Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[OH-].[Na+].[S:11](=O)([OH:13])[O-:12].[Na+]>>[CH2:6]([CH:2]1[C:3](=[O:5])[O:4][S:11](=[O:13])(=[O:12])[CH2:1]1)[CH2:7][CH3:8]
Reactant: O=S([O-])O
Reactant: C=C(CCC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCC1CS(=O)(=O)OC1=O

Procedure:
114 g. of α-methylene-pentanoic acid is reacted with sodium hydroxide to neutralize the carboxyl group. Sodium bisulfite (1 mol) solution is added and the reaction carried out as described in procedure 10)b) to obtain 4-n-propyl-1,2-oxathiolane-5-one-2,2-dioxide of an equivalent weight of 93.
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[N:7]=1.[CH3:29][C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[C:33]([CH3:35])[N:34]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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.O.COCCOC>[CH3:29][C:30]1[S:31][C:32]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=5)([CH2:14]4)[CH2:12]3)[N:7]=2)=[C:33]([CH3:35])[N:34]=1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nc(C)c(-c2nn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 24.3 %

Procedure:
6-bromo-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (P8, 170 mg, 0.370 mmol) was suspended in a degassed mixture of 1,2-Dimethoxyethane (DME) (6169 ply Water (1234 μl), then 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (266 mg, 1.110 mmol), SODIUM CARBONATE (118 mg, 1.110 mmol), 2-biphenylyl(dicyclohexyl)phosphane (25.9 mg, 0.074 mmol) and Tetrakis (86 mg, 0.074 mmol) were added. The mixture was then heated at 90° C. and stirred at that temperature for 3 hours. Then the reaction mixture was cooled down to room temperature and 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (266 mg, 1.110 mmol), 2-biphenylyl(dicyclohexyl)phosphane (25.9 mg, 0.074 mmol), SODIUM CARBONATE (118 mg, 1.110 mmol) and Tetrakis (86 mg, 0.074 mmol) were added again. The mixture was stirred at 90° C. for further 4 hours, then left stirring at room temperature overnight. The mixture was concentrated under reduced pressure and partitioned between AcOEt and water. Phases were separated, organic phase was dried over sodium sulphate and concentrated under reduced pressure. Crude product was purified by Preparative HPLC then further purified by flash chromatography (SiO2; eluent: DCM to DCM/MeOH 9:1) affording 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (E7, 44.3 mg, 0.090 mmol, 24.35% yield).
Reaction SMILES: C(O[C:9]1[CH:28]=[CH:27][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([OH:31])C>[Pd]>[OH:31][C:27]1[CH:28]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2O)CC1
Reaction time: 2 h

Procedure:
10% Palladium on carbon (0.75 g, 50% w/w) was added to a solution of tert-butyl 4-[4-(benzyloxy)phenoxy]piperidine-1-carboxylate (1.5 g) in ethanol (100 mL). The mixture was evacuated and purged with hydrogen twice and then stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through celite and the filter pad washed with ethanol. The filtrate was concentrated at reduced pressure to give tert-butyl 4-(hydroxyphenoxy)piperidine-1-carboxylate as a brown solid (1.24 g); NMR Spectrum: (CDCl3) 1.47 (s, 9H), 1.65-1.76 (m, 2H), 1.82-1.93 (m, 2H), 3.23-3.33 (m, 2H), 3.65-3.76 (m, 2H), 4.25-4.34 (m, 1H), 5.07 (s, 1H), 6.70-6.85 (m, 4H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][NH:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCC1>C(O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[C:18](=[CH:22][CH2:23][CH2:24][CH3:25])[NH:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1CNC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNC1
Product: CCCC=C1NC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.00 g (3.29 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]hydantoin and 0.30 ml (3.29 mmol) of n-butyraldehyde in 10 ml of ethanol, 0.05 ml (0.6 mmol) of pyrrolidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1→chloroform/methanol=10/1) to yield 0.43 g (36.5%, orange-yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH:21]=O)[CH3:2].[NH2:23][C:24]1[C:25]([C:38]([NH2:40])=[O:39])=[N:26][N:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:28]=1[CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[CH:21]1[NH:23][C:24]2=[C:28]([CH2:29][CH3:30])[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:26]=[C:25]2[C:38](=[O:39])[NH:40]1)[CH3:2]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C=O
Reactant: CCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Solvent: Cc1ccccc1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C1NC(=O)c2nn(Cc3ccccn3)c(CC)c2N1
Yield: 51.5 %

