Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44]CC6C=CC=CC=6)=[C:38]([O:52][CH3:53])[CH:37]=5)=[CH:32][N:31]=4)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[O:54][CH3:55])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[C:40]([O:42][CH3:43])[C:39]([OH:44])=[C:38]([O:52][CH3:53])[CH:37]=5)=[CH:32][N:31]=4)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[O:54][CH3:55]
Reactant: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(OCc6ccccc6)c(OC)c5)cn4)CC3)nc2)cc(OC)c1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(O)c(OC)c5)cn4)CC3)nc2)cc(OC)c1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 1,4-bis[5-(4-benzyloxy-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine (27.0 mg, 0.037 mmol) in methanol (1.0 mL) were added 10% palladium on charcoal (14.0 mg) and ammonium formate (14.0 mg, 0.220 mmol), and the resulting mixture was stirred at 70° C. for 2 hours. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. A solution of the residue in chloroform was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from methanol-chloroform-diethyl ether to yield the title compound as pale brown needles (melting point: 200.0-202.0° C.) (17.0 mg, yield: 85%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Si:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]O)=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>O1CCCC1>[C:30]([Si:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][I:25])=[CH:37][CH:36]=1)([CH3:29])[CH3:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Triphenyl phosphine (1.32 g, 5.03 mmol), imidazole (370 mg, 5.47 mmol) and iodine (1.16 g, 4.61 mmol) were added to an ice-cooled solution of 4-(tert-butyldimethylsilyloxy)benzyl alcohol [(1 g, 4.19 mmol), Tet. Lett. (2004), 45, 9617] in tetrahydrofuran (50 mL) and the mixture was stirred at 0° C. for 10 minutes and room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane, afforded the title compound in 41% yield, 600 mg.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[CH:16][CH:17]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: OB(O)c1ccnc2ccccc12
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CN1c2cc(-c3ccnc4ccccc34)sc2C(=O)NC1(C)C
Yield: 29.2 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), quinolin-4-ylboronic acid (173 mg, 1.00 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL), and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained yellow solid (62 mg) was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (47.2 mg, 29%) as a pale yellow solid:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].[Br:15]Br.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>ClC1C=CC=CC=1>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5]
Reactant: CCOC(=O)C(=O)c1ccccc1C
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccccc1CBr
Temperature: 0 °C
Yield: 9.9 %

Procedure:
To a solution of ethyl 2-methylbenzoylformate (10 g) in chlorobenzene (50 ml) were added a solution of bromine (10 g) in chlorobenzene (20 ml) and a suspension of 25%-hydrous benzoyl peroxide (1 g) in chlorobenzene (10 ml) over 2 hours and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled with ice-water and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a yellow oil. The oil was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give the desired ethyl 2-(bromomethyl)benzoylformate (1.4 g, yield: 10%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].FC(F)(F)C(O)=[O:18].ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:18])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCSc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCS(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cool to 0°-5° C. a stirred solution of 2-nitro-5-propylthioaniline (21.2 g) in methylene chloride (350 ml) and add trifluoroacetic acid (11.40 g), followed by the dropwise addition of 85% m-chloroperbenzoic acid (22.34 g) in methylene chloride (450 ml). Stir 30 minutes at 0° C., then warm to room temperature and stir 3.5 hours. Add chloroform to dissolve the solids, and extract the mixture with 10% sodium carbonate solution three times, extract with water once, filter over magnesium sulfate, then evaporate the organic solvent in vacuo. Recrystallize the residue from methanol to obtain 2-nitro-5-propylsulfinylaniline, m.p. 128°-130° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=[O:11])[C:7](F)(F)F)=[O:4].N1C=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:3]1(=[O:4])[O:5][C:6](=[O:11])[C:7]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12
Reactant: c1ccncc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC(=O)c2ccccc21
Reaction time: 2 h

