Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Cl:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].C(N(CC)CC)C.ClCCl.[C:39](OC(=O)C)(=[O:41])[CH3:40]>CN(C)C1C=CN=CC=1.CO>[C:39]([O:28][C:5]1[C:6]([CH2:25][CH2:26][CH3:27])=[C:7]([CH:23]=[CH:24][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Cl:22])(=[O:41])[CH3:40]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Cl)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Cl)ccc(C(C)=O)c1OC(C)=O
Reaction time: 1.33 h

Procedure:
To a solution of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-chlorobenzoic acid (1.0 g), which was prepared by the manner described in European Patent Application Publication No. 80,371, triethylamine (4.6 ml), 4-dimethylaminopyridine (8 mg) and dichloromethane (6 ml) was added acetic anhydride (3.1 ml) at 5° to 7° C., and the mixture was stirred well for 80 minutes. To the reaction mixture was added dropwise methanol (5 ml) to decompose the excess amount of acetic anhydride. The mixture was subjected to concentration, the residual oily product was poured into ice-water, and the precipitate was collected by filtration. Recrystallization from ethanol-water gave white crystals of 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-chlorobenzoic acid 975 mg). M.p. 146°-148° C.
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:27]([S:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([N+:50]([O-])=O)[C:43]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]([OH:40])=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:50][C:42]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:35]([S:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39]
Reactant: O=C(O)c1cc(SCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: Nc1cc(C(=O)O)cc(SCc2ccccc2)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 3-benzylthio-5-nitro-4-phenylbenzoic acid, and following the procedure described, 5-amino-3-benzylthio-4-phenylbenzoic acid is obtained with a melting point of 173°-174° C.
Reaction SMILES: [CH:1](=[C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24]C)=[O:23])=[CH:17][CH:18]=3)[C:13](=[O:26])[C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH:1](=[C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([OH:24])=[O:23])=[CH:17][CH:18]=3)[C:13](=[O:26])[C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCCC3=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2oc3c(c(=O)c2c1)CCCC3=Cc1ccccc1
Yield: 86.9 %

Procedure:
4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid, methyl ester (1.2 g) was hydrolized by treatment with 1% KOH in 95% ethanol (19.5 ml) at reflux temperature for 15 minutes. After cooling and acidification with 37% HCl the precipitate was filtered and washed with methanol and then with water to give 1 g of 4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid, m.p. 284°-286° C., NMR (CF3COOD) δppm: 2.12 (m) (2H, C-2 protons), 3.13 (m) (4H, C-1 and C-3 protons), 7.64 (m) (5H, phenyl protons), 8.14 (d) (1H, C-5 proton), 8.43 (bs) (1H, =CH--), 8.88 (dd) (1H, C-6 proton), 9.38 (d) (1H, C-8 proton).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O.[NH2:33][NH2:34]>CO>[CH2:16]([N:13]1[CH2:12][CH2:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([NH:33][NH2:34])=[O:31])=[CH:9][CH:8]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Solvent: CO
Solvent: O
Product: COc1cccc(C2(c3ccc(C(=O)NN)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methyl ester (9.5 g, 22.9 mmol) in methanol (60 mL) was added hydrazine hydrate (8 mL). The reaction mixture was heated to reflux for 36 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in toluene (50 mL) and concentrated under vacuum, and 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide was obtained in quantitative yield. The residue was used in the subsequent steps without purification. 1HNMR (400 MHz, CD3OD) δ 7.82 (d, 1H), 7.67 (d, 1H), 7.39-7.05 (comp, 8H), 6.86 (d, 1H), 6.80 (s, 1H), 6.67 (d, 1H), 3.69 (s, 3H), 3.38 (s, 2H), 2.62-2.37 (comp, 8H); MS (M+1) 416.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([C:25]([N:27]([CH2:34][CH3:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])=[C:23](I)[CH:22]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(=O)([O-])[O-].[Ag+2]>[Cl:20][C:21]1[CH:37]=[C:36]2[C:24]([C:25](=[O:26])[N:27]([CH2:34][CH3:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=32)=[CH:23][CH:22]=1
Reactant: CCN(C(=O)c1ccc(Cl)cc1I)c1ccccc1
Agent: [Ag+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCn1c(=O)c2ccc(Cl)cc2c2ccccc21
Temperature: 23 °C
Yield: 63 %

