Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([O:30][C:31]([CH2:33][N:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[CH3:35])=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:42][CH:43]=1)[CH3:35])=[O:32])[CH3:29]
Reactant: CCOC(=O)CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCOC(=O)CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-ethoxycarbonylmethyl-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=40:1) C29H29N3O5
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]CC)=[O:12])=[CH:6][C:5]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][CH3:25])[CH2:20][CH2:19]1)=[O:17]>C1COCC1.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][C:5]=1[C:16]([N:18]1[CH2:19][CH2:20][CH:21]([O:24][CH3:25])[CH2:22][CH2:23]1)=[O:17]
Reactant: CCOC(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Lithium hydroxide (0.752 g, 31.39 mmol) was added in one portion to ethyl 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetate (42) (2.03 g, 6.28 mmol) in THF (20 mL) and water (20 ml) at 25° C. under air. The resulting mixture was stirred at room temperature for 2 hours. The THF was evaporated and the mixture diluted with water (30 mL). The aqueous solution was acidified with 2N HCl and the product extracted into EtOAc (3×30 ml). The combined extracts were dried (MgSO4), filtered and evaporated to a give the desired material as a white solid (1.580 g, 85% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.54-1.84 (3H, m), 1.89-1.96 (1H, m), 3.12-3.20 (1H, m), 3.36 (3H, s), 3.45-3.53 (2H, m), 3.58 (2H, s), 3.60-3.66 (1H, m), 3.93-4.02 (1H, m), 7.01-7.06 (1H, m), 7.28-7.32 (2H, m); m/z (LC-MS, ESI+), RT=0.78 (M+H 296.3).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9](=[O:23])[C@@H:10]([NH2:22])[C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])[CH3:12].[OH:24][CH2:25][C@@H:26]1[CH2:28][C@H:27]1[C:29]#[C:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([C:41](O)=[O:42])[CH:35]=[CH:34]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:18]([O:17][C:15]([NH:14][C:11]([CH3:13])([CH3:12])[C@H:10]([NH:22][C:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([C:30]#[C:29][C@@H:27]3[CH2:28][C@H:26]3[CH2:25][OH:24])[CH:32]=2)[CH:37]=1)=[O:42])[C:9]([O:8][CH3:7])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1
Reactant: COC(=O)[C@@H](N)C(C)(C)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a stirring suspension of (S)-methyl-2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate (6.3, 1.6 g, 4.9 mmol) and 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid (6.2, 1.0 g, 3.8 mmol) in ACN (10 mL) at 0° C. was added triethylamine (2.1 mL, 15 mmol), followed by the portionwise addition of a solution of HATU (3.0 g, 7.9 mmol) in ACN (10 mL) and the reaction mixture was stirred at 0° C. for 75 min. The reaction was concentrated under reduced pressure to yield a residue, which was partitioned between MTBE and water. The organic layer was washed with 1M citric acid, water, saturated sodium bicarbonate (2×), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.4), which was carried through to the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[OH:14])[C:10]2[C:5](=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl-].[Cl-].[Ca+2]>CCO.[Zn]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:13]([C:11]1[C:10]2[C:5](=[C:6]([C:24]([F:25])([F:26])[F:27])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:29])([F:1])[F:28])[CH:12]=1)[OH:14]
Reactant: O=[N+]([O-])c1ccccc1C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: Nc1ccccc1C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Yield: 34.2 %

