Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>C(O)C>[N:30]1([C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[O:22])[CH2:8]3)[O:4][N:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: C1CNC1
Solvent: CCO
Product: CCc1ccc(C2CC(c3nc(N4CCC4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.174 mmol) of the oxadiazole from Example 25A in 1.10 ml of ethanol were added 198 mg (3.48 mmol) of azetidine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 46.9 mg (61% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH3:15][N:16]([CH2:27][CH2:28][CH2:29][CH2:30]Br)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C>CN(C)C=O>[CH3:15][N:16]([CH2:27][CH2:28][CH2:29][CH2:30][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CN(CCCCBr)S(=O)(=O)c1ccc(F)cc1
Reactant: COc1cccc2c1CC(CN)CC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(CNCCCCN(C)S(=O)(=O)c1ccc(F)cc1)CC2

Procedure:
The compound is prepared from 1 g of 2-aminomethyl-8-methoxytetralin (5.2 mmol), 1.7 g of N-methyl-N-(4-bromobutyl)-4-fluorophenylsulphonamide (5.2 mmol) and 0.73 ml of triethylamine (5.2 mmol) in 20 ml of dimethylformamide analagously to the working directions of Example 47.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:36][CH:35]=1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: O=C(NCCNCc1ccc(OC(F)(F)F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 4-(trifluoromethoxy)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 476 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.25 (1H, s) 8.04 (1H, t, J=5.52 Hz) 8.01 (1H, d, J=5.42 Hz) 7.77 (1H, d, J=5.47 Hz) 7.46 (1H, d, J=5.42 Hz) 7.42 (2H, d, J=8.69 Hz) 7.29 (1H, d, J=2.54 Hz) 7.23 (2H, d, J=8.44 Hz) 6.79 (1H, d, J=5.42 Hz) 6.43 (1H, dd, J=3.47, 1.90 Hz) 3.70 (2H, s) 3.35 (2H, q, J=6.49 Hz) 2.63 (2H, t, J=6.52 Hz)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[N:20]2)=[CH:15][CH:14]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[N:20]2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3ccc(CO)n3)cc2)c2cccc(F)c2c1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(-n3ccc(C=O)n3)cc2)c2cccc(F)c2c1=O
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 5-fluoro-1-{4-[3-(hydroxymethyl)-1H-pyrazol-1-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.300 g, 0.712 mmol) in 10 mL of dichloromethane containing crushed molecular sieves was added 4-methylmorpholine N-oxide (0.108 g, 0.925 mmol). After 10 minutes, tetrapropylammonium perruthenate (0.025 g, 0.071 mmol) was added. After an hour, the reaction mixture was filtered through celite and concentrated in vacuo. The crude material was subjected to chromatography on silica gel eluting with 0-3% MeOH in DCM to provide Ethyl 5-fluoro-1-[4-(3-formyl-1H-pyrazol-1-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 420.1 for M+H+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])(=[O:21])[CH3:20]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.6 %

Procedure:
To a suspension of 4-amino-3-methylbenzoic acid (60 g, 0.40 mol) in methylene chloride (800 mL) was added triethylamine (121 g, 1.19 mol). The solution became clear. Then, acetic anhydride (81 g, 0.79 mol) was added and the reaction mixture was stirred for 60 h at room temperature. The solvent was evaporated. The residue was diluted with water (400 mL) and extracted with ethyl acetate (3×600 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give the title compound as a tan solid (43 g, 56% yield). 1H-NMR (d6-DMSO, 300 MHz) δ 9.36 (s, 1H), 7.77 (s, 1H), 7.10 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H). LC/MS: tR=1.22 min, 194 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C(C)=CC=CC=1>C(OCC)C>[CH3:12][C:4]1[NH:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:2]2[C:3]=1[C:13](=[O:15])[N:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:25]=2
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1c(C)nc2ccccc2c1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Cc1[nH]c2ccccc2c2nn(-c3ccccc3)c(=O)c1-2
Temperature: 25 °C

Procedure:
