Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([CH2:11][CH3:12])[C@@H:7]1[C:13]([OH:15])=O.O1CCCC1.C(N(CC)CC)C.[N+:34](=[CH2:36])=[N-:35]>CCOCC>[N+:34](=[CH:36][C:13]([C@@H:7]1[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:3]=2[O:2][CH3:1])[C:9](=[O:10])[C@H:8]1[CH2:11][CH3:12])=[O:15])=[N-:35]
Reactant: CC[C@@H]1C(=O)N(Cc2ccc(OC)cc2OC)[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC[C@@H]1C(=O)N(Cc2ccc(OC)cc2OC)[C@H]1C(=O)C=[N+]=[N-]
Temperature: -15 °C
Yield: 58 %

Procedure:
To a solution of 14.65 g (50 millimoles) of trans-1-(2,4-dimethoxy-benzyl)-3-ethyl-4-oxo-2-azetidinecarboxylic acid prepared according to the preceding paragraph in 150 ml of anhydrous tetrahydrofurane 7.3 ml (52.5 millimoles) of triethyl amine are added and to the solution under stirring and ice-cooling 5.1 ml (52.5 millimoles) of ethyl-chloro-formiate are added. The mixture is cooled to -15° C., stirred at this temperature for 20 minutes and the precipitated triethyl amine salt is filtered off under argon. To the filtrate a cold solution of 22.5 g (150 millimoles) of diazomethane and 230 ml of ether is added. The solution is allowed to warm to room temperature under stirring and after 2 hours the reaction mixture is evaporated to dryness. The residue is a mixture comprising predominantly trans-4-diazoacetyl-1-(2,4-dimethoxy-benzyl)-3-ethyl-2-azetidinone and some methyl-trans-1-(2,4-dimethoxybenzyl)-3-ethyl-4-oxo-2-azetidine-carboxylate. The mixture thus obtained can be used as starting material in Example 3 directly, without purification. The benzene solution of the evaporation residue can be, however, subjected to column chromatography, if desired. (Adsorbent: Kieselgel 60. diameter 0.063-0.200 mm, eluant: benzene-acetone 7:2). Thus 9.2 g of trans-4-diazoacetyl-1-(2,4-dimethoxy-benzyl)-3-ethyl-2-azetidinone are obtained. Yield: 59%.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4].C(OC(=O)C)(=[O:23])C.C([O-])(=O)C.[K+]>C(O)(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:23])[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(ncn2CCCCCCO)n(C)c1=O
Yield: 90 %

Procedure:
3.4 g of 1,3-dimethyl-7-(6-bromohexyl)-xanthine are boiled overnight under reflux in 50 ml of glacial acetic acid to which 1 ml of acetic anhydride and 5 g of potassium acetate have been added. After evaporation of the solvent by distillation in vacuo the residue is dissolved in 50 ml of 5% sulfuric acid on the addition of 20 ml methanol. The solution is boiled under reflux for 1 hour. The mixture is extracted with chloroform. The chloroform phase is washed until it is neutral and concentrated in vacuo. 1,3-dimethyl-7-(6-hydroxyhexyl)-xanthine having a melting point of 80° C. is obtained in a yield of more than 90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=O)[CH2:7][CH2:6]2.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].N1CCCC1.C[OH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)[C:6]2=[O:31]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc2c(c1)CCC(=O)O2
Reactant: CO
Solvent: C1CCNC1
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of 10.0 g (56.1 mmol) of 6-methoxychromanone, 8.48 g (56.1 mmol) of 3-nitrobenzaldehyde and 4.7 mL (56.1 mmol) of pyrrolidine in 30 mL methanol was allowed to stir at room temperature under N2 atmosphere. After 48 hours, the reaction mixture was filtered and the precipitate washed with methanol and dried to yield 11.44 g of yellow powder (65%). A small sample was recrystallized from isopropylether/CH2Cl2 for analytical data. M.p. 157°-159° C.; MS: C: 311.0794;F: 311.0796; 1H NMR (AC 300, CDCl3): δ5.27 (d, 2H, J=1.9 Hz); 3.84 (s, 3H); IR: 1670, 1490 cm-1. Analysis: calculated: C. 65.59, H 4.21, N 4.50%; found: C. 65.33, H4.57, N 4.47%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].C(O)C>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:20][CH3:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester (5 g, 21.3 mol) was dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. Sodium hydride (1.02, 25.5 mmol, 60% in mineral oil) was added to the above solution in portions over 10 minutes. The mixture was stirred at room temperature for 30 minutes. Ethyl iodide (6.5 g, 42 mmol) was added to the above solution and the reaction mixture was stirred overnight. Ethanol (30 mL) was added to the reaction mixture and the mixture was poured into cold water (800 mL). The crude product was collected by filtration and used directly in next step without further purification (5 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][O:18][CH3:19])[C:4]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][NH2:26].C(O)(=O)C.C(Cl)Cl>ClCCCl>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][NH:26][CH2:6][C:5]1[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:4]=1[N:3]([CH2:1][CH3:2])[CH2:16][CH2:17][O:18][CH3:19]
Reactant: CCN(CCOC)c1ccc(C(F)(F)F)cc1C=O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
2-[Ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzaldehyde (3.7 g), 3,5-bis-trifluoromethyl-benzylamine (4.23 g), acetic acid (1.15 ml) are dissolved in 1,2-dichloroethane (30 ml), and thereto is added triacetoxy sodium borohydride (5.68 g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-ethyl-(2-methoxy-ethyl)-amine (3.38 g). MS (m/z): 503 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.[NH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[OH:32]>>[OH:32][C@@H:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[NH:26][C:2]1[N:3]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: O=c1c2c(ncn2Cc2ccccc2)nc(Cl)n1Cc1ccccc1
Product: O=c1c2c(ncn2Cc2ccccc2)nc(N[C@@H]2CCC[C@H]2O)n1Cc1ccccc1

