Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1[O:28][CH2:27][CH2:26]OCCOCCOCCOCCOC1.[NH2:29][C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[N:33]=[CH:32][C:31]=1[CH:42]=O.[NH4+].[Cl-]>C1COCC1>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N:34]1[C:30]2[NH:29][C:27](=[O:28])[CH:26]=[CH:42][C:31]=2[CH:32]=[N:33]1
Reactant: Nc1c(C=O)cnn1-c1ccccc1Cl
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1ccc2cnn(-c3ccccc3Cl)c2[nH]1
Temperature: -35 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
At −35° C., KHMDS (8.03 mL of 0.5 M in toluene, 4.01 mmol) was added to a slurry of methyl p,p-bis(2,2,2-trifluoroethyl)-phosphonoacetate (1.21 g, 3.82 mmol) and 18-crown-6 (506 mg, 1.91 mmol) in 3.0 mL of THF. After the resulting mixture was stirred at −35° C. for 10 min, a solution of 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbaldehyde (424 mg, 1.91 mmol) in THF (1.5 mL+1.5 mL rinsing) was added in via a syringe. The reaction mixture was slowly warmed to RT overnight, quenched with saturated NH4Cl, and extracted with EtOAc twice. The combined EtOAc layers were dried and concentrated to dryness. The resulting brown residue in THF (3.0 mL) at RT was treated with KHMDS (12 mL of 0.5 M in toluene, 6.0 mmol) and heated at 70° C. in an oil bath for 3 h. After the reaction mixture was cooled to RT, it was treated with saturated NH4Cl, and extracted with EtOAc twice. The combined EtOAc layers were dried and concentrated. The brown residue was loaded on an ISCO 12 g column (eluted with 25-65% EtOAc in Hexanes) to give the title compound (352 mg) as a yellow amorphous solid. MS (ESI, pos.ion) m/z: 246.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][CH2:28][S:29][CH3:30])[N:21]=3)[C:7]=2[CH:31]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:40])C=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][CH2:28][S:29]([CH3:30])=[O:40])[N:21]=3)[C:7]=2[CH:31]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CCSC)n2)[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CCS(C)=O)n2)[C@@H]1O
Yield: 32.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-1-(2-methylthioethyl)-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (262 mg) obtained in Example 57 was dissolved in dichloromethane (20 ml), and m-chloroperbenzoic acid (152 mg) was added under ice-cooling. The mixture was reacted for 30 minutes. The reaction mixture was poured in a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1-20:1) to give 182 mg (65%) and 89 mg (33%) of the title compounds, respectively.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH2:13][CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.O>[ClH:32].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]3[C:4]([OH:5])=[O:3])[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCCCN1CCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCCCN1CCCN1c2ccccc2CCc2ccccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
The above ester (0.83 g, 0.002 mol) was dissolved in a mixture of ethanol (8 ml), water (2 ml) and sodium hydroxide (0.58 g, 0.015 mol). The reaction mixture was stirred at room temperature for 50 h and at 50° C. for 5 h. Water (50 ml) and concentrated hydrochloric acid (3 ml) were added, and the resulting mixture was extracted with dichloromethane (3×10 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was re-dissolved in methanol (2 ml) and ethyl acetate (5 ml) and concentrated in vacuo. The solid residue was washed with a small amount of ethyl acetate and dried, affording 0.6 g (73%) of the title compound as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=3)=[O:26])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Product: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-chloro-pyridin-4-yloxy)-phenylamine (Example 105) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a beige solid: ES-MS: 407.9 [M+H]+; single peak at tR=9.99 min (System 2); Rf=0.30 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27](Br)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH:37][C:38]1[N:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27]([C:41]4[CH:40]=[N:39][C:38]([NH:37][CH3:36])=[N:43][CH:42]=4)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CN2CCOc3c(Br)cc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNc1ncc(-c2cc(OC(C)C)c(C)c3c2OCCN(Cc2c(C)cc(C)nc2OCc2ccccc2)C3=O)cn1
Temperature: 100 °C
Yield: 73.9 %

Procedure:
A solution of 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-9-bromo-6-methyl-7-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (116 g, 121 mg, 0.224 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (52.7 mg, 0.224 mmol) and sodium carbonate (2.0 M, 71.2 mg, 0.672 mmol) in 1,4-dioxane (2.0 mL) was degassed (N2) for 5 min, then PdCl2(dppf)-DCM (50.0 mg, 0.0610 mmol) was added. The reaction was heated at 100° C. for 1 hour. The reaction was diluted with water (25 mL) and EtOAc (25 mL). The layers were separated and the organic phase was dried with magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-9-[2-(methylamino)pyrimidin-5-yl]-7-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (128a, 94 mg, 74% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]1[C:16]([C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[O:18])=[C:15]([CH3:24])[NH:14][C:13]([CH3:25])=[C:12]1[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27].ClC1C([N+]([O-])=O)=CC=CC=1C=O.N/C(/C)=C\C(OC(C)C)=O.C(OCCOC)(=O)CC(C)=O>CC(O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([CH:11]2[C:16]([C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[O:18])=[C:15]([CH3:24])[NH:14][C:13]([CH3:25])=[C:12]2[C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[O:27])[CH:4]=[CH:5][CH:6]=1
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1Cl
Agent: C/C(N)=C/C(=O)OC(C)C
Agent: COCCOC(=O)CC(C)=O
Agent: O=Cc1cccc([N+](=O)[O-])c1Cl
Solvent: CC(C)O
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(N)c1Cl

