Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C

Procedure:
Following a procedure of P. Brookes, et al., J. Chem. Soc., 3165 (1957), 1-benzyl-4-piperidinone (44.6 g, 0.234 mol) and hydroxylamine hydrochloride (14.0 g, 0.201 mol) are added to 140 ml of dry pyridine and the resulting mixture is heated to 100° C. in an oil bath for 3 hours. The resulting solid is cooled overnight, filtered and crystallized from 1 liter of ethanol. The product is collected as colorless needles, 38.17 g, in two groups with melting point of 225°-237° C., decomposed depending upon the rate of heating.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[CH3:10][C:11]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH3:12].N1C=CN=C1.[Na+].[Cl-]>CN(C)C=O.O>[CH3:13][C:11]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1)([CH3:10])[CH3:12]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#CC1CCC(O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC1CCC(C#N)CC1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution maintained at 10° C., under nitrogen, of 11 g (87.8 mmoles) of 4-hydroxycyclohexanecarbonitrile (prepared according to Praefcke K. and Schmidt D., Z. Naturforsch (1980) 35b, 1451-4) in 50 ml of N,N-dimethylformamide, there is added dropwise 26.6 g (96.8 mmoles) of 1,1-dimethylethyldiphenylsilyl chloride, then by portions, 13.1 g (190 mmoles) of imidazole. Stirring is continued at room temperature during 3 days, before pouring the reaction mixture in water saturated with NaCl. The product is extracted with a hexane-ether (1:1) mixture. The organic phase is washed with a N HCl solution, then with water saturated with NaCl, before drying and concentration. The residue is purified by chromatography on a column of silica in dichloromethane to give 26.5 g (yield=85.9%) of a colorless thick oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1N2CN3CN(C2)CN1C3.Cl.[OH2:23]>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:3]([CH:2]=[O:23])[O:4][CH:5]=1
Reactant: FC(F)(F)c1coc(CBr)c1
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cc(C(F)(F)F)co1

Procedure:
2.95 g of the product of Stage E, 9 ml of water and 3.6 g of hexamethylenetetramine were refluxed for 1 hour. 9 ml of concentrated hydrochloric acid were added. Reflux was maintained for an additional 1 hour and the mixture was allowed to return to room temperature, diluted with water and extracted with methylene chloride. The extract was washed with water and dried and the solvent was evaporated to obtain 1.9 g of the expected product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]1[O:21][C@H:20]([CH2:22]O)[C@@H:18]([OH:19])[CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:22][C@H:20]1[O:21][CH2:16][CH2:17][C@@H:18]1[OH:19])(=[O:5])=[O:4]
Reactant: OC[C@H]1OCC[C@@H]1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OC[C@H]1OCC[C@@H]1O)C(F)(F)F

Procedure:
To a -20° C. solution, under argon, of 8.4 ml of trifluoromethanesulfonic anhydride in 75 ml of methylene chloride is added, dropwise, a solution of 5.9 g of product from Example 268 and 4.05 ml of pyridine in 25 ml of methylene chloride. The temperature is maintained below -10° C. during the addition. The progress of the reaction is monitored by tlc. The reaction is filtered and the filtrate concentrated in vacuo to an oily residue. The residue is purified by chromatography (silica gel: 50% ethyl acetate/hexane) to give 7.03 g of the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][N:9]=1.Br[CH2:20][CH2:21][O:22][CH3:23]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:20][CH2:21][O:22][CH3:23])[N:9]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCn1nc(Cl)c2ccccc2c1=O
Temperature: 50 °C
Yield: 70.6 %

