Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)(OC)=O.[CH3:21][NH:22][C:23](=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:26].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][N:22]1[C:23](=[O:31])[C:24]2[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:26]=[C:1]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:19][CH:20]=1
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Example 23 or 24 (100 g, 0.34 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (˜200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 45-55 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (66 g, Y=49%, P=98%).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:34])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]3[O:19][C:20]4[C:25]([CH:26]([C:27]5([C:30]([O:32]C)=[O:31])[CH2:29][CH2:28]5)[C:16]3=[CH:15][CH:14]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=1)=[O:6].Cl.C(OCC)(=O)C>CO>[CH3:3][N:4]([CH3:34])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]3[O:19][C:20]4[C:25]([CH:26]([C:27]5([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]5)[C:16]3=[CH:15][CH:14]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)C1(C2c3ccccc3Oc3nc(-c4ccc(C(=O)N(C)C)cc4)ccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2ccccc2C3C2(C(=O)O)CC2)cc1
Temperature: 60 °C

Procedure:
A 1 N aqueous solution of NaOH (0.5 mL, 0.500 mmol) was added to a solution of the product from Step 4 (11 mg, 0.026 mmol) in MeOH (1 mL) at room temperature. The mixture was heated to 60° C. for 3 h, cooled to room temperature and adjusted pH2-3 with 1 N aqueous HCl. Following addition of ethyl acetate (60 mL), the mixture was washed with brine (10 mL), dried (MgSO4) and concentrated to give 1-(2-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)cyclopropanecarboxylic acid as crude material (11 mg), which was taken to the next step directly. MS (ES+) m/z: 415 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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.O1CCOCC1>[OH:17][CH2:16][C@:11]([CH3:15])([CH2:10][C@H:9]([NH:18][C:19]([C:21]1[N:22]=[N:23][NH:24][CH:25]=1)=[O:20])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[CH:3][CH:4]=1)[C:12]([OH:14])=[O:13]
Reactant: Cc1ccccc1B(O)O
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
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: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(C[C@H](C[C@@](C)(CO)C(=O)O)NC(=O)c2c[nH]nn2)cc1
Temperature: 90 °C
Yield: 34.2 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 2-methylphenylboronic acid (25.1 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (13.3 mg). MS m/z [M+H]+ calc'd for C23H26N4O4, 423.20. found 423.2.
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>N1C=CC=CC=1>[Br:15][C:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:2][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc2cccnc2[nH]1
Reactant: [Br-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1[nH]c2ncccc2c1Br
Temperature: 0 °C
Yield: 32.5 %

