Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].[CH2:17]([N:24]([CH2:28][CH2:29]Cl)[CH2:25][CH2:26]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)C(C)C)(C)C>[CH2:17]([N:24]1[CH2:28][CH2:29][N:2]([C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccccc2)CC1
Yield: 102.5 %

Procedure:
A solution of 5.9 g (23 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and of 9.6 g (23 mmol) of benzylbis(2-chloroethyl)amine in 50 ml of N,N-diisopropylethylamine is heated at 127° C. for 3 h 30. After evaporation of the N,N-diisopropylethylamine, the reaction medium is hydrolyzed and then extracted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydroxide having a concentration of 1N, and with water, and then dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 8.9 g (64%) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate are obtained in the form of a yellow oil.
Reaction SMILES: C(O)(=O)C.C[O:6][C:7](=[O:34])[C@@H:8]([NH:15][C:16](=[O:33])[CH:17]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>Cl.O>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH:17]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[C:16]([NH:15][C@@H:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:7]([OH:34])=[O:6])=[O:33])=[CH:24][CH:23]=1)(=[NH:26])[NH2:27]
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N(C)C)C1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
[3-(4-Carbamimidoyl-phenyl)-2-(R,S)-dimethylcarbamoyl-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester acetic acid salt (7 g, 14.7 mmol) was dissolved in a mixture of hydrochloric acid (50 ml) and water (50 ml). After 15 hours stirring at room temperature the mixture was evaporated and after addition of water lyophilized. The residue was purified by chromatography on Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was lyophilized. Yield: 4.5 g (76%); MS m/z: 403.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH:26]=3)[C:15]=2[CH3:40])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=3)[O:31][CH2:32][C:33]([OH:35])=[O:34])[C:15]=2[CH3:40])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OCc3cccc(OCC(=O)OC(C)(C)C)c3)c3ccccn23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(=O)c2c(C)c(OCc3cccc(OCC(=O)O)c3)c3ccccn23)ccc1N
Yield: 88.3 %

Procedure:
The solution of 0.87 g (1.60 mmol) of methyl 2-amino-5-[(1-{[3-(2-tert-butoxy-2-oxoethoxy)benzyl]oxy}-2-methylindolizin-3-yl)carbonyl]benzoate in 3.0 ml of trifluoroacetic acid and 16 ml of dichloromethane at ambient temperature is stirred for 4 hours at ambient temperature. The reaction medium is poured into a saturated aqueous solution of sodium bicarbonate and the mixture is washed with ethyl acetate. The aqueous phase is acidified with a saturated aqueous solution of potassium hydrogen sulphate and then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. 0.69 g (88%) of a green solid is obtained.
Reaction SMILES: Br[C:2](C)([C:6]1[C:7](=[C:11](C)[CH:12]=[CH:13][CH:14]=1)[C:8]([O-])=[O:9])C([O-])=O.[C:17]([C:19]1[C:20]([OH:26])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][C:22]1[N:21]=[C:20]2[C:19]([C:17]3[NH:18][C:8](=[O:9])[C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:2]=3[O:26]2)=[CH:24][CH:23]=1
Reactant: Cc1cccc(C(C)(Br)C(=O)[O-])c1C(=O)[O-]
Reactant: Cc1ccc(C#N)c(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)oc1c3ccccc3c(=O)[nH]c21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of α-bromodimethylhomophthalate (2.00 g, 6.97 mmol) in DMF (15 mL) was added 3-cyano-2-hydroxy-6-methylpyridine (1.03 g, 1.1 eq) and potassium carbonate (4.82 g, 5 eq). The resulting mixture was allowed to stir at 100° C. for 4 h under inert atmosphere. The reaction was cooled to room temperature and concentrated in vacuo. The resulting solid residue was diluted with 1 N aqueous HCl (60 mL) and stirred for 30 min. The resulting suspension was filtered and the solids were washed with water. The aqueous filtrate was extracted with EtOAc (2×50 mL). The collected solids were added to the combined EtOAc extracts, and the resulting solution was dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude residue. The crude residue was recrystallized from toluene at −20° C. over 18 h, vacuum filtered and dried to provide compound 26a as a yellow solid. Yield=500 mg (29%).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:20]=[C:21]([F:23])[CH:22]=3)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:37]CN(C(C)C)C(C)C>CC#N>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([C:24]4[N:28]([CH3:37])[N:27]=[N:26][N:25]=4)[CH:20]=[C:21]([F:23])[CH:22]=3)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(F)C(c1cc(F)cc(-c2nnn[nH]2)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CI
Solvent: CC#N
Product: Cn1nnnc1-c1cc(F)cc(C(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C)(C)F)c1

