Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:38]1[N:39]([C:43]2[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=2[C:45](O)=[O:46])[N:40]=[CH:41][CH:42]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:45]([C:44]4[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=4[N:39]4[N:40]=[CH:41][CH:42]=[N:38]4)=[O:46])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=1
Reactant: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: CN(C)c1nc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)cc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-trifluoromethyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 11) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. Additionally, the reaction time was shortened to 30 minutes. MS (ESI) mass calcd. for O22H−23F3N8O, 472.47; m/z found 473 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.19-6.80 (m, 7H), 4.49-3.78 (m, 5H), 3.75-3.30 (m, 2H), 3.22-3.10 (m, 2H), 3.06-2.74 (m, 5H), 2.24-1.87 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14]OS(C)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH2:26]([N:33]1[CH2:6][CH2:7][C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)OCCc1ccoc1CCOS(C)(=O)=O
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3ccoc3CC2)cc1
Temperature: 102 °C

Procedure:
A solution of 2,3-di(2-methanesulfonyloxyethyl)furan (114 mmol) in dioxane (168 mL) is treated with potassium carbonate (337 mmol) and benzyl amine (70.1 mmol) and heated to 102° C. for 18 hours. The reaction is cooled, the precipitate removed by filtration, and the mother liquor concentrated to give a crude oil which is purified by silica chromatography (EtOAc/hexanes eluant) to provide 6-benzyl-5,6,7,8-tetrahydro-4H-furo[3,2-d]azepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:19]2[S:23][C:22]([C:24]([O:26]C)=[O:25])=[C:21]([CH3:28])[C:20]=2[CH3:29])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:19]2[S:23][C:22]([C:24]([OH:26])=[O:25])=[C:21]([CH3:28])[C:20]=2[CH3:29])=[CH:5][CH:4]=1
Reactant: COC(=O)c1sc(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2sc(C(=O)O)c(C)c2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
Methyl 5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-3,4-dimethylthiophene-2-carboxylate (step-5, 0.2 g, 0.45 mmol) was suspended in ethanol (10 ml). Aqueous solution of NaOH (0.09 g. 2.24 mmol in water 2 ml) was added to the reaction mixture at 0° C. The reaction mixture was heated at 80° C. under stirring for 1.5 hour. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Dilute hydrochloric acid was added to the separated aqueous layer to bring the pH of the solution to between 6 and 7. The resulting mixture was extracted with ethyl acetate (2×25 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound 9f (0.17 g, 86.0%).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([C:15]#[N:16])[C@H:10]([CH3:17])[CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>C1COCC1>[ClH:18].[CH3:17][C@H:10]1[CH2:9][NH:8][CH2:13][C@@H:12]([CH3:14])[N:11]1[C:15]#[N:16]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@@H]1CNC[C@H](C)N1C#N
Reaction time: 5 h

Procedure:
4-Cyano-cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.0 g) in 10 mL THF was treated with 4.0 N HCl/dioxane (25 mL), stirred for five hours and concentrated to provide 1.1 g of the title compound. 1H NMR (DMSO-D6, 300 MHz) δ ppm 1.24 (d, 6H, J=6.6 Hz), 2.65 (q, 2H, J=11.1 Hz), 3.27 (d, 2H, J=12.2 Hz), 3.63 (m, 2H); 13C (DMSO, 75 MHz) 16.73 (2C), 46.81 (2C), 50.80 (2C), 104.20.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]([O:17]CC)=[O:16])[N:10]=[N:9][C:8]=12)(=[O:3])[NH2:2]>Cl>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]([OH:17])=[O:16])[N:10]=[N:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CCOC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Agent: Cl
Product: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Temperature: 42.5 °C
Reaction time: 4 h
Yield: 25.04 %

Procedure:
Ethyl 8-Carbamoyl-3,4-dihydro-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazin-3-ylacetate (10.2 g) was suspended in hydrochloric acid (5 M, 50 mL). The suspension was stirred for 4 hours at 40-45° C. until hydrolysis was complete (TLC). The mixture was concentrated under reduced pressure to 20 mL and the solid product was collected and washed with acetone (3×20 mL). The product was dried under high vacuum to give the title compound. LCMS (ES−), m/z 237 (M−H−) in the solvent front. Yield 25.04%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(O)(=O)C>[Fe].CO>[NH2:13][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[OH:12]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1O
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cl)c(N)c1O
Temperature: 25 °C
Yield: 81 %

