Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[C:7]([CH2:10][OH:11])[N:6]=[CH:5][C:4]=2[O:3][CH2:2]1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[S:1]1[C:9]2[CH:8]=[C:7]([CH:10]=[O:11])[N:6]=[CH:5][C:4]=2[O:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCS2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)OCS2
Yield: 62.3 %

Procedure:
[1,3]oxathiolo[5,4-c]pyridine-6-methanol (0.92 g, 5.44 mmole) was treated with manganese (IV) oxide (3.83 g, 44 mmole) at RT in DCM (50 mL) to afford the aldehyde (567 mg, 62%) as a solid; MS (+ve ion electrospray) m/z 168 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[CH:28][C:27]([N:30]3[C@@H:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][O:32][C:31]3=[O:38])=[N:26][C:25]=12.FC1C=C(C2N(COCC[Si](C)(C)C)N=CN=2)C=CC=1C1C=NN2C=CC(N3[C@@H](C(C)C)COC3=O)=NC=12>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[CH:28][C:27]([N:30]3[C@@H:34]([CH:35]([CH3:36])[CH3:37])[CH2:33][O:32][C:31]3=[O:38])=[N:26][C:25]=12
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3F)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)cc3F)c2n1
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3F)c2n1
Yield: 48 %

Procedure:
(4S)-3-(3-(2-Fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.186 g, 48%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (4S)-3-(3-(2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one and (4S)-3-(3-(2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.507 g, 0.943 mmol), to produce a yellow solid. LCMS (APCI+) m/z 408.6 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 14.27 (broad s, 1H), 9.16 (d, J=7.8 Hz, 1H), 8.57-8.52 (m, 3H), 7.96-7.85 (m, 3H), 4.97-4.93 (m, 1H), 4.52-4.48 (m, 2H), 2.78-2.71 (m, 1H), 1.05 (d, J=7.1 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]([CH3:36])[C@@H:8]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)[C:9]([NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:5]([O:6][C@@H:7]([CH3:36])[C@@H:8]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:33])([F:35])[F:34])[CH:25]=1)[C:9]1[O:10][C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)=[N:12][N:11]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:38])[CH3:37]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of N′-((2R,3S)-3-(tert-butyldimethyl-silyloxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (1.05 g, 1.92 mmol) in CH2Cl2 (40 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (1.01 g, 3.85 mmol), iodine (980 mg, 3.85 mmol) and Et3N (1.1 mL, 7.70 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min and quenched with sat. aq. sodium thiosulfate (200 mL). The solution was extracted with CH2Cl2 (150 mL). The organic extract was washed with sat. aq. sodium thiosulfate (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a light brown solid, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes) to provide the title compound as a light yellow oil (900 mg, 89%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.22 (dm, J=8.8 Hz, 2H), 8.02 (dm, J=8.8 Hz, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.17 (dd, J=2.3, 8.6 Hz, 1H), 6.75 (d, J=9.2 Hz, 1H), 5.36 (dd, J=3.3, 9.4 Hz, 1H), 4.73 (dq, J=3.1, 6.1 Hz, 1H), 1.45 (d, J=6.3 Hz, 3H), 0.78 (s, 9H), 0.07 (s, 3H), −0.13 (s, 3H
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([O:21]CC)=[O:20])[CH:14]=1.O>Cl.C(O)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1
Reactant: CCOC(=O)c1cc(CN2C(=O)c3ccccc3C2=O)n(C)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(C(=O)O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of ethyl 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylate (8.13 g, 25.9 mmol) in hydrochloric acid (33 mL of 1 M) and acetic acid (33 mL) was heated at reflux intermittently for six hours and allowed to cool to room temperature; a precipitate formed. Water was added, and the solid was isolated by filtration, washed with water, and dried on the vacuum filter funnel for two days to provide 3.79 g of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylic acid as a brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:31][CH3:32])=[C:20](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]>CO.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:31][CH3:32])=[C:20]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)/C=C/c1cccc(-c2cnc(-c3ccc(OC(C)C)c(C#N)c3)s2)c1CC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(-c2cnc(-c3ccc(OC(C)C)c(C#N)c3)s2)c1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (2E)-3-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]-2-propenoate (D113) (1 g, 2.239 mmol) in Methanol (20 mL) was added Pd/C. The mixture was stirred at room temperature for 1 h. After filtration, the solvent was evaporated in vacuo to afford ethyl 3-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]propanoate (D114) (1 g). MS (ES): C26H28N2O3S requires 448.2. found 449.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.P(Br)(Br)[Br:22].CCOC(C)=O>C(Cl)Cl>[Br:22][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(Cc2ccc(OC(F)(F)F)cc2)cc1
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(Cc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A solution of alcohol 95 (0.18 g, 0.64 mmol) in CH2Cl2 (4 mL) was treated with PBr3 (115 μL 1.2 mmol). The reaction mixture was stirred at room temperature for 2 h, then EtOAc (150 mL) was added. The organic layer was washed with water (100 mL), the aqueous layer was re-extracted with EtOAc (100 mL), and the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with petroleum ether/EtOAc (9:1), to give 1-(bromomethyl)-4-[4-(trifluoromethoxy)benzyl]benzene (96) (0.14 g, 64%) as a white solid: mp (EtOAc/hexane) 33-35° C.; 1H NMR (CDCl3) δ 7.34-7.30 (m, 2H), 7.20-7.10 (m, 6H), 4.48 (s, 2H), 3.97 (s, 2H); HREIMS calcd for C15H1279BrF3O m/z (M+) 344.0024, found 344.0033; calcd for C15H1281BrF3O m/z (M+) 346.0003, found 346.0011.
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5].F[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([O:13][C:11]2[CH:10]=[CH:9][C:8]([F:14])=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])[C:2]=3[Cl:1])[CH:12]=2)=[C:26]([N+:32]([O-:34])=[O:33])[CH:27]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(O)ccc2F)c1Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cc3[N+](=O)[O-])ccc2F)c1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)-N-(2-fluoro-5-hydroxyphenyl)benzamide (2.0 g, 6.01 mmol) and 4-fluoro-3-nitroaniline (940 mg, 6.02 mmol) in N,N-dimethylformamide (12 mL) was added cesium carbonate (2.94 g, 9.02 mmol), and the mixture was stirred at 80° C. for 16 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off and washed with ethyl acetate. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (120 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (120 mL). The aqueous layer was extracted with ethyl acetate (120 mL). The combined organic layer was washed with saturated brine (120 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=20/80→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (1.66 g, 59%) as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.[F:21][C:22]1[C:27]2[B:28]([OH:31])[O:29][CH2:30][C:26]=2[CH:25]=[C:24]([OH:32])[CH:23]=1>>[F:21][C:22]1[C:27]2[B:28]([OH:31])[O:29][CH2:30][C:26]=2[CH:25]=[C:24]([O:32][C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=2)[CH:23]=1
Reactant: OB1OCc2cc(O)cc(F)c21
Reactant: CC(C)OCCOc1nc(Cl)cc(C(F)(F)F)c1C#N
Product: CC(C)OCCOc1nc(Oc2cc(F)c3c(c2)COB3O)cc(C(F)(F)F)c1C#N

