Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([C:21]1[CH:22]=[C:23](OS(C(F)(F)F)(=O)=O)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:15])[CH:16]([C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:24]=[C:23]([C:50]2[CH:51]=[CH:52][C:47]([C:46]([F:57])([F:56])[F:45])=[CH:48][CH:49]=2)[CH:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 79.8 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 5-[1-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-3-methyl-butyl]-4′-trifluoromethyl-biphenyl-3-yl ester (4.03 g, 6.27 mmol), 4-(trifluoromethyl)phenylboronic acid (1.34 g, 7.05 mmol), 1,2-dimethoxyethane (24 mL) and aqueous Na2CO3 (2 M, 3.2 mL, 6.4 mmol) was stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (1.45 g, 1.25 mmol) and heated to reflux (95° C.) for 1 h. The red-brown mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 solution (3×50 mL) and brine (2×50 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-benzyl-3-[2-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (3.2 g, 79%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1.[CH3:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([CH3:27])[C:20]=1[Mg]Br>C1COCC1>[CH2:5]([O:4][C:2]([N:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]1[C:20]1[C:21]([CH3:27])=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=1[CH3:18])=[O:3])[CH:6]=[CH2:7]
Reactant: COc1ccc(C)c([Mg]Br)c1C
Reactant: c1ccc2cnccc2c1
Reactant: C=CCOC(=O)Cl
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C=Cc2ccccc2C1c1c(C)ccc(OC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Allyl chloroformate (2.7 ml, 25 mmol) is added dropwise at 0° C. to a cooled mixture of isoquinoline (2.9 g, 23 mmol) and 2,6-dimethyl-3-methoxyphenylmagnesium bromide (prepared from 7.3 g of 2,6-dimethyl-3-methoxyphenyl bromide and 2.8 g of magnesium turnings) in THF (30 ml). After stirring for 2 h at room temperature, the reaction mixture is quenched with saturated NH4Cl and extracted with Et2O. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated to give 6.9 g of 1-(3-methoxy-2,6-dimethyl-phenyl)-1H-isoquinoline-2-carboxylic acid allyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=C(O)c1cc(Cl)ncc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)ncc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 0.66 g of 2-chloro-5-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give 2-chloro-5-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 2-chloro-5-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.48 g of 2-amino-4-tert-butylphenol, 0.59 g of triethylamine and 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and stirred while heating at 50° C. for one hour. The mixture was cooled to room temperature, and water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.75 g of N-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonictinamide.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=O)C.C(O)(=O)C.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].ClCCCl>[CH2:25]([N:32]1[CH:7]2[CH:6]([CH2:11][CH:10]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][CH2:8]2)[CH2:5][C:4]1=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CC1CC(Cc2ccccc2)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=C1CC2CC(Cc3ccccc3)CCC2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
A mixture of 8 g of (5-benzyl-2-oxo-cyclohexyl)-acetic acid ethyl ester, 3.4 g of acetic acid, 3.75 g of benzylamine, 50 mL of 1,2-dichloroethane and 7.7 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 100 mL chloroform and 40 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography eluting with 50% ethyl acetate in hexane gave 5 g of 1,5-dibenzyl-octahydro-indol-2-one.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([OH:26])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O.O>[Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1c2ccccc2sc2c(O)ccc(OCCN(CCCl)CCCl)c12
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCCN(CCCl)CCCl)c2c(=O)c3ccccc3sc12

Procedure:
A solution of 0.50 g of 1-(N,N-bischloroethylaminoethoxy)-4-hydroxythioxanthone in 10 ml of dimethylformamide is mixed with 0.22 g of tert-butyldimethylsilyl chloride, 0.20 g of imidazole and a catalytic amount of dimethylaminopyridine, and stirred at room temperature for 12 h. The solution is then added over water and extracted with ethyl acetate. The ethyl acetate extract is washed sequentially with saturated sodium bicarbonate and water, dried over sodium sulfate, concentrated and dissolved in a mixture of ethyl acetate: hexanes (1:4) and passed through a plug of alumina. The solid obtained after concentration is pure and weighed 0.48 g (70%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[N:26]1([C:24]([CH:7]([NH:6][C:4](=[O:5])[CH2:3][NH:2][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)NCC(=O)NC(CNC(=O)C2CCN(c3ccncc3)CC2)C(=O)N2CCCCC2)cc1