Procedure:
A 100-mL single-neck round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with methyl 4-chloro-3-nitrosalicylate (1.00 g, 4.32 mmol), glacial acetic acid (23 mL) and methanol (18 mL). The stirred solution was then treated with 325 mesh iron powder (2.41 g, 43.2 mmol) and heated at reflux for 30 min. After this time, the reaction was cooled to room temperature and filtered through a pad of celite 521. The pad was rinsed with methanol (10 mL) and the filtrates combined and partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and washed with water (2×100 mL) then dried over sodium sulfate. The suspension was filtered and the filtrate treated with decolorizing carbon (0.50 g) and warmed to reflux. The suspension was then re-filtered hot through a pad of celite 521 and the resulting filtrate concentrated to dryness under reduced pressure to afford methyl 3-amino-4-chlorosalicylate in 81% yield (0.70 g) as white solid: 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J=2.7 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 3.95 (br s, 2H), 3.94 (s, 3H); MS (ESI) m/z 202 [M+H]+.
Reaction SMILES: C(N(C(=O)C1C=CC(O)=CC=1)C1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:44][CH3:45])[CH3:43])=O>>[CH2:44]([N:42]([CH2:40][C:39]1[CH:19]=[CH:18][C:17]([O:22][CH2:39][CH2:40][N:42]([CH2:44][CH3:45])[CH3:43])=[CH:16][CH:15]=1)[C:43]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:45]
Reactant: CCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 115 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-ethyl-N-methylacetamide (7.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.4 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[N:9]1([CH2:8][C:4]2[N:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1cccc(CN2CCCCC2)n1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2cccc(CN3CCCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
To a solution of 2-bromo-6-piperidin-1-ylmethyl-pyridine (example 5) (8.0 g, 31.4 mmol) and 4-formylphenylboronic acid (6.1 g, 40.8 mmol) in toluene/ethanol (4/1, 320 ml) was added an aqueous solution of 2M potassium carbonate. After 15 minutes stirring under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.02 mmol) was added. After stirring for 17 h at 80° C. under a nitrogen atmosphere, the mixture was cooled to room temperature and filtered through decalite. Water was added and the product was extracted into ethylacetate. The combined organic phases were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded 4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzaldehyde (7.69 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:23])([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1.Cl>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:23])([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CC1(C(=O)O)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 90 °C
Yield: 58 %

