Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH:10]([CH3:12])[CH3:11])[CH2:4][N:3]1[CH:13]([CH3:15])[CH3:14].[Br:16]Br>C(Cl)Cl>[Br-:16].[O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH:10]([CH3:11])[CH3:12])[CH2:4][NH+:3]1[CH:13]([CH3:15])[CH3:14]
Reactant: BrBr
Reactant: CC(C)N1CN(C(C)C)C(=O)N(C)C1=O
Solvent: ClCCl
Product: CC(C)N1C[NH+](C(C)C)C(=O)N(C)C1=O
Product: [Br-]
Reaction time: 1 h
Yield: 54.4 %

Procedure:
21.3 g (0.1 mol) of 2,4-dioxo-hexahydro-1,5-diisopropyl-3-methyl-s-triazine are dissolved in 30 ml of methylene chloride and 24 g (0.15 mol) of bromine are added dropwise. The temperature is kept at 20° C to 30° C by cooling. After one hour, the orange-coloured precipitate which has formed is filtered off and recrystallised from isopropanol. 16 g (55%) of 2,4-dioxo-1,2,3,4-tetrahydro-1,5-diisopropyl-3-methyl-s-triazinium bromide are obtained as white crystals which melt at 210°-212° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.CCOCC>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (3.36 g of a 50% dispersion in mineral oil) was added portionwise to a stirred solution of the product of part (i) (17.43 g) in dry tetrahydrofuran (200 ml) and the mixture was stirred at room temperature for 1 hour. 4-Fluoronitrobenzene (9.87 g) was added dropwise and the mixture was stirred for a further 18 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with dichloromethane. The combined extracts were washed with water, dried (MgSO4) and evaporated to give an oil which solidified on trituration with ether. The solid was filtered off, washed with a little ether and crystallised from ethyl acetate/hexane to give the product, (13.51 g), m.p. 121°-122°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]([NH2:18])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16](/[N:18]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: C1COCCO1
Product: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 12-chloro-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (0.380 mmol, 100 mg) in 1,4-dioxane (3 mL) was added DMF-DMA (1.14 mmol, 147 mg). The mixture was stirred at 100° C. for 1 hour under nitrogen atmosphere. Then solvent was evaporated under reduced pressure, the residue was washed by ether to give 12-chloro-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (80 mg, 68% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 320.1 [M+H+]
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:37])[C@@H:16]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[C:32]([F:35])([F:34])[F:33])[C:24]2=[O:36])[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:18]1([CH2:17][C@H:16]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[C:32]([F:34])([F:35])[F:33])[C:24]2=[O:36])[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][C:6]([OH:38])=[O:5])[N:10]=2)=[O:37])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
A mixture of 3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (prepared as in Example 19, 130 mg, 0.24 mmol) in methylene chloride (3 mL) at room temperature was treated with trifluoroacetic acid (1 mL) and stirred for 3 h at room temperature. The reaction mixture was then diluted with chloroform (3 mL) and washed with an aqueous semi-saturated sodium bicarbonate solution. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo to afford 3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic acid (66 mg, 58%) as a white semi-solid: HR-ES(+) m/e calcd for C23H25N4O4F3 [M+H]+ 479.1901, observed 479.1901; 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.01 (dd, J=7.67, 15.13 Hz, 2H), 7.75 (t, J=7.56 Hz, 1H), 7.53 (d, J=2.13 Hz, 1H), 6.33 (d, J=2.13 Hz, 1H), 4.97-5.11 (m, 2H), 4.70 (d, J=18.11 Hz, 1H), 4.06 (t, J=7.46 Hz, 2H), 2.25 (t, J=7.35 Hz, 2H), 1.05-2.09 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].CC(C)([O-:46])C.[K+].[O:49]1[CH2:53][CH2:52][CH2:51]C1>>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH2:51][CH2:52][C:53]([OH:49])=[O:46])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [K+]
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added at room temperature potassium tert-butoxide (28 mg) and P-propiolactone (16 μl). The reaction solution is stirred overnight at room temperature, and then partitioned by adding ethyl acetate and 1N HCl. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→9:1) and LC/MS (CAPCEL PAK MGII (SHISEIDO), water:methanol=60:40→0:100, 40 ml/min) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (12 mg). MS (m/z): 672 [M+H]+.