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with 4-toluenesulphonyl chloride to give N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}-2-(4-toluenesulphonamido)aceta mide in S0 yield as a foam;
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH2:23][C:24](O)=[O:25])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[N:40]1([C:45]([NH2:47])=[NH:46])[CH:44]=[CH:43][CH:42]=[N:41]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH2:23][C:24](=[O:25])[NH:47][C:45](=[NH:46])[N:40]3[CH:44]=[CH:43][CH:42]=[N:41]3)[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Reactant: N=C(N)n1cccn1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(=N)n2cccn2)cc1
Yield: 38.9 %

Procedure:
To 120 mg pyrrolyl acetic acid from Step 4 was added 97 mg (0.6 mmol, 5 equiv.) of carbonyldiimidazole and 2 mL CH2Cl2. The reaction was mixed at room temperature for one hour, upon which time was added 88 mg (5 equiv.) 1H-pyrazole-1-carboxamidine hydrochloride, 0.16 mL (10 equiv.) triethylamine, and a catalytic amount of 4-dimethylaminopyridine. The reaction was mixed at room temperature for one hour, filtered to remove any precipitates formed, and washed with water. The organic phase was separated from the aqueous phase and concentrated to afford 59 mg crude N-ethyl-4-(1-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-5-phenyl-1H-pyrrol-2-yl)-benzamide, which was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:31]=1)[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:31]=[C:6]([C:7]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:16]3)=[C:10]([CH3:11])[N:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cncc(Br)c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cncc(Br)c4)n3n2)cc(OC)c1OC
Yield: 7.5 %

Procedure:
In a similar manner as described for Example 9, 5-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)nicotinamide (Intermediate 20) (0.15 g, 0.31 mmol) and 1,2,4-triazole (128 mg, 1.9 mmol) in pyridine (4 mL) and phosphorus oxychloride (0.087 mL, 0.93 mmol) gave 7-(5-bromopyridin-3-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.011 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.81-9.78 (m, 1H), 9.18 (s, 1H), 8.93-8.90 (m, 1H), 8.73-8.70 (m, 1H), 8.57 (s, 1H) 7.12 (s, 2H), 3.73 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 2.59 (s, 3H). MS m/z 471, 473 (M+1, M+3).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH3:11][O:12][NH2:13].[C:14]1(=[O:21])[CH:20]=[CH:19][CH2:18][CH2:17][CH:16]=[CH:15]1>C(O)(C)C>[CH3:11][O:12][N:13]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][C:14](=[O:21])[CH2:20]2
Reactant: CON
Reactant: O=C1C=CCCC=C1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CON1C2CCC1CC(=O)C2
Reaction time: 6 h
Yield: 20 %