Procedure:
22.4 g (0.08 mol) of the 4-(maleinamidyl)-phthalic acid manufactured according to Example 3, paragraph 1, are suspended in 150 ml of anhydrous methylene chloride and 37.8 ml of trifluoroacetic anhydride are added. The reaction mixture is stirred for 2 hours at 20°-25° C., whilst excluding atmospheric moisture. 30.5 g of pyridine are then added dropwise whilst cooling with ice (internal temperature 20°-25° C.). The reaction mixture is then stirred for a further 2 hours at 20°-25° C. and filtered, and the filter residue is washed with a little methylene chloride and dried under a high vacuum. 14.7 g (75% of theory) of 4-isomaleinimidyl)-phthalic anhydride are obtained in the form of slightly yellowish crystals; decomposition at 195°-207° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:11]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])#[CH:12].C(N(CC)CC)C>O1CCOCC1.[Cu]I.Cl[Pd]Cl>[CH:17]([Si:13]([C:11]#[C:12][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1)([CH:14]([CH3:16])[CH3:15])[CH:20]([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: Ic1ccn2ccnc2c1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[Si](C#Cc1ccn2ccnc2c1)(C(C)C)C(C)C
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
Combine 7-iodo-imidazo[1,2-a]pyridine (2.64 g, 10.82 mmol), ethynyl-triisopropyl-silane (3.61 mL, 16.23 mmol), copper (I) iodide (0.103 g, 0.541 mmol) and triethylamine (7.54 mL, 54.09 mmol) in 1,4-dioxane (50 mL). Bubble nitrogen through the mixture for five minutes. Add [1,1′-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.442 g, 0.541 mmol, 1:1 complex with dichloromethane). Attach a reflux condenser, and heat the mixture to 85° C., stir overnight (15 hours), and cool to room temperature. Filter the mixture through Celite® 521. Concentrate the solution in vacuo to a dark brown oil and use as is. MS(ES), m/z 299 (M+1).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>CN(C=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:2]=[C:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Yield: 78.6 %

Procedure:
1-([1,1'-Biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (1.03 g, 3.3 mmol) was alkylated by treating with 0.31 mL (3.3 mmol) of methyl bromoacetate and 132 mg (3.3 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.0 g (79% yield) of [[1-([1,1'-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 99°-102° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(Br)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1ccnc(-c2cc(C)c(Br)c(C)c2)c1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-4-methyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.90 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:25][C:26]1([CH3:42])[O:31][CH:30]([C:32]([NH:34][CH2:35][CH2:36][C:37](O)=[O:38])=[O:33])[C:29]([CH3:41])([CH3:40])[CH2:28][O:27]1>>[CH3:25][C:26]1([CH3:42])[O:31][CH:30]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:38])=[O:33])[C:29]([CH3:41])([CH3:40])[CH2:28][O:27]1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCCO
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 67 %

Procedure:
N-(3-Hydroxypropyl)linoleamide (3.38 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain of the title compound (yield: 67%)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:14])([C:6](=[O:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH3:5].Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:5][C:4]([CH3:14])([C:6](=[O:13])[CH:7]([N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:3]
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)C(=O)C(CCOc1ccccc1)n1cncn1

Procedure:
2.6 g of sodium hydride, 16.7 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one and 20.1 g of 1-bromo-2-phenoxyethane are reacted by a method similar to that of Example 1b.
Reaction SMILES: [CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][NH:10][C:9](=[O:19])[CH2:8][C:7]=3[CH:20]=[C:3]2[O:2]1.C(N(CC)CC)C.[CH3:29][N:30]=[C:31]=[O:32].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][N:10]([C:31]([NH:30][CH3:29])=[O:32])[C:9](=[O:19])[CH2:8][C:7]=3[CH:20]=[C:3]2[O:2]1
Reactant: O=C1Cc2cc3c(cc2C(c2ccccc2)=NN1)OCO3
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1N=C(c2ccccc2)c2cc3c(cc2CC1=O)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of 7,8-methylenedioxy-1-phenyl-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (130 mg, 0.46 mmol) in CH2Cl2 (5 ml) was added triethylamine (1 mL), DMAP (5 mg) and methylisocyanate (60 mg) and the mixture was stirred at 25° C. for 24 h. The reaction mixture was then poured into a separatory funnel containing water (50 mL) and the product was extracted with CH2Cl2 (3×40 mL). The combined extracts were dried over Na2SO4 and solvent removed in vacuo. Purification of the residue by chromatography (1:1 of ethyl acetate: hexane) resulted in the product as a white solid (92 mg, 59%), mp, 180°-182.5° C. 1H NMR (CDCl3) 8.60 (bs, 1H), 7.74 (m, 2H), 7.46 (m, 3H), 6.88 (s, 1H), 6.67 (s, 1H), 6.07 (bs, 1H), 6.03 (bs, 1H), 3.54 (s, 1H) 3.54 (s, 1H), 2.93 (s, 1.5H), 2.92 (s, 1.5H).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:23][C:8](=[O:10])[CH3:9])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(C)=O)c1

