Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=3)=[CH:37][CH:36]=2)([CH:14]([O:23][C:24]2[NH:28][C:27]3[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:26]=3[N:25]=2)COCC[Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=3)=[CH:39][CH:40]=2)([CH2:14][O:23][C:24]2[NH:25][C:26]3[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:27]=3[N:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cccc(C#N)c3)cc2)(C(COCC[Si](C)(C)C)Oc2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc3cc(Cl)c(Cl)cc3[nH]2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Temperature: 60 °C
Yield: 52.7 %

Procedure:
To a solution of 0.081 g of 4-(3′-cyano-biphenyl-4-yl)-4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester 52 (0.115 mmol) in 5 mL of tetrahydrofuran at room temperature was added 0.23 mL of a solution of TBAF (1M in THF, 0.23 mmol, 2 eq). The mixture was heated at 60° C. for 6 h. After cooling to room temperature, the mixture was partitioned between 15 mL of ethyl acetate and 15 mL of H2O. The organic layer was separated, washed with saturated brine, dried (Na2SO4), and concentrated by rotary evaporation to give the crude product as a pale foam (0.070 g) which was purified by flash column chromatography eluting with 30% ethyl acetate in hexanes to give 0.035 g of 4-(3′-cyano-biphenyl-4-yl)-4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester 53 as a pale foam and 0.024 g of recovered starting material. 1H NMR (300 MHz, CDCl3): δ 7.82-7.75 (m, 2H), 7.64-7.52 (dt, 1H), 7.61-7.46 (m, 5H), 7.26 (s, 1H), 4.51 (s, 2H), 3.85-3.83 (d, 2H), 3.18-3.10 (t, 2H), 2.32-2.28 (d, 2H), 2.04-1.98 (t, 2H), 1.42 (s, 9H). MS (ESI): Calcd m/z for C31H30Cl2N4O3.H+=577.2. Found m/z=576.7/578.7 [(M+1)+/(M+3)+].
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[O:37][C:36]([C:38]([F:41])([F:40])[F:39])=[C:35]([S:42](Cl)(=[O:44])=[O:43])[CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:35]1[CH:34]=[C:33]([CH3:32])[O:37][C:36]=1[C:38]([F:41])([F:39])[F:40])(=[O:44])=[O:43]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)c(C(F)(F)F)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-methyl-2-(trifluoromethyl)furan-3-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 72 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-methyl-2-(trifluoromethyl)furan-3-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[C:22]([F:25])([F:24])[F:23])=[N:15][CH:16]=2)[N:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:41]1([C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55](O)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44])[CH3:42]>N1C=CC=CC=1.C(Cl)Cl>[CH3:42][N:41]1[C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55]([N:4]([CH2:3][S:2][CH3:1])[C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]4[CH:16]=[N:15][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C@H:18]5[C:22]([F:25])([F:23])[F:24])=[N:13][CH:12]=4)[N:6]=3)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44]
Reactant: CSCNc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSCN(C(=O)Cn1cnc2c1c(=O)n(C)c(=O)n2C)c1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of (S)—N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 4.17 g, 46.0 mmol) and DCC (18.99 g, 92 mmol) in pyridine (230 mL) was heated for 30 minutes at 60° C. before theophylline 7-acetic acid (21.92 g, 92 mmol) was added in one portion. The reaction mixture was stirred at 60° C. and monitored by LCMS. After 2 hours, additional theophylline 7-acetic acid (21.92 g, 92 mmol) and DCC (18.99 g, 92 mmol) were added to drive the reaction to completion. The reaction mixture was diluted with CH2Cl2. The resulting precipitate (DCC urea) was filtered over Celite® and washed with CH2Cl2 (3×). The mixture was diluted with water and adjusted to pH 3 with aqueous 3M HCl. The organic and aqueous layers were separated and the aqueous layer was extracted with additional CH2Cl2 (3×). The combined organic layers were washed with aqueous 1M HCl (2×), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified using silica gel chromatography, eluting with EtOAc:Hex (70:30) to yield 18.5 g (31.4 mmol, 68%) of the title product as a thick oil; 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.16-8.03 (m, 2H), 7.99 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 5.33 (s, 2H), 5.12 (m, 3H), 3.82-3.65 (m, 2H), 3.43 (s, 3H), 3.18 (s, 3H), 2.31-2.09 (m, 4H), 2.06 (s, 3H); m/z found [M+H]+=590.37.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[ClH:23].[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[C:7]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cc(Cl)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(Cl)ccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
2-[4-(tert-Butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-4-chlorobenzamide (0.4 g, 0.64 mmol) was dissolved in 4 N HCl/p-dioxane (15 mL). After stirring for 30 min, the solution was concentrated in vacuo and the residue was purified by RPHPLC, eluting with a gradient of 20% through 60% acetonitrile in 0.05% aq HCl over 320 min. The clean product containing fractions were combined, partially concentrated and lypholyzed to give 0.0864 g (23%) of white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](/[N:8]=N/C2C=CC(C)=CC=2)=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[H][H]>CC(O)C.[Pt]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: CCCSc1nc(Cl)c(/N=N/c2ccc(C)cc2)c(Cl)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Product: CCCSc1nc(Cl)c(N)c(Cl)n1
Temperature: 20 °C