Reaction SMILES: C(OCC)(=[O:3])C.[Cl:7][C:8]1[C:9]([CH:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])=[CH:10][C:11]([CH2:14][C:15]#[N:16])=[N:12][CH:13]=1.CO.OO.[OH2:38]>CCCCCC>[Cl:7][C:8]1[C:9]([CH:17]([S:26]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:3])=[O:38])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])=[CH:10][C:11]([CH2:14][C:15]#[N:16])=[N:12][CH:13]=1
Reactant: N#CCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Reactant: O
Reactant: CCOC(C)=O
Agent: OO
Solvent: CO
Solvent: CCCCCC
Product: N#CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To an ethyl acetate (5 ml) solution of [5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]acetonitrile (387 mg, 0.92 mmol) were added methanol (5 ml), 31% aqueous hydrogen peroxide (3 ml) and hexaammonium heptamolybdate tetrahydrate (227 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture. Ethyl acetate and methanol were distilled off under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate. The product thus obtained was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=17:3 eluate was concentrated under reduced pressure to give the title compound (364 mg, 0.80 mmol, 87%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[O:13])=[C:4]([OH:14])[CH:3]=1.[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21](O)[C:17]=1[C:18]([OH:20])=[O:19].S(=O)(=O)(O)O>>[OH:15][C:16]1[CH:24]=[CH:23][C:22]2[N+:12]([O-:13])=[C:5]3[C:4](=[CH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=43)[O:14][C:21]=2[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1c(O)cccc1O
Reactant: O=Nc1c(O)cc(O)c2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(O)ccc2c1oc1cc(=O)c3ccccc3c-1[n+]2[O-]

Procedure:
2.84 g. 1,3-dihydroxy-4-nitrosonaphthalene, 2.31 g. 2,6-dihydroxybenzoic acid, 1.29 g. pyrolusite and 1.6 ml. concentrated sulphuric acid are reacted analogously to Example 1a). Yield 2.8 g.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([NH:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:22][CH3:23])[C:13]([O:20][CH3:21])=[N:14]2)=[O:6])C.C(=O)([O-])[O-].[K+].[K+].Cl>O.CO>[Br:19][C:17]1[CH:16]=[C:15]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[C:13]([O:20][CH3:21])=[N:14]2)=[C:9]([CH2:8][NH:7][C:5](=[O:6])[C:4]([OH:24])=[O:3])[CH:18]=1
Reactant: CCOC(=O)C(=O)NCc1cc(Br)cc2nc(OC)c(OC)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1nc2cc(Br)cc(CNC(=O)C(=O)O)c2nc1OC
Reaction time: 20 h

Procedure:
276 mg of N-(7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-oxalamic acid ethyl ester and 150 mg of potassium carbonate are suspended in 2 ml of water and 5 ml of methanol. The mixture is stirred for 20 hours and acidified with 1 N HCl, and the solid is filtered off and washed with methanol and diethyl ether. M.p.>300° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O>[C:1]([C:5]1[C:6]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(COc2c(C=O)cccc2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A suspension of 3-tert-butyl-2-hydroxybenzaldehyde (5.0 g, 28.1 mmol, 1.0 equiv), 4-methoxybenzyl chloride (4.4 g, 3.8 mL, 28.1 mmol, 1.0 equiv), powdered K2CO3 (7.8 g, 56.2 mmol, 2.0 equiv) and MeCN (100 mL) was refluxed for 6 hr. The yellow-green suspension was cooled to room temperature and allowed the stand for 48 hr. The