Procedure:
Treat 2-chloro-1,7-bis(phenylmethyl)purin-6-one with trans-2-aminocyclopentanol as described in Preparative Example 5 to give the title compound, a tan solid. FAB MS: M+1=416.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([OH:32])=O.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:33]1([C:30](=[O:32])[CH2:29][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:36][CH2:35][CH2:34]1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Reactant: C1CNC1
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: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {2-fluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (500 mg, 1.13 mmol) in 8 ml of anhydrous DMF at RT was added azetidine (129 mg, 2.26 mmol) and N,N-diisopropylethylamine (0.591 ml, 3.38 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (643 mg, 1.69 mmol) was added to the solution and stirred at RT for 4 hrs. The mixture was purified by column chromatography by loading directly to a preparative biotage reverse phase column (C-18) (50 g column) and eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The material was further purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexanes (30% to 90%) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 2H), 7.27 (t, J=8.4 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.20 (d, J=2.3 Hz, 1H), 4.74 (t, J=13.2 Hz, 2H), 4.27 (s, 2H), 4.17 (t, J=7.7 Hz, 2H), 4.04 (m, 4H), 3.40 (s, 2H), 3.35 (s, 3H), 2.85 (m, 2H), 2.14-2.29 (m, 3H), 1.85 (m, 2H), 1.41 (m, 1H), 1.36 (m, 2H), 1.11 (m, 1H), 0.93 (m, 1H), 0.60-0.71 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 482.4 (M+H)+. GPR119 Human EC50: 0.77 nM
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[C:3]([NH:10][C:11](=[S:13])[CH3:12])([NH:6][C:7](=[S:9])[CH3:8])[C:4]#[N:5].[C:16](=O)=[O:17].C(Cl)(Cl)(Cl)[Cl:20].Cl>CO.CCOCC>[ClH:20].[CH3:1][CH:2]([CH2:14][CH3:15])[C:3]([NH:6][C:7](=[S:9])[CH3:8])([NH:10][C:11](=[S:13])[CH3:12])[C:4](=[NH:5])[O:17][CH3:16]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCC(C)C(C#N)(NC(C)=S)NC(C)=S
Reactant: O=C=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCC(C)C(NC(C)=S)(NC(C)=S)C(=N)OC
Reaction time: 0.08 h
Yield: 66 %