The mixture of 3.6 g of ethyl 4-chloro-2-methylquinolin-3-carboxylate, 1.8 g of phenylhydrazine and 40 ml of xylene is refluxed for 4 hours, cooled to room temperature, diluted with diethyl ether and filtered. The residue is dissolved in 50 ml of 2 N aqueous sodium hydroxide, the solution washed with diethyl ether and its pH adjusted to 8.5 with ammonium chloride. The precipitate formed is collected, washed successively with hot water, methanol and diethyl ether, to yield the 4-methyl-2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one, showing in the IR-spectrum peaks at 874, 867, 858, 850, 822, 780, 765, 756, 750, 740 and 722 cm-1. Analogously the 4-methyl-2-(p-chlorophenyl)-pyrazolo[4-3,-c]quinolin-3(5H)-one is prepared, melting at 349°-350°.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[NH:5][C:6](=[O:27])[N:7]([CH:26]=1)[C@@H:8]1[O:25][C@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>CN(C=O)C>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][CH2:13][C@H:12]1[O:25][C@@H:8]([N:7]2[CH:26]=[C:3]([CH2:1][CH3:2])[C:4](=[O:28])[NH:5][C:6]2=[O:27])[CH2:9][C@@H:10]1[OH:11]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Reactant: NCc1ccccc1Br
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNCc3ccccc3Br)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
2.5 g of 2'-deoxy-5-ethyl-5'-O-(p-toluenesulphonyl)uridine were dissolved in 15 ml of DMF and added to 2-bromobenzylamine. The mixture was heated at 80° C. under nitrogen for 5 hours. The solvent was removed by evaporation and the residue was re-evaporated with toluene to given an oil. This was taken up in 20 ml of water/methanol (1:3) and stored in a refrigerator for 1.5 hours. A solid crystallized out and this was filtered off and washed with water/methanol (1:3) to give 0.99 g of 5'-(2-bromobenzylamino)-2',5'-dideoxy-5-ethyluridine, mp 144°-146° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8]CC2C=CC=CC=2)[CH:6]([O:16]CC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33].[CH2:34]([N:38]=[C:39]=S)[CH2:35][CH2:36][CH3:37].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:34]([NH:38][C:39]1[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][OH:25])[CH:6]([OH:16])[CH:7]([OH:8])[CH:2]2[N:1]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN=C=S
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCNC1=NC2C(CC(CO)C(O)C2O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
To a solution of Intermediate B (142 mg, 0.318 mmol) in dry THF (3 mL) was added a solution of butyl isothiocyanate (45.7 mg, 0.397 mmol) in dry THF (1 mL). The mixture was stirred at room temperature for 16 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (90 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 5 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give the aminooxazoline (87.2 mg, 52%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 15H), 4.83 (d, J=11.5 Hz, 1H), 4.80-4.76 (m, 1H), 4.77 (d, J=11.3 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.46 (d, J=11.2 Hz, 1H), 4.45 (s, 2H), 4.05 (dd, J=7.9, 4.4 Hz, 1H), 3.64 (t, J=5.9 Hz, 1H), 3.56 (dd, J=9.0, 4.2 Hz, 1H), 3.52-3.46 (m, 2H), 3.25-3.11 (m, 2H), 2.18 (dt, J=14.8, 3.4 Hz, 1H), 2.05-1.98 (m, 1H), 1.88 (ddd, J=15.1, 12.1, 3.7 Hz, 1H), 1.53-1.46 (m, 2H), 1.38-1.28 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1]/[C:2](/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:3](\Cl)/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:15]>CN(C)C=O.C(O)(=O)C>[NH2:15]/[C:3](/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2](\[Cl:1])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C(Cl)=C(/Cl)C(=O)OCC
Reactant: N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)/C(N)=C(/Cl)C(=O)OCC
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
