Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][NH:15][CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)=O)C>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)OCCCCC1CCCCC1
Reactant: CNCC1CCc2ccc(NC(C)=O)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(=O)Nc1ccc2c(c1)C(CN(C)CCCCC1CCCCC1)CC2

Procedure:
A mixture of 6-Acetylamino-1-(N-methylaminomethyl)indan (1.5 g), 4-cyclohexylbutan-1-ol mesylate (2.5 g), potassium carbonate (1.4 g), and a crystal of potassium iodide in MIBK (80 ml) were refluxed for 5 h. After cooling inorganic salts were filtered off and the solvent evaporated in vacuo. The remaining oil was subjected to column chromatography on SiO2 (eluted with ethyl acetate:heptane:triethylamine 80:20:4). The free base of the title compound was isolated as an oil. The sesquioxalate of 13a crystallized from acetone. Yield 1.6 g Mp: 145°-155° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:33])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with 4-phenoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (7.4 mg, 11%) having the following characteristics.
Reaction SMILES: C1COCC1.[Cl:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(N(CC)CC)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([CH2:7][Cl:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A THF (8 ml) solution of 4-chloromethylbenzoylchloride (5.3 g) was added dropwise at 0° C. to a THF (16 ml) solution of 1-tert-butoxycarbonylpiperazine (5.19 g) and triethylamine (2.82 g) and the solution was stirred at room temperature for 10 minutes. The reaction solution was concentrated and the obtained solid residue was washed with water and ethyl acetate, and dried to give a colorless solid of the title compound (9.44 g).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([NH2:11])[C@@H:9]([O:12][C:13](=[O:15])[CH3:14])[C@H:8]([O:16][C:17](=[O:19])[CH3:18])[C@@H:7]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:6]1)(=[O:3])[CH3:2].[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:43]([NH:42][C:40]([O:39][CH2:38][CH:36]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:37]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:41])=[S:44])[C@@H:9]([O:12][C:13](=[O:15])[CH3:14])[C@H:8]([O:16][C:17](=[O:19])[CH3:18])[C@@H:7]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
The amine from above (220 mg) was dissolved in pyridine (5 mL) and 9-Fluorenylmethoxycarbonyl isothiocyanate (180 mg, 0.65 mmol) and triethylamine (0.02 mL) was added. Then the resulting mixture was stirred at room temperature for 16 h. The solution was concentrated and the residue taken up in CH2Cl2 (20 mL) and diluted with saturated aqueous NaHCO3 (20 mL), then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. Flash chromatography of the residue (EtOAc:hexanes 2:3) gave (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(((9H-fluoren-9-yl)methoxy)carbonyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (360 mg, 89% yield over two steps). 1H NMR (600 MHz, CDCl3) δ 2.06 (s, 3H), 2.07 (s, 3H), 2.12 (s, 3H), 2.14 (s, 3H), 3.89 (ddd, 1H, J=2.4, 4.8, 9.6 Hz), 4.17 (dd, 1H, J=2.4, 12.5 Hz), 4.24 (dd, 1H, J=6.6, 6.6 Hz), 4.33 (dd, 1H, J=4.8, 12.5 Hz), 4.52 (s, 1H), 4.54 (s, 1H), 5.08-5.12 (m, 1H), 5.22 (dd, 1H, J=9.5, 9.6 Hz), 5.34 (dd, 1H, J=6.6, 9.5 Hz), 5.88 (d, 1H, J=6.6 Hz), 7.36 (dd, 2H, J=7.2, 7.8 Hz), 7.45 (dd, 2H, J=7.2, 7.8 Hz), 7.57 (d, 2H, J=7.8 Hz), 7.80 (d, 2H, J=7.2 Hz). 13C NMR (150 MHz, CDCl3) δ 20.62, 20.72, 20.77, 21.05, 46.49, 57.59, 61.65, 67.47, 68.40, 72.21, 72.87, 92.21, 120.09, 120.29, 124.84, 124.96, 125.32, 127.30, 127.83, 128.15, 128.25, 129.06, 141.37, 142.80, 152.16, 169.27, 169.34, 170.46, 170.72, 180.22.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 19.4 %

Procedure:
A mixture of 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (1.0 g, 5.0 mmol), 2-methoxyphenyl boronic acid (1.1 g, 7.2 mmol), [RhCl(cod)]2 (110 mg, 0.25 mmol) and TEA (5 mmol) in H2O (14 ml) and 1,4-dioxane (1 ml) was stirred at 90° C. in a sealed vial for 6 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc; The combined organic layers were dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/acetone) to provide 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-propionic acid methyl ester XXXVII (300 mg, 20% yield) as a yellow film.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][C@@H:26]2[CH2:28][C@H:27]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][C@@H:26]1[CH2:28][C@H:27]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: c1ccc([C@@H]2C[C@H]2NCn2nnc3ccccc32)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CN[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.3 %

