Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][C:16]([O:28][CH3:25])=[CH:15][CH:14]=4)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(Br)cc2c2cc(Cl)cnc21
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(/C=C/c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a solution of 9-benzenesulfonyl-6-bromo-3-chloro-9H-pyrido[2,3-b]indole (250 mg, 0.59 mmol, 1 equiv.) in anhydrous dioxane (25 ml) under Argon, Pd(PPh3)4 (102 mg, 0.09 mmol, 0.15 equiv.), K2CO3 (244 mg, 1.77 mmol, 3 equiv.), (E)-2′-(4-methoxyphenyl)ethenylboronic acid (110 mg, 0.77 mmol, 1.3 equiv.) and H2O (5 ml) are added respectively. The mixture is stirred at 100° C. overnight and then filtered over celite which is washed with AcOEt (20 ml) and THF (10 ml). The filtrate is concentrated under reduced pressure and the crude residue is purified over silica gel column (eluant CH2Cl2/PE 7:3). The product is obtained as a white solid (212 mg, 0.40 mmol) in 68% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([OH:16])=O)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:14]([C:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1)=[O:16]
Reactant: COc1cccc(CN)c1OC
Reactant: O=C(O)c1cccc2c([N+](=O)[O-])cccc12
Product: COc1cccc(CNC(=O)c2cccc3c([N+](=O)[O-])cccc23)c1OC
Yield: 55.1 %

Procedure:
Using 5-nitronaphthalene-1-carboxylic acid (250 mg, 1.15 mmol) and 2,3-dimethoxybenzylamine (0.18 ml, 1.20 mmol), the same operation as the Example 104(2) gave the title compound as a gray white solid (232 mg, 55.0%).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N+:29]([O-:31])=[O:30])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccccc3[N+](=O)[O-])c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.5 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.37 mg, 34.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.84 (d, 1H), 7.90 (m, 1H) 7.45 (m 1H), 7.30–7.20 (m, 5H), 7.20 (m, 2H), 6.98 (m, 2H), 6.89 (apparent d, 1H, J=7.7 Hz), 5.62 (apparent dd, 1H, J=4.1, 8.9 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 2.30–2.10 (m, 6H), 1:90 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])=[C:2]=[O:3].Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[F:30][C:16]([F:15])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:24][CH2:25][N:26]([C:2]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[O:3])[CH2:27][CH2:28]1
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1NC(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
A solution of methyl 2-isocyanatobenzoate (10.00 g, 56.4 mmol) in tetrahydrofuran (30 ml) was slowly added to a solution of 4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (14.3 g, 53.8 mmol, Sigma) and triethylamine 99% (8.99 ml, 64.5 mmol) in tetrahydrofuran (120 ml) at 0° C. The mixture was removed from the cooling bath and stirred at room temperature for 15 min, at which time LC/MS analysis indicated that the reaction was complete. EtOH (75 ml) and aqueous LiOH (2N, 95 ml) were then added, and the solution was stirred for 6 h at room temperature. Subsequently, aqueous HCl (2N, 150 ml) was added, and the resulting mixture was extracted with EtOAc (2×600 ml). The EtOAc extract was dried over MgSO4 and concentrated to an off-white solid. Recrystallization from EtOAc yielded 14.0 g (66%) of 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido) benzoic acid as a white solid, which was homogeneous by analytical high-performance liquid chromatography (>99%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[O:11]=[S:12]1(=[O:35])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]#[N:31])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:32][CH2:33][CH2:34][CH:14]2[NH:13]1>CS(C)=O>[O:35]=[S:12]1(=[O:11])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](=[N:9][OH:10])[NH2:31])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:32][CH2:33][CH2:34][C:14]2=[N:13]1
Reactant: N#CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NC(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1)=NO
Reaction time: 0.17 h