Procedure:
Palladium acetate (466 mg, 2.07 mol) was added to a suspension of silver carbonate (5.7 g, 20.7 mmol), triphenylphosphine (1.08 g, 4.15 mmol), and 4-chloro-N-ethyl-2-iodo-N-phenyl-benzamide I-14a (4.0 g, 10.4 mmol) in acetonitrile (52 ml). The reaction mixture was heated to reflux for 1 hour and cooled to 23° C. The mixture was filtered through a plug of celite and the filter cake was washed with ethyl acetate (50 ml) and diethyl ether (50 ml). The combined filtrates were washed with saturated sodium chloride (50 ml), dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by flash column chromatography (1% ethyl acetate in dichloromethane grading to 2% ethyl acetate in dichloromethane) to afford 9-Chloro-5-ethyl-5H-phenanthridin-6-one I-14b (1.68 g, 63%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.I[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH2:13][CH3:14])[CH:7]=1
Reactant: CCCI
Reactant: OCc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(Cl)ccc1CO
Temperature: 100 °C
Yield: 57.8 %

Procedure:
Charge 5-chloro-2-(hydroxymethyl)phenol (997 mg, 6.29 mmol, PREPARATION 7), iodopropane (1.17 g, 6.92 mmol), K2CO3 (1.74 g, 12.58 mmol) and DMF (6 mL) to a sealed tube. The reaction mixture was heated to 100° C. overnight. It was then poured into ice-water and extracted with ethyl acetate twice, washed the organic phase with water twice, brine and dried with Na2SO4, concentrated and purified by silica gel chromatograph to give the title compound (729 mg, 58%). 1H NMR (400 MHz, CDCl3): δ 1.05 (3H, t, J=7.2 Hz), 1.79-1.88 (2H, m), 3.96 (2H, t, J=6.4 Hz), 4.64 (2H, s), 6.85 (1H, d, J=1.2 Hz), 6.91 (1H, dd, J=1.6 Hz, 8.4 Hz), 7.20 (1H, d, J=8.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[NH:10]([CH2:13][CH3:14])[CH2:11][CH3:12].C(N(CC)C=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12]
Reactant: CCNCC
Reactant: Clc1c(Br)cncc1Br
Agent: CCN(C=O)CC
Solvent: CCOC(C)=O
Product: CCN(CC)c1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
A mixture of trihalopyridine VII (W=Br) (18.8 g, 70.0 mmol), Et2NH (21.7 mL, 0.210 mol), and N,N-diethylformamide (35 mL) was kept in a sealed high-pressure tube at 170° C. for 20 h. The reaction mixture was cooled to room temperature, dissolved in EtOAc (300 mL), and washed with 1M K2CO3 (200 mL) and water (8×200 mL). The organic layer was dried with MgSO4 and evaporated in vacuo to give a brown oil. Purification by flash chromatography (CH2Cl2) gave the title compound, 3,5-dibromo-4-(diethylamino)pyridine (VI, R1=R2=Et, W=Br), (20.3 g, 94%) as a yellow oil: Rf=0.45 (CH2Cl2); 1H NMR (250 MHz, CDCl3) δ1.01 (t, J=7.0 Hz, 6H), 3.26 (q, J=7.0 Hz, 4H), and 8.49 (s, 2H); 13C NMR (63 MHz, CDCl3) δ14.10, 46.05, 122.9, 151.9, and 154.1; IR (CHCl3) νmax 2976, 1553, 1457, 1167 cm−1; MS (EI+) m/z (rel intensity) 308 (15%, M+), 193 (100), and 264 (30); HRMS calcd for C9H12Br2N2 (M+) 305.9367. found 305.9366.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:63])[NH:41][C:42]([C:45]([N:47]3[CH2:52][CH2:51][N:50]([C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])[CH2:49][CH2:48]3)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:64]([CH3:66])[CH3:65])[NH:27][N:26]=1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[CH2:56]([O:55][C:53]([N:50]1[CH2:49][CH2:48][N:47]([C:45]([C:42]([NH:41][C:40]([CH2:39][CH2:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:29]3[C:25]([O:24][C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])=[N:26][NH:27][C:28]=3[CH:64]([CH3:66])[CH3:65])=[CH:32][CH:33]=2)=[O:63])([CH3:43])[CH3:44])=[O:46])[CH2:52][CH2:51]1)=[O:54])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole (39.5 g) in methanol (160 mL) was added sodium methoxide (28% methanol solution, 8.24 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added acetic acid (2.7 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (21.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 87.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (202 mg, 0.32 mmol) prepared in Example 60a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield the title compound (135 mg, 88%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C=O)C.CS(C)=O>[C:46]([O:45][C:43](=[O:44])[CH2:42][NH:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1)([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CNC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of N4-(4-amino-cyclohexylmethyl)-5-nitro-N2-(2-trifluoromethoxy-benzyl)-pyrimidine-2,4-diamine (88 mg, 0.20 mmol) in 2:1 DMF/DMSO (0.6 mL) was added N,N-diisopropylethylamine (35 μL, 0.30 mmol) followed by tert-butyl bromoacetate (22 μL, 0.15 mmol). The mixture was stirred at room temperature overnight then partitioned with EtOAc (15 mL) and water (5 mL). The layers were separated and the organics washed with water (2×5 mL) and brine. After concentration in vacuo, the residue was purified by column chromatography (silica gel, 97:3 DCM/MeOH) to afford (4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-acetic acid tert-butyl ester (51 mg, 61%) as a colorless oil, m/z 555 [M+1]+.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17]2[C:12](=[C:13]([OH:28])[CH:14]=[CH:15][CH:16]=2)[N:11]=1>C(O)C>[CH3:21][N:20]([CH3:22])[CH2:18][CH2:17][CH2:16][O:28][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[C:10]([NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[N:19]=[C:18]2[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2cccc(O)c2n1
Agent: [Na]
Solvent: CCO
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2cccc(OCCCN(C)C)c2n1
Yield: 90.8 %