Procedure:
The reaction of mixture of 1.31 g (2.85 mmol) 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole, 0.36 mL (5.70 mmol) methyl iodide, and 1.77 mL (9.97 mmol) DIEA in 8 mL MeCN was heated to reflux for 2.5 h. Then it was concentrated to remove the solvents. Then it was added 20 mL of CH2Cl2 and 5 mL of water and adjust pH=7-8 with aq NaHCO3. The water layer was extracted with CH2Cl2, and the combined organic layer was concentrated. The residue was separated by silica gel chromatography with CH2Cl2/MeOH/NH3 (2M) in MeOH to afford the title compound; 1H-NMR(CDCl3) δ 1.22(d, 3H, J=22 Hz), 1.29(d, 3H, J=22 Hz), 2.37 (t, 1H, J=8 Hz), 2.90 (t, 1H, J=8 Hz), 3.00 (m, 1H), 3.14 (m, 1H), 3.22 (m, 1H), 3.68 (J, 1H, J=6 Hz), 4.19 (s, 3H), 4.26 (s, 1H), 7.12-7.43 (m, 13H); Mass Spectrum: m/e=474 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[H-].[Na+].C[CH:23]([S:27][CH:28](S(C)=O)C)[S:24]([CH3:26])=[O:25]>O1CCCC1>[CH3:1][N:2]1[C:6]([CH:7]=[C:23]([S:24]([CH3:26])=[O:25])[S:27][CH3:28])=[C:5]([CH3:9])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: CC(SC(C)S(C)=O)S(C)=O
Reactant: COc1ccc(CSc2nc(C)c(C=O)n2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CSc2nc(C)c(C=C(SC)S(C)=O)n2C)cc1
Reaction time: 16 h

Procedure:
1,4-Dimethyl-5-formyl-2-(4-methoxybenzylthio)imidazole (8 g, 0.03 mole) in tetrahydrofuran (30 ml) was added to a mixture prepared by adding sodium hydride (1.8 g, 38 mmoles) to a solution of methyl methylsulfinylmethylsulfide (4.7 g, 38 mmoles) in tetrahydrofuran. The mixture was stirred for 16 hours, concentrated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase was dried with sodium sulfate, concentrated in vacuo and the residue chromatographed on silica gel eluted with ethyl acetate to give 1,4-dimethyl-2-(4-methoxybenzylthio)-5-[2-(methylsulfinyl)-2-(methylthio)ethenyl]imidazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](N)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:27][C:28]1C=CC(C(N)=O)=C[CH:29]=1>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([O:27][CH2:28][CH3:29])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C(N)=O)cc3)ccc21
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzamide-Using 4-hydroxybenzamide, the title compound was synthesized as a white solid. PMR (CDCl3): δ 1.35 (6H, s), 1.37 (6H, s), 1.76 (4H, s), 7.32 (2H, d, J~8.6 Hz), 7.48 (1H, d, J~8.4 Hz), 7.89-7.98 (3H, m), 8.17 (1H, d, J~1.9 Hz).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1)=O.[OH-:26].[Na+].Cl>>[OH:26][C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1
Reactant: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(N(C)S(C)(=O)=O)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2ccc3cnc(O)nn23)c(N(C)S(C)(=O)=O)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-N-methyl-methanesulfonamide (315 mg, 0.832 mmol) in 5M NaOH (10 mL, 10 mmol) was stirred at 80° C. After 3 h, HPLC and MS showed product formation with no SM. The mixture was cooled to RT and pH of the solution was adjusted to 4 by adding HCl. The mixture was repeatedly extracted from EtOAc. Combined organic was washed with brine and was dried over magnesium sulfate. After solvent evaporation, N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-N-methyl-methanesulfonamide was isolated as a solid (153 mg, 55%). LCMS (E/I+) 333 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:4]=1[Cl:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:3]=1[CH2:2][N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21]
Reactant: Clc1ccc(I)cc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(I)ccc1Cl
Temperature: 80 °C
Yield: 95.4 %

