Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O[CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23]>O>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23])=[CH:12][CH:11]=1
Reactant: O=C(CCl)NCO
Reactant: COc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
Into an ice-cooled mixture of 80 ml of acetic acid and 20 ml of 95% sulfuric acid, 16 g of anisol and 12.4 g of N-hydroxymethyl-2-chloroacetamide (refer to Beilsteins, Handbuch der Organischen Chemie, Vol. 2, 200) were added under agitation, and after stirring the reaction mixture for 30 min, it was left stand still for 2 days. Then, the reaction mixture was poured into iced water and the thus deposited white crystals were collected by filtration. The crystals were recrystallized from an aqueous ethyl alcoholic solution to obtain 8.7 g of the object product in a yield of 41%. The product melted at 101°-102° C., and showed infrared absorption peaks at 3320 cm-1 (due to NH), 1640 cm-1 (due to C=O) and 1260 cm-1 (due to --O--), respectively.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:13][C@@H](C1C=CC=CC=1)CO)[C@@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH2:13])[C@@H:8]([OH:12])[CH:9]([CH3:10])[CH3:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](O)[C@H](N[C@H](CO)c1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](O)[C@H](N)C(=O)OC(C)(C)C
Yield: 87.1 %

Procedure:
(2S,3S)-3-Hydroxy-2-((1S)-2-hydroxy-1-phenyl-ethylamino)-4-methyl-pentanoic acid tert-butyl ester (450 mg, 1.39 mmole, obtained from Reference Example 12) was hydrogenated using 10% palladium on carbon (120 mg) in methanol (100 ml) under atmospheric pressure at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 20-30% methanol in diethyl ether) to give (2S,3S)-2-amino-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester as a white solid (246 mg, 87%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[Br:21][C:5]1[S:1][C:2]([S:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:3][CH:4]=1
Reactant: CC(=O)NCCCSc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)NCCCSc1ccc(Br)s1
Temperature: 23 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
A mixture of N-(3-(thiophen-2-ylthio)propyl)acetamide (2.5 g, 11.6 mmol, 1.0 eq), NBS (2.1 g, 11.6 mmol, 1.0 eq) in DMF (5 mL) was stirred at 23° C. for 1 hour. The mixture was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated to give yellow oil N-(3-(5-bromothiophen-2-ylthio)propyl)acetamide (1.6 g, 46.8%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]#[CH:24])[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[OH:25][N:26]=[C:27](Cl)[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:23]2[O:25][N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=1
Reactant: C#Cc1cc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(Cl)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(-c3cc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a solution of tert-butyl N-(5-bromo-3-ethynyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (423 mg, 1.065 mmol) and N-hydroxy-4-methyl-benzimidoyl chloride (212.5 mg, 1.065 mmol) [Bioorganic & Medicinal Chemistry, 17(13), 4773-4785; 2009] in THF (10 mL) at ambient temperature was added Et3N (129.3 mg, 178.1 μL, 1.278 mmol) dropwise. The mixture was stirred at ambient temperature for 16 hours then at 65° C. for 2 hours. The mixture was concentrated in vacuo and the residue redissolved in DCM and washed with saturated aqueous NaHCO3 (×2) and brine (×1). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 20% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as a white solid (472 mg, 84% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.28 (s, 18H), 2.39 (s, 3H), 7.39 (d, 2H), 7.60 (s, 1H), 7.68 (d, 2H), 8.73 (d, 1H) and 8.82 (d, 1H) ppm; MS (ES+) 532.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Cl:24].[C:25](Cl)(Cl)=[O:26].C(N(CC)CC)C>ClCCCl>[Cl:24][C:23]1[C:6]2[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[N:1]=[C:25]=[O:26]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N)c2Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N=C=O)c2Cl
Reaction time: 0.17 h

Procedure:
A solution of 3.5 g (0.01 mol) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 60 ml of 1,2-dichloroethane is added dropwise while stirring to a solution of 1.5 g (0.015 mol) of phosgene in ice-cooled 1,2-dichloroethane so that the reaction temperature does not exceed 10°. Subsequently, the reaction mixture is heated at reflux while stirring for a further 10 minutes, whereupon it is cooled to ca 10° and made basic with triethylamine. There is thus obtained a solution of [6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate which can be stored in the cold for several hours with the exclusion of moisture. It is further processed without isolation of the isocyanate contained therein.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[S:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:18]([NH:17][C:8]2[S:9][C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[O:19])[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)Nc2nc(-c3ccco3)c(N3CCOCC3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
Compound 44 (145 mg, 0.400 mmol) was dissolved in pyridine (5 mL), acetic anhydride (0.19 mL, 2.00 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate:methanol=9:1) to afford the entitled Compound 54 (40.0 mg, 25%).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:16][CH2:15][CH:12]32)=[CH:7][CH:6]=1)([O-])=O>C(O)C.[Pd]>[ClH:1].[CH2:15]1[CH:12]2[C:13]3[C:8]([CH2:9][CH2:10][N:11]2[CH2:17][CH2:16]1)=[CH:7][CH:6]=[C:5]([NH2:2])[CH:14]=3
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CCCN1CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)C1CCCN1CC2

