Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[CH3:32]OCOC.C([O-])(=O)C.[Na+].P(Br)(Br)(Br)=O>C(Cl)Cl>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[C:18](=[CH2:32])[CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: COCOC
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: O=P(Br)(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12

Procedure:
Analogously to Example 9, 2.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione in 60 ml of methylene chloride is reacted with 60 ml of formaldehyde dimethylacetal, 2.0 g of sodium acetate, and 12.6 g of phosphorus oxybromide, and worked up, thus isolating 1.68 g of 17,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 226°-228° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH2:14][C:15]#[N:16])=[N:11][C:10]=2[CH:17]=1)(=[O:5])=[O:4].[C:18]([O:21][C:22](=O)C)(=O)[CH3:19]>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]([C:15]#[N:16])=[C:18]([O:21][CH3:22])[CH3:19])=[N:11][C:10]=2[CH:17]=1)(=[O:4])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CNS(=O)(=O)c1ccc2sc(CC#N)nc2c1
Product: CNS(=O)(=O)c1ccc2sc(C(C#N)=C(C)OC)nc2c1
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 2-cyanomethylbenzothiazole-5-sulfonic acid methylamide (120 mg, 0.45 mmol) and trimethyl orthoracetate (270 mg, 2.2 mmol) in acetic anhydride (2 mL) was heated at 100° C. for 5 hrs. The reaction mixture was cooled to room temperature. The resulting precipitate was isolated by filtration to yield 120 mg (83%) of 2-(1-cyano-2-methoxypropenyl)benzothiazole-5-sulfonic acid methylamide. The product was used in the subsequent step without further purification. MS (m/z, ES+): 324 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH2:12])[C:4]=2[O:3]1.C(N(C(C)C)C(C)C)C.Cl[C:24]([O:26]C)=[O:25]>O1CCCC1>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH:12][C:24]([OH:26])=[O:25])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(NN)c2O1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(NNC(=O)O)c2O1
Reaction time: 1 h

Procedure:
17.8 g of (1C) thus prepared and 12.9 g of ethyldiisopropylamine were dissolved in 200 ml of tetrahydrofuran. 9.45 g of methyl chloroformate was added drop-by-drop to the stirred solution, and the resulting mixture was stirred for one hour. The solvent then was evaporated, the residue was washed with water and extracted with ether, and the extract was dried. Part of the ether was evaporated from the extract and the remaining solution was cooled. The resulting solid was collected to give the methyl ester of 2-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)hydrazinecarboxylic acid (1D), as a white solid, m.p.; 101°-102° C.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:27]([NH:26][C:22]2[N:21]=[C:20]([C:8]3[C:9]4[C:14](=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=4)[NH:6][CH:7]=3)[CH:25]=[CH:24][N:23]=2)[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(C#N)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(C#N)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-1H-indole-6-carbonitrile (prepared by TBDMS protection of 1H-indole-6-carbonitrile) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[Br:21]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.O>CN(C)C=O>[Br:21][C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]3[NH:10][C:9](=[O:20])[N:8]([C@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[CH3:1])[C:12]3=2)[NH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]cc(Br)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (100 mg) in N,N-dimethylformamide (1 mL) was added N-bromosuccinimide (66 mg). The mixture was stirred at ambient temperature for 2 hours. To the mixture were added chloroform and water. The mixture was extracted with chloroform. The extract was washed saturated aqueous sodium hydrogencarbonate and brine, dried over MgSO4 and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in a small-amount of methanol and to the solution was added EtOAc. The precipitate was filtrated and washed with EtOAc to give 8-bromo-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (12 mg) as a white powder.
Reaction SMILES: CCOC(C)=O.CO.[Li+].[OH-].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18]>CO.O>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: COCOc1ccccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COCOc1ccccc1C(=O)O
Yield: 93.4 %