Procedure:
N,N-Diisopropylethylamine (14.5 ml) was added dropwise to a stirred suspension of O-methylhydroxylamine hydrochloride (2.32 g) in isopropyl alcohol (25 ml). After 30 minutes cyclohepta-2,6-dienone (3.0 g) in isopropyl alcohol (5 ml) was added dropwise. After 24 hours N,N-diisopropylethylamine (4.9 ml) was added. After 6 hours the mixture was allowed to stand at room temperature overnight. The mixture was evaporated under reduced pressure, diethyl ether added and the resulting mixture extracted with 2M hydrochloric acid (×3). The combined aqueous fractions were washed with diethyl ether (×3), neutralised with sodium hydroxide and extracted with diethyl ether (×3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Kugelrohr distillation gave 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (0.86 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:18]=[CH:19][CH:20]=2)[CH:10]([CH3:32])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[ClH:30].[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:32])[CH:16]=1)=[O:31]
Reactant: CC1CN(Cc2ccccc2)CCC1Oc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC1CNCCC1Oc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Dissolve N-[3-(1-benzyl-3-methyl-piperidin-4-yloxy)-phenyl]-2-chloro-4-fluoro-benzamide cis isomer 2 (preparation 81, 0.49 g, 1.09 mmol) in 1,2-dichloroethane (20 mL) and treat with 1-chloroethyl chloroformate (1.18 mL, 10.9 mmol), heat and stir at reflux. After 2 hr., cool to ambient temperature and concentrate to an oil. Dissolve residue in methanol (20 mL), heat and stir at reflux. After 1.5 hr., cool to ambient temperature. Load reaction mixture on an SCX column (10 g), wash with methanol, elute with 2M ammonia/methanol. Concentrate eluent. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride and converted to the mono hydrogen chloride salt to obtain the title compound (0.156 g, 39%). Mass spectrum: Obs. m/z 363.1281; Calc. m/z 363.1275; Analysis calculated for C19H21Cl2FN2O2.0.9H2O: C, 54.92; H, 5.53; N, 6.74. Found: C, 54.89; H, 5.33; N, 6.63.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.P([Cl:32])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:32])[C:2]([F:15])([F:14])[F:1])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Temperature: 82 °C
Yield: 83.6 %

Procedure:
Five grams (22.8 mmol) of 2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide, 12.26 g (45.6 mmol) of diphenyl chlorophosphate, 4.62 g (45.6 mmol) of triethylamine, and 25 ml of acetonitrile were introduced into a 100 ml flask and reacted for 22 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.53 g of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 83.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:38]=[N:39][C:40]([CH3:43])=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:37]4[CH:38]=[N:39][C:40]([CH3:43])=[N:41][CH:42]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cn1
Yield: 44.5 %

