Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15]C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.COCCOCCOC>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)CCCCCCOC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOCCOC
Solvent: C1CCOC1
Product: OCCCCCC/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To 150 ml of a mixture of tetrahydrofuran-diglyme (2:15) were added 12 g of 1-phenyl-8-(2-tetrahydropyranyloxy)-1-octyne and 3.35 g of lithium aluminum hydride. The mixture was heated and tetrahydrofuran was distilled off until the inner temperature became 120° C. After heating under reflux at the same temperature for 1 hour, the mixture was ice-cooled. Ice was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, water, sodium hydrogen carbonate solution, saline water in the order mentioned, dried, and then the solvent was distilled off. The residue was dissolved in 250 ml of methanol and 1.1 g of p-toluenesulfonic acid was added thereto. The mixture was stirred at room temperature for 1 hour and 2 ml of triethylamine was added to the mixture. Methanol was distilled off and the residue was purified by silica gel column chromatorgraphy (solvent: hexane-ethyl acetate=3:1) to give 7.5 g of (E)-8-phenyl-7-octen- 1-ol as an oily substance.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]([C:26]4[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=4[F:36])[C:18](=[O:22])[CH:17]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4F)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A suspension of 4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (127 mg, 0.424 mmol, prepared according to procedures described in Example 230 Step C substituting 2-chloro-5-ethylpyrimidine (Aldrich) for 2-chloro-5-cyclopropylpyrimidine), sodium hydride (60 wt % mineral oil, 21 mg, 0.51 mmol) and DMF (5 mL) was purged with Argon and then stirred at room temperature for 1 h. To the reaction was added 1,2-difluoro-4-(methylsulfonyl)benzene (90 mg, 0.47 mmol, Matrix Scientific) and then heated at 110° C. for 1 h. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a yellow solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 91 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 2 H), 7.83-7.91 (m, 2 H), 7.64 (dd, J=8.53, 6.78 Hz, 1 H), 7.13 (dd, J=7.53, 1.00 Hz, 1 H), 6.08 (dd, J=7.65, 2.64 Hz, 1H), 6.03 (d, J=2.51 Hz, 1 H), 4.54-4.63 (m, 1 H), 4.16-4.27 (m, 2 H), 3.60-3.70 (m, 2 H), 3.12 (s, 3H), 2.49 (q, J=7.53 Hz, 2 H),1.97-2.15 (m, 2 H),1.78-1.97 (m, 2H),1.21 (t, J=7.53 Hz, 3 H). MS (ESI) 473 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[N:15]=1.[C:31](=O)([O:35]CC)[O:32][CH2:33][CH3:34]>C1COCC1>[C:27]([O:26][C:24]([N:17]1[C:16]2[N:15]=[C:14]([CH2:13][C:31]([O:32][CH2:33][CH3:34])=[O:35])[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)OCC
Reactant: Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of diisopropylamine (47.7 mL, 364 mmole) in dry THF (250 mL) at 0° C. was added n-BuLi (2.5 M in hexanes, 145.6 mL, 364 mmole) dropwise. After 15 min, this solution was added dropwise to a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine (32.3 g, 130 mmole) and diethyl carbonate (56.8 mL, 481 mmole) in dry THF (400 mL) at −78° C. After 30 min, the mixture was quenched with saturated NH4Cl (500 mL), warmed to RT, and extracted with EtOAc (3×500 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. Drying under high vacuum overnight gave the title compound (42.52 g, 102%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=7.5 Hz, 1 H), 6.96 (d, J=7.5 Hz, 1 H), 4.18 (t, 2H), 3.75 (m, 4 H), 2.72 (t, 2 H), 1.91 (m, 2 H), 1.52 (s, 9 H), 1.24 (m, 3 H); MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=[O:6]>Br>[Br:1][C:4]([CH3:13])([CH3:3])[C:5]([C:7]1[CH:12]=[N:11][CH:10]=[N:9][CH:8]=1)=[O:6]
Reactant: CC(C)C(=O)c1cncnc1
Reactant: BrBr
Agent: Br
Product: CC(C)(Br)C(=O)c1cncnc1
Reaction time: 8 h

Procedure:
At room temperature, 11.8 ml (229.8 mmol) of bromine, dissolved in 111.5 ml of hydrobromic acid, were added to 28.7 g (191.5 mmol) of 2-methyl-1-(pyrimidin-5-yl)propan-1-one dissolved in 463 ml of hydrobromic acid. After the addition had ended, the reaction mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure. This gave 50.8 g (91%) of the desired product, which was reacted without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH:5]=O.[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[OH-].[Na+]>CO.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1ccc(C=O)cc1O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Yield: 14.1 %