suspension was diluted with EtOAc (50 mL) and filtered, washing the solids with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give brown oil. The oil was dissolved in EtOAc (150 mL) and the solution washed with H2O (125 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using dichloromethane and dry-loaded onto a column of silica gel (100 g) packed in heptanes. The column was eluted with heptanes (500 mL) followed by 2.5% EtOAc/heptanes (1000 mL). Product fractions were concentrated under reduced pressure to give a yellow oil. Seeding (seeds obtained by lengthy scratching with cold hexanes) of the oil induced crystallization. After crystallization was complete the yellow solid was pumped under high vacuum for 0.5 hr to give 7.5 g (89%) of 24.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([N+:12]([O-])=[O:13])([CH3:11])[CH3:10].C(O)(=O)C>C(O)C.[Zn]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N+:12]([C:9]([CH3:11])([CH3:10])[CH3:8])[O-:13]
Reactant: O=Cc1cccs1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1cccs1

Procedure:
To a suspension of thiophene-2-carbaldehyde (296.7 mg, 2.65 mmol), 1,1-dimethylnitroethane (542.9 mg, 5.27 mmol) and zinc (516.3 mg, 7.90 mmol) in ethanol (3.0 ml) was added acetic acid (946.6 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=1/2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17]1>>[ClH:1].[CH2:21]([N:18]1[CH2:19][CH2:20][CH:16]([NH:15][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Product: CNc1cc(OC)c(C(=O)NC2CCN(Cc3ccccc3)C2)cc1Cl
Product: Cl

Procedure:
By following general method C using 1.7 g. of 5-chloro-2-methoxy-4-methylaminobenzoic acid and 1.4 g. of 3-amino-1-benzylpyrrolidine, 2.1 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-2-methoxy-4-methylaminobenzamide hydrochloride was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:32][C:33]1([CH2:46]OS(C)(=O)=O)[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1>CC(N(C)C)=O>[F:32][C:33]1([CH2:46][O:25][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[C:15]([C:12]2[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=2)[CH:24]=[CH:23]3)[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(COS(C)(=O)=O)CC1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCOc1ccn2c(-c3ccc4cccc(OCC5(F)CCN(C(=O)OC(C)(C)C)CC5)c4n3)cnc2c1
Temperature: 90 °C
Yield: 13.4 %

Procedure:
2-(7-(2-Methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (0.050 g, 0.149 mmol) was dissolved in DMA (0.5 mL) and treated with Cs2CO3 (0.097 g, 0.29 mmol). After stirring for several minutes, tert-butyl 4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (0.053 g, 0.171 mmol) was added. The mixture was heated to 90° C. for 40 hours. The entire reaction mixture was applied to a SiO2 column and eluted with a gradient from 1-20% (6% NH4OH in MeOH)/ethyl acetate to provide the desired product (11 mg). MS ESI (+) m/z 551.1 (M+1) detected.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=C=O.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH:45][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[O:7])=[O:18])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]
Reactant: COc1cccc(N=C=O)c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)Nc3cccc(OC)c3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=500.4.