Procedure:
A suspension (+)-9-nitro-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline hydrochloride (1.83 g, 7.18 mmol) and 10% Pd-C (0.2 g) in ethanol (150 ml) was hydrogenated at 50 psi for 0.75 h. The solution was filtered and the filtrate was concentrated to a volume of 25 ml. It was then heated to reflux to dissolve all of the solid and upon cooling the product precipitated. The title compound was isolated as a white solid (1.37 g, 85%), m.p. 239-41.5° C.; [α]D +62.5° (c 1.13, MeOH). This salt was a single enantiomer by chiral CE.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26](Cl)[CH3:27])=[CH:22][N:21]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][C@H:26]([C:23]3[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[CH3:27])=[N:6][C:5]=2[N:18]=1
Reactant: CCC[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ccc(Cl)nc1
Product: CCC[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(Cl)nc2)nc2nc(N)sc12
Yield: 22.1 %

Procedure:
The title compound was prepared using General Method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol (70 mg, 0.245 mmol) and 2-chloro-5-[(1R)-1-chloroethyl]pyridine (Example 6b, 52 mg, 0.29 mmol). Purification by preparative HPLC yielded 23 mg (22% yield) of the title compound.
Reaction SMILES: [NH+]1C=CN[CH:2]=1.[N:6]1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)[CH:10]=[CH:9]N=C1.C(N)(C)C>>[CH:10]([NH:6][C:11]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[S:13](=[O:25])(=[O:24])[N:12]=1)([CH3:9])[CH3:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: c1c[nH+]c[nH]1
Solvent: CC(C)N
Product: CC(C)NC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with isopropylamine according to the general procedure Method A to give the title compound; m.p. 311-313° C.; IR (KBr): 3363, 3221, 2980, 1657, 1646,1615, 1601, 1572, 1532, 1494, 1339, 1284, 1267, 1155, 1106 cm−1; 1H-NMR (DMSO-d6, HMDS; d ppm): 1.10 (d, 6H, 2×CH3), 3.90 (m, 1H, NH—CH), 7.35 (m, 2H, 5-H+NH—CH), 8.35 (m, 2H, 6-H+8-H), 10.90 (bs, 1H, NH).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][O:8][C:9]1[C:10](I)=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.[Cu-]=O>[N:11]1[C:10]2[N:3]3[CH:4]=[CH:5][N:1]=[C:2]3[CH2:6][CH2:7][O:8][C:9]=2[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=1
Reactant: COC(=O)c1cnc(I)c(OCCc2ncc[nH]2)c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cnc2c(c1)OCCc1nccn1-2
Temperature: 110 °C

Procedure:
A mixture of methyl 5-(2-(1H-imidazol-2-yl)ethoxy)-6-iodonicotinate (373 mg, 1.00 mmol), Copper(I) oxide (14.3 mg, 0.10 mmol), Ninhydrin (35.6 mg, 0.20 mmol) and potassium carbonate (290 mg, 2.10 mmol) in dimethyl sulfoxide (10.0 mL) was heated at 110° C. for 2 hours. The mixture was poured into 20 ml of water and extracted with ethyl acetate (3×15 ml). The organic extracts were washed with water (3×15 ml), brine, dried over MgSO4 and concentrated. The residue (0.220 g, 90%) was used without further purification in the next step. MS (ESI+): 246.0. 1H NMR (500 MHz, CDCl3) δ 8.77 (d, J=1.9, 1H), 8.10 (s, 1H), 8.04 (d, J=1.9, 1H), 7.08 (s, 1H), 4.47 (t, J=5.1, 2H), 3.97 (s, 3H), 3.46 (t, J=5.1, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[N:4]=1)[CH3:2].Br.C([O-])(O)=O.[Na+]>CC(O)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[N:4]=1)[CH3:2]
Reactant: CCc1cccc(OC)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cccc(O)n1
Temperature: 90 °C