Procedure:
A solution of 2,8-bis(trifluoromethyl)-α-(2-nitrophenyl)-4-quinolinemethanol (636 mg, 1.53 mmol) in EtOH (30 mL) was treated with zinc dust (994 mg, 15.3 mmol) and CaCl2 (170 mg, 1.53 mmol), refluxed for 3 h, cooled, filtered through a pad of celite, concentrated in vacuo, purified by chromatography [SiO2; CH2Cl2] and the resulting solid recrystallised from CH2Cl2/heptane to give the title compound (202 mg, 34%) as a cream solid: mp 145.9-146.2° C.; IR νmax (Nujol)/cm−1 3413, 3339, 3094, 2924, 2854, 1611, 1586, 1462, 1313, 1295, 1155, 1132, 1111 and 1073; NMR δH (400 MHz, CDCl3) 1.40-1.79 (1H, s), 2.39-3.14 (1H, s), 3.84-4.58 (2H, s), 6.48-6.50 (1H, m), 6.59-6.62 (2H, m), 6.83 (1H, d, J 6.5 Hz), 7.15-7.18 (1H, m), 7.59 (1H, t, J 8.1 Hz), 7.99 (1H, d, J 9.0 Hz), 8.12 (1H, d, J 6.9 Hz) and 8.18 (1H, s); Anal. Calcd for C18H12F6N2O.0.25 H2O: C, 55.32; H, 3.22; N, 7.17. Found: C, 55.33; H, 3.34; N, 7.03.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CC(C)=O>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=3[CH:11]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2s1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A suspension of 2-cyano-6-hydroxybenzothiazole (1.0 g, 5.68 mmol) in acetone (5 mL) was prepared in a 100-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (0.94 g, 6.82 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then 4-(trifluoromethyl)benzyl bromide (1.49 g, 6.25 mmol) was added and the reaction mixture was heated at reflux for 15 h using a heated stir plate and oil bath. The reaction mixture was allowed to cool to ambient temperature and then filtered to remove inorganic salts. The filtrate was concentrated by rotoevaporation to provide 1.7 g (89% yield) of an off-white solid that was used without purification. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](I)[CH:4]=[N:3]1.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[N:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1cc(I)cn1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C#C[Si](C)(C)C)cn1
Temperature: 60 °C
Yield: 66.5 %

Procedure:
1-Methyl-4-iodo-pyrazole (18) (5.0 g 24.04 mmole) was dissolved in DMF (32 mL) and ethynyltrimethylsilane (4.76 mL, 3.31 g, 33.7 mmole) was added followed by diisopropylamine (4.46 mL, 3.21 g 31.78 mmole), copper(I) iodide (304 mg 1.59 mmole) and triphenylphosphine (1.26 g 4.81 mmole). The reaction was flushed with argon. Palladium acetate (351 mg 1.56 mmole) was added and the reaction was again flushed with argon. It was heated at 60° C. for 60 mins. The reaction was cooled, added to water (350 ml) and extracted with ether (3×100 mL). The organic solution was filtered from a brown solid which was washed with a little more ether. The organic solution was washed with water (3×80 mL), brine, dried and evaporated. The crude product was flash chromatographed (silica) using 1:4 ethyl acetate:cyclohexane and then 1:3 ethyl acetate:cyclohexane to give the title compound as a solid (2.85 g 67%). 1H-NMR (CDCl3, 500 MHz): δ 0.24 (s, 9H), 3.87 (s, 3H), 7.50 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OOC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl-].[Li+]>CN(C)C=O>[CH:24]1([C:30]([N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:9]3[N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:19][CH2:20]2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCCCC1
Reactant: c1ccc(-c2nc(NC3CCNCC3)nc3ccccc23)cc1
Agent: CN(C)C(OOn1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1CCC(Nc2nc(-c3ccccc3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a solution of 4-phenyl-N-(piperidine-4-yl)quinazolin-2-amine (0.34 g, 1.0 mmol), cyclohexanecarboxylic acid (0.15 g, 1.2 mmol), and triethylamine (1.38 mL, 10 mmol) in dimethylformamide (15 mL) was added O-(7-azabenzotriazol-1-yloxy)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.57 g, 1.5 mmol) and the solution was stirred at rt for 16 h. An aqueous 5% solution of lithium chloride (100 mL) was added and the resulting solid was filtered and recrystallized in methanol/methyl-tert-butyl ether to yield N-[1-(cyclohexylcarbonyl)piperidin-4-yl]-4-phenylquinazolin-2-amine (0.32 g, 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 11.81 (d, 1H), 7.70-7.65 (m, 4H), 7.56-7.53 (m, 3H), 7.21-7.16 (m, 1H), 5.26 (d, 1H), 4.52 (m, 1H), 4.34-4.28 (m, 1H), 3.92 (m, 1H), 3.28 (t, 1H), 2.94 (t, 1H), 2.51 (tt, 2H), 2.29-2.16 (m, 2H), 1.83-1.69 (m, 5H), 1.57-1.44 (m, 4H), 1.30-1.26 (m, 2H). MS (EI) for C26H30N4O: 415.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([NH:13][C:14]([NH:16][C:17]3[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=3)=[O:15])=[O:12])[CH:10]=[C:5]2[C:4]([CH3:34])=[N:3]1.[OH-].[Na+:36]>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([NH:13][C:14]([NH:16][C:17]3[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O-:25])=[O:24])=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=3)=[O:15])=[O:12])[CH:10]=[C:5]2[C:4]([CH3:34])=[N:3]1.[Na+:36]
Reactant: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2cnc3c(c2)c(C)nn3C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3ccc(OCC(=O)[O-])c(C(F)(F)F)c3)cc12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of ethyl 2-[4-({[(1,3-dimethypyrazolo[5,4-b]pyridin-5-yl)carbonyl-amino]carbonyl}amino)-2-(trifluoromethyl)phenoxy]acetate (0.11 g) in DMF (3 mL) was treated with 5N sodium hydroxide solution (1.6 mL). The mixture was stirred at room temperature for 1.25 h, and then concentrated under reduced pressure. The residue was taken up in water (4 mL), filtered, and the filtrate was cooled in an ice-bath and acidified to pH 4 with concentrated hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried under high vacuum. A portion of this material was suspended in water (5 mL) and treated with 5N sodium hydroxide solution (27 μL). The mixture was sonicated, filtered, and the filtrate lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 2.53 (s, 3H), 3.99 (s, 3H), 4.17 (s, 2H), 6.85 (d, J=8.8 Hz, 1H), 7.44-7.47 (br d, J=8.8 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 8.52 (s, 1H) 8.79 (d, J=1.6 Hz, 1H), 9.23 (d, J=1.6 Hz, 1H), 11.50 (br s, 1H). MS (ESI) m/z 450.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH2:42]O)[CH:35]=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=2)(=[O:54])=[O:53])=[C:47]([CH2:65][C:66]2[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=2[F:73])[CH:46]=1>C1COCC1.C(OCC)C>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]([CH2:42][CH2:41][CH2:40][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=2)(=[O:53])=[O:54])=[C:47]([CH2:65][C:66]2[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=2[F:73])[CH:46]=1
Reactant: OCCCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCCc2cccnc2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 0.25 h

