Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2)#[CH:17].Cl>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]1[C:18]2([C:16]3[O:8][C:7]4[C:2](=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=3)[N:22]([CH2:23][CH2:24][CH2:25]2)[CH2:21][CH2:20]1
Reactant: C#CC12CCCN1CCC2
Reactant: Oc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1cnc2cc(C34CCCN3CCC4)oc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Iodo-3-pyridinol (902 mg, 4.1 mmol), copper(I) iodide (116 mg, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (119 mg, 0.17 mmol) and triethylamine (570 mL, 4.1 mmol) were combined in DMF (4.5 mL) and stirred for one hour. 7a-Ethynyl-hexahydro-1H-pyrrolizine(460 mg, 3.4 mmol) in DMF (1.2 mL) was added dropwise and the mixture was heated at 60° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature and 2 N aqueous HCl was added. The heterogeneous mixture was washed with Et2O (2×), basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 extracts were combined, dried (MgSO4) concentrated and chromatographed (silica gel; CHCl3 /MeOH, 96:4) to afford an amber oil which solidified upon storage at -20° C. (405 mg, 52%): mp 39-41° C.; 1H NMR (CDCl3, 300 MHz) δ 1.86-1.97 (m, 6H), 2.24-2.34 (m, 2H), 2.68-2.76 (m, 2H), 3.21-3.28 (m, 2H), 6.77 (s, 1H), 7.12 (dd, J=8.5, 5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 8.46 (d, J=5 Hz, 1H); MS (CI/NH3) m/z: 229 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH2:17]Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-]>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(Cl)ccc2O1

Procedure:
43.0 g of 2-amino-4-chlorophenol was dissolved in 500 ml of anhydrous acetone containing 42.0 g of anhydrous potassium carbonate. That mixture was heated to reflux temperature and 23.0 g of ethyl 2,3-dibromopropionate was added slowly. In three additional portions each, additional ester and carbonate were added to the refluxing mixture until a total of 124 g of carbonate and 85.8 g of ester had been added. The mixture was refluxed for 21 hours. Solids were filtered from the mixture and the filtrate was stripped of solvent. The residue was taken up in water and the solution was extracted with ether. The ether extract was dried (MgSO4) and the solvent was stripped. The residue was recrystallized from ethanol, eluted through a silica gel column using a 4:30:66 by volume mixture of tetrahydrofuran, ethyl acetate and hexane as eluent, and the product was recrystallized from ethanol, and then from ether, to give 2 as white crystals, m.p.: 85.5°-86.5°.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-:11].[Na+].[CH3:13]O>>[CH3:13][O:11][C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: [OH-]
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CO
Agent: [Na+]
Product: COc1ccnc2[nH]ccc12

Procedure:
4-methoxy-7-azaindole 20 was prepared by reacting 4-chloro-7-azaindole 24 (prepared as described in Example 9) with sodium hydroxide in methanol as described by Girgis, N. et. al., J. Heterocyclic. Chem. 1989, 26:317-325.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:35][CH:36]([F:42])[C:37](OCC)=O>O1CCOCC1>[F:35][CH:36]([F:42])[C:37]1[N:13]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reactant: CCOC(=O)C(F)F
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
A mixture of N-[7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidin-5-yl]benzene-1,2-diamine (65 mg, 0.14 mmol) and ethyl difluoroacetate (0.3 mL, 2.8 mmol) in 1,4-dioxane (0.5 mL) was heated at 100° C. for 3 days. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 30:70 to 2:98) to afford 184 as a white solid (26 mg, 35%). LCMS (Method G): RT=8.03 min, M+H+=543. 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=8.1 Hz, 1 H); 7.91 (d, J=7.8 Hz, 1 H); 7.60 (t, J=53.8 Hz, 1 H); 7.45-7.37 (m, 2 H); 4.43 (m, 4 H); 4.02 (s, 2 H); 3.89 (t, J=4.7 Hz, 4 H); 3.74 (t, J=4.5 Hz, 4 H); 3.69 (t, J=6.2 Hz, 2 H); 3.21-3.07 (m, 3 H) and 2.37 (m, 4 H)
Reaction SMILES: [I-].[CH3:2][O:3][CH2:4][CH2:5][N:6]([CH2:34][CH2:35][O:36][CH3:37])[C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[S+:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[CH:16]=1)[N:11]=2.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[CH3:2][O:3][CH2:4][CH2:5][N:6]([CH2:34][CH2:35][O:36][CH3:37])[C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[S+:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=1)[N:11]=2.[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41]