Procedure:
Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of 4-chlorophthalazin-1(2H)-one (300 mg, 1.661 mmol) and 1-bromo-2-methoxyethane (462 mg, 3.32 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product. The crude material was purified via silica gel chromatography (90 g column, 5-45% EtOAc:Hex) to give the desired product 4-chloro-2-(2-methoxyethyl)phthalazin-1(2H)-one (280 mg, 70.6% yield) as a yellow solid. MS: MS m/z 223.15(M++1).
Reaction SMILES: [C:1]([C:4]1[C:10]([F:11])=[C:9](I)[C:7]([NH2:8])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2].[C:14]([Cu])#[N:15].O>CN(C=O)C>[C:1]([C:4]1[C:10]([F:11])=[C:9]([C:14]#[N:15])[C:7]([NH2:8])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(N)c(I)c1F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)c(N)c(C#N)c1F
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
In 2.5 mL of DMF, 0.5 g of 4-acetyl-2-chloro-5-fluoro-6-iodoaniline and 0.15 g of CuCN are heated at 130° C. for 4 hours. The mixture is cooled and 20 mL of H2O is added and stirring is continued for 0.5 hour. The precipitate is collected, washed with water, boiled in 50 mL of MeOH for 10 minutes and filtered. The MeOH filtrate is concentrated to give 0.32 g of the title compound, m.p. 180°-182° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C@H:17]4[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)=[C:13]([F:30])[CH:12]=3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.CCOC(C)=O>C(#N)C.O>[CH:1]1([C:4]2[CH:5]=[N:6][C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[C:13]([F:30])[CH:12]=3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(C4CC4)cn3)cc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1cc(Nc2ncc(C3CC3)cn2)ccc1[C@@H]1CNCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2-fluorophenyl)morpholine-4-carboxylate (180 mg) in acetonitrile (2 ml) and water (6 ml) was added trifluoroacetic acid (335 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 16 h. The reaction mixture was then cooled to room temperature and poured into EtOAc and washed with 4 M aq. NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel; gradient: CH2Cl2/MeOH/aq. NH3) to afford (R)-5-cyclopropyl-N-(3-fluoro-4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (57 mg, xx %) as an off-white solid. MS (ISP): 315.2 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][OH:6])=[O:4].CO.[CH3:9][C:10]([CH:12]=O)=O.[OH-].[Na+]>O>[CH3:12][C:10]1[CH:9]=[N+:5]([O-:6])[C:3]([OH:4])=[CH:2][N:1]=1
Reactant: CC(=O)C=O
Reactant: NCC(=O)NO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c[n+]([O-])c(O)cn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
100 mmol (9 g) glycine hydroxamic acid were cooled to −25° C. in 200 ml water and methanol each, 100 mmol (15.4 ml 40% solution) methylglyoxal were added dropwise and subsequently the pH was adjusted to approximately pH 11 with 10 ml 30% NaOH. Heating up to 5° C. was carried out in 2 h and concentrated under vacuum to half of the solvent volume. A pH 3 was adjusted with 20% HCl, precipitated solid was filtered off and dried. 7.28 g (52% yield) of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:8][C:9]1[C:10]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 103.8 %

Procedure:
N,N,N′-Trimethylethylenediamine (0.188 mL, 1.45 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 500 mg, 1.21 mmol) and DIPEA (0.250 mL, 1.45 mmol) in DMA (5 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated in vacuo to give the title compound (624 mg, 104%) as an orange solid, which was used without further purification; 1H NMR: 2.17 (6H, d), 2.89 (3H, d), 3.87-3.93 (3H, m), 6.84 (1H, s), 7.14 (1H, td), 7.31-7.38 (1H, m), 8.15 (1H, s), 8.39 (1H, d), 8.44 (1H, d), 8.69 (1H, s), 8.85 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 497.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:24][CH:25]([F:27])[F:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH3:28][N:29](C=O)C>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[F:26][CH:25]([F:27])[O:24][C:4]1[CH:3]=[C:2]([C:28]#[N:29])[C:10]2[C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[CH2:7][C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: O=C1c2c(I)cc(OC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: N#Cc1cc(OC(F)F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 150 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A mixture of 7-iodo-2-(4-trifluoromethoxy-benzyl)-5-difluoromethoxy-2,3-dihydro-isoindolone (0.125 g, 0.25 mmol), PdCl2(dppf)2 (0.009 g, 0.012 mmol), zinc (0.002 g, 0.03 mmol), zinc cyanide (0.035 g, 0.3 mmol) and DMF (3 mL) was stirred at 150° C. for 1 h. The reaction mixture was cooled to room temperature, dissolved in ethyl acetate (50 mL) and washed with water. Combined organic layer was dried (MgSO4), filtered and concentrated. Silica gel column chromatography using 10:1 hexane-ethyl acetate afforded 6-difluoromethoxy-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.02 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.80 (s, 2H), 6.60 (t, 1H), 6.87 (s, 1H), 7.21 (d, 2H), 7.37 (d, 2H), 7.42 (s, 1H), 7.53 (s, 1H). GC-MS: m/z 398 (M)+, 313 (M−85)+
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].Cl>CN(C)C=O>[O:16]=[C:14]1[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:21])[N:15]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:1]([OH:10])=[O:2]
Reactant: O=C1OCc2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
To a solution of 3H-isobenzofuran-1-one (18 g, 134 mmol) in dry N,N-dimethylformamide (110 mL) was added potassium phthalimide (27 g, 145 mmol). The mixture was stirred at reflux for 6 hours then cooled to 0° C. and treated with 1N hydrochloric acid (180 mL). The yellow solid thus formed was filtered, washed with water, with ethanol and dried in oven. Crystallization with ethanol afforded the title compound as white solid (27 g).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][N:24]4[CH:27]=[C:28]([CH2:30][NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[N:29]=[C:23]4[CH:22]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][N:24]3[CH:27]=[C:28]([CH2:30][NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[N:29]=[C:23]3[CH:22]=2)=[CH:17][CH:16]=1)[OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccn4cc(CNS(C)(=O)=O)nc4c3)cc2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@H](N)CF)cc3)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.2 %

