Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCOCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(Nc1ccc2c(c1)CCCN2CCCN1CCOCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of 1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-amine (190 mg, 0.690 mmol) in ethanol (10 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (393 mg, 1.380 mmol). The resulting suspension was then stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in ethyl acetate, followed by 5-10% (2M NH3 in MeOH) in dichloromethane, giving the desired N-(1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide 72 (132 mg, 0.343 mmol, 49.8% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3 Hz, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.56 (brs, 2H), 6.49 (s, 1H), 6.33 (brs, 2H), 3.60-3.56 (m, 4H), 3.26-3.17 (m, 4H), 2.66 (t, J=6.3 Hz, 2H), 2.34-2.28 (m, 6H), 1.89-1.81 (m, 2H), 1.69-1.63 (m, 2H). EI-MS (m/z, %) 384 (100, MH+), 270 (52). HPLC purity: 99%.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5]CC1C=CC=CC=1)=O.[H-].[Na+].[CH3:24][N:25]1[C:30]2[CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=[CH:34][C:29]=2[C:28](=O)[O:27]C1=O.Cl>CN(C=O)C.CCOC(C)=O>[OH:27][C:28]1[C:29]2[C:30](=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:34]=2)[N:25]([CH3:24])[C:3](=[O:5])[C:2]=1[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: COC(=O)c1ccc2c(=O)oc(=O)n(C)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(O)c(C(=O)OCc3ccccc3)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
To a solution of dibenzyl malonate (2.99 ml, 11.9 mmol) in DMF (41 ml) was added sodium hydride in portions. The cloudy grey mixture was stirred at room temperature for 20 min after which time a clear solution resulted. The solution was further stirred at 120° C. for 20 min before adding a solution of methyl 1-methyl-2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (2.82 g, 11.9 mmol) in DMF (41 ml). The resulting yellow solution was stirred at 120° C. for 3 hrs. The reaction mixture was cooled to room temperature, 2N HCl and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc 3×, the combined organics were washed with H2O (1×) followed by sat. NaCl (2×). The organic phase was then dried over MgSO4, filtered and concentrated to give a yellow solid. Purification was performed by ISCO using 10% to 50% Hex/EtOAc gradient, 40 g column to give 300 mg of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of tert-butyl (3,5-difluoro-4-nitrophenyl)acetate (4.34 g, 15.88 mmol) in DCM (10 ml), at 0° C., was added TFA (10 ml). The reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was concentrated in vacuo, slurried in heptane (10 ml), filtered and dried to provide the title compound as an orange solid (2.95 g, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COCCN(C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
Amine preparation: A mixture of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (see preparation of 121) (300 mg) and 2-bromopropane (1.20 mL) in MeCN (3 mL) with potassium carbonate (192 mg) were heated at 60° C. in a sealed tube for 7 days. The reaction mixture was cooled down, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-[isopropyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as an oil (131 mg). Treatment of this compound with HCl in DCM/MeOH and basic wash with aqueous sodium bicarbonate yielded the desired amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)(O)[O-].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[NH:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([O:18][C:15]4[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])=[CH:17][CH:16]=4)[C:20]=3[CH:27]=2)=[CH:33][CH:32]=1)[CH3:37]
Reactant: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(O)cc4)cc23)cc1)Nc1cccc(F)c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)Nc5cccc(F)c5)cc4)ncnc3[nH]2)cc1
Reaction time: 16 h

Procedure:
After dissolving 114 mg of 1-(3-fluorophenyl)-3-{4-[6-(4-hydroxyphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yloxy]phenyl}urea in 2 ml of dimethylformamide, there were added 44 mg (ca. 1 equivalent) of 2-chloroethyldiethylamine hydrochloride and 63 mg (2.5 equivalents) of potassium bicarbonate, and the mixture was stirred at 50–60° C. for 16 hours. There were then added 17 mg of 2-chloroethyldiethylamine hydrochloride, 20 mg of potassium bicarbonate and 1 ml of dimethylformamide, and the mixture was stirred overnight at the same temperature. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 33 mg of a crude solid containing the title compound. This was washed with ethyl acetate to obtain 5 mg of the title compound.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]1=O.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C.O.C(=O)(O)[O-].[Na+]>[NH2:15][C:13]1[S:14][C:2]2[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]=2[N:12]=1
Reactant: CC1(C)CC(=O)C(Br)C(=O)C1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)c2sc(N)nc2C1
Yield: 83.7 %