Procedure:
2′,3-O-Isopropylidene-5′-O-(sulfamoyl)aristeromycin. This was prepared from 2′,3′-O-isopropylidenearisteromycin (290 mg, 0.95 mmol, 1.0 equiv) using the general procedure for sulfamoylation. Purification by flash chromatography (4:1 EtOAc/MeOH) afforded the title compound as a thick oil (230 mg, 63%): Rf 0.70 (3:1 EtOAc/MeOH); [α]20D −6.6 (c 1.8, CH3OH); 1H NMR (600 MHz, CD3OD) δ 1.29 (s, 3H), 1.54 (s, 3H), 2.37 (q, J=12.0 Hz, 1H), 2.46-2.54 (m, 1H), 2.54-2.64 (m, 1H), 4.24 (dd, J=16.2, 6.6 Hz, 1H), 4.28 (dd, J=16.2, 6.6 Hz, 1H), 4.70 (t, J=6.0 Hz, 1H), 4.88-4.96 (m, 1H), 5.09 (t, J=6.6 Hz, 1H), 8.19 (s, 1H), 8.21 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 25.4, 27.7, 34.9, 44.5, 62.6, 71.1, 82.2, 84.8, 115.3, 120.6, 141.6, 150.7, 153.6, 157.4. b. N-Hydroxysuccinimidyl 2-(methoxymethoxy)benzoate. A solution of LiOH (660 mg, 27.5 mmol, 3.0 equiv) in MeOH (18 mL) and water (2 mL) was added to methyl 2-(methoxymethoxy)benzoate (1.81 g, 9.17 mmol, 1.0 equiv) and the reaction mixture was refluxed for 4 hours. The reaction mixture was concentrated and the residue was dissolved in H2O (20 mL) and the pH was adjusted to 3 then extracted with EtOAc (3×50 mL). The combined organic extracts were concentrated to afford 2-(methoxymethoxy)benzoic acid (1.56 g, 93%) which was directly carried onto the next step: 1H NMR (600 MHz, CDCl3) δ 3.54 (s, 3H), 5.34 (s, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.51 (t, J=9.0 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 57.0, 95.8, 115.1, 118.4, 122.9, 133.5, 134.9, 156.2, 166.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13]>C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH3:10])=[O:8]
Reactant: CC(C)(C)CO
Reactant: O=C(Cl)CCCCCBr
Solvent: c1ccccc1
Product: CC(C)(C)COC(=O)CCCCCBr

Procedure:
A solution of 6-bromohexanoyl chloride (10.0 g, 0.047 mol) and 2,2-dimethylpropanol (4.96 g, 0.056 mol) in benzene (100 ml) was heated under reflux for 2 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in dichloromethane (200 ml), washed with aqueous sodium hydroxide (2M, 50 ml), water (50 ml) and dried (Na2SO4). The solvent was evaporated off under reduced pressure to give the crude product which was further purified by column chromatography (alumina, dichloromethane) to give neopentyl 6-bromohexanoate as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cccc(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
0.29 g of 3-fluoro-benzoic acid (2.03 mmol) and 0.7 g of 4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.03 mmol) were dissolved in 25 ml of dichloromethane. Addition of 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) at 0° C. was followed by stirring the reaction mixture for 16 h at room temperature. 30 ml of dichloromethane were added, the organic layer was washed with aqueous saturated sodium chloride. The aqueous phase was re-extracted once with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (15:1). Fractions containing the product were combined, the solvent was evaporated to yield 0.88 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[C@@H:12]1[C@:17]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[C@H:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH2:15][C:14](=[O:35])[NH:13]1)[CH:2]=[CH2:3].[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39].[C:44]([O:48][C:49](=[O:52])[CH2:50]Br)([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[CH:12]1[C:17]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH2:15][C:14](=[O:35])[N:13]1[CH2:50][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:52])[CH:2]=[CH2:3].[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]
Reactant: C=CCOc1ccc(I)cc1[C@H]1NC(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(I)cc1C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 49 %