Procedure:
A mixture of 3-hydroxy-4-ethoxybenzaldehyde (0.350 g, 2.5 mmol), 3,4,5-trimethoxyacetophenone (0.443 mg, 2.5 mmol) and 50% w/v of aqueous sodium hydroxide (3.37 ml, 0.042 mol) in methanol (5 ml) at room temperature for 18 h. An orange solid was isolated by filtration, dissolved in ethyl acetate which was subsequently dried over MgSO4 and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) yielded 0.126 g (16.7%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.3 (m, 4H), 7.1 (dd, 1H), 6.9 (d, 1H), 5.75 (s, 1H), 4.2 (q, 2H), 3.95 (s×2, 9H), 1.5 (t, 3H). 13C-NMR (CDCl3) δ 190.0, 153.1, 150.0, 146.0, 133.7, 128.4. Mass Spectrum m/e (M+1) 359. Anal. Calcd. for C20H22O6: C, 67.03; H, 6.19. Found C, 66.74; H, 6.33.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14]3[CH:18]=[C:17]([C:19](O)=[O:20])[N:16]([CH3:22])[N:15]=3)=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14]3[CH:18]=[C:17]([C:19]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:20])[N:16]([CH3:22])[N:15]=3)=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1nc(-c2cncc(F)c2)sc1-c1cc(C(=O)O)n(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(-c2cncc(F)c2)sc1-c1cc(C(=O)NS(C)(=O)=O)n(C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-[2-(5-Fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-1H-pyrazole-5-carboxylic acid (0.08 g, 0.25 mmol) and methanesulphonamide (0.024 g, 0.25 mmol) were initially charged in ice-cooled dichloromethane (10 ml). 4-Dimethylaminopyridine (0.006 g, 0.05 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.053 g, 0.275 mmol) were added. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (dichloromethane/ethyl acetate eluent). This gave 0.074 g (72% of theory) of 3-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-N-(methylsulphonyl)-1H-pyrazole-5-carboxamide.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])O[CH2:12][CH3:13]>>[CH2:12]([O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)[CH3:13]
Reactant: CCOC([O-])[O-]
Reactant: O=C1CCCCCCC1
Product: CCOC1=CCCCCCC1
Yield: 44.2 %

Procedure:
In the presence of 0.3 g of paratoluenesulfonic acid, 20 g (0.16 mol) of cyclooctanone and 27 g (0.18 mol) of ethyl orthoformate were stirred at room temperature overnight. The resultant mixture was heated at 100° C. for 15 hours and distilled under reduced pressure to give 10.9 g (45% yield) of 1-ethoxycyclooctene having a boiling point of 97.5° to 98.5° C./25 mmHg.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[C:20](C=CCC)[CH:19]=2)(=[O:17])=[O:16])C=CC=1C(C)(C)C)=CCC.[CH3:32][SnH:33]([CH3:35])[CH3:34]>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([S:15]([CH2:7][CH2:6][CH2:5][CH2:1][Sn:33]([CH3:35])([CH3:34])[CH3:32])(=[O:17])=[O:16])=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCC=Cc1cc(S(=O)(=O)c2ccc(C(C)(C)C)c(C=CCC)c2)ccc1C(C)(C)C
Reactant: C[SnH](C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)CCCC[Sn](C)(C)C)cc1
Reaction time: 70 h
Yield: 20.3 %

Procedure:
The procedure described in Example 1 was employed except that 10.7 g (42.5 mmoles) of 3-butenyl-4-t-butylphenyl sulfone and 7.0 g (42.5 mmoles) of trimethyltin hydride were the reactants. The irradiation proceeded for 70 hours. Recrystallization of the product from petroleum ether afforded 3.6 g of 4-(p-t-butylphenyl-sulfonyl)butyltrimethylstannane, m.p. 80°-81.8° C. The presence of both the sulfonyl and trimethyltin moieties was indicated by strong infrared absorption bands at 1300 cm-1, 1282 cm-1, 1147 cm-1 (--SO2 --) and 780 cm-1 [(CH3)3Sn--] employing a KBR disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following:
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]=C=O>>[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:47][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][C:25]([OH:27])=[O:26])=[O:17]
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C=Nc1ccccc1F
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1ccccc1F
Yield: 13 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 2-fluorophenyl isocyanate as described in Example 16 in a 13% yield; ESMS, (M+1)+464.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH:19]=[CH:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH:20]=[CH:21][CH2:22][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: BrC=CCCBr
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Product: Fc1ccc(-n2ccc3cc(OCC=CCBr)ccc32)cc1

Procedure:
In analogy to example 3.1, 1-(4-Fluoro-phenyl)-1H-indol-5-ol and 1,4-dibromobutene were converted to yield 5-(4-Bromo-but-2-enyloxy)-1-(4-fluoro-phenyl)-1H-indole as colorless liquid, MS: 359 (M, 1Br).
Reaction SMILES: Cl.[CH2:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]1[CH2:4][CH2:5][CH:6]2[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:2]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCC2CCCCC2C1
Agent: Cl
Product: O=C(CN1CCC2CCCCC2C1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46 %