Procedure:
To a stirred solution of (4S,5R)-4-Fluoromethyl-5-{4-[2-(methanesulfonylamino-methyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (75 mg, 0.14 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid (0.3 mL) drop wise at 0° C. then stirred at room temperature for 2 hours. The reaction mixture is concentrated and stripped with CH2Cl2 to afford title compound (88 mg, crude) which is used as is in the next step. LC-MS (m/z): [M+H]=393.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:13]=[C:12]([CH3:29])[N:11]=2)[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:29][C:12]1[N:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=2)[C:1]#[N:2])[CH:15]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=1
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)cc(Nc2cc(C#N)ccn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2CCNCC2)cc(Nc2cc(C#N)ccn2)n1
Yield: 138.8 %

Procedure:
To a solution of tert-butyl 4-(2-((4-cyanopyridin-2-yl)amino)-6-methylpyridin-4-yl)piperidine-1-carboxylate (216 mg, 0.550 mmol) in CH2Cl2 (2.2 mL) was added trifluoroacetic acid (1.1 mL) and stirring was maintained for 2 hr. Concentrated to dryness afforded 2-((6-methyl-4-(piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile (1×TFA salt by 1H NMR) as a yellow solid (224 mg, >99%); 1H NMR (400 MHz, DMSO) δ 10.47 (br s, 1H), 8.65 (br s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.38 (br s, 1H), 8.07 (s, 1H), 7.36 (s, 1H), 7.32 (d, J=5.1 Hz, 1H), 6.80 (s, 1H), 3.40 (m, 2H), 3.02 (m, 2H), 2.93 (m, 1H), 2.47 (s, 3H), 1.96 (m, 2H), 1.76 (m, 2H); ESI-LRMS m/z [M+1]+=294.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:30]2[CH:31]=[C:32]([C:36]3[O:41]C(C)(C)[O:39][C:38](=O)[CH:37]=3)[CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:38](=[O:39])[CH2:37][C:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:31]=1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as an orange oil (207 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[C:25]2[CH2:29][CH2:28][CH2:27][CH:26]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:25]1([C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([NH:16][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[CH2:7]2)=[O:30])[CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1C1=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
The mixture of 2-(2-cyclopent-1-enyl-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (151) (190 mg, 0.47 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (152) as white solid (182 mg, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=[CH:37][N:36](C(N2C=NC=C2)=O)[CH:35]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:36]([CH3:37])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 65 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.2 g, 0.1.3 mmol) and dimethylamine (2N in THF, 0.7 ml, 1.4 mmol) in THF (10 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide (0.35 g, 67% yield): mp, 163-165° C.; 1HNMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.90 (s, 3H, NCH3), 2.98 (dd, J=5, 15 Hz, 1H, CH2), 3.05 (s, 4H, NCH3+CH2), 3.91 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 5.81-5.87 (m, 1H, CHN), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 7.11-7.17 (m, 3H, Ar), 7.45 (d, J=7.0 Hz, 1H, Ar), 7.62 (t, J=8.0 Hz, 1H, Ar), 8.73 (d, J=8.8 Hz, 1H, Ar), 9.53 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 14.5, 24.8, 34.8, 35.5, 37.1, 51.3, 64.7, 111.9, 113.8, 115.4, 116.1, 117.9, 120.1, 120.2, 122.7, 124.7, 131.3, 135.8, 137.5, 138.1, 150.6, 168.1, 169.2, 169.3, 170.0; Anal Calcd for C24H25F2N3O6: C, 58.89; H, 5.15; N, 8.58. Found: C, 58.53; H, 4.78; N, 8.51.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+:26]>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([O-:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1.[Na+:26]
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
68 g of powdered 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are suspended in 300 ml of water. A solution of 7.7 g of sodium hydroxide in 30 ml of water is added and the mixture is stirred at room temperature for 30 minutes, whereupon most of the carboxylic acid dissolves. The undissolved product is filtered off and rinsed with water and the filtrate is concentrated in vacuo. The yellowish crystalline residue is dried in vacuo at 100° C. Yield: 73.4 g of the sodium salt. Melting point 325° C.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([C:19]2[NH:20][N:21]=[C:22]([Cl:24])[N:23]=2)=[O:18])[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.[CH3:32][O:33][CH2:34][CH2:35]O>O1CCOCC1>[CH3:32][O:33][CH2:34][CH2:35][O:12][C:11](=[O:13])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:19]1[NH:20][N:21]=[C:22]([Cl:24])[N:23]=1)=[O:18])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:2][CH:3]=1
Reactant: COCCO
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1nc(Cl)n[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: COCCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nc(Cl)n[nH]1
Temperature: 80 °C
Yield: 95 %

