution was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate=2:1 in volume) to obtain 4-methyl-2-(6-o-tolyloxy-2-pyridinyl)pyrimidine (2.4 g, yield 76%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[CH:14][C:15]([C:22]#[N:23])=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:10]([CH3:25])([CH3:24])[C:9]=2[CH:26]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][C:10]1([CH3:24])[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[C:19]=2[C:20](=[O:21])[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]3)=[CH:26][C:9]1=2
Reactant: O=C1CNCCN1
Reactant: CC1(C)c2cc(OCCBr)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)c2cc(OCCN3CCNC(=O)C3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To DMF solution (5 mL) of 8-(2-bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A7-24, 30 mg, 0.07 mmol), piperazin-2-one (44.9 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) were added at room temperature and stirred at 80° C. for 18 hr. After cooling to room temperature, the mixture was extracted with ethyl acetate washed with saturated brine. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by preparative TLC (dichloromethane/methanol) to obtain the title compound (white solid, 24 mg, 80%).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24](=[O:26])[NH2:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-]>C1COCC1.O>[C:24]([C:21]1[N:22]=[CH:23][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:27])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=1)(=[O:26])[NH2:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(N)=O)cn3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cnc(C(N)=O)cn2)cc2c1C(CC(=O)O)OB2O
Yield: 52.7 %

Procedure:
A solution of [6-(5-carbamoyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (77 mg, 0.21 mmol) in THF (4 mL) was treated with LiOH (35 mg, 0.84 mmol) in water (4 mL) at room temperature for 1 h. The reaction was concentrated to dryness. The residue was diluted with water and adjusted to pH 3. The mixture was purified by preparative HPLC to give the title compound (38 mg). 1H NMR (300 MHz, CD3OD) δ 8.76 (s, 1H), 8.46 (s, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 5.73-5.69 (m, 1H), 3.33-3.18 (m, 1H), 2.42 (s, 3H), 2.38-2.33 (m, 1H). MS found: (M+H)+: 344.1.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[K+].Br[C:54]1[N:59]=[C:58]([CH2:60][C:61]([O:63][CH3:64])=[O:62])[CH:57]=[CH:56][CH:55]=1.[C:65](=[NH:78])([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:64][O:63][C:61](=[O:62])[CH2:60][C:58]1[CH:57]=[CH:56][CH:55]=[C:54]([N:78]=[C:65]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[N:59]=1
Reactant: COC(=O)Cc1cccc(Br)n1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(N=C(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C

Procedure:
To a solution of Pd2(dba)3 (4.0 mg, 0.0040 mmol), BINAP (41 mg, 0.065 mmol), and potassium tert-butoxide (490 mg, 4.35 mmol) in toluene (10 mL) was added methyl (6-bromopyridin-2-yl)acetate (1 g, 4.35 mmol) and benzophenone imine (1.1 mL, 6.52 mmol). The reaction was degassed for 15 minutes and then heated at 100° C. for 15 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The crude residue was taken up in ethyl acetate (200 mL), filtered over celite, and washed with water. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via MPLC (0-100% EtOAc/Hex gradient) to afford title compound. LC/MS (M+H)+ 331.
Reaction SMILES: C(OC([NH:11][CH:12]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([N:23]([CH:32]([CH3:34])[CH3:33])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[O:22])[C:16]2[CH:35]=[CH:36][CH:37]=[CH:38][C:15]=2[C:14]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[N:13]1)=O)C1C=CC=CC=1.[BrH:45]>C(O)(=O)C>[BrH:45].[NH2:11][CH:12]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([N:23]([CH:32]([CH3:34])[CH3:33])[C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[O:22])[C:16]2[CH:35]=[CH:36][CH:37]=[CH:38][C:15]=2[C:14]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[N:13]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)OCc3ccccc3)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.00 g of 2-[3-(N-benzyloxycarbonyl-amino)-2-oxo-5-pyridin-3-yl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (1.690 mmol), prepared as in Intermediate 30, in 6 mL glacial acetic acid was saturated with hydrogen bromide gas and stirred at ambient temperature for 16 hrs. The reaction mixture was evaporated in vacuo to a residue and triturated with diethyl ether. The resulting slurry was filtered, washed with diethyl ether, and dried under high vacuum to provide 1.062 g of the title compound as a dihydrobromide salt. 1H NMR (300 MHz, CD3 OD) -- =9.06 (m, 2H), 8.85 (m, 1H), 8.21 (dd, 1H, J=5.8, 8.1), 7.84 (m, 1H), 7.61 (d, 1H, J=8.3), 7.50 (m, 2H), 7.27 (m, 2H), 7.10 (d, 2H, J=8.8), 5.25 (s, 1H), 4.52 (d, 1H, J=16.7), 4.31 (d, 1H, J=16.7), 3.88 (s, 3H), 1.07 (m, 6H); MS (ESI): [M+H]+ =458.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][OH:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CN(C)C.[C:22](Cl)(=[O:24])[CH3:23].Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:22]([O:17][CH2:16][C:11]1[N:12]=[C:13]([CH3:15])[NH:14][C:10]=1[S:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: Cc1cc(C)cc(Sc2[nH]c(C)nc2CO)c1
Reactant: CC(=O)Cl
Agent: CN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(=O)OCc1nc(C)[nH]c1Sc1cc(C)cc(C)c1