Procedure:
28 g of 2-bromo-5,5-dimethylcyclohexane-1,3-dione and 11.7 g of thiourea are dissolved in 200 ml of ethanol. After the weakly exothermic reaction has subsided, the mixture is refluxed for a further 6 hours. The solution is diluted with 400 ml of water and neutralised with saturated sodium bicarbonate solution. The precipitated crystals are collected by filtration and dried in vacuo at 80° C., affording 21 g of 2-amino-5,5-dimethyl-7-oxo-4,5-dihydro-6H-benzthiazole with a melting point of 203°-205° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[N:4][CH:3]=1.O.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:18])=[N:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ncc(F)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)ccc2ncc(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (1.683 g, 8.25 mmol) was dissolved in 1,4-dioxane (100 ml) and water (50 ml) was added. The solution was cooled to 0° C. and sodium periodate (5.29 g, 24.75 mmol) was added, followed by osmium tetroxide (9 mL of 4% aqueous solution). The stirred mixture was allowed to warm to rt, then stirred at rt for 1 h. The mixture was then treated with a further 100 ml of water and sodium periodate (10.58 g, 49.5 mmol) and stirred at rt for 1 h. The mixture was evaporated to approximately 50 ml and the residue was extracted with 20% methanol in DCM (3×300 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (mainly as the methyl hemiacetal) as an off-white solid (1.531 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
To a cooled (0° C.) solution of 1.75 g (10.0 mmol) of 4-chloro-2-fluoronitrobenzene in 15 mL of EtOH was added 2.97 mL (30.0 mmol) of piperidine dropwise over 5 min. The solution stirred at 0° C. for 10 min and then at 23° C. for 30 min. The mixture was poured into water (225 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with saturated aq NaHCO3 and brine (30 mL each) and then dried (Na2SO4). Concentration afforded 2.33 g (97%) of the title compound as an orange oil which crystallized on standing: Mass spectrum (ESI, m/z): Calcd. for C11H13ClN2O2, 241.1 (M+H), found 241.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6](O)[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)=[CH2:8])[CH3:2].S(Br)([Br:25])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)[CH2:8][Br:25])[CH3:2]
Reactant: C=C(C1CCN(C(C)=O)CC1)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)C1CCN(C(C)=O)CC1)NC=O
Reaction time: 0.25 h

Procedure:
3.3 g (10.5 mmol) of 4-(1-acetylpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane, and 0.98 ml (12.6 mmol) of thionyl bromide are added dropwise at room temperature. After 11/2 hours, 20 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, N-potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].O>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH2:7][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc(Br)cc(C(=O)OCc2ccccc2)c1N
Yield: 52.1 %

Procedure:
A solution of methyl 2-amino-5-bromo-3-methylbenzoate (5 g, 20.4 mmol) in benzyl alcohol (4.43 g, 40.9 mmol) and sodium methoxide (0.37 g, 2.04 mmol, 30% in methanol) was refluxed in xylene (10 ml) for 5 hours. Then, water was added, the phases were separated and the combined organic solvents were removed in vacuo. The residue was purified by column chromatography to obtain benzyl 2-amino-5-bromo-3-methylbenzoate (3.40 g, 43.3% of theory, 83.6 area % GC) as a pale brown solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[C:13]([F:19])[CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH3:21])([CH3:20])[C:10]=1[CH3:22])([OH:3])=[O:2].Cl.[C:24]1([N:30]=[CH:31][CH2:32][CH:33]=NC2C=CC=CC=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[C:17]2[C:12]=1[C:11]([CH3:21])([CH3:20])/[C:10](=[CH:22]\[CH:33]=[CH:32]\[CH:31]=[N:30]\[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[N:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: CC1=[N+](CCCCCC(=O)O)c2cc(F)cc(F)c2C1(C)C
Reactant: C(CC=Nc1ccccc1)=Nc1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)/C(=C\C=C\C=N\c2ccccc2)N(CCCCCC(=O)O)c2cc(F)cc(F)c21
Temperature: 120 °C