Procedure:
To a solution of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (61 mg, 0.13 mmol), 5-bromo-2-methylpyrimidine (18 mg, 0.11 mmol), PdCl2(PPh3)2 (6 mg, 10%) and aqueous solution of Cs2CO3 (2 mol/L, 0.13 mL) in 1,4-dioxane (1 mL) was heated to reflux overnight. The reaction was quenched with water. The organic layer was separated, dried and concentrated to give the residue, which was purified by column chromatography to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-1,3-oxazinan-2-one (22 mg, 39%). 1H NMR (CDCl3): 1.42 (m, 1H), 1.48 (d, 3H), 1.67 (m, 1H), 1.71-1.99 (m, 4H), 2.11-2.41 (m, 3H), 2.52 (s, 3H), 2.72 (m, 1H), 3.53 (m, 2H), 5.62 (m, 1H), 6.89-7.04 (m, 4H), 7.15-7.33 (m, 4H), 8.70 (s, 2H). LC-MS Method 2 tR=1.184, m/z=450; 1H NMR (CDCl3) 1.20 (d, 1H), 1.27-1.40 (m, 1H), 1.49 (d, 3H), 1.59-1.70 (m, 1H), 1.71-2.07 (m, 4H), 2.11-2.33 (m, 3H), 2.70 (s, 3H), 2.90 (m, 1H), 3.46-3.61 (t, 2H), 5.67 (m, 1H), 6.90-7.11 (m, 4H), 7.26 (m, 4H), 8.57-8.83 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([Li])CCC.[O:18]1CCC[CH2:19]1>>[Br:12][C:9]1[C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([CH:19]=[O:18])=[CH:11][CH:10]=1
Reactant: Brc1ccc(Br)c2cnccc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=Cc1ccc(Br)c2cnccc12
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 5,8-dibromoisoquinoline (4.0 g. 13.9 mmol) in tetrahydrofuran (120 mL) at −78° C. under nitrogen atmosphere was added dropwise a solution of n-butyllithium (2.3 M in hexane, 7.3 mL, 16.8 mmol). The reaction mixture turned dark. After stirring for 15 minutes, the reaction, mixture was quenched by adding N,N-dimethylformamide (4.6 mL). After stirring at −78° C. for an additional 1 h, the reaction mixture was quenched with water, extracted with mixture of ethyl acetate/hexane (2:8), washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the 8-bromo-5-isoquinolinecarboxaldehyde (0.10 g), followed by 5-bromo-8-isoquinolinecarboxaldehyde (1.0 g) as white solids.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])(C)(C)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].O>CCOCC>[F:18][C:19]([F:26])([F:25])[C:20]([C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1)=[O:21]
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
5.00 g (20.57 mmol) of 3-bromo-5-fluorobenzotrifluoride were stirred in 60 ml of dry ether and admixed dropwise at −78° C. under a protective gas atmosphere (argon) with 1.33 ml (20.75 mmol) of tert-butyllithium solution [cf. also trifluoroacylation: H. K. Nair, D. M. Quinn Bioorganic & Medicinal Chemistry Letters 3(12), 2619-22 (1993); G. J. Pork et al., J. Org. Chem. 22, 993 (1957)]. Subsequently, the reaction mixture was stirred at −78° C. for 45 minutes and then added dropwise, with the aid of a syringe, in portions at −78° C., to a solution of 3.71 g (26.17 mmol) of ethyl trifluoroacetate in 40 ml of dry ether. Thereafter, the entire reaction mixture was stirred first at −78° C. for 10 minutes and then at room temperature for one hour. For workup, the entire reaction mixture was added to water and extracted with ether. The organic phase was removed and dried at 40° C. under reduced pressure (not less than 10 mbar owing to the high volatility of the compound). This gave 4.06 g (75.9% of theory) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]-ethanone, which was isolated as the hydrate.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[N:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][C:22]=3[CH3:31])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[F:32][CH:33]1[CH2:36][NH:35][CH2:34]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[F:32][CH:33]1[CH2:36][N:35]([C:28](=[O:29])[CH2:27][C:24]2[CH:23]=[C:22]([CH3:31])[C:21]([O:20][CH2:19][CH2:18][C@@H:16]3[CH2:17][C@@H:15]3[CH:12]3[CH2:13][CH2:14][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:8]=4)[CH2:10][CH2:11]3)=[N:26][CH:25]=2)[CH2:34]1
Reactant: Cc1cc(CC(=O)O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1
Reactant: FC1CNC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)N2CC(F)C2)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The mixture of [6-(2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethoxy)-5-methylpyridin-3-yl]acetic acid (25 mg, 0.058 mM), 3-floroazetidine (8.7 mg, 0.116 mmol), EDC (17 mg, 0.087 mmol), HOBt (13 mg. 0.087 mmol) and triethyl amine (33 μL, 0.232 mmol) in 2 mL of DCM was stirred for 16 hrs at room temperature. The volatiles were then removed in vacuo and the residue was dissolved in CH3CN and water (1/1, 1.5 ml) and submitted to the Rahway High Throughput Purification Group to be purified. The HTP group used an HP mass-directed LC eluting with a gradient of 20-80% acetonitrile in water with 0.05% formic acid buffer to purify the compound. The desired product was obtained with 97.5% purity measured via Gilson HPLC analytical analysis. LCMS (ESI) m/z 486 [M+H]+. GPR119 Human EC50: 8 nM
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH2:1]([O:5][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Br:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C(Cl)CCCCCBr
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCOC(=O)CCCCCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled, stirred solution of 39 g (0.52 mol) of butanol and 42 g (0.52 mol) of pyridine in 550 mL of ether was added dropwise 100 g (0.47 mol) of 6-bromohexanoylchloride. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was washed with water, 5% NaHCO3, and again with water. The organic layer was dried (MgSO4), the solvent was removed by rotary evaporation, and the residue was distilled at reduced pressure, bp 120°-125° C. (0.1 mm). A colorless oil was obtained, mass 111 g (94%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1.CC([O-])(C)C.[K+].O>C1COCC1>[Br:1][C:2]1[C:3]([O:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and cyclopropylmethanol (970 uL, 12 mmol) in THF (50 ml) was treated with KOtBu (3.3 g, 15 mmol). After stirring at rt for 12 h, the mixture was treated with water (150 ml) and extracted with EtOAc (3×50 ml); the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 30%) in hexanes to afford the title compound (1.3 g, 48%) as a yellow solid. LCMS (M+H)+=274.