Procedure:
To a solution of 3.2 g of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride in 165 mL of pyridine is added dropwise, at 0° C. under an argon atmosphere, a solution of 5.04 g of pyridinium tribromide in 35 mL of pyridine. The reaction mixture is then stirred at 0° C., and then poured onto a mixture of 250 g of crushed ice and 750 ml of distilled water. The suspension is filtered and the solid is washed with twice 25 mL of distilled water and then dried in the open air. 0.87 g of methyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate is obtained in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[S:29][C:30]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:31]=2[N:32]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:35]=[CH:36][C:30]6[S:29][C:28]([CH3:27])=[N:32][C:31]=6[CH:33]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1nc2cc(B(O)O)ccc2s1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6sc(C)nc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzothiazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.91 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([Br:23])[N:22]=2)=[O:17])[CH2:3]1.C[Si]([N:28]=[C:29]=[O:30])(C)C.C(N(CC)CC)C.CO>O1CCCC1>[NH2:28][C:29]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([Br:23])[N:22]=2)=[O:17])[CH2:3]1)=[O:30]
Reactant: C[Si](C)(C)N=C=O
Reactant: N[C@@H]1CCCN(c2c(F)cccc2NC(=O)c2nc(Br)c[nH]2)C1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)N[C@@H]1CCCN(c2c(F)cccc2NC(=O)c2nc(Br)c[nH]2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of imidazole 12 (29 mg, 0.076 mmol), trimethylsilyl isocyanate (18 mg, 0.15 mmol) and triethylamine (31 mg, 0.30 mmol) in tetrahydrofuran (1 mL) was stirred at r.t. for 4 h. Methanol (1 mL) was added and the mixture was stirred at r.t for 1 h. The solvents were removed in vacuo and chromatographic purification (ethyl acetate-hexane) of the residue gave urea 15 (21 mg, 64%) as a colorless oil. LCMS m/e (M+H+)=425.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([N+:13]([O-])=O)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[C:6]([NH2:13])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(F)(F)F)n1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(C(F)(F)F)n1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To a solution of 6-methoxy-3-nitro-2-(trifluoromethyl)pyridine (3.61 g) in 95% Ethyl alcohol (162 ml) was added tin(II) chloride dihydrate. It was heated to 70° C. for 3 hr. After it was cooled to room temperature, it was poured over ice water and adjusted to pH 11 with 2N NaOH. It was stirred well with ethyl acetate and filtered through celite. The organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated. The flash column chromatography (SiO2, 3˜8% EtOAc in heptane) gave the title compounds (2.20 g, 71%). 1H NMR (CDCl3) δ 3.81, 6.70, 7.05; 19F NMR (CDCl3) δ 65.73; IR (liq.) 2434 (w), 2389, 2272, 2229, 2174, 1488 (s), 1436 (s), 1426 (s), 1276 (s), 1170 (s), 1102 (s, b), 1050 (s), 1024 (s), 740 (s), 658 (s) cm−1 HRMS (ESI) calcd for C7H7N2OF3+H1 193.0589. found 193.0581. Anal. Calcd for C7H7F3N2O: C, 43.76; H, 3.67; N, 14.58; F, 29.66. Found: C, 43.61; H, 3.49; N, 14.49.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]#[C:25][CH3:26])[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:12](=[O:15])[CH2:13]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O.CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:9]([CH2:23][C:24]#[C:25][CH3:26])[CH2:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:12](=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCC(CN(C(=O)CCl)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC#CCC1CN(c2cccc(Cl)c2)C(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the chloroacetamide from Step H (1.68 g, 4.23 mmol) in 15 mL of dry DMF at 0° C. was added Cs2CO3 (3.08 g, 9.48 mmol). The solution was stirred for 30 minutes, then allowed to warm to room temperature. After 14 hours, the reaction was poured into 50% EtOAc/hexane, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. This material was purified by silica gel chromatography (20-40% EtOAc/hexane) to yield the titled product.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.[OH-].[K+].NN.O>C(O)CO>[CH:1]1([CH2:6][C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ncccc1C(=O)C1CC=CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ncccc1CC1CC=CC1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
Cyclopent-3-en-yl[2-(methyloxy)pyridin-3-yl]methanone (Preparation 29, 10 g, 49.3 mmol), potassium hydroxide (85%, 16.8 g, 0.3 mol), and hydrazine (6.33 g, 198 mmol) in ethylene glycol (100 ml) were heated to 180° C. and stirred for 18 h. Water was added and the product was extracted with hexane:ethyl acetate (50:50). The combined organic extracts were washed with brine and concentrated in vacuo. The crude oil was purified by flash chromatography eluting with ethyl acetate:hexane (10:90) to give a colourless oil (4.75 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[CH3:28][CH2:29][O:30]C(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([O:15][C:29](=[O:30])[CH3:28])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5S,7R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-hydroxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.21 g) in THF (5 mL) was added DEAD (0.09 mL), triphenylphosphine (0.15 g), and acetic acid (0.035 mL). After stirring overnight at room temperature, the mixture was concentrated. Purification by chromatography (Silica gel: 25% EtOAc/hexane, Chromatotron) afforded the titled compound (0.151 g). MS (m/z) 511 (MH+), mp 149.8° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:28][CH2:29][CH2:30][CH3:31])[CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH2:28]([N:12]([CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=1)[CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:14]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(Cc1cccc(CC(=O)OC)c1)C1CCN(c2nc3ccc(Cl)cc3s2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1cccc(CC(=O)O)c1)C1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of [3-[[butyl[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]amino]methyl]phenyl]acetic acid methyl ester (28 mg), 2N sodium hydroxide (0.15 mL), tetrahydrofuran (1 mL) and methanol (0.5 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid and concentrated under reduced pressure. The solution was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate to give the title compound (19 mg). Yield: 68%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:56]([O:60][CH3:61])(=[O:59])[CH:57]=[CH2:58]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C)C=O>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2](/[CH:58]=[CH:57]/[C:56]([O:60][CH3:61])=[O:59])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)/C=C/c1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)c(OC)c1
Temperature: 115 °C
Reaction time: 15 h
Yield: 85.5 %