48.2 g (0.2 mol) of diethyl dichloromaleate were dissolved in 80 ml of dimethylformamide and 2 ml of glacial acetic acid, and the mixture was warmed to 100° C. Ammonia gas was then passed in. During this operation, the temperature increased to about 120° C. After 30 minutes, the temperature dropped back to 100° C.; the reaction was then complete. The solvent was then removed by vacuum distillation. The residue was taken up in methylene chloride, and the solution was washed with water. The methylene chloride solution was evaporated in a rotary evaporator. 38.9 g (87.8% yield) of diethyl aminochloromaleate were obtained as a yellow oil which solidified on trituration to form needle-shaped crystals (m.p. 84° C.-86° C.).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:29][NH:30][CH3:31]>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:25])([F:26])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:19])([CH3:20])[CH3:18])[C:14]([N:30]([CH3:31])[CH3:29])=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Reactant: CNC
Agent: Cl
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N(C)C)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and dimethylamine hydrochloride as starting materials and isolated (31 mg, 57%); MS (ESI, m/z): 416.6 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12](=O)[CH3:13])[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClC(Cl)C>[CH3:9][C:8]1[N:23]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]([CH3:13])=[CH:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CC(C(C)=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-phenylhexane-2,5-dione (0.330 g, 1.735 mmol) in dichloroethane (5 ml) was added triethylamine (0.725 ml, 5.20 mmol), followed by ethyl 2-aminoacetate hydrochloride (0.291 g, 2.082 mmol). The reaction was stirred overnight at room temperature, after which LCMS showed formation of the desired product. The reaction mixture was purified directly on an ISCO automated chromatography system (silica gel) using an EtOAc/hexane gradient. The desired fractions were collected and concentrated in vacuum and the crude mixture was taken directly to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Br[CH:18]([CH2:24]Br)[C:19]([O:21][CH2:22]C)=[O:20]>CC(C)=O.CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[O:10][CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:24][NH:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)C1CNc2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
3-Amino-4-hydroxy-benzonitrile (180 mg, 1.34 mmol) was dissolved in acetone (1.4 mL). To the solution was added K2CO3 (555 mg, 4.02 mmol) and ethyl 2, 3-dibromopropanoate (380 mg, 1.46 mmol). The mixture was heated to reflux for 16 h. After cooling to room temperature the reaction mixture was filtered and concentrated in vacuo to give an oil. The oil was dissolved in methanol and was purified by silica gel chromatography (0-10% dichloromethane/hexanes) to afford methyl 6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (148 mg, 0.68 mmol). The methyl ester was isolated as methanol was used for loading the compound on silica resulting in transesterification. 1H NMR (400.0 MHz, DMSO-d6) δ 6.98 (dd, J=2.0, 8.2 Hz, 1H), 6.93-6.90 (m, 2H), 6.34 (s, 1H), 5.13 (t, J=3.3 Hz, 1H), 3.66 (s, 3H), 3.50-3.41 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ncccc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ncccc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 4.1 g of 5-{4-(1-methylimidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 31) and 160 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.45 g of the title compound, melting at 231-232° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.Cl[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C>ClCCl>[CH2:32]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1)[C:31]1[CH:34]=[CH:35][CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1NCCc2ccc(NCc3ccccc3)cc21
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Sodium triacetoxyborohydride (1.29 g, 6.16 mmol) was added to a stirred solution of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 3.08 mmol), 4-chlorobenzaldehyde (431 mg, 3.08 mmol) and acetic acid (183 μl, 3.08 mmol) in anhydrous dichloromethane (25 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (50% ethyl acetate in dichloromethane) to yield the title compound as a pale yellow solid (287 mg, 16%). HPLC retention time 4.09 min. Mass spectrum (ES+) m/z 287 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:16])[C:5]2([CH:19](C#N)[C:20]([O:22]C)=O)[C:17]#[N:18].C[OH:27]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:19][C:20](=[O:22])[NH:18][C:17]3=[O:27])[C:6](=[O:16])[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8]2=[CH:9][CH:10]=1
