Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([C:42]3C=CC=CC=3F)=[N:38]OC=2C)=NC=1.C(N)(C)C>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:38][CH:37]([CH3:42])[CH3:36])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 98 %

Procedure:
As described for example 84f, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (150 mg, 0.46 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (160 mg, 98%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:17][C:15]=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.CN.CO>CN(C)C=O.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:17][CH3:15])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: CNC(=O)c1cnc(Cl)cn1
Reaction time: 18 h
Yield: 27 %

Procedure:
5-Chloropyrazine-2-carboxylic acid (1.99 g, 12.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), and HOBt.H2O (591 mg, 3.86 mmol), WSCI.HCl (1.35 g, 7.02 mmol), N-methylmorpholine (2.76 mL, 25.1 mmol) and 40% methylamine/methanol solution (2.92 mL, 37.6 mmol) were added, followed by stirring for 18 hours. To the reaction solution, water (50 mL) was added, and extraction was carried out twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-75%) to afford the desired compound (585 mg, yield 27%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:11]2[N:12]([CH2:19][CH3:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[CH2:19]([N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:10]2[CH2:9][NH:8][CH2:22][CH2:21][C:11]1=2)[CH3:20]
Reactant: CCn1c2c(c3ccccc31)CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CCn1c2c(c3ccccc31)CNCC2
Temperature: 25 °C
Yield: 90 %

Procedure:
2-Benzyl-5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g) was dissolved in EtOH (10 mL), treated with 10% Pd/C (150 mg) and stirred under an atmosphere of hydrogen at RT. The reaction mixture was filtered through Celite® (diatomaceous earth) and concentrated. Purification by flash chromatography (10% MeOH/CH2Cl2) afforded 5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (90%) as a viscous oil.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[C:13]#N.C(C(C(C([O-])=O)O)O)([O-])=[O:38]>C(Cl)Cl>[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:38]
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C#N
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (1.0M in hexanes; 132 μL, 132 μmol) was added to a solution of 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile (44.2 mg, 120 μmol) in CH2Cl2 (2.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Saturated aqueous Na/K tartrate solution (2.0 mL) was then added, and the resulting mixture was stirred for 15 min, then partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 15% EtOAc/hexanes) provided 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 370.1; Observed: 371.2 (M++1).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]([OH:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:16](C)=O.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C.[OH-].[Na+]>[CH:1]1([N:7]([CH3:16])[CH2:8][CH:9]([OH:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(O)CNC1CCCCC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(O)CN(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(cyclohexylamino)-propan-2-ol (crude 2.6 g) in DCE (30 mL) were added successively HCHO (35% in water, 2.1 mL, 24.8 mmol), Na(OAc)3BH (10.5 g, 49.6 mmol) and acetic acid (1 mL) at ice-cold conditions. The resulting mixture was allowed to stir at rt for 16 hours. The reaction was diluted with ethyl acetate and basified with 1N NaOH. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on silica-gel (230-400 mesh) eluting with 5% MeOH/DCM to provide 1-(cyclohexyl(methyl)amino)propan-2-ol. Yield: 1.0 g
Reaction SMILES: [F:1][C:2]1([C:16](OCC)=[O:17])[CH2:7][CH2:6][C:5]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1([CH2:16][OH:17])[CH2:3][CH2:4][C:5]2([O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(F)CCC2(CC1)Oc1ccccc1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1(F)CCC2(CC1)Oc1ccccc1O2
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 350B (23 g) in tetrahydrofuran (150 mL) was added lithium aluminum hydride (3.11 g). The mixture was stirred overnight. Aqueous 2N NaOH solution was added dropwise to the reaction mixture. The mixture was then diluted with ethyl acetate (600 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product which was loaded on a 600 g analogics column and eluted with 10% to 20% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:42])[CH2:10][CH2:11][CH2:12][C:13](=[O:41])/[CH:14]=[CH:15]/[C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@@H:18]([Cl:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH2:39][CH3:40])=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl>[Si:1]([O:8][C@H:9]([CH3:42])[CH2:10][CH2:11][CH2:12][C@H:13]([OH:41])/[CH:14]=[CH:15]/[C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@@H:18]([Cl:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH2:39][CH3:40])=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/C(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1Cl
Solvent: ClCCl
Product: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 74.7 %