Procedure:
A solution of 1-(6-ethoxy-5-formyl-3-pyridylsulfonyl)-4-ethylpiperazine (1.1 g, 4.9 mmol, from step (a) above) and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide (1.2 g, 4.9 mmol) in toluene (10 mL) was heated to reflux for 4 hours and the solution was concentrated under vacuum. The resulting product was recrystallised from ethyl acetate to give a pale brown solid (1.4 g, 52%).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4](/[CH:7]=[C:8](/[C@H:10]2[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[C:22]([CH3:30])([CH3:29])[C:20](=[O:21])[C@H:19]([CH3:31])[C@@H:18]([OH:32])[C@@H:17]([CH3:33])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)\[CH3:9])[N:3]=1.C(C(C)=[O:39])(F)(F)F.OS([O-])(=O)=O.[K+].C([O-])(O)=O.[Na+].CSC>CC#N.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].O>[CH3:1][C:2]1[S:6][CH:5]=[C:4](/[CH:7]=[C:8](/[C@H:10]2[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[C:22]([CH3:30])([CH3:29])[C:20](=[O:21])[C@H:19]([CH3:31])[C@@H:18]([OH:32])[C@@H:17]([CH3:33])[CH2:16][CH2:15][CH2:14][C@H:13]3[O:39][C@H:12]3[CH2:11]2)\[CH3:9])[N:3]=1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: CC(=O)C(F)(F)F
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CSC
Solvent: O
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 57 %

Procedure:
To solution of epothilone C (100 mg, 0.21 mmol) in CH3CN (2.5 mL) and 0.0004 M Na2EDTA (1.5 ml) at 0° C. were added excess CF3COCH3 (1 mL) followed by 2 KHSO5.KHSO4.K2SO4 (potassium peroxymonosulfate) (325 mg, 0.53 mmol) and NaHCO3 (75 mg, 0.89 mmol). The reaction mixture was stirred for 35 min then treated with dimethylsulfide (0.50 mL) and water (3.75 mL). The reaction mixture was warmed to room temperature, extracted with EtOAc (4×10 mL), dried over MgSO4, filtered, and concentrated. The residue was chromatographed with 55% EtOAc/hexanes to give epothilone A (59 mg, 57%) and compound A (30 mg, 29%) as a white solid. m/z: 494(M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=[O:23]>>[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22]([NH:17][CH:15]([C:5]1[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=1)[CH3:16])=[O:23]
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: Cc1cc(C(=O)O)cc(Br)n1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(Br)n1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (387 mg, a yellow solid) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.0 mmol, Amine-5, single enantiomer) and 2-bromo-6-methylisonicotinic acid (223 mg, 1.0 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:30][NH:31][C:32]1[S:33][C:34]([S:38]([NH2:41])(=[O:40])=[O:39])=[C:35]([CH3:37])[N:36]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:41][S:38]([C:34]1[S:33][C:32]([N:31]([CH3:30])[C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:14][CH:13]=2)=[N:36][C:35]=1[CH3:37])(=[O:39])=[O:40]
Reactant: O=C(O)Cc1ccc(-c2cc(F)ccc2F)cc1
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3cc(F)ccc3F)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At room temperature, 1.00 g (4.0 mmol) of (2′,5′-difluoro[1,1′-biphenyl]-4-yl)acetic acid and 0.54 g (4.0 mmol) of 1-hydroxy-1H-benzotriazole hydrate are initially charged in 15 ml of dimethylformamide. 0.84 g (4.0 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 0.77 g (4.0 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. Most of the dimethylformamide is removed at 50° C. under high vacuum, and the residue is stirred 3 times with in each case 50 ml of water and filtered off, stirred with 50 ml of isopropanol and filtered off once more. Removal of the solvent under reduced pressure gives the compound of Example 87 in the form of a slightly yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21].CN(C=O)C.C(N(CC)CC)C>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CN
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 73.6 %