Procedure:
A stirred solution of 4,6-dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine (Step (3), 1.1 kg) in 2-propanol (16.6 kg) was hydrogenated for 1 h at 40° C./3.2 bar over a platinum on carbon catalyst (0.81 kg, 50% w/w Pt/C). The hydrogen gas pressure was released and the reactor flushed with nitrogen. The reaction mixture was filtered. The collected solid was washed with 2-propanol (1.7 kg) and the combined filtrates were concentrated under reduced pressure. The residual oil was cooled to 20° C. and dissolved in ethyl acetate (5 kg) and water (5.51) was added. The pH of the stirred mixture was adjusted to pH 2 by the addition of 3M aqueous hydrochloric acid (800 ml). The phases were allowed to separate and the aqueous phase was discharged. Water (2.751) was added to the organic phase and the pH was adjusted to 2 by the addition of a small amount of 3M HCl (45 ml). The aqueous phase was separated and the organic phase concentrated under reduced pressure at 30-50° C., to give 4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine as a reddish viscous oil containing ethyl acetate that was dissolved in ethanol (8.5 kg). Solvent (6.51 of ethanol/ethyl acetate) was then removed by distillation at reduced pressure. A further portion of ethanol (4.5 kg) leas added to the residue and the distillation repeated to remove 6.5 l of solvent. The ethanol solution of the product was used without further purification in the following step.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:16]=1[CH2:17][NH:18][C:19]1[C:20]([CH2:25][NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O.O>[CH3:13][O:14][C:15]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:16]=1[CH2:17][N:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][C:20]=2[CH2:25][N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[C:1]1=[O:2]
Reactant: COc1ccc(CNc2cccnc2CNC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3ncccc32)c(OC)c1
Temperature: 150 °C

Procedure:
Carbonyldiimidazole (1.22 g, 7.53 mmol) was added to a solution of the material from Step C in dimethylformamide (20 mL) and the reaction was heated to 150° C. overnight. The reaction was diluted with water and extracted with dichloromethane, and the organic phase dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 30 to 100% ethyl acetate in methylene chloride gradient elution), which gave the title compound (0.10 g). MS 483.3 (M+1).
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[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1)(=O)C.C[O-].[Na+].C(Cl)(Cl)Cl>CO>[C@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]1[OH:4]
Reactant: COC(=O)Cc1cccc(-c2ccccc2O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(-c2ccccc2O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Methyl 3-(2-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyloxy)phenyl)phenylacetate (3.96 g, 6.9 mmol, from Part E, EXAMPLE 2) was dissolved in methanol (50 ml), sodium methoxide (100 mg) was added and the solution stirred at room temperature for two hours. The reaction mixture was neutralized with Dowex-50W ion exchange resin (H+ form), filtered and concentrated in vacuo. Chromatography (silica, 9:1 CHCl3 :methanol) gave methyl 3-(2-(α-D-mannopyranosyloxy)phenyl)phenylacetate (2.8 g, quantitative yield (~100%)).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Product: COc1cc2c3c(cccc3c1N1CCN(C)CC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-6-bromo-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.5 g, from Example Z) was reacted with N-methylpiperazine (30 mL) following the procedure of Example 18 to give 0.5 g of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-5-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.3 g) at 40 psi in the presence of Pd/C (10%) in DMA (20 mL) afforded 0.2 g of the title compound as the free base. A solution of acetyl chloride (0.03 mL) in ethanol (1mL) was added to a solution of 2-hydroxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.12 g, 0.4 mmol) in ethanol (5 mL). The solution was stirred for 30 minutes, and the precipitate was filtered, washed with ether, and dried to give 0.13 g of the title compound as the HCl salt, mp 296-300° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10]C(=O)O[C:7](=[O:12])[C:6]=2[CH:13]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>CS(C)=O.CCOC(C)=O>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:13][C:6]=1[C:7]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)=[O:12]
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(O)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 2): A mixture of 6-hydroxy-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione (360 mg, 2 mmol) and 4-aminomethyl-1-diphenylmethylpiperidine (420 mg, 1.5 mmol) in DMSO (5 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with AcOEt and washed twice with brine. The organic layer was dried over MgSO4 and evaporated, and then the residue was purified by column chromatography on silica gel to give 2-amino-5-hydroxy-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 520 mg (63%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[F:17][C:18]1([F:38])[CH2:25][C@H:24]2[C@H:20]([CH2:21][NH:22][C@@H:23]2[CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH2:19]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([N:22]2[CH2:21][C@H:20]3[C@H:24]([CH2:25][C:18]([F:17])([F:38])[CH2:19]3)[C@H:23]2[CH2:26][N:27]2[C:28](=[O:37])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]2=[O:36])=[O:9])[N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1NC[C@@H]2CC(F)(F)C[C@@H]21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A mixture of 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid (208 mg), (1S,2S,5R)-2-(7,7-difluoro-3-azabicyclo[3.3.0]oct-2-ylmethyl)-isoindole-1,3-dione (273 mg), DIPEA (0.41 mL) in dry DMF (6 mL) was stirred at RT for 4 h. The reaction mixture was directly purified by preparative HPLC to give the title compound (130 mg, 28%) as an oil. LC-MS: tR=1.02 min; [M+H]+=521.99
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)=[O:21]
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1cccc(Br)c1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 84.1 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.96 g, 87%). EI-MS m/z 350 (M-H)-
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13]C)[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[CH:7]=[N:8]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH:7]=[N:8]2
Reactant: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c2c(O)cc(O)cc2ncn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.2 %