Procedure:
A solution of enone 13 (425 mg, 0.67 mmol) in 7 mL of dichloromethane was cooled to −30° C. and stirred rapidly while solid (R)-methylCBS-borane complex (350 mg, 1.20 mmol) was added in one portion. The resulting solution was stirred at −30° to −20° C. for 1 h. TLC analysis at this stage showed no starting material left and the reaction mixture was quenched with 2 mL of methanol, the cooling bath was removed and the mixture was stirred at 25° C. 60 min. The mixture was concentrated in vacuo to remove solvents and the residual products were purified by FCC on silica gel (40 g Silicycle cartridge, 500 mL of 10% EA-hexanes, then 500 mL of 20% EA-hexanes) to yield 316 mg (74% yield) of (15S)-alcohol 14; 1H NMR (CDCl3): 0.04 (s, 6H), 0.87 (s, 9H), 0.93 (t, J=6 Hz, 3H), 1.10 (d, J=4.8 Hz, 3H), 1.24-1.88 (m, 24H), 2.10-2.32 (m, 4H), 3.45 (m, 1H), 3.80 (m, 2H), 4.03 (m, 4H), 4.61 (dt, J=2.4, 14.4 Hz, 1H), 5.56 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccc(F)c(CBr)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)ccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27]1(O)[CH2:32]CCC[CH2:28]1>CCO.CCO.CCO.CCO.[Ti]>[I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:20][CH2:32][CH2:27][CH2:28][CH2:22]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2
Reactant: OC1CCCCC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2
Reaction time: 0.5 h

Procedure:
5 g (11 mmol) of tert.butyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 30 g (300 mmol) of cyclohexanol and 1 g (4 mmol) of tetraethyl orthotitanate are stirred at 125° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution is then stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered over siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained cyclohexyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 181°-182°.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:13])=[CH:4][C:3]=2[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH2:28][CH2:29][OH:30]>C(Cl)Cl>[OH:13][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:12][C:11]2=[CH:10][C:6]=1[C:7]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:9]
Reactant: O=C(O)c1cc2c(cc1O)OCO2
Reactant: NCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCCCO)c1cc2c(cc1O)OCO2
Yield: 64 %

Procedure:
4,5-Methylenedioxysalicylic acid was activated by carbonyldiimidazole in methylene chloride and combined with 3-aminopropanol in essentially an identical manner as for Example 1 above. An acidic quench and subsequent purification by flash chromatography (SiO2) using (1:1) hexane-ethyl acetate gave 3-(2-hydroxy-4,5-methylenedioxybenzamido)-1-propanol as a waxy white solid in 64% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]2)=[C:4]([CH:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)[CH:3]=1.Cl.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CC(C)([O-])C.[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C(C)=CC=CC=1>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]3)=[C:4]([CH:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]3)[CH:3]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CCCCN1CCN(c2ccc(Br)cc2C2CCC(C)(C)CC2)CC1
Reactant: C1CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCCCN1CCN(c2ccc(N3CCC3)cc2C2CCC(C)(C)CC2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (50 mg, 0.123 mmol) produced in Example (57b), azetidine hydrochloride (17 mg, 0.185 mmol), sodium t-butoxide (47 mg, 0.492 mmol), palladium(II) acetate (3 mg, 0.0123 mmol), tri-t-butylphosphonium tetrafluoroborate (11 mg, 0.0369 mmol) and xylene (1 mL) was stirred for 3 hours at an external temperature of 100° C. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was filtered through Celite. The solvent was distilled off by nitrogen stream to the filtrate. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-[4-azetidin-1-yl-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ccc(F)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ccc(F)cn1
Temperature: 25 °C
Yield: 1.5 %

Procedure:
A mixture of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (200 mg, 0.57 mmol), 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol (940 mg, 5.69 mmol), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) and triethylamine (0.5 mL) in dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen for 1 hr at 120° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was concentrated under vacuum and the crude product (80 mg) was purified by preparative HPLC to give 3.7 mg (1%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-fluoropyridin-2-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (300 MHz, DMSO) delta 8.54 (d, J=2.7 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.15 (d, J=1.2, 1H), 7.84 (q, 1H), 7.78-7.72 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.24 (q, 1H), 7.10-7.04 (m, 3H), 6.37 (s, 1H), 5.03 (s, 1H), 4.60 (t, J=4.5 Hz, 2H), 3.81 (d, J=4.5 Hz, 2H), 1.82 (s, 3H); LC-MS: m/z=+435 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1C=CC=CC=1.ClCCCl.[CH3:30][O:31][C:32]1[C:33]([CH3:49])=[C:34]([CH3:48])[C:35]2[O:40][C:39]([CH2:42][C:43](Cl)=[O:44])([CH3:41])[CH2:38][CH2:37][C:36]=2[C:46]=1[CH3:47]>O>[CH3:30][O:31][C:32]1[C:33]([CH3:49])=[C:34]([CH3:48])[C:35]2[O:40][C:39]([CH2:42][C:43]([N:17]3[CH2:16][CH2:15][N:14]([CH2:13][C:4]4[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=4[O:2][CH3:1])[CH2:19][CH2:18]3)=[O:44])([CH3:41])[CH2:38][CH2:37][C:36]=2[C:46]=1[CH3:47]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CN2CCN(C(=O)CC3(C)CCc4c(C)c(OC)c(C)c(C)c4O3)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution composed of 2.54 g (0.01 mol) of 1-(2,3,4-trimethoxyphenyl)methylpiperazine, 0.95 g of pyridine and 50 ml of 1,2-dichloroethane was added 3.56 g (0.012 mol) of the (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetyl chloride prepared above and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography. The eluate was further purified by recrystallization from a 95:5 (v/v) mixture of hexane and ethyl acetate to give 1.4 g of 1-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetyl]-4-(2,3,4-trimethoxybenzyl)piperazine [Compound (28)] having the following physical characteristics.
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:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[C:18](O)[CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].CC[C@@]1(O)C(=O)OCC2C(N3C(=CC1=2)C1N=C2C=CC(O)=C(CN(C)C)C2=CC=1C3)=O.CC[C@@]1(O)C(=O)OCC2C(N3C(=CC1=2)C1N=C2C(C(N)=CC=C2)=CC=1C3)=O.CC[C@@]1(O)C(=O)OCC2C(N3C(=CC1=2)C1N=C2C(=CC=1C3)C([N+]([O-])=O)=CC=C2)=O.CC[C@@]1(O)C(=O)OCC2C(N3C(=CC1=2)C1N=C2C(=CC=1C3)C=C1OCOC1=C2)=O.CC[C@@]1(O)C(=O)OCC2C(N3C(=CC1=2)C1N=C2C(=CC=1C3)C(Cl)=C1OCOC1=C2)=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: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]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Agent: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1
Agent: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(Cl)c4c(cc3nc2-1)OCO4
Agent: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1