Procedure:
To 1-(5-carboxypentyl)-4,6-difluoro-2,3,3-trimethyl-3H-indolium (50 mg) was added malonaldehyde bis(phenylimine) monohydrochloride (37.6 mg), acetic anhydride (2 ml) and acetic acid (1 ml). This mixture was heated to 120° C. for 1 hour after which time it was cooled to room temperature. This crude reaction mixture (ca. 32 mg/ml product) was used without purification as further described.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:25])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:2]2[N:3]=[C:4]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[C:8]([CH3:25])[C:6]=3[N:7]=2)=[CH:41][N:42]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 96.6 %

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (1.49 gm) was reacted with 985 mg 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to yield 1.62 g tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate. 150 mg of this crude intermediate was subjected to General Procedure D and subsequently reacted with 84 mg D-lactic Acid via General Procedure B to give 106.3 mg of 399 after reverse phase HPLC purification. MS (Q1) 499.3 (M)+
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH2:18][CH3:19])=[N:14][C:13]=1[CH3:20])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[SH2:21]>N1C=CC=CC=1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH2:18][CH3:19])=[N:14][C:13]=1[CH3:20])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[S:21])[NH2:2]
Reactant: S
Reactant: CCNc1nc(C)c(C(=O)NC(C#N)c2cccs2)s1
Solvent: c1ccncc1
Product: CCNc1nc(C)c(C(=O)NC(C(N)=S)c2cccs2)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
0.85g of 2-ethylamino-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide (5) was dissolved in 2ml of pyridine and the reaction solution was stirred for 6 hours at 60° C. while introducing hydrogen sulfide gas. After removing the pyridine, the residue was recrystallized from ethylacetate to obtain 0.86g (Yield 91%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[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[NH:18][C:19]2[C:25](=[CH:26][C:14]=1[CH2:13]3)[CH:24]=[CH:23][C:21](=O)[CH:20]=2)=[O:11].C[OH:29].C(Cl)(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][CH2:2][C@@:3]1([OH:27])[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:25]([CH:24]=[C:23]([OH:29])[CH:21]=[CH:20]2)=[CH:26][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(=O)cc-3[nH]c2-1
Reactant: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1

Procedure:
Naturally available mixture of 10 and 11-hydroxy camptothecin (1.0 g) is dissolved in anhydrous trifluoroacetic acid (5 ml) and anhydrous methanol (10 ml) to form a homogeneous solution of the quaternized components of the mixture. The homogeneous solution is then absorbed over enough silica gel (60 A; 60-230 mesh) to form a thick slurry. This slurry is dried by evaporating methanol and excess acid in vacuo on a rotary evaporator, leaving a powdery mass. The powder is then loaded over a pre-equilibrated silica gel column using chloroform. The column is washed using 1000 ml of a solvent mixture of 80% chloroform-20% methanol to remove non polar impurities, occluded trifluoroacetic acid and 11-hydroxcamptothecin (fraction A). Elution is then continued with chloroform-methanol-triethyl amine (in the approximate ratio of 1:1:0.01) and the band migrating away from the origin is collected using this eluent (Fraction B). Fractions A and B are evaporated separately and analyzed. Fraction B corresponds to the 10-hydroxy camptothecin isolate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:20]=[C:21]4[C:30](=[CH:31][CH:32]=3)[C:29]3[N:25]([CH:26]=[C:27]([C:33]5[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][N:34]=5)[N:28]=3)[CH2:24][CH2:23][O:22]4)=[CH:17][CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH:38]([N:37]1[C:33]([C:27]2[N:28]=[C:29]3[C:30]4[CH:31]=[CH:32][C:19]([C:18]5[N:14]([CH:11]6[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]6)[N:15]=[CH:16][CH:17]=5)=[CH:20][C:21]=4[O:22][CH2:23][CH2:24][N:25]3[CH:26]=2)=[N:34][CH:35]=[N:36]1)([CH3:40])[CH3:39]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCN(C)CC3)cc1OCC2
Yield: 27.3 %