Procedure:
step 3—A mixture of 26 (530 mg), 48% HBr (1.05 mL) and HOAc (10 mL) in a sealed tube was heated at 90° C. overnight. The reaction mixture was cooled to RT, carefully poured into saturated aqueous NaHCO3 solution, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated to afford 2-ethyl-6-hydroxypyridine (28) as a light yellow solid.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:11])[CH3:10].Cl>>[C:9]([O:7][C:6]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1O
Agent: Cl
Product: CC(=O)Oc1ccccc1C
Reaction time: 3 h
Yield: 95 %

Procedure:
Into a spherical flask provided with a condenser, a dropping funnel and containing 2 moles of o-cresol, 2.4 moles of acetyl chloride are introduced in 15 minutes. The bath is kept at 110° C. until the release of hydrochloric acid is completed, i.e. after about 3 hours, and then the o-cresol acetate as obtained is distilled under vacuum:
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:13]=[C:12]([N:14]([CH3:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl[C:24]1C2C(=CC=CC=2)N=C(CCl)N=1.CNC1C=CC(O)=CC=1>C(O)(C)C.Cl>[Cl:2][CH2:3][C:4]1[N:13]=[C:12]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:24])=[CH:19][CH:20]=2)[CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CN(c1ccc(O)cc1)c1nc(CCl)nc2ccccc12
Reactant: ClCc1nc(Cl)c2ccccc2n1
Agent: CNc1ccc(O)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[(2-Chloromethyl-quinazolin-4-yl)-methyl-amino]-phenol hydrochloride: To 4-chloro-2-chloromethyl-quinazoline (200 mg) suspended in isopropanol (3 ml) was added 4-methylamino-phenol (389 mg) and followed by HCl (12 M, 2 drops). The reaction was stirred overnight at room temperature. The resulting precipitate was filtered to give 391 mg of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as the hydrochloride salt. 1H NMR (MeOH-d4) δ 7.28 (m, 4H), 6.90 (m, 4H), 4.8 (s, 2H), 3.8 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[C:18]3[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)=O.C(Cl)Cl.O.CO>[CH3:24][CH:23]([CH3:25])[CH2:22][N:21]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:8])[C:18]=2[N:19]=[CH:20]1
Reactant: CC(C)Cn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=CO
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Yield: 43.8 %

Procedure:
Palladium hydroxide on carbon, Pearlman's catalyst, (0.25 g) was added to a solution containing N,N-bis(phenylmethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 0.95 mmole, Example 4) in formic acid (20 mL). The reaction was heated at reflux for about 16 hours at which time more catalyst (0.2 g) was added and heating was continued until the reaction was complete as indicated by thin layer chromatography (silica gel; 5% methanol in methylene chloride). The reaction mixture was diluted with water (20 mL), methylene chloride (40 mL) and methanol (10 mL) then filtered. The filtrate layers were separated and the organic layer was concentrated under vacuum. The residue was recrystallized from dimethyl formamide then suspended in methanol and stirred before being isolated by filtration and dried to provide 0.1 g of a solid. The melting point and spectral properties of this material matched those of an authentic sample.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:27])[N:12]([CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.O.NN>C1COCC1>[NH2:16][CH2:15][CH2:14][N:12]1[CH:13]=[C:8]([CH:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][C:11]1=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 2-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-1H-isoindole-1,3(2H)-dione (295 mg) in mixed solvent (EtOH:THF=4.4 mL:2.2 mL) was added hydrazine hydrate (329 μL) and the mixture was stirred at ambient temperature for 1 hour. The resulting mixture was evaporated in vacuo and the residue was diluted with chloroform (10 mL). The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=99:1-96:4) to afford 1-(2-aminoethyl)-5-(diphenylmethyl)-2(1H)-pyridinone (154 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8].[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>CN1C(=O)CCC1.CCOC(C)=O.O>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc2[nH]cnc2c(Cl)c1Br
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nc2[nH]cnc2c(F)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in NMP is added KF (3.00 equivalents) and 18-crown-6 (0.20 equivalents) at room temperature. The resulting mixture is refluxed with stirring for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:42]=[CH:43][C:44]([F:65])=[C:45]([C:47]2([CH3:64])[C:53]([F:55])([F:54])[CH2:52][O:51][CH2:50][C:49]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[N:48]2)[CH:46]=1.C(OC(C)(C)C)=O>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([F:65])=[C:45]([C:47]3([CH3:64])[C:53]([F:54])([F:55])[CH2:52][O:51][CH2:50][C:49]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[N:48]3)[CH:46]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(N)ccc2F)C(F)(F)COC1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CC(C)(C)OC=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C(F)(F)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-Chloro-pyridine-2-carboxylic acid (0.085 g, 0.54 mmol) in dry DMF (3.0 mL), Et3N (0.22 mL, 1.6 mmol) and EDCl (0.128 mg, 0.81 mmol) and HOAt (0.11 g, 0.81 mmol) and tert-butyl 5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylcarbamate (0.201 g, 0.54 mmol) were added and stirred at rt for 24 h. upon completion of the reaction, reaction mixture was poured into a rapidly stirred ice cold water to obtain precipitate. Yield=220 mg, (80%). TLC (30% ethyl acetate in Hexane): Rf=0.4, LCMS: RtH8=1.78 [M+H-Boc]+=413.0, 414.8,
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[N+:27]([O-])([OH:29])=[O:28]>S(=O)(=O)(O)O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16](=[CH:15][C:14]=1[CH2:13]3)[C:17]([N+:27]([O-:29])=[O:28])=[CH:18][CH:19]=[CH:20]2)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c([N+](=O)[O-])cccc3nc2-1
Reaction time: 36 h