Procedure:
10-hydroxycamptothecin; topotecan; 9-aminocamptothecin; 9-nitrocamptothecin; 10,11-methylenedioxycamptothecin; 9-amino-10,11 methlenedioxycamptothecin; 9-chloro-10,11-methylene-dioxycamptothecin; and mixtures thereof.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NCc1cccnc1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Ex-17A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in tetrahydrofuran (10 mL) was added 3-(aminomethyl)pyridine (0.58 g, 5.7 mmol) and the reaction was stirred for 30 min at room temperature. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×25 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.67 g (99%) of 4-acetyl-N-pyridin-3-ylmethylbenzenesulfonamide as a white solid, mp 143–144° C. 1H-NMR (300 MHz, CDCl3) δ 8.50–8.52 (m, 1H), 8.41 (d, 1H, J=2.7 Hz), 8.06 (d, 2H, J=8.7 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.6–7.63 (m, 1H), 7.21–7.25 (m, 1H), 5.05 (brs, 1H), 4.22 (d, 2H, J=5.7 Hz), 2.66 (s, 3H). HRMS (EI) Calcd. for C14H14N2O3S: 290.0725 (M+); Found: 290.0726.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(O)CC2)nc(Cl)n1
Yield: 57 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and 4-hydroxypiperidine (681 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (1:1 v/v) as eluent to yield the title compound (779 mg, 57%) as white crystals. MS ISP (m/e): 228.2/230.2 (100/35) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.73 (s, 1H), 4.78 (d, 1H), 3.95 (br m, 2H), 3.75 (m, 1H), 3.25 (m, 2H), 2.22 (s, 3H), 1.75 (m, 2H), 1.33 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([CH2:12][CH2:13][CH3:14])[NH:10][N:9]=1
Reactant: CCCc1[nH]ncc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCCc1[nH]nc(Br)c1-c1ccccc1
Temperature: 82 °C
Reaction time: 16 h
Yield: 15.2 %

Procedure:
To a solution of 4-phenyl-5-propyl-1H-pyrazole (1.43 g, 7.68 mmol) in acetonitrile (38.0 mL), was added N-bromosuccinimide (1.50 g, 8.45 mmol). The reaction mixture was stirred at 82° C. After 16 h, the reaction mixture was quenched with 2 M Na2CO3 (aq.) to pH 12 and the organics were separated. The aqueous layer was extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated to give a dark oil. This oil was purified by silica gel flash chromatography to give the title compound as a yellow oil (0.310 g). LCMS m/z=265.1, 267.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]OC1C(Cl)=CC(C=O)=C(F)C=1>O>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: O=Cc1cc(Cl)c(OCc2nc3ccccc3[nH]2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 0.290 g, 1.7 mmol, prepared as described in Scheme 12 of Example 15) was dissolved in N,N-dimethylformamide (20 mL, 200 mmol). Sodium hydride (60% dispersion in oil, 0.852 g, 2.13 mmol) was added to the solution and after the mixture was stirred for 20 minutes at room temperature, 2-chloromethyl-1H-benzoimidazole (106, 0.28 g, 1.7 mmol) was added to the reaction. The obtained mixture was heated to 80° C. and stirred overnight. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of ethyl acetate (40 to 100%) in hexane to give the desired compound (142, 0.233 g, 45%).