Procedure:
In a manner similar to the method described in example 1e, racemic (2′R, 3R,4′S)-2′-(2-allyloxy-5-iodo-phenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (5 g, 6.6 mmol) prepared in example 18c was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethyl-formamide to give racemic (2′R, 3R, 4′S)-2′-(2-allyloxy-5-iodo-phenyl)-1′-[(tert-butoxycarbonyl)methyl]-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield: 2.8 g, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 4.05 g of 2-benzyloxyphenol and 9.5 ml of N,N-dimethylformamide was added dropwise to a mixture of 0.80 g of sodium hydride and 20 ml of N,N-dimethylformamide under ice cooling, and the mixture was stirred for 30 minutes. A mixture of 7.1 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 17 ml of N,N-dimethylformamide was added dropwise at the same temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed once with 1N hydrochloric acid and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-nitrobenzene.
Reaction SMILES: [CH2:1]([C:3]([OH:32])([CH2:30][CH3:31])[C:4]#[C:5][CH2:6][O:7][CH2:8][C:9]1[C@:10]2([CH2:27][CH2:26][C@H:25]3[C:15](=[CH:16][CH:17]=[C:18]4[C@:23]3([CH3:24])[C@@H:22]([OH:28])[CH2:21][C@H:20]([OH:29])[CH2:19]4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:11])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>[Pd].CO>[CH2:1]([C:3]([OH:32])([CH2:30][CH3:31])[CH2:4]/[CH:5]=[CH:6]\[O:7][CH2:8][C:9]1[C@:10]2([CH2:27][CH2:26][C@H:25]3[C:15](=[CH:16][CH:17]=[C:18]4[C@:23]3([CH3:24])[C@@H:22]([OH:28])[CH2:21][C@H:20]([OH:29])[CH2:19]4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:11])[CH3:2]
Reactant: CCC(O)(C#CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CCC(O)(CC)C/C=C\OCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The fraction (0.3 g) containing 17-(4-ethyl-4-hydroxy-2-hexynyloxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene obtained in Example 11 (2), 5% palladium/barium sulfate (0.3 g), quinoline (0.03 ml, 0.2538 mmol) and methanol (6.8 ml) were subjected to reaction using a procedure similar to that of Example 29(1) (4 hours) and worked up to give a mixture (0.80 mg) containing the targeted compound.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[NH2:27][CH2:28][C@@:29]([CH3:34])([CH:31]1[CH2:33][CH2:32]1)[OH:30]>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([NH:27][CH2:28][C@@:29]([CH:31]2[CH2:33][CH2:32]2)([OH:30])[CH3:34])=[O:9])=[CH:20][CH:19]=1)#[N:17]
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@](O)(CN)C1CC1
Product: C[C@](O)(CNC(=O)c1cnc(OCC2CC2)c(-c2ccc(C#N)cc2)c1)C1CC1

Procedure:
The title compound was synthesized from 5-bromo-6-cyclopropylmethoxy-nicotinic acid (example 31 a) by Suzuki reaction with 4-cyanophenyl-boronic acid (in analogy to 31 c) and amide coupling with (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol (WO 2006/106054) (in analogy to example 31b), to give the title compound as a white solid, MS (ISP): 392.2 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1[N:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][N:33]=1>CS(C)=O.CCOC(C)=O>[CH2:39]([O:38][C:35]1[CH:34]=[N:33][C:32]([N:15]2[CH2:14][CH2:13][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:20]([S:21]([CH3:24])(=[O:22])=[O:23])=[C:3]([F:2])[CH:4]=3)[CH2:17][CH2:16]2)=[N:37][CH:36]=1)[CH3:40]
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reactant: CCOc1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(C)(=O)=O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.8 %

Procedure:
4-((1R,2R)-2-(((3-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step D product, 200 mg, 0.53 mmol) was dissolved in DMSO (5 ml) at RT under N2 and Cs2CO3 (517 mg, 1.588 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-ethoxypyrimidine (101 mg, 0.635 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 100° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, evaporated. The crude material was purified by flash column (25 g SNAP, 15˜50% EtOAc in hexane) to afford 56 mg (23%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 2H), 7.90 (m, 1H), 7.30 (m, 2H), 4.60 (m, 4H), 4.00 (t, 2H), 3.60 (m, 2H), 3.20 (s, 3H), 2.93-2.80 (m, 2H), 1.96 (d, 1H), 1.85 (d, 1H), 1.43 (m, 5H), 1.25 (m, 1H), 1.15 (m, 1H), 0.80-0.71 (m, 2H), 0.12-0.08 (m, 1H). MS (ESI) m/z 464 [M+H]+. GPR119 Human EC50: 1.65 nM.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]([NH2:51])[CH3:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][CH:49]([NH:51][C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22])[CH3:50]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
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
Product: CC(C)NC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 130.1 %