Procedure:
2.51 ml (18.0 mmol) of triethylamine are added to a solution of 1.25 g (18.0 mmol) of hydroxylamine hydrochloride in 4 ml of DMSO and the suspension is stirred for 10 minutes. The precipitate is filtered off and the filtrate is concentrated. 992 mg (3.00 mmol) of the product of Step A of Example 27 are added to the filtrate and the solution is stirred at 75° C. for 1 hour 30 minutes. The solution is allowed to return to ambient temperature, and precipitation of the reaction mixture is brought about using water. The precipitate is filtered off to yield the title product.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].O>CN(C=O)C.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>[OH:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: Cc1c(O)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(O)cccc1C#N
Temperature: 120 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a solution of 3-bromo-2-methylphenol (20.0 g) in DMF (250 mL) were added copper(I) cyanide (19.0 g) and tetrakis(triphenylphosphine)palladium(0) (3.70 g), and the mixture was heated with stirring at 120° C. for 16 hr under nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with tert-butyl methyl ether to give the title compound (7.00 g).
Reaction SMILES: Cl.O1CCOCC1.Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([NH:20][CH3:21])=[O:19])[C:12]([Cl:26])=[CH:11][N:10]=1.[CH2:27]([N:29]1[CH:38]2[CH2:39][CH2:40][CH:30]1[C:31]1[CH:32]=[C:33]([NH2:41])[CH:34]=[CH:35][C:36]=1[CH2:37]2)[CH3:28].C(=O)([O-])[O-]>COCCO>[Cl:26][C:12]1[C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([NH:20][CH3:21])=[O:19])=[N:14][C:9]([NH:41][C:33]2[CH:34]=[CH:35][C:36]3[CH2:37][CH:38]4[N:29]([CH2:27][CH3:28])[CH:30]([CH2:40][CH2:39]4)[C:31]=3[CH:32]=2)=[N:10][CH:11]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C2CCC1c1cc(N)ccc1C2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1C2CCC1c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
2-methoxyethanol (8.6 mL), 4N HCl in p-dioxane (0.215 mL, 1.2 eq) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (129 mgs, 1 eq) and (+/−)-12-Ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine was heated to 120° C. for 2 h. The mixture cooled to room temp treated with 3 equivalents of MP-carbonate and stirred for 30 min. Filtration, followed by concentration and purification by ISCO chromatography (12 gram column, SiO2, gradient 20% EtOAc/hexane to 100% EtOAc) gave (+/−)-2-[5-Chloro-2-(12-ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (45 mg, 11%). MP: 218-221° C.; 1H-NMR (CDCl3) δ 11.10 (s, 1H), 8.65 (d, J=8.1 Hz, 1H), 8.1 (s, 1H), 7.51-7.47 (m, 2H), 7.28-7.26 (m, 1H), 7.12-7.10 (m, 1H), 7.00 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.52-6.49 (m, 1H), 3.89-3.84 (m, 2H), 3.58-3.55 (m, 2H), 3.05-3.03 (m, 1H), 3.04 (d, J=5.1 Hz, 3H), 2.61-2.51 (m, 3H), 2.25-2.21 (m, 2H), 1.18-1.10 (m, 3H); LC/MS (ESI+): 463.34 (M+H).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N1C(C)(C)CCCC1(C)C.N1CCCCC1.[Li]CCCC.[CH:49](=[O:52])[CH2:50][CH3:51]>C1COCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH:49]([OH:52])[CH2:50][CH3:51])[C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CCC(O)c1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
A −40° C. solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramnethyl piperidine and n-BuLi at 0° C. for 30 min.). The mixture was then allowed to warm to 0° C. for 2 h. The reaction mixture was cooled to −30° C. and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stiffed at −30° C. for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+: 424.2. Other electrophiles such as disulfide may be used to quench the anion.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36]N)=[CH:32][CH:31]=1>>[CH3:26][CH:24]([CH3:25])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:34]4[C:33](=[CH:32][CH:31]=[C:30]([CH3:29])[CH:35]=4)[NH:36][CH:2]=3)[CH2:11][CH2:12]2)[CH:17]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]cc(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].I[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14].ClCCl>O1CCCC1>[CH3:14][O:13][Si:12]([CH2:11][CH2:10][CH2:9][C:5]1[N:4]=[CH:3][NH:2][N:1]=1)([O:17][CH3:18])[O:15][CH3:16]
Reactant: c1nc[nH]n1
Reactant: CO[Si](CCCI)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[Si](CCCc1nc[nH]n1)(OC)OC
Reaction time: 4 h

Procedure:
5 g (72 mmol) of 1,2,4-triazole were dissolved in 100 ml of absolute tetrahydrofurane and 1.73 g (72 mmol) of sodium hydride were added. The reaction mixture was stirred for 4 hours, after which 10 ml of iodopropyltrimethoxy silane (52 mmol) were added and the reaction mixture was heated under reflux for 18 hours. 20 ml of dichloromethane were then added and the reaction mixture was filtered. The solvent was removed at 150-155° C. under reduced pressure (8 mbar) and then filtered. The yield was 6.4 g (50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:24][C:18]3[N:19]=[CH:20][N:21]=[C:22](O)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:24][C:18]3[N:19]=[CH:20][N:21]=[C:22]([Cl:27])[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Temperature: 140 °C
Reaction time: 3 h