Procedure:
(2S,4S)-5-Biphenyl-4-yl-4-[(5-chloro-2H-[1,2,4]-triazole-3-carbonyl)-amino]-2-hydroxymethyl-pentanoic acid (10 mg, 23 μmol, 1.0 eq.) was dissolved in 2-methoxyethanol (0.8 mL) followed by the addition of 4 M of HCl in dioxane (117 μL). The resulting mixture was heated and maintained at 80° C. for about 3.5 hours. The mixture was concentrated and purified by preparative HPLC to yield the title compound (7.2 mg, 95% purity). MS m/z [M+H]+ calc'd for C24H27ClN4O5, 487.17. found 487.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[S:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])(=[O:23])[NH2:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:29][C:28]3[CH:30]=[CH:31][C:25]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:26][CH:27]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 77 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro- 1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-sulfamoylaniline (87 mg, 0.506 mmol) to give 190 mg of the title compound (77%): mp 263°~267° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.21 (s, 1H), 8.20 (bs, 1H), 7.81 (d, 1H, J=8.0 Hz), 7.63 (d, 1H, J=8.0 Hz), 7.24 (bs, 2H), 7.19 (bs, 2H), 5.17~5.28 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.55~2.70 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:24]2[C:33]3[C:32](=[O:34])[CH2:31][C@@H:30]([CH2:35][CH2:36][CH3:37])[CH2:29][C:28]=3[NH:27][C:26]([CH3:38])=[C:25]2[C:39]#[N:40])[CH:5]=[C:6]([O:21][CH2:22][CH3:23])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[N+:18]([O-])=O.C(O)(=O)C>C1COCC1.[Zn]>[NH2:18][C:11]1[CH:12]=[C:13]([F:17])[C:14]([F:16])=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:6]([O:21][CH2:22][CH3:23])=[CH:5][C:4]([C@H:24]2[C:33]3[C:32](=[O:34])[CH2:31][C@@H:30]([CH2:35][CH2:36][CH3:37])[CH2:29][C:28]=3[NH:27][C:26]([CH3:38])=[C:25]2[C:39]#[N:40])=[CH:3][C:2]=1[Br:1]
Reactant: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(OCc2cc(F)c(F)cc2[N+](=O)[O-])c(OCC)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(OCc2cc(F)c(F)cc2N)c(OCC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (4R,7S)-4-[3-Bromo-4-(4,5-difluoro-2-nitro-benzyloxy)-5-ethoxy-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (Example 72 g, 10.6 g) and acetic acid (19.6 ml) in THF (400 ml) was cooled to 0° C. Zinc dust (27.6 g) was added in portions under vigorous stirring. The mixture was stirred for 2 h at 0° C. and then filtered. The solids were washed with dichloromethane and the combined filtrates were washed with sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.