Procedure:
In dry methylene chloride (85 ml)was dissolved 1.7 g (6.8 mmol)of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methanol (41d), followed by addition of 2.10 g (20.8 mmol)of trimethylamine. To this solution, acetyl chloride was added dropwise with stirring under ice-cooling. At the same temperature, the mixture was stirred for 30 minutes, then, 8.3 ml of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate)to obtain 1.55 g of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methyl acetate (41b)as oil (yield 78%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Nc2ccccc2)o1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 5-bromo-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide (1.0 mmol) in toluene (7.5 mL) was added aniline (1.3 mmol), tris(dibenzylidineacetone)dipalladium(0) (“Pd2dba”) (Aldrich) (0.05 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (“BINAP”) (0.1 mmol), and potassium tert-butoxide (“t-BuOK”) (1.5 mmol), and the resulting mixture was refluxed overnight. The reaction was then cooled to room temperature, passed through a plug of silica and concentrated. Purification of the dark brown residue by HPLC afforded the product. Yield: 40%. MS: 362 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[CH2:14][CH2:13][CH2:12][CH:8]([C:9]([NH2:11])=[O:10])[CH2:7]1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+]>>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:6]2[CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH2:11])=[O:10])[CH2:7]2)=[O:21])=[CH:18][CH:17]=1
Reactant: NC(=O)C1CCCNC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)N2CCC[C@@H](C(N)=O)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
Concentrated sulfuric acid is added to the reaction mixture obtained in Example 4 (amount: 30 g, net weight of (R)-nipecotamide: 3 g) to adjust the pH to 9. To the mixture, p-Methylbenzoyl chloride (8.0 g, 2.2 equivalents) was slowly added dropwise, and the pH of the reaction mixture was kept from 7 to 9 by a 30% aqueous sodium hydroxide solution. After completion of the dropwise addition, the solution was stirred at 15° C. for 3 hours and the precipitated crystal was filtered off. The crystal was dried under reduced pressure to obtain the title compound as white crystal (4.4 g, yield: 760).
Reaction SMILES: [CH2:1]([N:4]([CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][CH2:13]1)[CH3:18])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C=CCN(C)CCCCCCOC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C)CCCCCCOC1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
3 g of allyl-methyl-[6-(piperidin-4-yloxy)-hexyl]-amine (Ex. 49.1) are dissolved in 50 ml of methylene chloride and treated with 5.3 ml of Hünig Base (di-isopropyl-ethylamine) and 1.9 g of 4-bromo-phenylsulphonyl chloride. The reaction mixture is stirred at room temperature for 3 hours, treated with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and concentrated. The brown oil is purified on silica gel with ethyl acetate/methanol (9:1). There are obtained 2.6 g of allyl-[6-[1-(4-bromo-phenylsulphonyl)-piperidin-4-yloxy]-hexyl]-methyl-amine which are converted into the fumarate, MS: m/e 473 (M+H+, 1Br).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][C:34]1[S:35][C:36]([S:40](Cl)(=[O:42])=[O:41])=[C:37]([CH3:39])[N:38]=1>ClCCl>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([S:40]([C:36]5[S:35][C:34]([CH3:33])=[N:38][C:37]=5[CH3:39])(=[O:42])=[O:41])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-((2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine hydrochloride (Intermediate 15, 0.050 g, 0.153 mmol), dichloromethane (1.5 mL), and triethyl amine (0.043 mL, 0.306 mmol) was added 2,4-dimethyl-thiazole -5-sulfonyl chloride (0.049 g, 0.229 mmol) and the reaction stirred at room temperature for 2 hours. The solution was concentrated and purified by flash column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes to afford the desired product.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12](=[O:20])[NH:13][C:14]=1[CH:15]=[CH:16][N:17](C)C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+]>CN(C)C=O>[C:2]1([C:1]2[N:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12](=[O:20])[NH:13]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1ccc2c(-c3ccccc3)nccc2[nH]1
Reaction time: 7 h
Yield: 56.8 %