Procedure:
A suspension of 141 mg (0.41 mmol) of 7 in 1.66 mL of MeOH and 4.15 mL of Et2O was cooled to -20° C. (CO2 /CCl4), and HCl gas was passed through the mixture via septum inlet for 5 minutes, until most of the solids had dissolved and the solution was saturated with HCl. The mixture was placed in the freezer in a desiccator for 66 hours and then concentrated in vacuo to produce a white foamy solid. The solid was broken up, washed with three portions of anhydrous Et2O, dried in vacuo to give 111 mg (66%) of 1 as an off-white solid which decomposed on heating and also decomposed after several days in a freezer.
Reaction SMILES: [CH2:1]([O:23][CH:24]([CH3:32])[C:25]([O:27]C(C)(C)C)=[O:26])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[CH:33](O)=O>C(OCC)C>[CH2:1]([O:23][CH:24]([CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: O=CO
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCOC(C)C(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCOC(CC)C(=O)O
Temperature: 40 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
A mixture of tert-butyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaen-1-yloxy)propanoate (2.09 g, 4.58 mmol) in HCOOH (9 ml) was stirred at 40° C. under N2-atmosphere for 6 hrs. The reaction mixture was diluted with diethyl ether (100 mL), washed with water (30 mL), dried (MgSO4), filtered and evaporated under reduced pressure. Dry-flash on silica gel (50 g) eluting with toluene-toluene (85:15) yielded 1.44 g of the crude title compound. Flash chromatography on silica gel (30 g) eluting with heptane-heptane/(EtOAc w/5% HCCOH) 98:2-95:5-80:20 yielded 1.07 g (58% yield) of the title compound as a liquid. 1H NMR (200 MHz, CDCl3) δ 0.97 (t, 3H), 0.99 (t, 3H), 1.64-1.91 (m, 4H), 2.00-2.23 (m, 4H), 2.78-2.87 (m, 10H), 3.42-3.66 (m, 2H), 3.85 (dd, 1H), 5.26-5.46 (m, 12H). MS (electrospray) (neg): 399 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)#[CH:19]>CCCCCCC.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]#[C:19][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2cccnc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (83 mg, 80%); 1H NMR δ (CDCl3): 8.76-8.74 (m, 1H), 8.50-8.53 (m, 1H), 7.76-7.73 (m, 1H), 7.49-8.46 (m, 2H), 7.24-7.20 (m, 1H), 6.88-6.85 (m, 2H), 3.78 (s, 3H); LCMS m/z: 209.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8](Cl)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
(2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-carbamic acid ethyl ester (300 mg, 0.96 mmol) was dissolved in 10 mL of tetrahydrofuran and benzylamine (0.103 mL, 0.96 mmol) was added followed by triethylamine (0.194 mL, 1.91 mmol) and the reaction mixture was stirred at 60° C. overnight. The solvent was removed and the solid was partitioned in ethyl acetate/water (50 mL/30 mL), the organic layer was dried over MgSO4, concentrated and purified by column chromatography on silica eluting with a gradient of 0% to 10% of methanol in ethyl acetate in to give 323 mg of the title compound as a yellow solid.
Reaction SMILES: C[CH2:2][O-:3].[Na+].[H-].[Na+].C(=O)(OCC)OCC.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH2:28][OH:29])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCO>[O:3]=[C:2]1[N:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23][C@H:24]2[CH2:28][O:29]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC[C@@H]2C1
Temperature: 80 °C

Procedure:
A NaOEt solution, prepared from sodium hydride (60% dispersion in mineral oil) (0.990 g, 26 mmol) and 100 mL EtOH, diethyl carbonate (9.00 mL, 74 mmol) and (S)-4-N-BOC-2-hydroxymethyl-piperazine (2.17 g, 10 mmol) was heated at 80° C. The reaction was cooled to RT and filtered. The filtrate was concentrated to dryness to give an off-white amorphous solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH3:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([OH:19])=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH3:20])[C:4]([CH:1]([CH3:3])[CH3:2])=[C:12]2[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CC(C)c1c(-c2ccncc2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C(C)C)n2C

Procedure:
The above compound was prepared from 2-isopropyl-1-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].[CH2:36]([C:40]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH2:45][NH:46][CH2:47][CH2:48][C:43]=2[C:42](=[O:49])[O:41]1)[CH:37]([CH3:39])[CH3:38].FC1C=CC(C2(CC(C)C)C3CNCCC=3C(=O)O2)=CC=1>C1COCC1.ClCCl>[CH2:36]([C:40]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH2:45][N:46]([C:2]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:4])[CH2:47][CH2:48][C:43]=2[C:42](=[O:49])[O:41]1)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CC(C)CC1(c2ccc(F)cc2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1NC(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 106.4 %