Procedure:
120 ml of triethylamine and 56.7 ml of acetic anhydride were added dropwise to a stirred solution of 70.5 g of m-anisidine in 500 ml of a methylene chloride under ice cooling. After completion of the dropwise addition, the reaction mixture was washed and dried, and insolubles were filtered off. The filtrate was concentrated, and the residue was recrystallized from hexane-ethyl acetate to afford 80.9 g of N-(3-methoxyphenyl)acetamide as pale yellow needles. Melting point: 81° to 82° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.Cl>O1CCOCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: COC(=O)COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)COC1(c2ccccc2)CCNC1
Reaction time: 1 h

Procedure:
To tert-butyl 3-(2-methoxy-2-oxoethoxy)-3-phenylpyrrolidine-1-carboxylate (160 mg, 0.00048 mol) was added 4 M of hydrogen chloride in 1,4-dioxane (1 mL) and the resulting solution was stirred for 1 h. The reaction mixture was then concentrated in-vauco and the crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:14][C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:7]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:9])[CH:10]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Product: COc1cc(I)c(Cl)cc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 96.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 67 and using 5-chloro-4-iodo-2-methoxybenzoic acid (1 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (612 mg) described in Preparation Example 47, the title compound (1.5 g) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH:9]C(=O)OCC)=[S:8]>[OH-].[Na+]>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH2:9])=[S:8]
Reactant: CCOC(=O)NC(=S)Nc1nncs1
Agent: [Na+]
Agent: [OH-]
Product: NC(=S)Nc1nncs1
Yield: 72.5 %

Procedure:
A solution of 10 g of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl]carbamic acid, ethyl ester (from Preparation 1) in 150 ml of 1N sodium hydroxide was heated at reflux for ninety minutes. The solution was cooled and concentrated by evaporation under reduced pressure. The precipitated solid was collected by filtration and dissolved in 20 ml of water. The aqueous solution was acidified by addition of 200 ml of 1N hydrochloric acid. The product was collected by filtration and recrystallized from N,N-dimethylformamide to give 5 g of 1,3,4-thiadiazol-2-ylthiourea. m.p. 253° C. p Analysis calc. for C3H4N4S2 :
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH:9]1[CH:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]=O)[C:12]2=[CH:11][CH:10]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:6]#[N:7])=[CH:19][C:18]1[C:12]2[C:13](=[CH:14][CH:9]=[CH:10][CH:11]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1cccc2ccccc12
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=Cc1cccc2ccccc12
Yield: 85.8 %

Procedure:
To a solution of 7.8 g of cyanoacetic acid ethyl ester and 10.0 g of 1-naphthylaldehyde in 150 ml of benzene were added 2 ml of piperidine and 2 ml of acetic acid, the mixture was heated under reflux for 3 hours while removing water formed during the reaction using a molecular sieve. After cooling, the reaction mixture was washed successively with a saturated sodium bicarbonate aqueous solution, water, diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from benzene-hexane to obtain 13.8 g of 2-cyano-3-(1-naphthyl)propenoic acid ethyl ester as light yellow crystals.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:30])[CH:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[N:8]([C:10](=[O:21])[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH3:9])C.C(O)C.[H][H]>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:7]2[N:8]([CH3:9])[C:10](=[O:21])[CH:11]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]2=[O:30])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)N(C)C(=O)Cc1c(C)cc(C)cc1C
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C2C(=O)C(Cc3ccc(Cl)cc3)N(C)C2=O)c(C)c1
Yield: 68.3 %