Reactant: CO
Reactant: COC(=O)CN1C(=O)C(C#N)(C(C#N)C(=O)OC)c2cc(Cl)ccc21
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)C2(CC(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
A suspension of methyl [5-chloro-3-cyano-1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetate, intermediate 46, (10.56 g, 29.19 mmol) in dry methanol (190 ml) was purged with hydrogen chloride at −78° C. for 45 minutes. The suspension was allowed to warm up to ambient temperature and further heated up to reflux for 4 hours. The solvent was removed in vacuo, the remaining solid was suspended in glacial acetic acid (300 ml) and heated up to reflux for 5 hours. Evaporation under reduced pressure gave a red-brown oil, which was redissolved in ethyl acetate (300 ml). The solution was washed with water (2×200 ml), the aqueous washes were once back-extrated with ethyl acetate (200 ml) and the organic extracts were dried (MgSO4) to give the title compound (10.87 g, quant.) as solidified foam (HPLC purity: 91%). MS (ESI+): 323.2; MS (ESI−): 321.1
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][S:11]([CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][S:21][CH:22]=[CH2:23])=[O:17])(=[O:13])=[O:12].CN(C)C=[O:27]>>[CH:10]([S:11]([CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][S:21]([CH:22]=[CH2:23])=[O:27])=[O:17])(=[O:13])=[O:12])=[CH2:9]
Reactant: C=CSCCNC(=O)CCS(=O)(=O)CCCl
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CS(=O)CCNC(=O)CCS(=O)(=O)C=C
Reaction time: 1 h

Procedure:
0.8 g Triethylamine was added to a solution of 2.0 g Intermediate 2 in 10 ml dimethylformamide. After stirring 1 hour the mixture was filtered and the filtrate evaporated. The residue was recrystallised form ethyl acetate and then from dichloromethanepetrolether. Yield 1.1 g; Mp. 93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=O)[CH3:11])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:11])=[N:9][CH:8]=2)[CH:7]=1
Reactant: CC(=O)NCc1ccc(F)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc2ccc(F)cn12
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
In a round-bottomed flask, N-(5-fluoro-pyridin-2-ylmethyl)-acetamide (653 mg, 3.88 mmol) was dissolved in toluene (19 ml) and phosphorus oxychloride (0.66 ml, 7.1 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath overnight then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-70% EtOAc) to give 255 mg (44%) of 6-fluoro-3-methyl-imidazo[1,5-a]pyridine as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.61 (d, J=5.3 Hz, 1H), 7.38-7.50 (m, 2H), 6.67 (ddd, J=9.7, 7.6, 1.9 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][CH:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28]>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: N=C(NO)N1CCCCC1
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(N5CCCCC5)no4)CS3)cc2c1

Procedure:
[(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]acetic acid prepared in Example 75 and N-hydroxypiperidinecarboxamidine were reacted according to the same procedure as Example 262 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Br)cc(OCc2ccccc2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
(3-Benzyloxy-5-bromo-phenyl)-acetic acid ethyl ester (2.50 g, 7.2 mmol) was added to a solution of 4-(trifluoromethyl)phenyl boronic acid (1.5 g, 8.0 mmol) and K2CO3 (14.4 mmol, 2 M aq.) in DME (25 mL). Nitrogen was bubbled through the reaction mixture for 10 minutes before addition of tetrakis(triphenylphosphine)palladium(0) (10% wt) and the resultant mixture was heated to 80° C. for 4 hours under inert atmosphere. The reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with sat. Na2CO3, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give (5-benzyloxy-4′trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (2.2 g) as a colourless gum in 74% yield. 1H NMR (CDCl3) δ 7.59-7.54 (m, 2H), 7.48-7.30 (m, 8H), 7.13-7.11 (m, 2H), 6.94-6.91 (m, 1H), 5.12 (s, 2H), 4.16 (q, 2H), 3.64 (s, 2H), 1.27 (t, 3H).