Procedure:
Bromomethyl-2-chloro-5-iodo-benzene (60) (400 mg, 1.2 mmol) and potassium phthalimide (693 mg, 1.5 mmol) were stirred in dry DMF (20 mL) and heated to 80° C. for 3 hours. After cooling, the suspension was filtered and concentrated in vacuo, and the residue was partitioned between water (30 mL) and Et2O (30 mL). The aqueous phase was extracted with ether (20 mL×3). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 63 (455 mg, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.92-7.86 (m, 2H), 7.78-7.75 (m, 2H), 7.54-7:50 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 4.93 (s, 2H). MS (m/e) (API-ES) 397.9 (M)+, m.p. 134-136° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:29]#N.[Na+]>CC(O)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH3:29])[C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(C)[C@H](C(C)C)CO3
Yield: 87.3 %

Procedure:
Compound 121 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.010 g, 0.028 mmol) with paraformaldehyde (0.008 g, 0.280 mmol) and NaCNBH3 (0.009 g, 0.140 mmol) in AcOH (1 mL) to afford 0.009 g (90%) of (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-4-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. This material (0.009 g, 0.025 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (0.5 mL) and AcOH (1 mL) to afford 0.006 g (86%) of Compound 121 as a yellow solid. Rf 0.6 (9:1 CH2Cl2;MeOH); 1H NMR (400 MHz, CDCl3) δ 12.49 (broad s, 1H), 7.13 (s, 1H), 7.06 (d, 1H, J=8.9), 7.02 (d, 1H, J=8.9), 4.43 (dd, ABX, 1H, J=10.9, 1.8), 3.86 (dd, ABX, 1H, J=10.9, 2.9), 3.03 (s, 3H), 2.93–2.88 (m, 1H), 2.02–1.91 (m, 1H), 0.99 (d, 3H, J=6.9), 0.95 (d, 3H, J=6.9).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[K+]>O>[NH2:10][C:8](=[N:9][C:12](=[O:13])[O:14][CH3:15])[S:7][CH3:6]
Reactant: COC(=O)Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 69.5 parts of 2-methyl-2-thiopseudourea sulfate and 47 parts of methyl chloroformate in 1000 parts of water at 0°C is added dropwise 56.9 parts of potassium hydroxide in 200 parts of water. The reaction mixture is stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride extract is dried and the solvent evaporated at reduced pressure to give 45 g of methyl N-(1-amino-1-methylthiomethylene)carbamate melting at 72°-77°C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(#N)C.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CN1CCc2cc(OC)c(OC)cc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3 g, 13.06 mmol) was suspended in acetonitrile (40 ml); potassium carbonate (3.61 g, 26.1 mmol) and methyl 2-bromoacetate (3.00 g, 19.59 mmol) were added; and the reaction mixture was stirred under microwave irradiation at 100° C. for 1 hour. Then the mixture was diluted with ethyl acetate and washed with water, brine and dried over Na2SO4. The organic layer was evaporated and the resulting crude was purified by flash chromatography on silica gel (DCM:MeOH:TEA 100:1:1) affording the title compound (2.6 g, 9.81 mmol, 75% yield). MS/ESI+ 266.1 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:20]1([C:24](=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][C:27]=2[CH3:33])[CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:20]1([C:24](=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:9][CH2:10]3)=[CH:28][C:27]=2[CH3:33])[CH2:23][CH2:22][CH2:21]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1cc(O)ccc1CC(=O)N1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (50 mg, 0.177 mmol) was dissolved in toluene (1 ml) and 1-(azetidin-1-yl)-2-(4-hydroxy-2-methylphenyl)ethanone (36.4 mg, 0.177 mmol), triphenylphosphine (55.8 mg, 0.213 mmol), and DIAD (41.4 μl, 0.213 mmol) added and the mixture stirred at RT overnight. The mixture was diluted with ethyl acetate (20 mL), washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel, Biotage 25M, eluting with a gradient eluant of 0-100% EtOAc/Hexane to afford afford the title compound. LC/MS (m/z): 469 (M+H)+. GPR119 Human EC50: 0.73 nM.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21])[CH:4]=[CH2:5].CC1C=CC(S(O[CH2:33][C@@H:34]2[O:36][CH2:35]2)(=O)=O)=CC=1>CCCCCC.CN(C)C=O>[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:8]=1[O:21][CH2:33][CH:34]1[CH2:35][O:36]1)[CH:4]=[CH2:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: C=CCOc1cc(OCc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCc2ccccc2)ccc1OCC1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.3 g, 0.11 mole of 60% mineral oil dispersion) was washed with hexane and suspended in 100 mL of N,N-dimethylformamide. To this suspension was added a solution of 25.4 g (0.10 mole) of 2-allyloxy-4-(benzyloxy)phenol in 100 mL of DMF. The mixture was stirred at room temperature for 30 minutes and then 22.8 g (0.10 mole) of (2R)-(−)-glycidyl tosylate was added. The mixture was heated at 60° C. under nitrogen for 2 hours and then at 35° C. for 15 hours. The solvent was removed in vacuum and replaced with 800 mL of methylene chloride. The resulting solution was washed with 200 mL of water and the water back-extracted with 200 mL of methylene chloride. The combined organic phases were washed with 400 mL of saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to a brown solid. Column chromatography on silica gel with methylene chloride as eluant gave 28.5 g of the (S)-enantiomer of the title compound as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[I:13][CH2:14][C:15](=O)[CH3:16].B(F)(F)F.CCOCC>C1C=CC=CC=1>[I:13][CH2:14][C:15]1([CH3:16])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(=O)CI
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(CI)OCCC2=C1Cc1ccccc12