Procedure:
A mixture of tert-butyl-4-(5-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.184 mmol) and LiAlH4 (35.0 mg, 0.921 mmol) in THF (5.00 mL) was refluxed for 1 h. At the end of reaction, H2O was added to quench reaction. After filtration, the filtrate was evaporated to afford the crude product, which was purified by reverse phase combiflash eluting with 0-50% gradient CH3CN in 0.5% NH4HCO3 and followed by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give 160 (23 mg, 27% yield) as white solid. LCMS (ESI): RT=4.93 min, m/z: 459.4 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 8.53 (d, J=8.5 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.39 (d, J=1.5 Hz, 1H), 5.94-5.91 (m, 1H), 4.57 (s, 4H), 4.15 (s, 1H), 2.84-2.82 (m, 2H), 2.16 (s, 3H), 2.15-2.12 (m, 2H), 1.94-1.89 (m, 2H), 1.10-1.79 (m, 2H), 1.50 (s, 6H)
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:13][NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>O.CO.[Zn]>[C:3]1([CH2:13][N:14]2[C:15](=[O:25])[C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:22]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(NCc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]n1Cc1cccc2ccccc12
Yield: 44.1 %

Procedure:
A solution of sodium hydroxide (4.13 g) in water (80 ml) was added to a solution of N-(1-naphthylmethyl)-2-nitrobenzamide (7.6 g) in methanol (60 ml). Zinc powder (3.35 g) was then added to the mixture which was heated under reflux for 24 hours. After cooling, the zinc residue was separated by filtration and the methanol was partially evaporated. The residual solution was then adjusted to pH7 with hydrochloric acid. The precipitated solid was collected, dried and purified by column chromatography, eluting with methylene chloride/ether/methanol (50/50/5 v/v) to give 1,2-dihydro-2-(1-naphthylmethyl)-3H-indazol-3-one (3.0 g), as a white solid after washing with acetone, m.p. 198-200° C. (acetone/ether).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:6]=[N:5]1.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([O:10][CH2:9][C:8]2[N:4]([CH3:3])[N:5]=[N:6][C:7]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:22][CH:23]=1
Reactant: Cn1nnc(-c2ccccn2)c1CO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a suspension of sodium hydride (55%, 92 mg, 2.10 mmol) in THF (3 mL) was added a solution of (3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-methanol (400 mg, 2.103 mmol) in THF (5 mL) under ice cooling. The mixture was then allowed to warm up to room temperature and stirred for 30 min. Again under ice cooling was added a solution of 3,6-dichloropyridazine (315 mg, 2.10 mmol) in THF (5 mL) and the resulting mixture stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (630 mg, 99%) as a white solid. MS: m/e=303.0 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([OH:13])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)=O>>[N+:1]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:13])=[O:12])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)=O
Product: O=C(O)c1cccc([N+](=O)[O-])c1

Procedure:
Netherlands Appln. No. 66-01366 (Chemical Abstract, Vol. 68 95548A) discloses a process for the preparation of 3-nitrobenzoic by adding anhydrous nitric acid to a mixture of benzoic acid and sulfur trioxide. After the addition is completed, the sulfor trioxide is evaporated to obtain a white solid which is recrystallized from a mixture of alcohol and water to obtain pure 3-nitrobenzoic acid, m.p. 141° C.