Procedure:
Isopropyl 2-methoxyethyl 4-(3-amino-2-chloro-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate ##STR31## 27.5 g (61 mmol, purity 96.5%) of isopropyl 2-methoxy-ethyl 4-(2-chloro-3-nitrophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate, obtained by reaction of equimolar amounts of 2-chloro-3-nitrobenzaldehyde, isopropyl β-aminocrotonate and methoxyethyl acetoacetate in 2-propanol at the reflux temperature, are suspended in 500 ml of methanol and hydrogenated in the presence of Raney nickel (about 1.5 g, water-moist) under normal pressure and temperature until the end of the uptake of hydrogen (1 hour). The catalyst is filtered off and the residue obtained after concentration is purified by flash chromatography (toluene/ethyl acetate 1:0→5:1). Crystallization from toluene gives 24.0 g (93% of theory) of the title compound of melting point 118°-122° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12](O)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C=[N+]=[N-])(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C(Cl)Cl.CO.C1COCC1.O>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:17])([F:18])[F:16])=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under nitrogen atmosphere 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (288 mg, 1.12 mmol) was dissolved in a 4:1 mixture of dry DCM and MeOH (12.5 mL) and trimethylsilyl diazomethane (134 mg, 1.176 mmol; 2.0M solution in n-hexane) was added dropwise. After 10 min. stirring at room temperature excess trimethylsilyl diazomethane was destroyed by the addition of a few drops acetic acid. The solvent was evaporated to afford the crude methylester as a yellow solid which was redissolved in dry THF and nitrogen atmosphere. LiAlH4 (50 mg, 1.34 mmol) was added in several small portions and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was cooled down to 0° C. and excess LiAlH4 was hydrolyzed by adding MeOH (5 mL), H2O (10 mL) and 2N aq. HCl (5 mL). After extracting with DCM the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to afford the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 8.05-8.09 (d, 2H), 7.43-7.58 (m, 3H), 4.75 (s, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[N:14]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a solution of 4-chlorosulfonylbenzoic acid (2 g, 9.07 mmol) in dichloromethane (10 mL) was added a solution of pyrrolidine (1.29 g, 1.51 mL, 18.1 mmol) in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the white solid obtained was washed with water (50 ml) and diethyl ether (10 ml) and dried under vacuum to give 4-pyrrolidin-1-ylsulfonylbenzoic acid (700 mg, 30%). ESI-MS m/z calc. 255.0. found 256.3 (M+1)+; Retention time: 1.18 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.49 (s, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 3.17 (t, J=6.7 Hz, 4H), 1.65 (t, J=6.7 Hz, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([N:13]2[CH2:14][CH2:15][O:11][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCO1
Reactant: OCCc1cccc(Br)c1
Product: O=C1OCCN1c1cccc(CCO)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 2-(3-bromophenyl)ethanol and 1,3-oxazolidin-2-one.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[C:19]([F:37])=[C:20]([C@@H:25]([CH:34]3[CH2:36][CH2:35]3)[NH:26]C(=O)OC(C)(C)C)[CH:21]=[CH:22][C:23]=2[Cl:24])=[O:17])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[ClH:24].[NH2:26][C@H:25]([CH:34]1[CH2:36][CH2:35]1)[C:20]1[C:19]([F:37])=[C:18]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)=[O:17])[C:23]([Cl:24])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(Cl)c(C(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1F)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](c1ccc(Cl)c(C(=O)c2ccc(CO)cc2)c1F)C1CC1
Yield: 155.3 %