Procedure:
To 1.5 g of triphenylphosphine dissolved in 25 ml of THF is added 0.909 g of diisopropyl azodicarboxylate. After 15 minutes at room temperature, 0.61 g of 3-pyrid-3-ylpropan-1-ol is introduced and the mixture is left at 20° C. for 15 minutes. 1.36 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide are introduced and the mixture is left at room temperature for 18 hours. The medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a toluene/ethyl acetate mixture passing from a ratio of 9/1 to 5/5 (v/v). 5 ml of 2M hydrochloric acid are added to the product obtained, dissolved in diethyl ether, and the solvents are then evaporated off. The residue is taken up in diisopropyl ether to give, after filtration, 0.55 g of the expected product.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[C:9]([C:18]2[C:19]([Cl:28])=[CH:20][C:21]([Cl:27])=C([CH:26]=2)C(O)=O)=[N:10][N:11]([CH3:17])[C:12]=1[O:13][CH:14]([F:16])[F:15]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[C:9]([C:18]2[C:19]([Cl:28])=[CH:20][C:21]([Cl:27])=[C:1]([CH:26]=2)[C:2]([Cl:4])=[O:3])=[N:10][N:11]([CH3:17])[C:12]=1[O:13][CH:14]([F:16])[F:15]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reaction time: 6 h

Procedure:
20.5 g (160 mmol) of oxalyl chloride were added dropwise to a solution of 7.7 g (20 mmol) of 5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-2,4-dichlorobenzoic acid in 300 ml of toluene. After 6 hours stirring at reflux temperature, the reaction mixture was concentrated. Yield: quantitative.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH2:2]1.[CH2:16]=[CH:17][CH:18]=[CH2:19]>>[CH:10]1[C:5]2[C:4]3([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH:17]=[CH:18][CH2:19][CH:3]3[CH2:2][S:1][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC=C
Reactant: CCOC(=O)C1=CCSc2ccccc21
Product: CCOC(=O)C12CC=CCC1CSc1ccccc12
Yield: 44 %

