Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CC[C@@H](O)C1.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:35]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:19][CH:18]=3)[C:9]=12>>[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C@H:35]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:21][CH:22]=3)[C:9]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C)C5)c5ncnc(N)c45)cc3)nc2c1
Agent: O[C@@H]1CCNC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn([C@H]5CCN(C)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
N2-(4-{4-amino-1-[(3S)-1-methyltetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from (R)-(−)-3-pyrrolidinol in a manner analogous to that used for the preparation of rac-N2-{4-[4-Amino-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine. The compound was formed as a white solid (0.126 g, 20%). 1H NMR (DMSO-d6, 400 MHz) 1H NMR (DMSO-d6, 400 MHz) 2.31-2.35 (m, 2H), 2.31 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 2.67-2.76 (m, 3H), 3.05 (t, 1H), 5.40 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.84 (s, 1H); RP-HPLC Rt 11.129 min, 100% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 455 (MH+).
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH3:17])[C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[C:4]([CH3:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:16]=[C:15]([CH3:17])[C:5]([O:6][CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]3)=[C:4]([CH3:18])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cc(C)c1OCC1CCCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cc(C)c(OCC3CCCN(C)C3)c(C)c2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine (531 mg, 1.70 mmol) in toluene (10 mL) was added 3-methoxyphenylboronic acid (319 mg, 2.10 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), and 2M sodium carbonate (1.7 mL, 3.4 mmol). The mixture was stirred at 100° C. overnight and cooled to room temperature. The solution was partitioned between water and ethyl acetate. The organic layer was washed twice with water, brine, and dried. The solvent was removed and the residue purified on silica gel, eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, to give 3-[4-(3-methoxyphenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:22]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:22])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: Clc1nc2ccccc2c2c1ncn2Cc1ccccn1
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2Cc1ccccn1
Temperature: 150 °C

Procedure:
A mixture of 2.4 g of 4-chloro-1-(2-pyridylmethyl)-1H-imidazo[4,5-c]quinoline and 50 mL of 15% ammonia in methanol was placed in a bomb and heated at 150° C. for 6 hours. After cooling, the reaction mixture was filtered. The solid was slurried with aqueous sodium bicarbonate, collected and dried to provide 1.9 g of crude product. The crude product was recrystallized from 350 mL of ethanol to provide 1.25 g of a solid, m.p. 278°-284° C. The mother liquor was concentrated to a volume of 50 mL to provide a second crop of 0.32 g, m.p. 275°-281° C. The two crops were combined for analysis. Analysis: Calculated for C16H13N5 : % C, 69.8; % H, 4.8; % N, 25.4; Found % C, 69.7; % H, 4.8; % N, 25.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH2:13])=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:9]1.Cl[C:22]1[N:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].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.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([NH:13][C:22]2[N:32]=[CH:31][CH:30]=[CH:29][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:9]1
Reactant: Nc1cc(-c2ccc(F)cc2)nn1-c1ccccc1Cl
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1cccnc1Nc1cc(-c2ccc(F)cc2)nn1-c1ccccc1Cl
Temperature: 110 °C
Yield: 90.2 %

Procedure:
To a dried 15 mL tube was added 1-(2-chlorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-amine (300 mg, 1.04 mmol), synthesized in the same manner as intermediate G, ethyl 2-chloronicotinate (194 mg, 1.04 mmol), Pd2(dba)3 (48 mg, 0.05 mmol), BINAP (65 mg, 0.10 mmol), and Cs2CO3 (679 mg, 2.09 mmol). The flask was degassed followed by addition of toluene (4 mL) and the mixture was then heated to 110° C. for 20 h. The mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 45% to 90% acetonitrile in water to afford 410 mg (90%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.17 (s, 1H), 8.46 (dd, 1H), 8.22 (dd, 1H), 7.89 (dd, 2H), 7.48-7.64 (m, 4H), 7.23 (s, 1H), 7.12 (t, 2H), 7.84 (dd, 1H), 4.24 (q, 2H), 1.32 (t, 3H); ES-MS m/z 437.2 (MH+); HPLC RT (min) 4.38.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][N:21]=[C:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO.O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][NH:21][CH:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1=NCCn2c1cc1c2-c2ccc(OC3CCCC3)cc2CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1NCCn2c1cc1c2-c2ccc(OC3CCCC3)cc2CC1
Yield: 31 %