Reactant: COCCN(CCOC)c1ccc2nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[s+]c2c1
Reactant: O=C(O)C(F)(F)F
Agent: [I-]
Solvent: ClCCl
Product: COCCN(CCOC)c1ccc2nc3ccc(N4CCNCC4)cc3[s+]c2c1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
3-(Bis(2-methoxyethyl)amino)-7-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenothiazin-5-ium iodide was dissolved in CH2Cl2 and trifluoroacetic acid (1:1 mixture) and heated at 50° C. for 2 to 4 h. The mixture was allowed to cool to RT and the solvent was evaporated to give a residue, which was purified by flash silica gel chromatography. Isolated 15 mg of a dark blue solid as the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[C:9]([NH2:15])[CH:8]=1)=[O:4].[N:27]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]([C@H:5]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:14][N:27]=[N:15][C:9]=2[CH:8]=1)=[O:4]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)NC(=O)OCc1ccccc1
Reactant: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]nnc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of benzyl (R)-1-(methoxycarbonyl)-2-(3,4-diamino-5-methylphenyl)ethylcarbamate (250 mg, 0.58 mmol) in acetic acid (6 mL) and water (10 mL) was added a solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 mL), dropwise over several minutes at room temperature. The resulting mixture was stirred at room temperature for 30 min, then cooled to 0° C. A mixture of ammonium hydroxide and water (1:1, 15 mL) was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice. The organic layers washed with brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by flash column chromatography (1:1 ethyl acetate/hexanes) on silica gel to afford the title compound as a tan solid (155 mg, 72% yield). 1H-NMR (CDCl3, 300 MHz) δ 7.34 (s, 1H), 7.32–7.28 (m, 6H), 6.93 (s, 1H), 5.40 (d, J=8.1 Hz, 1H), 5.13–5.02 (m, 2H), 4.76–4.69 (m, 1H), 3.73 (s, 3H), 3.28 (dd, J=13.9, 5.5 Hz, 1H), 3.16 (dd, J=13.9, 6.2 Hz, 1H), 2.64 (s, 3H). LC/MS: tR=2.30 min, 369 (MH)+.
Reaction SMILES: O.[ClH:2].[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:11][O:12][NH2:13].C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C>[ClH:2].[CH3:11][O:12][N:13]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: CON
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CON=C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Piperidinone hydrochloride monohydrate (5 g, 32.5 mmol), methoxyamine hydrochloride (4.18 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol) were taken into 100 mL of ethanol and stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate evaporated to afford a white solid. The crude solid was dissolved in water, made basic with solid potassium carbonate, and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to afford a clear, colorless liquid. It was converted to its hydrochloride salt by treating with ethereal hydrogen chloride to give 233 g, m.p. 140°-141° C. C6H12N2O·HCl: Calc.: C, 43.77; H, 7.96; N, 17.02. Found: C, 43.78; H, 7.96; N, 17.08.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[OH-:33].[Li+].C[O:36]CCOC>O.C(OCC)(=O)C.C1COCC1>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[C:20]([OH:22])=[O:36])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:33]
Reactant: COCCOC
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc3c(c2)OCO3)C(=O)O1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc2c(c1)OCO2)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 278 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4-methylenedioxyphenyl)methyl]dihydrofuran-2-(3H)-one in 10.25 ml of ethylene glycol dimethyl ether and 5.15 ml of water is treated dropwise, at RT, with 2,53 ml of a 1M lithium hydroxide solution. After that, the reaction mixture is stirred at RT for 3 h, diluted with ethyl acetate and THF, and washed in a separating funnel until neutral with a mixture consisting of 31 ml of sat. ammonium chloride solution and 2.6 ml of 10% citric acid solution, followed by saline and water. The title compound, which is subjected to further processing without any further purification, is obtained after drying over sodium sulfate and removing the solvent. FAB-MS (M+H)+ =458.