Procedure:
To a mixture of 7.3 g (0.112 g-atom) of zinc powder (−325 mesh) and 120 mL of anhydrous tetrahydrofuran was added 10.7 mL (0.084 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 10.8 mL (0.084 mole) of ethyl bromodifluoroacetate in 10 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 14.8 g (0.056 mole) of benzotriazol-1-ylmethyl-(trans-2-phenyl-cyclopropyl)-amine in 60 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 1.7 g of 2,2-difluoro-3-(trans-2-phenyl-cyclopropylamino)-propionic acid ethyl ester as a oil.
Reaction SMILES: [O:1]=[C:2]([NH:17][CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:19]([O:21]C)=[O:20])[CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>[OH-].[Na+].O1CCCC1>[O:1]=[C:2]([NH:17][CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:19]([OH:21])=[O:20])[CH2:3][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(OC)c1)NC(=O)CC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(NC(=O)CC(c2ccccc2)c2ccccc2)C(=O)O)cc1OC
Temperature: 25 °C

Procedure:
α-[(1-Oxo-3,3-diphenylpropyl)amino]-3,4-dimethoxybenzenepropionic acid, methyl ester (6.0 g) in 1N sodium hydroxide, tetrahydrofuran, and methanol was allowed to stir at room temperature for several hours. The mixture was evaporated to 50% volume and poured into ethyl acetate and water. The layers were separated and the aqueous layer was brought to pH 2 using concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (2×50 ml) and the combined extracts were washed with water, brine, dried over magnesium sulfate, filtered and evaporated at reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][OH:12])=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:12][CH2:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[CH:8][C:9]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:4]([OH:6])=[O:5])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1CO
Product: CC(=O)OCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl

Procedure:
1.3 g of 2-chloro-3-hydroxymethyl-4-methanesulfonyl benzoic acid and 30 ml of acetic anhydride, was refluxed for 3 hours under heating. The reaction mixture was concentrated under reduced pressure. Then, 50 ml of water was added thereto and warmed for 1 hour. Precipitated solid was collected by filtration, washed with water and dried to obtain 1.35 g of the desired product. Melting point: 219°-223° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[N:34][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])=[N:36]2)=[CH:31][CH:30]=1.[OH:52][C@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54](O)=[O:55].C(N(CC)CC)C>CN(C=O)C>[OH:52][C@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54]([N:49]1[CH2:50][CH2:51][N:46]([C:33]2[C:32]3[C:37](=[CH:38][C:29]([CH3:28])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:34]=2)[CH2:47][CH2:48]1)=[O:55]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Under an N2 atmosphere, BOP (138 mg, 0.31 mmol) was added in a single portion to a stirring solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (100 mg, 0.31 mmol), (R)-2-hydroxy-4-methylpentanoic acid (41 mg, 0.31 mmol), and triethylamine (43 μL, 0.31 mmol) in DMF (0.5 ml). After stirring the mixture for 1 h at room temperature, it was partitioned between H2O and ether. The organic phase was washed with H2O (3×20 mL), dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 20% EtOAc and 80% CH2Cl2 gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one as a light yellow solid (89 mg, 60%). LC/MS: m/z 435.1 (M+H)+ at 2.93 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=7.9, 1.7 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.41-7.37 (m, 1H), 7.30 (dd, J=8.5, 1.5 Hz, 1H), 7.06-7.04 (m, 1H), 6.98-6.94 (m, 1H), 4.51-4.45 (m, 1H), 4.04-3.80 (m, 6H), 3.72-3.62 (m, 3H), 2.56 (s, 3H), 2.12-1.99 (m, 1H), 1.57-1.49 (m, 1H), 1.38-1.32 (m, 1H), 1.05 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:21]3[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Yield: 94.7 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), then ethyl isonipecotate (0.12 ml, 0.78 mmol) and diisopropylethylamine (0.15 ml, 0.88 mmol) were added, followed by heating under reflux for 3 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain a yellow oil (0.27 g, 94%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[CH3:10]
Reactant: CCN
Reactant: Cn1cc(C=O)cn1
Solvent: C1CCOC1
Product: CCNCc1cnn(C)c1

Procedure:
prepared by reaction of the commercially available 1-methyl-1H-pyrazole-4-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][OH:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCC1CCO1
Reactant: N#Cc1cnc(N)cc1Cl
Product: N#Cc1cnc(N)cc1OCC1CCO1

Procedure:
From intermediate 16 and oxetan-2-ylmethanol, reacted in an analogous manner to the preparation of intermediate 34. (UPLC-MS 3) tR 0.45 min; ESI-MS 206.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl.[OH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][CH2:19][C@H:14]([OH:13])[CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: O[C@H]1CCCNC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1
Temperature: 175 °C
Yield: 37.5 %