Procedure:
In an manner similar to that described in Example 16 the product of Example 17 was reacted with butadiene to give the title compound as a yellow oil (8.57 g, 44%).
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[C:20]([CH3:24])([CH3:23])[CH2:21][O:22][C:18]=2[CH:17]=1.[Li].[B:28](OC)([O:31]C)[O:29]C>C1COCC1>[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]2[C:20]([CH3:24])([CH3:23])[CH2:21][O:22][C:18]=2[C:17]=1[B:28]([OH:31])[OH:29]
Reactant: COB(OC)OC
Reactant: COc1ccc2c(c1)OCC2(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1B(O)O)OCC2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
s-BuLi (35 mL, 1.3M in cyclohexane) was added to TMEDA (6.6 mL) at −78° C. drop wise within 30 min, 20 mL of THF was added to keep stirring. After 20 min, 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran (5.4 g, 30.3 mmol) in THF (30 mL) was added into the lithium solution slowly. The solution was stirred at −78° C. for 1.5 h and trimethyl borate (18 mL) was added. The mixture was warmed to room temperature and stirred at room temperature overnight. The solution was acidified to pH=5-6 and extracted with ethyl acetate. The organic layer was concentrated and the resulted residue was purified on column chromatography (silica gel, dichloromethane/petroleum ether=3/1) to give the crude product, which was sonicated with petroleum ether. The white precipitate was filtered and dried to give 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-ylboronic acid (3.55 g, 53%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:23]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:23]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCCC[C@H]2CCNC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@H](CCCOCc3ccccc3)C2)c1
Temperature: 99 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 3(S)-[3-(benzyloxy)propyl]pyrrolidine (330 mg, 1.51 mmol) and 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (592 mg, 1.66 mmol, 1.1 equiv.) in 10 mL of anhydrous toluene were added successively at room temperature sodium tert-butoxide (290 mg, 3.02 mmol, 2.0 equiv.), tris(dibenzylideneacetone)dipalladium(0) (94 mg, 0.09 mmol, 0.06 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 105 mg, 0.18 mmol, 0.12 equiv.). The mixture was degassed and purged with nitrogen (3 cycles) and then heated to 98-100° C. After 4 h, the mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. After drying over Na2SO4, the solvent was evaporated, and the residue was purified by CC (SiO2, CH2Cl2/EtOAc 8:1 to 3:1) to obtain the title product (746 mg, 68%) as a light yellow oil. LC-MS (ESI) m/z 496 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][N:11]([C:23]([C:22]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=4[F:20])=[O:24])[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: COc1ccc(F)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)c1
Reaction time: 6 h

Procedure:
7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (62 mg, 0.20 mmol), 2-fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and Et3N (56 μL, 0.40 mmol) were combined in DCM (1 mL) and the mixture was stirred for 6 h. The mixture was diluted with DCM and was washed with 1N HCl, sat. aq. sodium bicarbonate and brine. The organics were dried over sodium sulfate and were evaporated. The crude material was purified by silica gel chromatography eluting with 0-40% ethyl acetate in hexanes to provide (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5-methoxyphenyl)methanone. ESI-MS m/z calc. 426.1. found 427.5 (M+1)+. Retention time: 2.12 minutes (3 min run). NMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 1H), 7.13-7.07 (m, 2H), 7.05-6.96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J=3.2 Hz, 1H), 6.08-5.98 (m, 1H), 4.69 (d, J=13.1 Hz, 1H), 3.80 (s, 3H), 3.63-3.44 (m, 2H), 3.33 (t, J=12.8 Hz, 1H), 2.19 (d, J=13.8 Hz, 1H), 2.09-1.96 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]#[CH:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][O:1][C:2]1[C:6]([CH2:7][C:8]#[CH:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C#CCc1c(O)noc1-c1ccccc1
Product: C#CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 83.8 %

Procedure:
3-Hydroxy-5-phenyl-4-propargylisoxazole (1.00 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.96 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (1.44 g, 84%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O-:34])=[O:33])[CH2:28][CH2:27]2)=[CH:22][C:21]=1[O:35][CH3:36]>C(O)CCC>[C:5]([O:33][C:32]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:6]3[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[C:21]([O:35][CH3:36])[CH:22]=2)[CH2:27][CH2:28]1)=[O:34])([CH3:9])([CH3:6])[CH3:4]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1cc(N2CCN(C(=O)[O-])CC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
2,4-dichloro-5-(trifluoromethyl)pyrimidine (800 mg) and potassium carbonate (510 mg) were dissolved in n-butanol (15 ml), dropwisely added with a reaction solution, in which 4-(4-amino-3-methoxyphenyl)piperazin-1-carboxylate (1.13 g) was dissolved in n-butanol (5 ml), and stirred at room temperature overnight. Then, the mixture was distilled under reduced pressure to remove the solvent, added with ethyl acetate, and washed with saturated brine. The washed organic layer was dried with sodium sulfate, and concentrated under reduced pressure. The concentrated mixture was purified by column chromatography to obtain a target compound (430 mg).