Procedure:
3-Cyclopentyloxy-5,6,10,11-tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole (0.8 g) was dissolved in a mixture of 50 ml of methanol and 5 ml of water under argon. The solution was treated portionwise with 0.3 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 30 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 30 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.8 g of amorphous, brown solid, was chromatographed on 30 g of silica gel with methylene chloride/methanol mixtures (50:1 to 20:1). The isolated crude product was dissolved in a 25-fold amount of hot ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.34 g (31 %) of 3-cyclopentyloxy-5,6,8,9,10,11-hexahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 187°-189° C. (dec.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N.[H][H]>C1COCC1.CO.[Ni]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc2[nH]ncc2c1
Reaction time: 8 h

Procedure:
To a suspension of 1H-indazole-5-carbonitrile (0.235 g, 1.64 mmol) in THF (6 mL) was added 2 mL of 2 N ammonia in methanol and the flask was charged with 0.05 g Raney® 2800 nickel. A hydrogen balloon was attached to the flask and the system was purged 3 times with hydrogen. After stirring vigorously overnight the reaction mixture was diluted with methanol and filtered through a pad of celite. The solvent was evaporated in vacuo to provide 1-(1H-indazole-5-yl)methanamine.
Reaction SMILES: [CH3:1][CH:2]([O:4][CH:5]1[C:14]2[C:9](=[C:10]([CH3:26])[CH:11]=[C:12]([C:16]([CH:18]3[CH:23](Cl)[CH2:22][CH2:21][CH2:20][C:19]3=[O:25])=[O:17])[C:13]=2[CH3:15])[S:8](=[O:28])(=[O:27])[CH2:7][CH2:6]1)[CH3:3].[C:29]1([SH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClC1C2CCS(=O)(=O)C=2C=CC=1C(C1C(Cl)CCCC1=O)=O.C(S)C>>[CH3:1][CH:2]([O:4][CH:5]1[C:14]2[C:9](=[C:10]([CH3:26])[CH:11]=[C:12]([C:16]([CH:18]3[CH:23]([S:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21][CH2:20][C:19]3=[O:25])=[O:17])[C:13]=2[CH3:15])[S:8](=[O:28])(=[O:27])[CH2:7][CH2:6]1)[CH3:3]
Reactant: Sc1ccccc1
Reactant: Cc1cc(C(=O)C2C(=O)CCCC2Cl)c(C)c2c1S(=O)(=O)CCC2OC(C)C
Agent: O=C1CCCC(Cl)C1C(=O)c1ccc2c(c1Cl)CCS2(=O)=O
Solvent: CCS
Product: Cc1cc(C(=O)C2C(=O)CCCC2Sc2ccccc2)c(C)c2c1S(=O)(=O)CCC2OC(C)C