Procedure:
To a 2 ml N,N-dimethylformamide solution of 150 mg (0.36 mmol) of the compound obtained in Example 15, 8 mg (0.036 mmol) of palladium acetate, 22 mg (0.072 mmol) of tri-o-tolylphosphine, 0.15 ml (1.08 mmol) of triethylamine, and 97 μl (1.08 mmol) of methyl acrylate were added, and the mixture was stirred at 115° C. in a sealed tube for 15 hours. Then, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 130 mg (85%) of the captioned compound.
Reaction SMILES: [CH:1]1([N:5]([CH3:28])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21]OC)=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25]C)[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:21][C:17]1[CH:18]=[C:19]([Cl:20])[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:8]([OH:25])=[C:7]([CH:12]=2)[C:6]([N:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:28])=[O:27])=[C:15]([Cl:24])[CH:16]=1
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)N(C)C3CCC3)c2)c(Cl)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O)C1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Step F in dichloromethane (2.2 ml) at room temperature was added boron tribromide (1M in dichloromethane, 1.5 ml, 1.5 mmol). The reaction mixture was stirred at room temperature for about two hours, and quenched with water (20 ml). After stirring for about 15 minutes, the solution was extracted with dichloromethane (3×15 ml). The combined organic extracts were washed with brine (50 ml), treated with activated carbon, filtered through diatomaceous earth, dried and concentrated to give the title compound (163 mg) as an off-white solid which was used in the next step without further purification. MS (APCl−) Calc: 457.0, found: 456.0 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:1]([CH2:2][CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:21])=[O:10])=[CH:7][CH:6]=1)[CH3:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(CO)c1ccc(C(=O)[O-])cc1
Reactant: Oc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)COc2ccccc2)cc1
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of 4-(1-hydroxypropan-2-yl)benzoate (100 mg, 0.52 mmol), phenol (78 mg, 0.8 mmol), triphenylphosphine (216 mg, 0.8 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (166 mg, 0.8 mmol) at room temperature. The mixture solution was stirred for 18 hours. Then tetrahydrofuran was removed in vacuo. The residue was purified by column chromatography (silica-gel, petroleum/ethyl acetate=6:1) to give methyl 4-(1-phenoxypropan-2-yl)benzoate as a colorless oil (100 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.23-7.29 (m, 2H), 6.85-6.95 (m, 3H), 3.98-4.11 (m, 2H), 3.91 (s, 3H), 3.27-3.34 (m, 1H), 1.43 (d, J=6 Hz, 2H).
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:15]=2)[CH:11]=1.C(OCC)(=O)C>[Cu](I)I.O.CCCCCC>[C:20]([N:14]1[CH:13]=[C:12]2[C:16]([C:17]([CH3:19])=[CH:18][C:10]([NH2:2])=[CH:11]2)=[N:15]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(Br)cc2cn(C(C)(C)C)nc12
Reactant: CN1CCCC1=O
Agent: I[Cu]I
Agent: N
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc2cn(C(C)(C)C)nc12
Temperature: 95 °C
Reaction time: 10 h

Procedure:
Copper oxide (I) (2.7 g), NMP (150 mL), and concentrated aqueous ammonia (150 mL) were added to 5-bromo-2-(tert-butyl)-7-methyl-2H-indazole obtained in the above-described Step 1 (40.3 g). The reaction solution was stirred in a portable reactor at 95° C. for 10 hours. The reaction solution was cooled to room temperature, and ethyl acetate (500 mL), hexane (200 mL), and water (300 mL) were added. After separation, the organic layer was washed successively with water four times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum to obtain 2-(tert-butyl)-7-methyl-2H-indazol-5-amine as a purple solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[C:20]([O:24][C:25](=[O:36])[NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28]O)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:20]([O:24][C:25](=[O:36])[NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][N:4]1[C:3](=[O:19])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])[C:5]1=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Yield: 49 %

Procedure:
5-Bromo-1-(2,6-difluoro-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (synthesized according to the method of BMCL 2004 14(19) 4967-4973) (2.77 g, 8.37 mmol), ((R)-2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (2.08 g, 8.78 mmol), and triphenylphosphine (3.29 g, 12.5 mmol) were added to anhydrous tetrahydrofuran (70 mL) and stirred for a short time. To this solution was slowly added diethylazodicarboxylate (1.95 mL, 12.5 mmol), followed by stirring at room temperature for 12 hrs in a nitrogen atmosphere. Following concentration, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford 2.26 g of the compound as a white foam (yield 49%).
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl[C:21]([O:23][CH2:24][CH2:25][CH2:26]C)=[O:22].O1CCC[CH2:29]1>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][N:17]([C:21]([O:23][CH2:24][CH:25]([CH3:26])[CH3:29])=[O:22])[CH2:16][CH2:15]1
Reactant: O=C1C(Cl)=C(N2CCNCC2)C(=O)c2ccccc21
Reactant: CCCCOC(=O)Cl
Reactant: C1CCOC1
Product: CC(C)COC(=O)N1CCN(C2=C(Cl)C(=O)c3ccccc3C2=O)CC1
Reaction time: 0.33 h

Procedure:
A solution of 830 mg of 3-chloro-2-piperazinyl-1,4-naphthoquinone in 50 ml of tetrahydrofuran was added dropwise to a solution of 0.39 ml of butyl chloroformate in 10 ml of tetrahydrofuran. This mixture was stirred for 20 minutes, then filtered and the filtrate concentrated to an oil. The oil was recrystallized from ether/hexane, giving 360 mg of the desired product, mp 92°-94° C.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(CN2CCCCC2)cc1
Temperature: 110 °C
Yield: 50.9 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-piperidin-1-ylmethyl-phenylamine (95.14 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 2 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 92 mg (51%) of yellow solid mp 185-186° C.; HRMS (ESI) m/z calcd for C22H23N3O2 362.18546. found 362.18631 (M+H)+1.