Procedure:
Ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexanecarboxylate (Intermediate 72, 900 mg, 2.85 mmol) was added to 6M aq. hydrochloric acid (0.951 mL, 5.71 mmol) in acetic acid (5 mL). The reaction mixture was heated to 90° C. for 48 h and then concentrated under vacuum. The residue was taken up in a minimal volume of ethyl acetate and a white solid precipitated. The solid was collected by filtration, washed with acetonitrile and dried to provide the product acid (475 mg) as a white solid. LCMS [M−H]=286.3
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH2:9][CH2:10][N:11]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:12][CH2:13][N:14]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[O:7])[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[C:62]1([CH3:72])[CH:67]=[CH:66][C:65]([S:68](Cl)(=[O:70])=[O:69])=[CH:64][CH:63]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:68]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:13][CH2:12][N:11]([S:35]([C:38]1[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=1)(=[O:36])=[O:37])[CH2:10][CH2:9][N:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:46])=[O:47])([C:65]1[CH:66]=[CH:67][C:62]([CH3:72])=[CH:63][CH:64]=1)(=[O:70])=[O:69]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOC(=O)N(CCN(CCN(CCCCCCCCCO)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N(CCN(CCN(CCCCCCCCCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To 5.47 g of 16-butoxycarbonyl-10, 13,16-tri(p-toluenesulfonyl)-10, 13,16-triazahexadecanol in 200 ml of CH2Cl2, 2.95 g of Et3N was added and the mixture was cooled to 0° C. To the well stirred solution was added dropwise at 0° C. 0.22 g of 4-dimethylaminopyridine and then 1.67 g of p-toluenesulfonyl chloride in 100 ml of CH2Cl2 was added. The reaction was continued overnight at room temperature. A 0.04 g amount of 4-dimethylaminopyridine and 0.33 g of p-toluenesulfonyl chloride were added at 7° C. and stirring was continued for 4 hours. The mixture was extracted with water twice. The organic layers were dried over MgSO4, filtered and evaporated under reduced pressure and eluted with CH2Cl2 and CH2Cl2/ethyl acetate (100/1 v/v). About 4.21 g of product was obtained. The preparation scheme is shown below:
Reaction SMILES: [Mg].[F:2][C:3](S(C1C=CC=CC=1)(=O)=O)(S(C1C=CC=CC=1)(=O)=O)[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH2:5][OH:6].O>C(Br)Br.C[Si](Cl)(C)C.CO>[F:2][CH2:3][CH:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=1)[CH2:5][OH:6]
Reactant: CC(C)Cc1ccc(C(CO)C(F)(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: BrCBr
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(C(CO)CF)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
One drop of CH2Br2 and then 1 drop of TMSCl were charged into a 5 mL solution of magnesium ribbon (707 mg, 29.1 mmol, 45.0 eq) in MeOH. The solution was cooled to 0° C., and then a 5 mL solution of 3-fluoro-2-(4-isobutylphenyl)-3,3-bis(phenylsulfonyl)propan-1-ol (317 mg, 0.646 mmol, 1.0 eq) in MeOH was added dropwise thereto. The solution was stirred for 2 hours at 0° C., and then water was charged thereto to stop the reaction. The aqueous solution was acidified using 1 M HCR. The aqueous layer was extracted with methylene chloride and then the extract was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure by distillation, and then the resultant product was purified by column chromatography (hexane:ethyl acetate=7:3) to obtain 3-fluoro-2-(4-isobutylphenyl)propan-1-ol (119 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[B:26]1(B2OC(C)(C)C(C)(C)O2)[O:30]C(C)(C)C(C)(C)[O:27]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)=[CH:3][C:2]([B:26]([OH:30])[OH:27])=[CH:7]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(B(O)O)cn(C)c2=O)nc1
Temperature: 70 °C
Yield: 94.6 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 132b (580 mg. 1.42 mmol), bis(pinacolato)diboron (1.2 g, 4.5 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), X-phos (71 mg, 0.15 mmol), potassium acetate (294 mg, 3.0 mmol), and 1,4-dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 70° C. for 2 h. Then it was filtered and the filtrate was evaporated under reduced pressure. The residue was washed with petroleum ether to afford 132c (500 mg, 94%) as a white solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 373.1
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[NH:15]2)[CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[OH:10])[CH3:2].[NH4+].[Cl-].C1COCC1.O>CO.[Fe]>[NH2:11][C:8]1[CH:7]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[NH:15]2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[OH:10]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(N)c1O
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of 4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (Compound 1) (431 mg, 1.0 mmol) and NH4Cl (268 mg, 5.0 mmol) in MeOH:THF:H2O=2:1:1 (8 mL) was added iron power (280 mg, 5.0 mmol) and the reaction mixture was heated to reflux for 1.0 h. The reaction mixture was cooled to room temperature and filtered. The filtered mass was washed with methanol (5.0 mL). The filtrate was concentrated in vacuo to afford 4-(3-amino-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one as a white solid (386 mg, 96.3%), which was used directly for the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([N:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([O:24][CH:22]1[CH2:23][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (2.57 mL, 33.3 mmol) and triethylamine (11.6 mL, 83.1 mmol) were added to a solution of commercially available N—BOC-3-hydroxy azetidine (4.8 g, 27.7 mmol) in tetrahydrofuran (100 mL) under nitrogen atmosphere at room temperature. The reaction liquid was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid at room temperature, and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to quantitatively obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH2:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.[O:44]1CCCC1.B.C1COCC1.OO.[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[CH2:12][CH2:13][OH:44])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1
Reactant: C1CCOC1
Reactant: C=CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COC(CCO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)allyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (84 mg, 0.133 mmol) in tetrahydrofuran (2 mL, 0.133 mmol) at 0 C was added Borane-THF (0.267 mL, 0.267 mmol). The reaction was allowed to slowly warm to room temperature over 1.5 h. The reaction was recooled to 0 C and treated with hydrogen peroxide (30%) (1.3 mL, 0.133 mmol) followed by sodium hydroxide (0.6 mL, 2.400 mmol). After stirring for 30 min, the reaction was diluted with ether and quenched by addition of sat'd ammonium chloride. The mixture was extracted with ether, washed with brine, dried over magnesium sulfate, filtered and concentrated. It was purified by column chromatography (30% to 47% EtOAc/Hex) to give title compound (61 mg, 0.094 mmol, 70.6% yield) as white foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.02 (s, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.30 (m, 2H), 7.06 (t, J=8.8 Hz, 2H), 6.70 (bs, 1H), 5.64 (AB, Δν=17.1 Hz, J=10.7 Hz, 2H), 5.07 (t, J=6.7 Hz, 1H), 3.75 (m, 2H), 3.57 (m 2H), 3.38 (m, 2H), 2.95-3.25 (m, 2H), 2.05-2.25 (m, 2H), 1.85 (m, 2H), 1.43 (s, 9H), 0.90 (t, J=8.5 Hz, 2H), −0.06 (s, 9H). LC/MS (HPLC method 3): tR=4.29 min, 648.2(MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])=[CH:27][C:26]=1[Cl:43].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:43][C:26]1[CH:27]=[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38](=[O:42])[N:39]([CH3:40])[CH3:41])[C:29]2[O:33][CH2:32][O:31][C:30]=2[C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CN(C)C(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 72.1 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), N′-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N,N-dimethylurea (193 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (254 mg, 72%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.45 (t, 2H), 3.81 (s, 6H), 3.60 (m, 4H), 3.94 (s, 3H), 4.10 (d, 2H), 4.20 (t, 2H), 6.15 (s, 2H), 6.84 (t, 1H), 7.08 (s, 1H), 7.20 (s, 1H), 7.82 (s, 1H), 8.34 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 597/599.