Procedure:
The target compound was prepared in the same manner as described in Example II-2 except that 4-(2-propyl)oxy-5,8-dimethyl-6-(3-chloro-1-oxocyclohexan-2-yl)carbonylthiochroman-1,1-dioxide and benzenethiol were used instead of 4-chloro-5-(3-chloro-1-oxocyclohexan-2-yl)carbonyl-2,3-dihydrobenzothiophene-1,1-dioxide and ethanethiol, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1)[C:5](O)=[O:6].CC[N:41]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:27])[CH3:28])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=2)(=[O:30])=[O:31])[CH:12]=1)[C:5]([NH2:41])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(=O)O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(N)=O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 3-fluoro-4-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)benzoic acid (500 mg, 0.936 mmol) in DMF (10 mL) was added EDC HCl (269 mg, 1.40 mmol) followed by HOBt and NH3 (284 mg, 1.87 mmol). The reaction was stirred at RT for 1 h, then quenched with ice cold water (20 mL) to get a precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give the crude product (250 mg). MS (ESI, pos. ion) m/z: 534.1 (M+1).
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)(OCC1C=CC=CC=1)=O>C(O)C.[Pd]>[C:18]([NH:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCNCC1
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
N-CBZ-4-(BOC-amino)-piperidine (3.0 g, 9.0 mmol) was dissolved in ethanol (100 mL) and transferred into a Parr shaker bottle. After adding 10% palladium on carbon (0.5 g), the mixture was shaken under an atmosphere of hydrogen at 50 psi for 0.75 h on a Parr apparatus. The catalyst was removed by filtration through a pad of Celite. The filter cake was washed with ethanol and the combined filtrate and washings were concentrated in vacuo to yield 1.8 g (100%) of crude 4-(BOC-amino)-piperidine as a pale yellow oil. This product was used immediately in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:23]1[CH2:26][CH:25]([C:27]2[O:28][CH:29]=[C:30]([CH3:32])[N:31]=2)[CH2:24]1>>[CH3:32][C:30]1[N:31]=[C:27]([CH:25]2[CH2:26][N:23]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:24]2)[O:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: Cc1coc(C2CNC2)n1
Product: Cc1coc(C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)n1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-4-methyl-oxazole was used as the amine.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[Cl:6][C:7]1[N:8]=[C:9](Cl)[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:14]=[CH:13][C:11]=2[N:12]=1>C1COCC1.[Cu]I>[Cl:6][C:7]1[N:8]=[C:9]([CH:1]([CH3:3])[CH3:2])[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CC(C)[Mg]Br
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)c1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A mixture of CuI (152 mg, 0.8 mmol) and isopropylmagnesium bromide (1.6 ml, 1.6 mmol; 1.0M in THF) in anhydrous THF (5 ml) was stirred at −78° C. for 30 minutes. To this mixture was added a solution of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine (60 mg, 0.2 mmol) in THF (4 ml). The resulting mixture was stirred at −78° C. for another 2 hours before warming up to room temperature. The reaction was quenched by adding a solution of saturated aqueous ammonium chloride and concentrated ammonia (4:1 ratio; 5 ml). The mixture was extracted with EtOAc and the extracts dried over Na2SO4. Solvents were concentrated in vacuo and the crude residue was used in the next step without further purification. The resulting compound was characterized as follows: MS (m/z) 302.1 [M+H]+; HPLC Rt=4.72 minutes (Method A).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCCCC1
Temperature: 60 °C
Yield: 13.3 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from the previous step was treated with piperidine (0.116 mL, 1.17 mmol), tetrabutylammonium iodide (0.39 mmol) and N,N′-diisopropylethylamine (0.78 mmol) in N,N′-dimethylformamide. The mixture was heated to 60° C. for 56 h and cooled to room temperature. Water was added and the solid filtered off and dried. The crude solid was purified by preparative HPLC (phenylhexyl reverse phase column) and the obtained solid triturated with water (10 mL) and drops of methanol, then filtered off and dried under high vacuum to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(piperidin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (29 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.80 (brs, 1H), 9.10 (brs, 1H), 8.55 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.37-7.42 (m, 2H), 7.26 (m, 1H), 6.96 (m, 1H), 6.48 (s, 1H), 4.26-4.30 (m, 2H), 3.99 (s, 3H), 2.72-2.76 (m, 2H), 2.40-2.50 (m, 4H), 1.48-1.52 (m, 4H), 1.37-1.39 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 561 (M+H)+.
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].[CH2:27]1[O:40][C:39]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][C:29]=2[O:28]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[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].[CH2:27]1[O:40][C:39]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:30][C:29]=2[O:28]1
Reactant: O=C(O)COc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C([O-])COc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of camptothecin (10 mg, 0.029 mmol), 3,4-methylenedioxyphenoxyacetic acid (8 mg, 0.042 mmol), EDCI (28 mg, 0.15 mmol), DMAP (2 mg, 0.02 mmol) and dichloromethane (3 ml) was stirred in the room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl3:CH3OH 9:1) to afford 8 mg camptothecin-20-O-3,4-methylenedioxyphenoxyacetate, yield: 53.0%, mp.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH2:11]>>[C:1]([S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC=C
Reactant: CC(C)(C)S
Product: CC(C)(C)SCCCCCCSC(C)(C)C