Procedure:
To a boiling solution of 120 ml of absolute toluene and 7.5 g (0.25 mol) of sodium hydride there are added dropwise 79.9 g (0.199 mol) of 2-(4-chlorobenzyl)-N-(2,4,6-trimethylphenylacetyl)-sarcosine ethyl ester in 200 ml of absolute toluene, and the batch is refluxed while being monitored by thin-layer chromatography. When the reaction is complete, ethanol is added dropwise, while cooling in an ice-bath, until no more hydrogen escapes. After the mixture has been evaporated under reduced pressure, the residue is taken up in water and the mixture is acidified with concentrated hydrochloric acid at 0° C. to 20° C. The precipitate is filtered off with suction and recrystallised from chloroform/n-hexane. 48.4 g (68.4% of Theory) of 5-(4-chlorobenzyl)-1-methyl-3-(2,4,6-trimethylphenyl)-pyrrolidine-2,4-dione of melting point >230° C. are obtained.
Reaction SMILES: ClC1C=C(C=CC=1)N.ClC1C=CC2C(=C([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)C=CC=2)N=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[NH:28]1[C:27]2[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=2[CH:21]=[CH:20]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Nc1cccc(Cl)c1
Product: O=C1NCCc2[nH]ccc21
Yield: 47.2 %

Procedure:
Prepared according to Example 102, using 3-chloroaniline (220 μl, 2.099 mmol, Sigma Aldrich), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 125 mg, 0.420 mmol). and 1.0 M LHMDS, 1.0M in THF (2099 μl, 2.099 mmol, Sigma Aldrich) and stirring at 25° C. for 30 min. Purification by column chromatography (silica gel 1 to 5% MeOH/DCM) provided 2424(3-chlorophenyl)amino)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (27 mg, 16.5%). 1H NMR (400 MHz, CDCl3) δ ppm 12.09-12.31 (1H, m) 8.03 (2H, d, J=1.00 Hz) 7.57-7.60 (1H, m) 7.50-7.55 (1H, m) 7.33-7.41 (4H, m) 7.17-7.22 (1H, m) 7.12-7.15 (1H, m) 6.88-6.93 (1H, m) 5.23-5.28 (1H, m) 3.55-3.62 (2H, m) 2.67-2.73 (2H, m). m/z (ESI, +ve) 389.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH:5]([CH3:23])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[OH:22]>C(O)(=O)C.[Pt](=O)=O>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[CH:3]1[CH2:4][CH:5]([CH3:23])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[OH:22]
Reactant: CC1C=C2N(C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(O)CC[C@H]3[C@H]12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC1CC2N(C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 11 from Example 10, being 350 mg in 10 ml acetic acid was added 100 mg catalytic platinum dioxide and the resulting mixture was evacuated and flushed with hydrogen. The reaction was shaken overnight at room temperature under 40 Psig hydrogen pressure. The solution was filtered and concentrated to a residue. The residue was worked up with ethyl acetate, the organic layer was then concentrated under vacuum, diluted with ethyl acetate, washed with aqueous NaHCO3, brine, dried, concentrated to yield the title compound 12. Mass Spec: 320, (M+1).
Reaction SMILES: [CH2:1]1[C@@H:6]([C:7]#[N:8])[N:5]([C:9]([C@@H:11]([NH2:23])[C:12]23[CH2:21][C:19]4([OH:22])[CH2:20][CH:14]([CH2:15][CH:16]([CH2:18]4)[CH2:17]2)[CH2:13]3)=[O:10])[C@@H:4]2[C@H:2]1[CH2:3]2.[CH3:24][C:25]([CH3:27])=O>>[CH3:24][C:25](=[N:23][C@@H:11]([C:12]12[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:20][C:19]([OH:22])([CH2:18]3)[CH2:21]1)[CH2:13]2)[C:9]([N:5]1[C@H:6]([C:7]#[N:8])[CH2:1][C@H:2]2[C@@H:4]1[CH2:3]2)=[O:10])[CH3:27]
Reactant: CC(C)=O
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2
Product: CC(C)=N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Saxagliptine form H-1 (100 mg) was suspended in acetone (1 ml). The suspension was stirred for 24 hours at room temperature, after which it was filtered and dried on air, yielding 54 mg of crystalline product