Procedure:
To 550 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 419 mg of glycine ethyl ester hydrochloride were added 3 ml of DMF and 607 mg of triethylamine, followed by stirring at 85° C. for 5.5 hours. The resulting reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The extract was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1 to 3:1 to obtain 503 mg of the titled compound. Mp.146.1° C. 1H NMR (CDCl3): 1.30 (3H, t, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 4.31 (2H, d, J=5.2 Hz), 5.97 (1H, br. s), 7.54-7.63 (5H, m), 7.67-7.70 (2H, m), 7.79 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:28][NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][C:32]([C:30](=[O:31])[NH:29][CH3:28])=[CH:33][CH:34]=3)[S:17][C:10]=12
Reactant: O=C1NCCC1C(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5CCNC5=O)cc4F)c3s2)cc1
Temperature: 100 °C
Yield: 23.8 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxopyrrolidine-3-carboxamide (15.0 mg, 0.030 mmol), 4-(methyl carbamoyl)phenylboronic acid (16.2 mg, 0.091 mmol), tetrakis(triphenylphosphine)palladium (6.97 mg, 0.0060 mmol), Na2CO3 (0.0754 ml, 0.15 mmol) and DME (10 mL). The reaction mixture was stirred at 100° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (3.6 mg, 23.7%). LRMS (APCI pos): >99% purity, 254 nm, m/e 505 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.47 (d, 1H), 7.84-8.00 (m, 6H), 7.32-7.46 (m, 2H), 6.65 (d, 1H), 3.38-3.56 (m, 3H), 2.95 (s, 3H), 2.34-2.62 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([OH:26])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:60][C@H:61]([CH2:64][CH2:65][CH2:66][CH3:67])[CH2:62][OH:63]>CN(C=O)C.O>[OH:63][CH2:62][C@H:61]([NH:60][C:24]([C:23]1[N:5]2[CH:6]=[C:7]([CH3:22])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:16])([F:15])[F:17])[C:18]([F:19])([F:20])[F:21])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:26])[CH2:64][CH2:65][CH2:66][CH3:67]
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Reactant: CCCC[C@@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.39 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]-pyridine-3-carboxylic acid Example 91A and 163 mg (0.43 mmol) of HATU were initially charged in 2.5 ml of DMF. 0.2 ml (1.17 mmol) of N,N-diisopropylethylamine and 50.3 mg (0.43 mmol) of (R)-(−)-2-amino-1-hexanol were then added, and the mixture was stirred at RT overnight. 10 ml of water were added, the reaction solution was extracted twice with 20 ml of ethyl acetate and the combined organic phases were washed with 20 ml of water and with 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative RP-HPLC (acetonitrile-water+0.1% formic acid), the product fractions were combined and concentrated to dryness and the residue was dissolved in a mixture of 1.5 ml of tert-butanol and 2 ml of water and lyophilized overnight. This gave 42 mg of the target compound (95% pure, 21% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5]([C:19](O)=[O:20])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1.[CH3:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[NH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5]([C:19]([NH:25][C:24]([CH3:26])([C:27]([O:29][CH3:30])=[O:28])[CH3:23])=[O:20])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1
Reactant: COC(=O)C(C)(C)N
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.1 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (300 mg), methyl 2-methylalaninate (134 mg), HOBt (219 mg), WSC (275 mg) and N,N-diisopropylethylamine (0.834 mL) in THF (3.18 mL) was stirred at room temperature for 17 hr, and water was added. The precipitate was collected by filtration, and washed with water and hexane to give the title compound (336 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].N1CCCCC1>CCO>[O:23]=[C:15]1[NH:14][C:22]2[C:17](/[C:16]/1=[CH:1]\[C:3]1[CH:11]=[C:10]3[C:6]([C:7]([C:12]#[N:13])=[N:8][NH:9]3)=[CH:5][CH:4]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: N#Cc1n[nH]c2cc(C=O)ccc12
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1n[nH]c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12
Temperature: 75 °C
Yield: 81.9 %