Procedure:
Step 3 tert-Butyl N—[(R)-{3-[(4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)carbonyl]-4-chloro-2-fluorophenyl}(cyclopropyl)methyl]carbamate (265 mg, 0.48 mmol) was treated with a 4M hydrogen chloride solution in 1,4-dioxane (5 ml) at room temperature for 60 minutes. Material that had precipitated out was re-dissolved by the addition of methanol before the mixture was concentrated in vacuo. The residue was re-concentrated from methanol before the addition of a small amount of ethyl acetate and diethyl ether to elicit precipitation. The solids were collected by filtration and were dried in a vacuum oven furnishing [4-({3-[(R)-amino(cyclopropyl)methyl]-6-chloro-2-fluorophenyl}carbonyl)phenyl]methanol hydrochloride as a white solid (138 mg)
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: COCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: COCCOc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)ccc2F)c(F)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 192. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (dd, J=8.6, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.91 (s, 1H), 7.01-6.91 (m, 2H), 4.82 (dd, J=10.3, 3.8 Hz, 1H), 4.32-4.12 (m, 3H), 4.05-3.85 (m, 2H), 3.75 (s, 3H), 3.74-3.65 (m, 2H), 3.32 (s, 3H), 3.06 (dd, J=16.5, 7.8 Hz, 1H), 2.10-2.02 (m, 1H), 1.82-1.57 (m, 5H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH:23](OC)OC)=[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]2[OH:20].Cl.[OH2:29]>CC(O)=O>[Cl:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][N:10]2[CH2:11][CH2:2][O:29][CH2:8][CH2:9]2)=[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]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[OH:20]
Reactant: O
Reactant: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl)OC
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)c1csc(-c2cc(O)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-quinolin-4-ol (5.0 g, 12.3 mmol) was dissolved in HOAc (100 mL) and 1.4 N HCl/H2O (50 mL). The reaction mixture was heated to 60° C. with stirring for 2 hrs. After cooled back to room temperature and concentrated, the residue was co-evaporated with toluene (2×50 mL). Then the crude was dissolved in DCM (100 mL) and cooled to 0° C. with stirring. Morphiline (1.6 g, 18.4 mmol) and NaHB(OAc)3 (3.9 g, 18.4 mmol) were added to the reaction mixture. After stirring at room temperature for 1 h, the reaction mixture was washed with sat. NaHCO3, brine and dried by Na2SO4. After concentration, the crude was purified by silica gel chromatography to afford 5.0 g of 8-chloro-2-(4-isopropyl-thiazol-2-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-ol as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([SnH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].C(Cl)(Cl)(Cl)Cl>O1CCCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])/[C:16](=[CH:15]/[C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=1)/[C:17]([NH2:19])=[O:18])[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(N)=O)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(N)=O
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amide (1.13 g, 4.12 mmol) prepared in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (23 ml) in nitrogen atmosphere, and tetrakistriphenylphosphine palladium(0) (95.2 mg, 0.082 mmol) was added under cooling with ice, and then a tetrahydrofuran solution (17 ml) of tri-n-butyltin hydride (5.2 ml, 19.3 mmol) was dropwise added. After stirring for 30 minutes, carbon tetrachloride was added to terminate the reaction, and potassium fluoride was added, followed by stirring for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give (E)-2-(tributylstannyl)-3-(4-tert-butyldimethylsilyloxyphenyl)acrylamide (1.51 g, 65%) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:35])[C@@H:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:36](O)(=[O:39])[CH:37]=[CH2:38].Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:35])[C@@H:29]([NH:34][C:36](=[O:39])[CH:37]=[CH2:38])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)N[C@@H](CC(C)C)C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 0 °C

Procedure:
480 mg of (2S)-2-amino-4-methyl-pentanoic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide was dissolved in 10 ml of THF, cooled to 0° C., and the resulting solution was treated with 0.1 ml of acrylic acid, 0.16 ml of pyridine and 376 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 1 hour and at room temperature for 2 hours. The resulting solution was treated with saturated sodium bicarbonate, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound of formula (162 mg, 31%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][C:10]([CH3:13])([O-:12])[CH3:11].[K+]>O1CCCC1>[C:10]([O:12][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)([CH3:13])([CH3:11])[CH3:9]
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 89.9 %

Procedure:
After dissolving 3.00 g of 2,6-dichloropyrazine in 40 ml of tetrahydrofuran, 2.26 g of potassium tert-butoxide was added and the mixture was stirred for 5.5 hours at room temperature. The reaction solution was distilled off under reduced pressure, ethyl acetate was added to the residue and filtration was performed with NH silica gel and silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (3.38 g, 90% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1cc(C)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C)cc(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylphenyl)propanoate (400 mg) in methanol (4.0 ml) and THF (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (249 mg) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[CH2:15].O>C1(C)C=CC=CC=1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[F:10][C:11]1[CH:12]=[C:13](/[CH:14]=[CH:15]/[B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)[CH:16]=[CH:17][CH:18]=1
Reactant: C=Cc1cccc(F)c1
Reactant: CC1(C)OBOC1(C)C
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: O
Solvent: C1=CCCC=CCC1
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2cccc(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 11 mg of chloro(1,5-cyclooctadiene)-rhodium(I) dimer and 0.61 mL of 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in 15 mL toluene was added dropwise 1.0 mL of 3-fluorostyrene, and stirred at room temperature for 4 hours. The reaction solution was added with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude product was purified and separated by silica gel column chromatography (diethyl ether:n-hexane=1:19), to afford 311 mg of the title compound as a pale yellow oil.