Procedure:
Camptothecin (25 g) in concentrated sulfuric acid (500 mL) was cooled in an ice-bath. To it was then added 70% nitric acid (30 mL), drop-wise to control the reaction temperature. The reaction mixture was then stirred for 36 hours, poured into excess crushed ice and the organic portion was extracted out using chloroform. The combined organic fraction was washed with freshly prepared 10% sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. Solvent was removed and the residue was purified by flash silica gel column using hexane/ethyl acetate (1:1) as eluent to furnish 2.7 g of 9-nitrocamptothecin.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (82) and benzyl bromide according to General Procedure B. Yield 319 mg (59%), MP 197° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.95 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.52 (s, 2H), 7.15-7.28 (m, 6H), 7.46 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H); EIMS: 537 (M+1). Anal. (C27H25ClN4O4S) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:7]2[C:8]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[C:5]3[C@H:16]4[NH:17][C@@H:12]([CH2:11][C:6]2=3)[CH2:13][CH2:14][CH2:15]4)=[CH:21][CH:20]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C[C@H]2CCC[C@@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (226 mg, 1.0 mmol; Example 118A) and 1-chloro-4-vinylbenzene (277 mg, 1.99 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.03-1.17 (m, 1H), 1.28-1.43 (m, 2H), 1.65 (d, J=13 Hz, 1H), 1.76-1.94 (m, 2H), 1.98 (d, J=17 Hz, 1H), 2.40 (s, 3H), 2.90 (dd, J=17, 8 Hz, 1H), 2.97-3.15 (m, 2H), 3.47-3.54 (m, 1H), 4.15-4.27 (m, 1H), 4.31-4.44 (m, 2H), 6.93-6.99 (m, 2H), 7.15 (s, 1H), 7.18 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 365 367 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=O)=[CH:32][CH:31]=1)[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:16][O:15][C:14](=[O:17])[NH:13][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:9][CH:10]3[CH2:12][CH2:11]3)[C:37]([CH2:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:27][CH3:28])=[CH:31][CH:32]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: COC(=O)Nc1ccc(NCC2CC2)c(N)c1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(NC(=O)OC)ccc3n2CC2CC2)cc1

Procedure:
Following general procedure 13B: Methyl 3-amino-4-[(cyclopropylmethyl)amino]-phenylcarbamate (4.0 g, 17.0 mmol), DIPEA (5 mL), 4-ethoxyphenylacetic acid (3.06 g, 17.0 mmol) and HATU (7.10 g, 18.7 mmol) were combined. The desired product (3.34 g, 52%) precipitated out of the reaction mixture. 1HNMR (CDCl3): δ 7.65 (d, J=2.0 Hz, 1H), 7.37 (br., 1H), 7.26 (d, J=4 Hz), 7.12 (d, J=9.0 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 6.74 (br., 1H), 4.25 (s, 2H), 3.98 (q, J=7.4 Hz, 2H), 3.87 (d, J=7.2 Hz, 2H), 3.79 (s, 3H), 1.38 (t, J=7.4 Hz, 3H), 1.05–0.97 (m, 1H), 0.52–0.47 (m, 2H), 0.25–0.20 (m, 2H). MS (ESI) (M+H)+=380.