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:35])[CH2:25][C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][C:27]=2[O:33][CH3:34])[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>[N:20]1([C:24](=[O:35])[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[O:33][CH3:34])[CH2:23][CH2:22][CH2:21]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: COc1cc(O)ccc1CC(=O)N1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(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 (75 mg, 0.266 mmol) was dissolved in toluene (1 ml) and 1-(azetidin-1-yl)-2-(4-hydroxy-2-methoxyphenyl)ethanone (59 mg, 0.069 mmol), triphenylphosphine (105 mg, 0.399 mmol), and DIAD (78 μl, 0.399 mmol) added and the mixture stirred at RT overnight. The mixture was concentrated in vacuo and the residue purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 0-100% water:acetonitrile+0.1% TFA to afford the title compound. LC/MS (m/z): 485 (M+H)+. GPR119 Human EC50: 7.1 nM.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:39])=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])=[N:32][CH:33]=2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>ClCCl>[Cl:15][C:16]1[C:17]([CH3:39])=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])=[N:32][CH:33]=2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Cyanuric chloride (0.43 g, 2.3 mmol) was added to N,N-dimethylformamide (0.18 mL, 2.3 mmol) at room temperature. After the formation of a white solid (10 minutes), methylene chloride (10 mL) was added, followed by 5-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (0.6 g, 2 mmol). After addition, the mixture was stirred at room temperature overnight, then diluted with dichloromethane and washed with sat. NaHCO3 solution. The organic layers were dried over MgSO4, concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (0.58, 90%). LCMS calculated for C19H23Cl2NO2 (M+H)+: m/z=381.1; Found: 381.0.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])#[N:2].[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[NH4+].C(O)(=O)CC>CCCCCCC.O>[C:1]([C:3](=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])#[N:2]
Reactant: CCCCC(CC)COC(=O)CC#N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCC(=O)O
Solvent: O
Solvent: CCCCCCC
Product: CCCCC(CC)COC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Into a 500 ml four-neck round-bottom flask, equipped with a mechanical stirrer, a thermometer and a condenser is charged with 62.2 g (0.32 mol) of 2-Ethylhexyl cyanoacetate (EHCA) and 81.0 g (0.45 mol) of Benzophenone (BP) (molar ratio EHCA:BP=0.71:1) and 27.7 g (0.36 mol) of ammonium acetate and 81.0 g (1.1 mol) of propionic acid and 81.0 g of heptane. The mixture is heated under stirring. When the temperature reach 110° C., a mixture of propionic acid, water, heptane is distilled off over a period of 5 hours at normal pressure. Heptane phase is returned back to the flask. Then the reactant is cooled to 90° C., and 100 ml of hot water is added to the reaction mixture. The mixture is kept at 85° C. for 10 minutes, and then transferred to a funnel for separation. To a flask equipped with a column 256.0 g of crude 2-ethylhexyl 2-cyano-3,3-diphenylacrylate solution is added. Rectification is carried out at 1 mbar. 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate is distilled out at 210° C. (vapor). After distillation, light yellow 2-ethylhexyl 2-cyano-3,3-diphenylacrylate is obtained. Reaction yields are as indicated in table 1 and assume recycle of unreacted benzophenone and 2-EHCA.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.ClCCl.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:10][CH:11]=2)[NH2:16])=[CH:32][CH:31]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NNc1ccc(OCc2ccccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(Pyrid-2-ylmethoxy)phenylhydrazine (66.2 g; 308 mmol), prepared as in step 3, was added to a solution of 86 mL diisopropylethylamine and 900 mL dichloromethane. 4-Chlorobenzyl chloride (74.4 g; 462 mmol) and tetrabutylammonium bromide (29.8 g; 92.4 mmol) and an additional 100 mL dichloromethane were added and the reaction was stirred at ambient temperature for 24 hours. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated. The residue was washed with 9:1 diethyl ether, methanol to afford 1-(4-chlorobenzyl)-1-[4-(pyrid-2-ylmethoxy)phenyl] hydrazine as a beige solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])[CH3:3].[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].[H-].[Na+].C([Li])CCC>C1COCC1>[CH3:4][C:2]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2([CH:17]([CH3:18])[CH3:19])[CH2:26][C:24]([OH:25])=[CH:23][C:22](=[O:27])[O:20]2)=[CH:12][CH:13]=1)([CH3:3])[CH3:1]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)C(=O)CCc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1(CCc2ccc(NC(=O)OC(C)(C)C)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared from [4-(4-methyl-3-oxo-pentyl)-phenyl]-carbamic acid 1,1-dimethylethyl ester obtained in Example PPPPP (2.1 g, 7.2 mmol), methyl acetoacetate (2.1 g, 18.1 mmol), 60% NaH (0.80 g, 20 mmol), and n-butyllithium (14 mL of 1.5M, 21 mmol) in THF as described in General Method 6. The product was carried on crude to the next step.