Procedure:
Sodium metal (103 mg, 4.49 mM) was dissolved in absolute ethanol (20 ml) and the solution added to a suspension of 2-[(2-methylphenyl)amino]-4-(N-methylphenylamino)-8-hydroxyquinazoline (1.6 g, 4.49 mM) in ethanol (100 ml). The mixture was heated until a clear solution was produced and then the ethanol was evaporated off. Toluene (25 ml) was added and again the mixture was evaporated to dryness. The residue was dissolved in toluene (50 ml) and to this solution was added a solution of N,N-dimethylaminopropylchloride (546 mg, 4.49 mM) in toluene (75 ml). The resulting mixture was heated at reflux temperature overnight, cooled, washed with water (×2), dried and evaporated to dryness, to give a browny-yellow oil. This oil was crystallised from ether/pentane to give the title compound (0.9 g) as buff-coloured flakes, m.p. 77°-79°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[N:6]=[C:5]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)(=O)C>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:6]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccc(F)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccc(F)cc12

Procedure:
Ethyl 2-[5-fluoro-1-(4-nitrobenzyl)-1H-indazol-3-yl]acetate (137 mg, 0.383 mmol) was dissolved in methanol (20 mL). 10% Pd/C (10 mg) was added, and reacted under hydrogen atmosphere for half an hour. TLC (petroleum ether:ethyl acetate=2:1) indicated that starting material disappeared. It was filtered to remove solid, rotate evaporated to dryness to remove the solvent, and the resulting solid was used for the next step directly.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:36])[C:25]2=[N:26][CH:27]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:29]=[C:24]2[NH:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:20][C:21]1([CH3:36])[C:25]2=[N:26][CH:27]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:29]=[C:24]2[N:23]([C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[C:3]=2[CH3:19])[CH2:22]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(-c2cncc(F)c2)nc2cnccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(F)c2)nc2cnccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(5-fluoropyridin-3-yl)-3-methyl-1,7-naphthyridine (100 mg, 0.365 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (85 mg, 0.365 mmol), sodium tert-butoxide (70.2 mg, 0.731 mmol) and XPhos precatalyst (26.9 mg, 0.037 mmol) in toluene (4 mL) at 110° C. for 2 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(5-fluoro-3-pyridinyl)-3-methyl-1,7-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.52-9.64 (1H, m), 8.74 (1H, t, J=1.8 Hz), 8.63 (1H, d, J=2.7 Hz), 8.59 (1H, d, J=5.9 Hz), 7.76-7.82 (1H, m), 7.67 (1H, d, J=2.3 Hz), 7.55-7.59 (1H, m), 5.84 (1H, d, J=2.3 Hz), 3.81-3.93 (2H, m), 3.70-3.79 (4H, m), 2.95-3.07 (4H, m), 2.40 (3H, s), 1.60 (3H, s), 1.54 (3H, s). Mass Spectrum (ESI) m/e=471.2 (M+1).
Reaction SMILES: C(O[C:4](=[O:30])[CH:5]([C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C.[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]([NH2:40])[NH:37][N:36]=1)=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]2[NH:40][C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)=[C:5]([CH2:6][CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:4](=[O:30])[N:37]2[N:36]=1)=[O:34]
Reactant: CCOC(=O)C(CCC1CCCCC1)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(CCC3CCCCC3)c(=O)n2n1
Temperature: 120 °C
Yield: 10 %

