Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]2[C:16]([CH:19]=O)=[CH:17][N:18]=[C:13]2[C@H:12]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:11][CH2:10]1.[CH3:29][C:30]([S@:33]([NH2:35])=[O:34])([CH3:32])[CH3:31].C(=O)(O)[O-].[Na+]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:30]([S:33](/[N:35]=[CH:19]/[C:16]1[N:14]2[CH2:15][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:10][CH2:11][C@@H:12]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:13]2=[N:18][CH:17]=1)=[O:34])([CH3:32])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(/C=N/S(=O)C(C)(C)C)cnc21
Temperature: 60 °C
Reaction time: 6 h
Yield: 97.2 %

Procedure:
Titanium (IV) ethoxide (239 mg, 1.05 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (205 mg, 0.524 mmol) and (R)-2-methylpropane-2-sulfinamide (79 mg, 0.655 mmol) in tetrahydrofuran (8 mL). The reaction mixture was heated to 60° C. After 6 h, the reaction mixture was allowed to cool to ambient temperature. Saturated sodium bicarbonate was added and the mixture was extracted with dichlormethane (3×). The organic extracts were dried with magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (252 mg). MS 495.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1.[H-].[Na+].[CH3:24]I>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][N:14]([CH3:24])[C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1
Reactant: CI
Reactant: O=C1Cc2cc(OCc3cccc(F)c3)ccc2C=CN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C=Cc2ccc(OCc3cccc(F)c3)cc2CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
In a dried flask under an inert atmosphere, 70 mg (0.25 mmol) of 8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one were dissolved in 5 ml of tetrahydrofurane, and the solution cooled to 0° C. Thereupon, 14 mg (0.3 mmol) of sodium hydride (50% in oil) were added and stirring continued at 0° C. for 15 min. Finally, 17 μl (0.3 mmol) of methyliodide were added. The reaction mixture was left to warm to RT and stirring continued for 90 min. For completion of the reaction, the mixture was heated to 40° C. during 2 h. For the working-up, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in 10 ml of ethylacetate, the solution extracted with 4 ml of water, then dried over sodium sulfate and evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a 2:1-mixture of heptane and ethylacetate as the eluent. There were obtained 51 mg (69% of theory) of 8-(3-fluoro-benzyloxy)-3-methyl-1,3-dihydro-benzo[d]azepin-2-one as a yellowish solid; MS: m/e=297 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:18]=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:21])=[CH:14][C:15]=3[C:16]2([CH3:20])[CH3:19])=[CH:8][CH:7]=1>C1COCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:21])=[CH:14][C:15]=3[C:16]2([CH3:19])[CH3:20])=[CH:8][CH:7]=1
Reactant: CC1(C)c2cc(O)ccc2-c2ccc(C#CCCO)cc21
Solvent: C1CCOC1
Product: CC1(C)c2cc(O)ccc2-c2ccc(CCCCO)cc21

Procedure:
7-(4-Hydroxybut-1-ynyl)-9,9-dimethyl-9H-fluoren-2-ol is hydrogenated to completion in THF on palladium/active carbon. The catalyst is filtered off, the solvent is removed in vacuo, and the residue is employed in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=O)[O:8][CH:7]=1)=[O:5])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[CH2:19])[CH:14]=[CH2:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][N:16]([CH2:17][CH:18]=[CH2:19])[CH2:13][CH:14]=[CH2:15])[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(C=O)c1
Reactant: C=CCNCC=C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=CCN(CC=C)Cc1cc(C(=O)OCC)co1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 5-formyl-3-furancarboxylic acid ethyl ester (prepared as described in Tetrahedron (1996), 52(12), 4245-56) (1.61 g) in dichloromethane (20 ml) was added diallylamine (1.18 ml). The solution was treated with glacial acetic acid (0.55 ml) and then sodium triacetoxyborohydride (4.2 g). The suspension was stirred at room temperature for 3.5 h. The suspension was treated with ethanol (80 ml) and stirred at room temperature for 25 mins. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The phases were separated and the organic phase washed with saturated aqueous sodium hydrogen carbonate (100 ml) and brine (50 ml). The combined aqueous phases were extracted with ethyl acetate (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was dissolved in methanol and applied equally onto SCX sulphonic acid ion exchange cartridges (10 g×4, pre-treated with methanol). The cartridges were eluted with methanol followed by 10% 0.880 ammonia in methanol; evaporation of the basic fractions in vacuo gave the title compound as a mobile oil (2.06 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[N:14]=[C:13]2[N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=[CH:17][C:12]2=[CH:11][CH:10]=1.[Br-].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1([NH:1][C:9]2[N:14]=[C:13]3[NH:15][CH:16]=[CH:17][C:12]3=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3cc[nH]c3n2)cc1