Procedure:
After adding 200 ml of phosphorus oxychloride to 20 g of the 6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol synthesized in Production Example 153-2, the mixture was stirred at 140° C. for 3 hours and the reaction mixture was cooled to room temperature and the reaction mixture was concentrated. Ice water was added to the residue, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated to dryness to obtain 12 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O.CN(C=O)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([Cl:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
A mixture of commercially available 2-(3-nitrophenyl)acetic acid [CAS no. 1877-73-2] (25.8 g, 142 mmol, Eq: 1.00) and thionyl chloride (25.4 g, 15.5 ml, 214 mmol, Eq: 1.5) in toluene (141 ml) and DMF (208 mg, 221 μl, 2.85 mmol, Eq: 0.02) was stirred at 80° C. for 2 h. The hot solution was filtered through a Sartorius filter, the filtrate was evaporated and dried in HV to give the 2-(3-nitrophenyl)acetyl chloride (28.12 g, 141 mmol, 98.9% yield) as a yellow solid, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38]([OH:40])=[O:39]>>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([N:36]2[CH2:43][CH2:42][CH2:41][C@H:37]2[C:38]([OH:40])=[O:39])=[O:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1CCCN1C(=O)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (1.0 g) and L-proline (713 mg) were subjected to a similar reaction described in Reference 2 to give N-triphenylmethyl-2-[(S)-2-carboxypyrrolidino)carbonylthioethylamine (475 mg) which was then dissolved in a mixture of anhydrous dimethylformamide (1.5 ml) and anhydrous acetonitrile (4 ml). After addition of dicyclohexylcarbodiimide (256 mg) and 4-aminohenol (256 mg), the reaction solution was stirred at room temperature for 5 hours and was then concentrated under reduced pressure. The concentrated solution was dissolved in chloroform (50 ml), followed by washing in turns with an aqueous solution of 10% citric acid, a saturated sodium bicarbonate solution, water and a saturated solution of sodium chloride. The chloroform layer was dried by use of anhydrous sodium sulfate and was then concentrated under reduced pressure. The residual substance was purified by silica gel column chromatography using a solvent system of chloroform/methanol (20:1 v/v) to obtain N-triphenylmethyl-2-[(S)-2-(4-hydroxyphenyl)aminocarbonylpyrrolidino]carbonylthioethylamine (0.45 g: yield 79.0%). From the product triphenylmethyl was removed in a similar manner to that described in Example 4 to produce 2-(S)-2-4-hydroxyphenyl)aminocarbonylpyrrolidino]carbonylthioethylamine (crude formate: 445 mg). This product was dissolved in anhydrous methanol (7 ml). To the reaction solution were added triethylamine (873 μl) and mitomycin A (380 mg: 0.87 molar equivalent). The mixture was treated in a similar manner to that described in Example 1 to obtain Compound 45 (160 mg) in the form of grayish blue powders with a yield of 39%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:14]([CH3:16])([CH3:15])[C:13]([O:12][CH2:10][CH3:11])=[O:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Br
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-4-chlorophenol (250 mg; 1.21 mmol) and ethyl-2-bromoisobutyrate (450 μl; 3.0 mmol) in DMF (5 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and heated at 120° C. for 4.5 hours. Water was added and the reaction mixture was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a yellow sticky solid (320 mg; 83%).
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[C:7]([CH:10]([C:14](=O)[CH3:15])[C:11](=O)[CH3:12])(=[O:9])[CH3:8]>CO>[C:7]([C:10]1[C:11]([CH3:12])=[N:5][N:4]([C:1]([NH2:3])=[NH:2])[C:14]=1[CH3:15])(=[O:9])[CH3:8]
Reactant: N=C(N)NN
Reactant: CC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)c1c(C)nn(C(=N)N)c1C
Temperature: -10 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
1.86 g of aminoguanidine hydrochloride were added to a solution of 3.0 g of triacetylmethane and 30 ml of methanol with cooling at -10° C., and the reaction mixture was stirred for one day with cooling with ice. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=5/1) and then recrystallized from ether-chloroform to obtain 484 mg of 4-acetyl-3,5-dimethyl-1H-pyrazole-1-carboxamidine.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10](=[O:12])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc2[nH]ccc12
Reaction time: 16 h

Procedure:
To a mixture of 1H-indole-4-carboxylic acid (322 mg, 2.00 mmol), tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (554 mg, 2.00 mmol), and diisopropylethylamine (700 μL, 4.00 mmol) in DMF (3 mL) was added HATU (950 mg, 2.50 mmol) and the solutions stirred for 16 h. The solvent was removed and the resulting residue was purified by silica gel chromatography, using a gradient of 70% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 557 mg (66%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:24]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)=[O:29])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:40](O)(=[O:43])[CH:41]=[CH2:42].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:24]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:40](=[O:43])[CH:41]=[CH2:42])=[O:29])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: C=CC(=O)O
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 9 %

Procedure:
302 mg of (2S)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-amide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.15 ml of acrylic acid, 0.18 ml of pyridine and 0.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 30 mins and at room temperature for 2 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (31 mg, 9%).