Procedure:
A mixture containing 13.4 g of 5-benzoyl-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinone, 100 ml of dimethylformamide and 12 g of ammonium acetate was heated with stirring on a steam bath for 7 hours and then concentrated on a rotary evaporator. The remaining solid residue was treated with 100 ml of water, the mixture filtered, the collected solid air-dried, recrystallized from ethanol and dried in a vacuum oven at 90°-95° C. to yield 6.3 g of 5-phenyl-1,6-naphthyridin-2(1H)-one, m.p. 261°-263° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([F:23])[CH:15]=1)=O>O=P(Cl)(Cl)Cl>[C:2]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([F:23])[CH:15]=1)#[N:1]
Reactant: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])c(F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc([N+](=O)[O-])c(F)c1
Yield: 97.5 %

Procedure:
A solution of intermediate ethyl 5-(aminocarbonyl)-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate (36.8 mg, 114.5 mmol) in POCl3 (500 mL) was heated to 70° C. for 2 h. TLC analysis indicated that there was complete conversion of starting material. Excess POCl3 was removed under reduced pressure and the remaining solids were poured over ice. The pH was adjusted to 8 using 5 N NaOH and the solution was filtered. The product was dried over night under reduced pressure to afford a light brown solid (33.85 g, 111.6 mmol) in 97% yield. 1H-NMR (DMSO-d6) δ 13.32 (br s, 1H), 8.21 (app t, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.73 (dd, J=12.4, 2.0 Hz, 1H), 7.51 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H); HPLC RT=3.16 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]=O>[Pt].C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10])[CH:8]=[O:11]
Reactant: O=O
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [Pt]
Solvent: CC(=O)O
Product: Cc1cc(C=O)cc(C)c1O
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 75 %

Procedure:
Into a 300-ml stainless steel Parr bomb is placed 25 g of 2,4,6-trimethylphenol, 2.0 g of 5 percent platinum on carbon and 75 ml of acetic acid. The bomb is pressurized to 250 psig with O2 and heated to 75° C. The bomb is held at this temperature for 4.5 hours. The material is filtered through celite and the acetic acid is removed by rotary evaporation. A 75 percent yield of 3,5-dimethyl-4-hydroxybenzaldehyde is obtained. This material is further purified using a toluene slurry wash (m.p. 111° C.-113° C.). The principle by-product is 2,6-dimethyl p-benzoquinone.
Reaction SMILES: [CH3:1][CH2:2][C:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=[CH:20]2)=[O:11].[Sn]>[Pt]=O.[Fe].[Zn]>[CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22]([NH2:26])[CH:21]=[CH:20]2)=[O:11]
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc([N+](=O)[O-])ccc3nc2-1
Agent: O=[Pt]
Agent: [Fe]
Agent: [Sn]
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(N)ccc3nc2-1

Procedure:
In order to obtain the product of the general formula (I') wherein R3' is an amino group, 10-nitrocamptothecin, its tetrahydro derivative or its 1-acyl-tetrahydro derivative is subjected to a conventional reductive reaction contemplated for reducing a nitro group to an amino group. Usually, Clemensen' reduction method (a combination of dilute mineral acid and tin, iron or zinc) or a catalytic reduction method is used for this purpose. Advantageously, 10-nitrocamptothecin is dissolved in a solvent and hydrogenated at room temperature under atmospheric pressure in the presence of a small amount of platinum oxide. In this case, the desired 10-aminocamptothecin can be obtained by removing the catalyst from the reaction mixture by filtration and evaporating the solvent under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.BrC1CC1>CS(C)=O.CCOCC>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH:5]2[CH2:2][CH2:1]2)=[CH:10][CH:9]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: Brc1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a degassed solution of potassium tert-butoxide (2.08 g, 18.51 mmol) in dry dimethylsulphoxide (6 mL), 4-bromo-benzenethiol (3.5 g, 18.5 mmol) was added and the mixture was stirred for 15 min at ambient temperature under nitrogen. Bromocyclopropane (4.4 mL, 55.5 mmol) was added afterwards and the reaction mixture was heated at 80° C. for 24 h in a sealed vessel. The mixture was cooled, diluted with ether (150 mL) and washed with water (100 mL). The aqueous layer was extracted with ether (3×50 mL). Combined organic extracts were finally dried with anhydrous magnesium sulfate. 1-Bromo-4-cyclopropylsulfanyl-benzene was obtained after evaporation of the solvent as yellow liquid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[O:29])=[CH:26][N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[C:26]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:25][CH:24]=[N:23][CH:22]=2)=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(NC(=O)c2cncnc2Cl)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)c2cncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 120 °C
Yield: 24.2 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (15 mg, 0.06 mmol), 4-chloro-N-(3-methoxyphenyl)pyrimidine-5-carboxamide (14 mg, 0.05 mmol, prepared according to R. Tadiparthi et al PCT Int. Appl. 2007031829, 22 Mar. 2007), DIEA (50 μl, 0.29 mmol) and cesium fluoride (17 mg, 0.11 mmol) were suspended in tert-butanol (2 ml) and the mixture was heated at 120° C. in a sealed tube for 18 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 10%, dichloromethane-methanol) to obtain 6 mg (5% yield) of the title compound.