Procedure:
To an ice-cold solution of triphosgene (36 mg, 0.123 mmol) and triethyl amine (75 mg, 0.737 mmol) in anhydrous THF (15 mL) was added tert-butyl 2-(aminomethyl)phenylcarbamate (100 mg, 0.369 mmol) in anhydrous THF (2 mL). The reaction mixture was stirred at 0° C. for 15 min., then warmed to room temperature and concentrated to dryness. The residue was re-dissolved in anhydrous dichloromethane (15 mL), a solution of 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (100 mg, 0.369 mmol) (prepared according to the methods described for 3-(4-fluorophenyl)-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one, Scheme 1) in anhydrous dichloromethane (2 mL) was added, and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes) to provide tert-butyl 2-((3-isobutyl-1-oxo-3-phenyl-1,3,4,5,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxamido)methyl)phenylcarbamate as a colorless oil (68 mg, 21% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.78-0.97 (m, 6H), 1.50-1.55 (m, 9H), 1.55-1.69 (m, 1H), 1.77 (dd, J=14.51, 7.35 Hz, 1H), 2.22-2.42 (m, 3H), 3.12-3.46 (m, 1H), 3.50-3.63 (m, 1H), 3.88 (d, J=18.84 Hz, 1H), 3.89-3.90 (m, 1H), 4.25-4.36 (m, 2H), 4.44 (d, J=18.84 Hz, 1H), 5.78 (d, J=5.65 Hz, 1H), 7.01 (dd, J=7.54, 1.13 Hz, 1H), 7.14-7.26 (m, 2H), 7.26-7.42 (m, 4H), 7.69 (d, J=8.29 Hz, 1H), 8.46-8.57 (m, 1H); MS m/z 542 (M+Na)+, 518 (M−H)−.
Reaction SMILES: [CH3:1]N(C)C(N1CC=C(C2NC3N=CN=C(C4C=C(F)C=C(N)C=4C)C=3C=2)CC1)=O.C1C2C(Cl)=NC=NC=2NC=1.CN(C)C(N1CC=C([C:50]2[NH:81][C:53]3[N:54]=[CH:55][N:56]=[C:57]([C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([N:64]5CC[C:71]6[C:66](=[CH:67][CH:68]=[C:69]([C:74](O)([CH3:76])[CH3:75])[CH:70]=6)[C:65]5=[O:78])[C:59]=4[CH2:79]O)[C:52]=3[CH:51]=2)CC1)=O>>[C:74]([C:69]1[CH:68]=[CH:67][C:66]([C:65]([NH:64][C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([C:57]3[C:52]4[CH:51]=[CH:50][NH:81][C:53]=4[N:54]=[CH:55][N:56]=3)[C:59]=2[CH3:79])=[O:78])=[CH:71][CH:70]=1)([CH3:1])([CH3:76])[CH3:75]
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(N5CCc6cc(C(C)(C)O)ccc6C5=O)c4CO)ncnc3[nH]2)CC1
Agent: Clc1ncnc2[nH]ccc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]ccc12

Procedure:
Intermediate 51 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with 6-chloro-7-deazapurine and Intermediate 5 with Intermediate 48.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 1-cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (101 mg, 0.31 mmol) and L-Alanine (561 mg, 6.29 mmol) in 0.5 M sodium methoxide/methanol (12 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted with methyl t-butyl ether (2×30 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (8 mL). The resulting white suspension was extracted with ethyl acetate (30 mL), dried and concentrated in vacuo to give the title compound as a white solid (117 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.52 (bs, 1H), 10.11 (br s, 1H), 8.30 (d, 1H), 8.07 (m, 1H), 7.67 (t, J=8 Hz, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 4.83 (q, 1H), 1.68 (d, J=7.4 Hz); MS: (+) m/z 378.29 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][C:10](=[CH2:22])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].S(Br)([Br:25])=O.O>C(Cl)Cl>[Br:25][CH2:22][CH:10]([CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C(CCOCC(=O)OCC)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COCCC(CBr)C(O)C(NC=O)C(=O)OCC
Reaction time: 0.17 h

Procedure:
7.5 g (23.6 mmol) of ethyl 6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-4-methylene-hexanoate are dissolved in 75 ml of CH2Cl2 and 2.2 ml (28.3 mmol) of thionyl bromide are then added dropwise at room temperature to this solution. After 1 hour 50 ml of water are added and the reaction mixture is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and once with brine. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and concentrated by evaporation giving ethyl 4-bromomethyl-6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-hexanoate as a yellow oil which is further reacted without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:4].O=[CH:15][CH:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:17]#[N:18]>C(O)(=O)C>[C:17](/[C:16](/[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:15]\[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:18]
Reactant: CCOC(=O)CCNCC(=O)OC
Reactant: N#CC(C=O)c1cccnc1
Solvent: CC(=O)O
Product: CCOC(=O)CCN(/C=C(\C#N)c1cccnc1)CC(=O)OC
Temperature: 80 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
To an acetic acid (30 mL) solution of ethyl 3-{[(methoxycarbonyl)methyl]amino}propanate (6.720 g) was added a crude product of 3-oxo-2-(3-pyridyl)propanenitrile (7.826 g), and the mixture was stirred at 80° C. for 2 days. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with water, and sodium carbonate was added thereto for neutralization, followed by extracting the solution with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate, which was then filtered for separation. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/3), to obtain the title compound (7.521 g, yield 83%). The ESI/MS data of the compound are given below.