Procedure:
A mixture of 71 mg (0.171 mmol) of 2-(4-benzyloxy-benzoyl)-4-cyclohexyl-butyric acid ethyl ester, 24 mg (0.171 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 7 mg (20 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 3 mL of chlorobenzene was heated at 120° C. overnight. The reaction mixture was then concentrated to a residue which was purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) desired 5-(4-benzyloxy-phenyl)-6-(2-cyclohexyl-ethyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C29H31N3O4 [M++H]+: 486.23, found: 486.2. This material was then converted to 5-(4-benzyloxy-phenyl)-6-(2-cyclohexyl-ethyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (559) via the well known LiOH saponification protocol (10% yield over 2 steps); LC-MS—calcd for C28H29N3O4 [M++H]+: 472.22, found: 472.2.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[CH:26]=[CH:27][C:4]([NH:3][C:41]([CH:38]3[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]3)=[O:42])=[CH:5][CH:6]=2)=[N:14][CH:13]=1)=[O:25]
Reactant: Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (1.0 g, 2.24 mmol) in DMF (15 mL) were added, piperidine-1,4-dicarboxylic acid mono-t-butyl ester (510 mg, 2.22 mmol), triethylamine (0.94 mL, 6.74 mmol), 1-hydroxybenzotriazole monohydrate (350 mg, 2.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (514 mg, 2.68 mmol) under ice cooling. The resulting solution was then stirred under ice cooling for 1 hour, and at room temperature for 17 hours. This reaction solution was concentrated under reduced pressure. The residue was diluted with water and ethyl acetate, whereupon a white powder was precipitated. The white powder was filtered, then washed with water, and subsequently washed with ethyl acetate, to thereby yield 1.04 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[P:28](=[O:37])(Cl)([S:32][CH2:33][CH2:34][CH3:35])[O:29][CH2:30][CH3:31]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:28](=[O:37])([S:32][CH2:33][CH2:34][CH3:35])([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)[O:29][CH2:30][CH3:31]
Reactant: Oc1ccc2nc3ccccc3cc2c1
Reactant: CCCSP(=O)(Cl)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCSP(=O)(OCC)Oc1ccc2nc3ccccc3cc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Hydroxyacridine (1.90 grams; 0.01 mole), triethylamine (1.01 grams; 0.01 mole), tetrahydrofuran (30 ml) and toluene (20 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to about 0° C. and O-ethyl S-propyl phosphorochloridothioate (2.01 grams; 0.01 mole) dissolved in toluene (23 ml) was added with stirring over a period of about 20 minutes. After the addition was completed stirring was continued for 3 hours allowing the mixture to warm up to room temperature. Stirring was continued overnight. After this time the reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was washed, treated with charcoal and stripped of solvent leaving yellow/green oil as the residue. This residue was subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-ethyl O-acridin-2-yl S-propyl phosphorothioate as a yellow brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][C:17](=[O:24])[C:16]=3[N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Br:25]Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:25][CH:18]1[C:17](=[O:24])[C:16]2[N:15]=[C:14]([C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[C:2]([Cl:1])[CH:3]=3)[N:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1
Reactant: O=C1CCCc2cnc(-c3ccc(N4CCOCC4)c(Cl)c3)nc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1c2nc(-c3ccc(N4CCOCC4)c(Cl)c3)ncc2CCC1Br
Reaction time: 1 h

Procedure:
2-(3-Chloro-4-morpholin-4-yl-phenyl)-6,7-dihydro-5H-quinazolin-8-one (328 mg, 0.95 mmol) is dissolved in acetic acid (7 ml) and HBrconc. (7 ml). Bromine in HBrconc. (0.95 ml 1N solution) is added at room temperature. After stirring for one hour the mixture is poured onto ice, neutralized with NaHCO3 and the product is extracted with ethyl acetate. 1H-NMR (400 MHz; DMSO-d6): 9.10 (s, 1H), 8.43 (s, 1H), 8.28 (d, 1H), 7.30 (d, 1H), 5.21(dd, 1H), 3.76 (brs, 4H), 3.09 (brs, 4H), 3.00-2.40 (m, 4H); LC-MS (m/z, ES+): 422 (MH+), Retention time: 3.05 mins (LC-MS method 2)