Procedure:
To an ice-cooled mixture of 365 mg (1.17 mmol) of 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone, prepared according to the procedures described in Example 18 or 19, and 10 ml of CH2Cl2, 3 ml of BBr3 (31.7 mmol) was added. The mixture was stirred at room temperature for 2 days. The solvent was evaporated, the obtained residue treated with a cold NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and evaporated to yield a solid which purification by flash chromatography on silica gel (loaded with CH2Cl2 and eluted with 66% EtOAc in hexane) gave 165 mg of 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (40% yield) as a white solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH3:15][Si:16]([CH3:24])([CH3:23])[O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([C:19](=[O:20])[CH:18]([O:17][Si:16]([CH3:24])([CH3:23])[CH3:15])[CH3:22])[CH:12]=[CH:11]2
Reactant: CC(O[Si](C)(C)C)C(=O)Cl
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Mg]
Product: COc1ccc2cc(C(=O)C(C)O[Si](C)(C)C)ccc2c1

Procedure:
When Z is a group which is convertible to a suitable leaving group, the conversion of Z can take place either before step A or thereafter, but before step B. For example, when the magnesium Grignard of 2-bromo-6-methoxynaphthalene is contacted with (S) 2-trimethylsiloxypropionyl chloride, (S) 1-(6-methoxy-2-naphthyl)-2-trimethylsiloxypropan-1-one is obtained. Regeneration of the hydroxyl group by hydrolysis affords (S) 2-hydroxy-1-(6-methoxy-2-naphthyl)propan-1-one. Further reaction with methanesulfonyl chloride then affords (S) 1-(6-methoxy-2-naphthyl)-2-methanesulfonyloxy propan-1-one, which is processed according to step A. Alternatively, the ketone can first be ketalized according to step A and the regeneration of the hydroxyl group and the formation of the sulfonate ester can occur subsequently but prior to step B.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[C:6]([CH:5]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 15.0 g (74.1 mmol) of methyl 3-ethoxy-4-methoxybenzoate in 45 mL of acetic acid was treated with 15 mL of conc nitric acid dropwise over 12 min. The reaction was kept at 55° C. for 45 min, cooled to 25° C. and poured into ice water. The product was extracted into methylene chloride and the extracts were washed with water and dil sodium hydroxide, dried and evaporated. The yield was 17.8 g of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate as yellow crystals: mass spectrum (electrospray, m/e): M+H 256.0.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:7][CH:8]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([CH2:2][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1nc(Nc2cccc(Cl)c2)ncc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-(chloromethyl)-N-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (544 mg), potassium phthalimide (626 mg), and N,N-dimethylformamide (5.44 mL) was stirred at room temperature for 20 hours. The reaction liquid was concentrated under reduced pressure, and then to the residue was added ethyl acetate (150 mL), followed by washing with water (50 mL) three times, and then with saturated brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain crude 2-({2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione as a pale yellow powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3.[N+](=[CH2:20])=[N-]>O1CCCC1.CCOCC>[CH3:20][O:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CO)C2
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCC1Cc2cc(C)c3c(c2O1)CCC(=O)N3
Temperature: 25 °C
Reaction time: 36 h
Yield: 88 %

Procedure:
To a solution of 2,3,6,7,8,9-hexahydro-2-hydroxymethyl -5-methylfuro-[2,3-f]quinoline-7-one (300 mg) in tetrahydrofuran (100 ml), silica gel (10 g) and a solution of diazomethane in ether (200 ml) were added, and stirred at room temperature for 36 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 280 mg of the target product as a pale yellow powder (88%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CO.[C].[Pd]>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:4]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(Oc2ccc(N)nc2)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 122.5 %

Procedure:
To a solution of tert-butyl {2-methyl-5-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (19.5 g, 45.3 mmol) in methanol (200 mL) was added palladium carbon (50% water-containing product, 2.99 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (17.5 g, 98%) as a pale-yellow oil.