Procedure:
Proceeding as in Example 1, but substituting 2-(octahydroisoquinolin-2(1H)-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 222, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(octahydroisoquinolin-2(1H)-yl)acetamido)propanamide (20.6 mg, 46%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): 10.21 (s, 1H), 7.96 (d, 1H), 7.60 (d, 2H), 7.29-7.31 (m, 5H), 7.19-7.23 (m, 2H), 6.98-7.04 (m, 4H), 4.68 (m, 1H), 4.49 (s, 2H), 3.29-3.79 (m, 2H), 2.77-3.01 (m, 2H), 2.63-2.73 (m, 2H), 2.01-2.99 (m, 2H), 0.81-1.86 (m, 12H). MS (EI) for C33H38FN3O4. found 560.6 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13]([OH:15])=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([N:29]([C:13](=[O:15])[CH2:12][C:7]2[NH:6][C:5]3[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=3[S:9](=[O:10])(=[O:11])[N:8]=2)[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852, 0.2 g, 0.546 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 22a, 0.138 g, 0.546 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.573 mmol). Then N-methylmorpholine (0.116 g, 1.15 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 16 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C24H32IN3O5S 601.11. found 602.6 [M+H+].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH:32]([C:35]1[O:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42]2[C:43]([OH:53])=[N:44][N:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:46]=2)[N:39]=1)([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:32]([C:35]1[O:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42]2[C:43]([O:53][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:44][N:45]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:46]=2)[N:39]=1)([CH3:34])[CH3:33]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CC(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 15.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.976 g), 4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (0.83 g), potassium carbonate (0.691 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (244 mg, yield 16%) as colorless crystals. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 106-108° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.Cl.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH:20]([NH2:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[C:6]([NH:23][CH:20]([CH2:21][CH3:22])[CH2:19][O:18][C:17]2[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:13])([F:27])[F:28])[CH:16]=2)[N:7]=1
Reactant: CC(C)c1nc(N)nc(Cl)n1
Reactant: CCC(N)COc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(COc1cccc(C(F)(F)F)c1)Nc1nc(N)nc(C(C)C)n1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
2.6 g (0.015 mol) of 2-amino4-chloro-6-isopropyl-1,3,5-triazine, 4.0 g (0.015 mol) of 1-(3-trifluoromethylphenoxy)-2-aminobutane hydrochloride and 6.2 g (0.045 mol) of potassium carbonate were added to 50 ml of dimethylformamide (DMF). The mixture was heated at 80° C. for 3 hours, added into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and filtered and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) gave 4.2 g (76%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13](I)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8].C[Si](C)(C)[C:25]#[C:26][C:27]1([CH3:31])[CH2:30][O:29][CH2:28]1.CN(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.[Cu]I.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:25]#[C:26][C:27]4([CH3:31])[CH2:30][O:29][CH2:28]4)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8]
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: NC1=NC2(CO1)c1cc(Br)c(F)cc1Oc1ncc(I)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C#Cc2cnc3c(c2)C2(COC(N)=N2)c2cc(Br)c(F)cc2O3)COC1
Reaction time: 4 h
Yield: 42.2 %

Procedure:
A vial charged with Pd(PPh3)4 (0.73 g, 0.63 mmol), copper(I) iodide (0.48 g, 2.52 mmol), 7-bromo-8-fluoro-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (3.0 g, 6.30 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (1.06 g, 6.30 mmol) and 13 mL DMF was degassed with argon and treated with DIPA (4.49 mL, 31.5 mmol). The resulting slurry was allowed to stir at RT for 18 h at which point an additional portion of copper(I) iodide (0.48 g, 2.52 mmol) was added. After stirring for an additional 4 h the reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3×100 mL). The resulting suspension was filtered through a glass frit and the filtrate was dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography [0-50% (9:1 CH2Cl2:MeOH)/CH2Cl2] provided 7-bromo-8-fluoro-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.18 g, 2.66 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]([OH:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(O)c2cccs2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ncccc1CN1CCC(CC(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
12.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-hydroxy-2-(2-thienyl)ethyl]piperidine and 30.2 ml of triethylamine were dissolved in 72 ml of dimethyl sulfoxide, and a mix solution of 17.2 g of sulfur trioxide-pyridine complex and 90 ml of dimethyl sulfoxide was added dropwise thereinto under ice-cooling. After completion of the dropwise addition, the mixture was further stirred at room temperature for 30 minutes. An aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 9.6 g of the title compound as a pale yellow oil.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[CH2:16]([OH:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>O>[CH2:16]([O:21][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)CO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 330.9 %

Procedure:
To dimethylformamide solution (78 ml) containing 4-chloronitrobenzene (15.7 g) and neopentyl alcohol (10.6 g) was added by portions sodium hydride (60% content, 4.8 g) under ice-cooling. The mixture was stirred under ice-cooling for 1 h. The mixture was warmed to room temperature and stirred further for 1 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained oily substance was distilled under reduced pressure to give 4-neopentyloxynitrobenzene (69 g), boiling point: 120–125° C./0.1 mmHg.