Procedure:
A 1 dram vial was charged with aniline (2-3 equiv), and 0.200 mL of the 588 stock solution of bromide in toluene was added. A catalyst stock solution containing 3 mmol Pd(OAc)2, 3 mmol biphenyl-2-yl-di-tert-butyl-phosphane and 15 mL of toluene was prepared and 0.050 mL of the catalyst solution was added to the reaction. An excess of NaOtBu was added as a solid to the reaction. The vial was placed in an 80° C. oven for 60 minutes (shaken several times over the hour). After cooling, the reaction was neutralized with 0.100 mL of TFA. After 30 minutes the sample was evaporated and resolvated in 0.300 mL of DMSO. The desired compound was isolated by preparative HPLC/MS. MS (ESI) [M+H+]+=210.4.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH:27]=O)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][C:30]1([CH3:46])[CH2:39][C@H:38]([NH2:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=2)[NH:31]1.C(Cl)Cl.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Si:1]([O:8][C@H:9]([CH2:27][NH:40][C@@H:38]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=2)[NH:31][C:30]([CH3:46])([CH3:29])[CH2:39]1)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cc1ccc2c(c1)[C@@H](N)CC(C)(C)N2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C)CC(C)(C)N2
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4-oxobutan-2-ylcarbamate (0.148 g, 0.360 mmol) and (S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-amine (0.0886 g, 0.360 mmol) in DCM (7.19 ml, 0.360 mmol) was added trimethoxymethane (0.394 ml, 3.60 mmol). The resulting solution was stirred for 1 hour at which time, sodium triacetoxyborohydride (0.229 g, 1.08 mmol) was added. The solution was then stirred for 30 minutes, quenched with saturated Rochelle's salt and stirred for an additional 20 minutes. The mixture was transferred to a sep. funnel containing DCM and H2O. The aqueous layer was washed 4× with DCM. The organic layers were combined, washed 1× with brine, dried with MgSO4, filtered and concentrated to afford the title compound. MS m/z: 642 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25](OC)=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1)[CH3:2].O.[OH-].[Li+].C1C=CC2N(O)N=[N:55]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.O.CN(C=O)C>[NH2:55][C:25](=[O:26])[CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][C:14]1[C:13]([C:29]([F:30])([F:31])[F:32])=[CH:12][N:11]=[C:10]([NH:9][C:8]2[CH:7]=[CH:6][C:5]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[CH:4][C:3]=2[CH2:1][CH3:2])[N:15]=1
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)OC)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reaction time: 18 h

Procedure:
tert-Butyl 4-(3-ethyl-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I43) (177 mg, 0.282 mmol) was dissolved in THF (10 mL), and a solution of lithium hydroxide monohydrate (59.0 mg, 1.41 mmol) in water (2 mL) was added. The mixture was stirred for 18 hours then concentrated. The residue was suspended in saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulphate) and evaporated. The residue was dissolved in THF (10 mL) and DMF (1 mL) at 30° C. and HOBt (50 mg, 0.37 mmol), EDCl (65 mg, 0.37 mmol) and DIPEA (0.246 mL, 1.41 mmol) were added. After ten minutes ammonium carbonate (135 mg, 1.41 mmol) was added and the mixture was stirred for 18 hours at 30° C. The mixture was concentrated, the residue diluted with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate phases were washed with brine (25 mL), dried (sodium sulfate) and evaporated. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I44) (122 mg, 71% over two steps) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.28-7.22 (m, overlaps with CHCl3), 7.22-7.15 (m, 1H), 7.13-7.05 (m, 3H), 5.38 (s, 1H), 5.15 (s, 1H), 4.25 (s, 2H), 3.64 (s, 2H), 3.11-2.99 (m, 4H), 2.80 (t, J=12.1 Hz, 2H), 2.69-2.60 (m, 3H), 1.84 (d, J=12.3 Hz, 2H), 1.69-1.60 (m, 2H), 1.49 (s, 9H), 1.23 (t, J=7.6 Hz, 3H). LCMS: rt 6.65 min; m/z 612.2 [M+H]+, 556.1 [M-tBu+2H]+; m/z 610.2 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1.[Li].C([Li])CCC.CCCCCC.[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[O:30][C:31]3[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=3[CH2:33][N:34]([C:35](Cl)=[O:36])[C:28]=2[CH:27]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][O:12][C:35]([N:34]2[CH2:33][C:32]3[CH:38]=[CH:39][CH:40]=[CH:41][C:31]=3[O:30][C:29]3[CH:42]=[CH:43][C:26]([Cl:25])=[CH:27][C:28]2=3)=[O:36])=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: OCCCNCc1ccncc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCCCNCc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 40.9 %