Procedure:
To a solution of indene-3-ethanol (15 g) in 150 ml of benzene, iodoacetone (12 g) is added. The mixture is heated at reflux with 5 ml of boron trifluoride-etherate and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After a total of 2 hours the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluate gives the title compound, identical to the compound of the same name described in Example 463.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H-].[Na+].Br[CH2:12][C:13]([CH3:24])=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[C:13]([CH3:24])[CH2:12][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)=[CH:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: CC(=Cc1ccc(C(C)C)cc1)CBr
Reactant: Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C(C)C)cc1)COc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of p-cresol (3.50 g, 32.3 mmol) in DMF (70 mL) was added sodium hydride (a 60% liquid paraffin dispersion, 1.42 g, 35.5 mmol) under nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 1-(3-bromo-2-methyl-1-propenyl)-4-isopropyl benzene (9.0 g, 35.5 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 8.20 g (yield 91%) of the title compound. Oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].N1C=CC=CC=1.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:40](=[O:41])[CH2:39][Cl:38])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)CCl)cc1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.52 g of the compound obtained in Example 5 step B), 25 ml of DCM and 0.5 g of pyridine were mixed. 0.54 ml of chloroacetyl chloride in 10 ml of DCM was then added over 5 minutes at 20° C. The reaction mixture was stirred for 2 hours at 20° C. and then concentrated under vacuum at 20° C. The residue was extracted with AcOEt and washed with water, then with 1N hydrochloric acid and then with water. It was dried over sodium sulfate and the solvent was evaporated off to give the expected product, which crystallized from isopropyl ether. m=0.6 g. M.p.=232° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.CCCCC>[C:13]1([S:19]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Br:1])=[C:3]3[CH:10]=[CH:9]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Yield: 72.5 %

Procedure:
4-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 1 Eq.) was dissolved in dry THF and cooled in an ice-bath. NaH (60% dispersion in mineral oil, 305 mg, 1.2 Eq.) was added portionwise. The resultant mixture was stirred at 0 ° C. for 45 minutes and benzene sulfonyl chloride (1.076 g, 1.2 Eq.) was added slowly dropwise. The resultant mixture was stirred at 0 ° C. for a further 75 minutes and then the solvent was removed in vacuo. The residue was partitioned in EtOAc/sat. NH4Cl and extracted with EtOAc (3×50 mL). The combined organics were washed with sat. aq. Na2CO3 (1×20 mL), brine (1×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (20% EtOAc/80% hexanes), followed by recrystallization from EtOAc/hexanes. The product was filtered and then washed with pentane obtaining the title compound as a white powder (1.24 g, 73% yield); 1H NMR (DMSO D6) 6.8(1H, d), 7.6-7.66(3H, m), 7.72-7.76(1H, m), 8.0(1H, d), 8.1(2H, m), 8.24-8.26(1H, m); LC/MS M+1; (obs.)339.1; LC/MS M−1 (obs.) 337.1.