Procedure:
To a mixture of 6-formyl-1H-indazole-3-carbonitrile (1.10 g, 6.4 mmol) and 2-oxindole (871 mg, 6.5 mmol) in EtOH (25 mL) was added piperidine (0.1 mL, 1 mmol). The resulting mixture was refluxed (oil temp. 75° C.) for 90 min, then cooled to rt. The resulting precipitate was collected by suction filtration and dried to give the title compound as an orange solid (1.5 g, 82%) 1H NMR (400 MHz, DMSO-d6) δ 14.6 (s, 1H), 10.66 (s, 1H), 8.09 (s, 1H), 8.01 (d, J=8.5 Hz, 1H) 7.78 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.83 (t, J=7.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[NH:20][C:19](=S)[C:18]([CH3:22])=[N:17]1.[NH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[N:20]=[C:19]([NH2:23])[C:18]([CH3:22])=[N:17]1
Reactant: N
Reactant: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)NC1=S
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)N=C1N
Temperature: 120 °C
Yield: 42.5 %

Procedure:
6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4(3H)-thione (Example 45 Step 3, 319 mg, 0.84 mmol) was taken up in ammonia (7M in MeOH, 10 mL, 70.00 mmol) and the resulting mixture was heated in the microwave reactor at 120° C. for 2 h. The solvent was evaporated and ammonia (7M in MeOH, 10 mL, 70.00 mmol) was added and the reaction was heated using MW for 1 h at 120° C. The solvent was evaporated and the resulting residue was taken up in DCM and saturated NaHCO3 and poured into a phase separator. The organic phase was dried and concentrated. The crude product was purified by flash chromatography using a gradient of 0-100% EtOAc in heptane followed by a gradient of 0-40% MeOH with 1% NH3 in DCM. The desired fractions were evaporated to give the title compound (130 mg, 43% yield) as a mixture of diastereomers in a 1:1 ratio as determined by NMR: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41-1.49 (m), 1.76-1.89 (m), 1.89-1.95 (m), 1.95-2.06 (m), 2.21 (s), 2.23 (s), 3.16 (m), 3.41 (d), 3.51 (dd), 3.69 (dd), 3.92 (t), 4.07-4.12 (m), 6.45 (d), 6.47 (d), 6.57 (br. s.), 6.61 (br. s.), 6.82 (d), 7.25 (d), 7.26 (d); MS (ES+) m/z 366.0 [M+H]+.
Reaction SMILES: [N:1]1([C:5](=[O:26])[CH2:6][C:7]2[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH2:13][C@@H:14]3[CH2:16][C@@H:15]3[CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9][C:8]=2[F:25])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:34](=O)([O:40]N1C(=O)CCC1=O)[O:35][CH2:36][CH:37]1[CH2:39][CH2:38]1>ClCCl.[NH4+].[Cl-]>[CH:37]1([CH2:36][O:35][C:34]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:10]3[CH:23]=[CH:24][C:7]([CH2:6][C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:26])=[C:8]([F:25])[CH:9]=3)[CH2:22][CH2:21]2)=[O:40])[CH2:39][CH2:38]1
Reactant: O=C(OCC1CC1)ON1C(=O)CCC1=O
Reactant: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F)N1CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCC3CC3)CC2)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-((1R,2S)-2-{2-[4-(2-azetidin-1-yl-2-oxoethyl)-3-fluorophenoxy]ethyl)cyclopropyl)piperidine (Step B, Example 11; 0.30 g, 0.93 mmol) in dichloromethane (4.6 mL) under a nitrogen atmosphere was added triethylamine (0.36 mL, 2.6 mmol) and cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (0.35 g, 1.67 mmol). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (10 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 25% EtOAc in heptane) provided the title compound as an off white semi-solid. LC/MS (m/z): 459.3 (M+H)+. GPR119 Human EC50: 2.0 nM.
Reaction SMILES: [NH2:1][CH2:2][P:3]([CH2:10][CH:11]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[C:6]([O:5][P:3]([CH2:10][CH:11]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])([CH2:2][NH:1][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:35])=[O:4])([CH3:8])([CH3:9])[CH3:7]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CN)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(CP(=O)(CNC(=O)c1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of di-tert-butyl 2-{[(aminomethyl)-(tert-butoxy)phosphoryl]methyl}pentane-1,5-dioate (1.222 g, 3.0 mmol) and benzoyl chloride (0.46 mL, 4.0 mmol) in dichloromethane (10 mL) was added triethylamine (0.56 mL, 4.0 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (15 mL), washed with 1 N HCl (25 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (ethyl acetate/hexanes=2/1) to give 1.259 g of colorless oil (74% yield).