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH2:28][OH:29])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1.[CH2:41](N(CC)CC)C.CS(Cl)(=O)=O.C[O-].[Na+]>C1COCC1.O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH2:28][O:29][CH3:41])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](COC)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate (165 mg) and triethylamine (215 μl) were dissolved in THF (4 ml), and methanesulfonyl chloride (60 μl) was added under ice-cooling. The mixture was stirred at 0° C. for 2 hr, and sodium methoxide (28% methanol solution, 600 mg) and methanol (2 ml) were added, and the mixture was further stirred at 75° C. for 3 hr. The mixture was cooled to room temperature and diluted with water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object product (142 mg).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]2[C:8]=1[CH:9]=[CH:10][CH2:11]2.O>CCCCCC.C1COCC1.CCCCCC>[CH3:5][C:4]1[CH:11]=[CH:12][C:13]([CH3:16])=[C:2]2[C:3]=1[CH:2]=[CH:3][CH:4]2[C:5]1[CH:14]=[CH:15][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[C:12]2[C:8](=[C:7]([CH3:6])[CH:15]=[CH:14][C:13]=2[CH3:16])[CH:9]=[CH:10]1
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1ccc(C)c2c1C=CC2Cc1ccccc1C1C=Cc2c(C)ccc(C)c21
Temperature: -70 °C
Reaction time: 1 h

Procedure:
4.12 ml (10.3 mmoles) of n-BuLi 2.5 M in hexane are added to a solution of 1.48 g of 4,7-dimethyl indene (XVIII) (10.3 mmoles; obtained as described above) in 55 ml of a mixture of THF-hexane 2/1. At the end of the addition, the mixture is left under stirring for 1 hour. It is then cooled to −70° C. and a solution of 2.3 g of the brominated compound having formula (XX) (7.37 mmoles) in THF/hexane are added dropwise. The mixture is left to rise to room temperature and is left to rest for 6 hours. It is then poured into water and is extracted with ethyl ether. The organic phase is washed until neutrality and dehydrated on sodium sulfate. The residue obtained by evaporation of the solvent is purified by silica gel chromatography eluating with petroleum ether. After evaporation of the eluant 2.0 g of the bis-indenyl ligand having formula (XXI) and indicated below, are obtained (72% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (350 mg, 2.55 mmol) and 3,4-dichlorobenzyl alcohol (542 mg, 3.06 mmol) were dissolved in tetrahydrofuran (7.0 mL), and triphenylphosphine (803 mg, 3.06 mmol) and a 40% diethyl azodicarboxylate toluene solution (1.40 mL, 3.06 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 65:35 (v/v)), whereby the objective title compound was obtained as a white solid (676 mg, yield: 89%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[CH:32](OC)(OC)OC.C(O)(=O)C.C([O-])(O)=O.[Na+]>O>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N:25]4[CH:32]=[N:30][N:29]=[N:28]4)=[CH:26][CH:27]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(OC)OC
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(N)cc3)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-n4cnnn4)cc3)CC2)nc1

Procedure:
The product of step A (60 mg, 0.16 mmol), sodium azide (13 mg, 0.2 mmol), trimethyl orthoformate (0.3 mL, 2.7 mmol), and acetic acid (0.15 mL, 2.6 mmol) were heated at 80° C. for 6 hours. The solution was cooled and diluted with water. The solution was neutralized with NaHCO3 and extracted with DCM. The organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified via reverse-phase HPLC (C18: gradient 10-100 water/acetonitrile 0.1% formic acid) which yielded the title compound. MS (ESI) m/z 420 [M+H]+. GPR119 Human EC50: 0.07 nM
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:19])[CH2:8]2)C(=O)C2=CC=CC=C12.O.NN.C(O)(=O)/C=C/C(O)=O>C(O)C>[CH2:12]([N:10]1[CH2:11][CH:7]([CH2:6][NH2:5])[CH2:8][C:9]1=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CC(CN2C(=O)c3ccccc3C2=O)CN1Cc1ccccc1
Agent: NN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O
Product: NCC1CC(=O)N(Cc2ccccc2)C1

Procedure:
54 g (0.16 mol) of 4-phthalimidomethyl-1-benzyl-pyrrolidin-2-one are stirred into 1.3 l of ethyl alcohol after the addition of 32 g of hydrazine hydrate for 4 hours at room temperature. The precipitate (phthalic acid hydrazide) is removed by suction filtering the filtrate is evaporated down. 500 ml of methylene choloride are added to the residue which is then extracted three times with 100 ml of water. The organic phase is dried and evaporated down. The residue remaining is dissolved in 500 ml of methanol and 20 g (0.17 mol) of solid fumaric acid are added in batches thereto, with stirring, at boiling temperature. As the mixture cools, colorless crystals are precipitated, which are then suction filtered and washed with methanol and ether.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH2:47][C:48](O)=[O:49])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:42]2[CH:41]=[N:40][C:39]3[C:43]2=[N:44][CH:45]=[N:46][C:38]=3[NH:37][C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(benzyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H-NMR (500 MHz; DMSO-d6) δ 10.81 (brs, 1H), 8.60 (d, 1H), 8.36 (m, 1H), 8.28 (m, 2H), 7.73 (m, 2H), 7.46 (d, 2H), 7.40 (t, 2H), 7.34 (t, 1H), 5.41 (s, 1.2H), 5.29 (s, 0.8H), 5.23 (s, 2H), 4.57 (s, 0.8H), 4.28 (s, 2.4H), 4.09 (m, 2.0H), 3.88 (t, 0.8H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.COC1C=CC([Mg]Br)=CC=1.O=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]1[C:37]([O:39]CC)=[O:38]>C1COCC1.CCOCC.CCOCC>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]2[C:37]([OH:39])=[O:38])=[CH:4][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl (1RS)[1-Hydroxy-1-(4methoxyphenyl)1-3-phenylindene-2-carboxylate. To dry magnesium turnings (0.88 g, 36 mmol) under an argon atmosphere was added, portionwise, a solution of p-bromoanisole (4.5 ml, 36 mmol) in 5% THF/Et2O (37 ml). The resulting p-methoxyphenyl magnesium bromide solution was added to a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in Et2O (300 ml) under an argon atmosphere at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min. The mixture was partitioned between 3M HCl (100 ml) and EtOAc (200 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo to provide a yellow oil which was treated with Et2O/hexanes. The solid which formed was collected by filtration (3.47 g). The filtrate was concentrated under reduced pressure and purified by flash chromatography. The material which was isolated was treated with Et2O/ hexanes, and the additional solid which formed (1.76 g, 75% total yield) was collected by filtration to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:31]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:29])[C:20]=2[N:21]2[CH2:26][CH2:25][CH2:24][C:23]([F:28])([F:27])[CH2:22]2)[N:13]=1.Cl>CO.O1CCOCC1>[NH2:31][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:29])[C:20]=1[N:21]1[CH2:26][CH2:25][CH2:24][C:23]([F:27])([F:28])[CH2:22]1)=[O:30]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(F)(F)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
To a solution of tert-butyl 2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (57 mg, 0.1 mmol) in MeOH (2 mL) was added HCl in 1,4-dioxane (4 M, 5 mL). After stirring at room temperature for 18 hr the mixture was concentrated under reduced pressure. Purification via preparative HPLC gave 287 as a white solid (29 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.65 (s, 1H), 7.37-7.28 (m, 1H), 7.06-6.99 (m, 2H), 6.13 (s, 2H), 3.75 (s, 3H), 3.32 (t, J=11.0 Hz, 2H), 3.17-3.12 (m, 2H), 2.08-1.95 (m, 2H), 1.92-1.84 (m, 2H). LCMS (ES+) m/z 455.0 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].O.[NH2:16][NH2:17]>CCOCC>[O:11]=[S:10]1(=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:2])[NH:17][NH:16]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: NN
Solvent: O
Solvent: CCOCC
Product: O=C1NNS(=O)(=O)c2ccccc21
Reaction time: 8 h
Yield: 50.5 %

Procedure:
2-Chlorosulfonyl-benzoic acid methyl ester (7.04 g, 30 mmol) was added to hydrazine hydrate (66 mmol) stirring rapidly in 300 mL ether. The reaction was stirred overnight in an open flask and allowed to slowly concentrate. The remaining solvent was concentrated and the residue was treated with HOAc (3 mL) and DCM. The solution was washed with water, dried over MgSO4, and concentrated to give 3 g of a white solid.