Procedure:
A mixture of Intermediate 24b (394 mg, 2.30 mmol), (S)-3-hydroxypiperidine hydrochloride (1.00 g, 7.27 mmol) and DIPEA (1.27 mL, 7.30 mmol) in DMA (8 mL) was heated in the microwave at 170-180° C. for 9.5 h. The cooled mixture was concentrated in vacuo and applied to an SCX-2 cartridge (70 g), washing with methanol then eluting basic components with 0.4-2 M ammonia in methanol. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the title compound as a pale brown solid (204 mg, 38%). LCMS (Method 3): Rt 2.02 min, m/z 237 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]1.[NH2:21][NH2:22]>C(O)C>[I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:21][NH2:22])=[O:13])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2I)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccccc2I)CC1

Procedure:
Synthesized according to General Procedure C: 6{27} (4.87 g, 12.5 mmol, 1 equiv.), anhydrous hydrazine (1.2 mL, 37.6 mmol, 3 equiv.), ethanol (25.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{27} (4.08 g, 87%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.17 (br s, 1H), 7.82 (dd, 1H, J=1.2, 7.6 Hz), 7.37 (dd, 1H, J=1.6, 7.6 Hz), 7.29 (dt, 1H, J=1.2, 7.2), 6.91 (dt, 1H, J=1.6, 7.6 Hz), 3.85 (br s, 2H), 3.52 (s, 2H), 3.08 (s, 2H), 2.54 (br s, 8H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 140.2, 139.5, 130.2, 128.7, 128.0, 100.6, 61.2, 60.6, 53.7, 52.9.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:61][CH2:60][N:59]([C:62]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[O:63])[CH2:58][CH2:57]2)[CH2:52][CH2:51]1.C(N(CC)CC)C>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38](=[O:47])[NH:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:36][CH2:37]1)=[O:34])[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]2[CH2:55][CH2:54][CH:53]([N:56]3[CH2:57][CH2:58][N:59]([C:62]([O:64][CH2:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[O:63])[CH2:60][CH2:61]3)[CH2:52][CH2:51]2)=[O:12])[CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 147.2 %

Procedure:
To a solution of a crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (300 mg) in N,N-dimethylformamide (4.5 ml) were added benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (684 mg) and triethylamine (0.629 ml), followed by stirring at room temperature for 20.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide a crude product of benzyl 4-{1-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-ylcarbamoyl]piperidin-4-yl}piperazine-1-carboxylate as a pale yellow oil (501 mg). This was dissolved in ethanol (10 ml) and N,N-dimethylformamide (5.0 ml). 1,4-cyclohexadiene (0.633 ml) and 10% palladium on carbon (144 mg) were added thereto, followed by stirring at 65° C. for 1.5 hr. The reaction mixture was allowed to cool down to room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=10:1, then 5:1). Fractions containing the target compound were concentrated to give the residue (56.3 mg). The residue was purified by LC-MS. Fractions containing the target compound were concentrated, which were partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and to the residue was added diethyl ether to suspend a solid. This was collected by filtration, and dried under aeration to provide the titled compound as pale yellow powder (12.7 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.C(O)(=[O:20])C>O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:20])[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=1
Reactant: COC(=O)CCCCCc1ccc(C#N)cc1
Reactant: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 11 %

Procedure:
The compound (620 mg) obtained in the above (1) is dissolved in a mixture of acetic acid (30 ml) and water (5 ml), and thereto is added chromic anhydride (1.3 g)/acetic acid (2 ml), and the mixture is stirred at room temperature for 17.5 hours. The mixture is diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution, and purified by silica gel column chromatography (n-hexane/ethyl acetate=5:1→2:1) to give the title compound (70 mg, 11%), and the starting compound (365 mg, 59%) is also recovered.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:30].CO.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:30][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=2)[CH:8]=1
Reactant: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl)OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COC(COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl)OC
Temperature: 80 °C
Yield: 0.1 %

Procedure:
8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-quinolin-4-ol (512 mg, 1.25 mmol) was dissolved in pyridine (10 mL). POCl3 (2.30 mL, 25.0 mmol) was added slowly. The reaction was heated at 80° C. for 4 hours. The reaction was cooled to 0° C. and methanol (5 mL) was added. The reaction was neutralized with a sat NaHCO3(aq) solution. The product was extracted with EtOAc (3×20 mL). The combined organics were dried with Na2SO4, filtered and was concentrated. 4,8-dichloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-quinoline (0.275 mg, 52%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>ClCCl>[Cl:13][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(Cl)c1
Yield: 73.9 %

Procedure:
A mixture of 8.26 g of ethyl 4-aminobenzoate, 8.26 g of N-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight. The mixture is washed with saturated NaHCO3 solution and dried Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated and hexane added. Chilling gives 7.38 g of ethyl 3-chloro-4-aminobenzoate, m.p. 82°-83° C.