Procedure:
A 20-mL vial was charged with ((2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1.57 g, 4.76 mmol, ASW MedChem Inc., New Brunswick, N.J.), HATU (2.17 g, 5.72 mmol, ChemImpex International Inc., Wood Dale, Ill.), propan-2-amine (0.450 mL, 5.28 mmol, Sigma-Aldrich, St. Louis, Mo.), DIPEA (1.70 mL, 9.76 mmol) and DMF (8 mL). The mixture was stirred at room temperature for 2.5 h. The reaction mixture was partitioned between water (80 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). and the combined organic phases were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL), then brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford di-tert-butyl (2R)-2-((1-methylethyl)carbamoyl)-1,4-piperazinedicarboxylate (2.30 g) as a light-brown foam.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([I:10])[C:3]=1[N:11]=[C:12]=[O:13].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>ClCCl>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([I:10])[C:3]=1[NH:11][C:12]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[O:13]
Reactant: Cc1cc(I)c(N=C=O)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: Cc1cc(I)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the crude 2,3-difluoro-6-iodo-4-methylphenyl isocyanate from D20, 4-amino-1-N-Boc piperidine (480 mg), and dichloromethane (5 ml) was stirred at room temperature for 18 h then evaporated and directly purified by chromatography on silica gel 20 g eluting with 10-50% ethyl acetate in hexane to give the title compound, 300 mg. M−−H=494.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:12]#[N:13].O.N>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:12]#[N:13])([CH3:10])[CH3:9]
Reactant: N#C[Cu]C#N
Reactant: CC(C)c1cccc(Br)c1
Agent: N
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C#N)c1

Procedure:
5.15 g (25.87 mmol) m-bromo-isopropyl-benzene and 2.69 g (30.04 mmol) copper cyanide are stirred in 2.50 ml of pyridine for 24 hours at 180° C. Then 15 ml of water, 15 ml of toluene and 15 ml conc. ammonia solution are added, then the mixture is extracted. The organic phase is dried and evaporated to dryness.
Reaction SMILES: CO.C(O)(C)C.[OH-].[Na+].[C:9](I)([C:12]([C:15]([C:18]([C:21]([C:24]([F:27])([F:26])[F:25])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10]>O>[CH:9]([C:12]([C:15]([C:18]([C:21]([C:24]([F:25])([F:26])[F:27])([F:22])[F:23])([F:19])[F:20])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Into a 1 l four-necked flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, 256 g of methanol, 3 g of isopropyl alcohol and 46.4 g (1.16 mol) of sodium hydroxide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 223 g (0.5 mol) of C6F13I was dropwise added thereto over a period of one hour. After completion of the dropwise addition, heating and refluxing were continued for 6 hours. The conversion was more than 99.9%. The reactor was cooled to room temperature, and then, 300 g of water was added to dissolve precipitated sodium iodide. The crude reaction solution was separated into two layers, and the fluorocarbon layer (lower layer) was further washed twice with 300 g of water to obtain 145 g (purity: 99.9%) of C6F13H. In the reactor, no formation of tar was observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]([OH:34])=[O:11]
Reactant: O=P([O-])(O)O
Reactant: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Yield: 98.1 %

Procedure:
To a solution of 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (1.87 g, 4.28 mmol) in acetonitrile (12.0 ml) were added an aqueous solution (7.0 ml) of sodium dihydrogen phosphate (4.01 g, 33.42 mmol), an aqueous solution (7.0 ml) of sodium hypochlorite (1.74 g, 19.33 mmol) and an aqueous hydrogen peroxide (1.89 ml, 30%) and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (1.90 g, 4.20 mmol, 98%).