Procedure:
The addition of tertiary-butyl mercaptan to 1,5-hexadiene according to the reaction:
Reaction SMILES: C(N1CC[C@@H]([CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([NH:19][C:20]2[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]3[C:23]([CH:24]4[CH2:34][CH:25]4[CH2:26][O:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])C1)C.[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42]CC1C=C(F)C=CC=1S(Cl)(=O)=O)[CH3:36].NC1C(C(OC)=O)=C2C([C@H]3C[C@H]3CO2)=CC=1>>[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:16]([NH:19][C:20]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]2[C:23]([C@H:24]3[CH2:34][C@H:25]3[CH2:26][O:27]2)=[CH:22][CH:21]=1)(=[O:17])=[O:18])[CH3:36]
Reactant: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Cl
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Product: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 95, starting from 2-[2-((R)-1-ethyl-pyrrolidin-2-yl)-ethyl]-4-fluorobenzenesulfonyl chloride (intermediate 230) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)c1cc2c(cc1O)CCC2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4c(cc3C(C)=O)CCC4)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
1-(6-Hydroxyindan-5-yl)-ethanone (275 mg), 4-chloro-6,7-dimethoxyquinoline (173 mg), and 4-dimethylaminopyridine (286 mg) were suspended in o-dichlorobenzene (5 ml) to prepare a suspension which was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (37 mg, yield 13%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Br)cc1C(=O)Nc1ccccc1Cl
Yield: 19.7 %

Procedure:
Prepared according to Procedure A using 2-amino-5-bromobenzoic acid (5.0 g, 23.1 mmol) and SOCl2 (7.0 mL, 95.9 mmol) in benzene (50 mL), followed by 2-chloroaniline (7.3 mL, 69.3 mmol) and CHCl3 (50 mL). The product was purified by two chromatographies in CH2Cl2 to provide 1.48 g of a yellow orange solid (20%). 1H NMR (CDCl3) δ: 8.36 (dd, J=1.2, 8.2 Hz, 1H); 8.20 (br s, 1H); 7.62 (d, J=2.1 Hz, 1H); 7.42 (dd, J=1.3, 8.0 Hz, 1H); 7.34 (dd, J=2.2, 8.8 Hz, 1H); 7.28-7.33 (m, 1H); 7.09 (dt, J=1.4, 7.7 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 5.57 (br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 86.2 %

Procedure:
A heterogenous reaction mixture of 2-(S)-iodomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (compound (4) obtained from above, 25 g, 0.08 mol), triethylamine (11.2 mL, 8.12 g, 0.08 mol) in methanol (250 mL) and 5% palladium on carbon (2.5 g, 10 wt %, Pd/C) was allowed to react at room temperature under a blanket of hydrogen gas overnight and until HPLC showed less than 1% starting material (˜7 hours). The reaction mixture was filtered and the filtrate was concentrated to a residue. The residue was dissolved in distilled water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with 1 M aqueous H3PO4 (2×100 mL) followed by saturated NaHCO3 (233 100 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (12.78 g, 85.9% yield). 1H NMR (CDCl3): δ 1.16 (d, 3H, CH3), 1.47 (s, 9H, 3×CH3), 1.50–1.82 (m, 2H, CH2), 1.84–2.03 (m, 2H, CH2 ), 3.34 (m, 2H, CH2) and 3.86 (m, 1H, CH); [M+H]+ at m/z 186.