Procedure:
By the procedure described in Example 11, 3-(4-pyridylmethylamino)-1-propanol (1.0 g, 3.4 mmol) in 30 mL of THF was converted to its lithium salt with 1.6M n-butyllithium in hexane (2.1 mL, 3.4 mmol) and reacted with the product of Example 2 (1.0 g, 3.4 mmol) to yield 590 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25]O)=[CH:22][C:21]=3[CH2:27][CH3:28])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:54]1[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:54]4[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]4)=[CH:22][C:21]=3[CH2:27][CH3:28])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(Cl)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {5-[5-(3-chloro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-4-ethyl-2-thienyl}methanol (0.17 g, 0.41 mmol) that was obtained in Example 15 (15b), carbon tetrabromide (0.18 g, 0.53 mmol), triphenylphosphine (0.14 g, 0.53 mmol), methyl 3-azetidinecarboxylate hydrochloride (93 mg, 0.62 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (0.15 g) in a yield of 73% as a pale yellowish oily product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[C:20]([NH:28][C:29]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:20]([NH:28][C:29]1[CH:38]=[C:37]([O:39][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
82 mg of potassium carbonate and 0.047 mL of benzyl bromide were added to 1 mL of N,N-dimethylformamide solution containing 80 mg of methyl 2-(benzamido)-4-hydroxybenzoate at room temperature and stirred at the same temperature for 3 hours. Ethyl acetate and 1.0 mol/L hydrochloric acrd were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 75 mg of methyl 2-(benzamido)-4-(benzyloxy)benzoate as white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:26])=[C:4]([C:9]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]2[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])=[CH:10][CH:11]=1)[C:5](OC)=[O:6].C[Al](C)C>O1CCOCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][CH2:14][N:15]([CH2:16][C:17]3[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:5](=[O:6])[C:4]=2[C:3]=1[CH3:26]
Reactant: COC(=O)c1c(OCCNCc2c(C)cc(C)[nH]c2=O)ccc(Br)c1C
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCOc3ccc(Br)c(C)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of methyl 3-bromo-6-(2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]amino}ethoxy)-2-methylbenzoate (126c, 134 mg, 0.317 mmol) in 1,4-dioxane (1 mL) was added trimethylaluminum (2.0M in heptanes, 32.0 mg, 0.440 mmol). The reaction mixture was stirred at room temperature for 30 minutes, heated at 55° C. for 2 hours, and then 75° C. for 4 hours. The reaction mixture was cooled to room temperature, the solvent removed under vacuum, and the residue was stirred vigorously with EtOAc (25 mL) and 10% aq. solution of Rochell's salts. Once the mixture became homogeneous, the layers were separated and the organic layer was purified directly by column chromatography (silica gel, (7N NH3 in MeOH) in EtOAc) to give 7-bromo-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (126d, 36 mg, 27% yield) as a light tan solid.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[P:22]([O-:40])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[K+].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:21]=[C:4]1[NH:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:8])[N:3]1[CH2:2][O:40][P:22](=[O:23])([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCl
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1COP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
A mixture of 250 kg 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 270 kg of potassium dibenzyl phosphate, 6 kg of potassium carbonate, 0.75 kg of potassium iodide, and 500 kg of acetonitrile is heated at 70° C. to reflux for 2 to 5 hours or until the reaction is essentially complete. The reaction mixture is cooled to 40° C. to 65° C. and filtered. The solution is stirred with at least 11 kg of activated carbon and filtered using a filter-aid. The reaction solvent is replaced by adding toluene in portions and vacuum distilling. The resulting slurry is cooled to less than 5° C. The title compound is collected by filtration and washed with cold toluene. The wet cake is dried at 50° C. under vacuum to give phosphoric acid dibenzyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester, 315 kg (70% yield); mp 118.6-119.7° C.
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: CCN(CC)CC
Solvent: ClCCl
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: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:51]4[C:46](=[N:47][CH:48]=[CH:49][CH:50]=4)[NH:45][C:44]3=[O:52])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[C:51]4[C:46](=[N:47][CH:48]=[CH:49][CH:50]=4)[N:45]([S:58]([CH3:57])(=[O:60])=[O:59])[C:44]3=[O:52])[CH2:41][CH2:42]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC1
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4ncccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one which was prepared by the method of Referential Example 7 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[N:8](C(C)(C)C)[CH:7]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]c2nc(Cl)ccc2c1=O
Temperature: 70 °C
Yield: 93.1 %

Procedure:
The product from Example 21a (0.282 gm, 0.91 mmol) was combined at room temperature with 2 mL of TFA containing 2 drops of sulfuric acid. The resulting mixture was heated at 70° C. for 16.5 h. The volatiles were removed under vacuum and the residue suspended in water. The product was collected by vacuum filtration, water washed and dried under vacuum to give the title compound as a cream colored solid (0.214 gm, 93%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(3-chlorophenyl)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((benzo-1,3-dioxol-5-yl)amino)-4-(3-chlorophenyl)benzoic acid 52 mg of a yellow solid.