Procedure:
This compound was prepared from 6-chloro-2-(2-isopropoxyethoxy)-4-(trifluoromethyl)nicotinonitrile and 7-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.06 (d, J=6 Hz, 6H), 3.52-3.55 (m, 1H), 3.59-3.61 (t, J=4.8 Hz, 2H), 4.26-4.28 (t, J=4.8 Hz, 2H), 5.07 (s, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.38 (s, 1H), 9.39 (s, 1H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:8][CH2:9][CH2:10]O>>[Cl:8][CH2:9][CH2:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCl
Agent: Cl
Product: ClCCC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dihydropyran (85 g, 1.01 moles) and 0.2 mL of concentrated HCl were added to a 500 mL 3-necked round-bottomed flask equipped with a magnetic stirrer, a thermocouple, a reflux condenser and a nitrogen bubbler. The mixture was cooled to 0° C., and then 2-chloro-ethan-1-ol (80.5 g, 1.01 moles) was added dropwise at a rate sufficient to maintain the temperature below 10° C. After the addition was complete (about 2 hr.), the mixture was allowed to warm to room temperature and stirred for 1 hr. The clear yellow solution was distilled under vacuum.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([F:9])([F:8])[CH2:6][NH2:7].C(N(CC)C(C)C)(C)C.Cl[C:20]([CH3:35])([CH3:34])[CH:21]([N:32]=[O:33])[CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[N+:29]([O-:31])=[O:30]>C(#N)C>[NH2:3][CH2:4][C:5]([F:9])([F:8])[CH2:6][NH:7][C:20]([CH3:35])([CH3:34])[C:21](=[N:32][OH:33])[CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[N+:29]([O-:31])=[O:30]
Reactant: CC(C)(Cl)C(CCn1ccnc1[N+](=O)[O-])N=O
Reactant: NCC(F)(F)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(NCC(F)(F)CN)C(CCn1ccnc1[N+](=O)[O-])=NO
Reaction time: 0.5 h

Procedure:
To a mixture of 1,3-diamino-2,2-difluoropropane dihydrochloride (title A diamine) (1.10 g, 6.01 mmol) and N,N-diisopropylethylamine (2.72 g, 21.04 mmol) in acetonitrile (10 mL) at 40° C. was added 4-chloro-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-nitrosopentane (Example 3, step (B)) (0.50 g, 1.90 mmol) in small portions with stirring under nitrogen atmosphere. After the addition, the stirring was continued for an additional 30 minutes and the solvent was removed on a rotary evaporator. The paste obtained was treated with silica gel and the silica gel powder impregnated with the compound was loaded onto a silica gel column and eluted with CH3OH—CH2Cl2 (5:95). The fractions containing compound were collected and evaporated to give the title product as a light yellow colored solid. Yield: 0.42 g (66%), mp. 112-114° C.; 1H NMR (CDCl3) d 1.19 [s, 6H, C(CH3)2], 2.88 [m, 4H, C(═N)CH2 & NHCH2], 3.71 (t, 3H, JHF=13.19 Hz, CH2NH2), 4.72 (t, 2H, J=7.26, CH2CH2N), 7.11 & 7.26 (2s, 2H, nitroimid-H) and 10.79 (s, 1H, NOH). MS m/e 335 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[N:1]1([C:39]([C:38]2[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=2[CH2:36][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3([CH2:28][O:27][C:26]4[CH:29]=[C:30]5[C:34](=[CH:35][C:25]3=4)[CH2:33][CH2:32][O:31]5)[C:16]2=[O:15])=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21)N1CCCCC1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using piperidine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 1′-[2-(piperidin-1-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (88%) as a colorless solid: mp 168-170° C.; 1H NMR (300 MHz, DMSO-d6) δ7.42-7.10 (m, 6H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.65-6.44 (br, 1H), 6.39 (s, 1H), 4.90-4.64 (m, 4H), 4.54-4.39 (m, 2H), 3.77-3.42 (br, 2H), 3.21-3.07 (m, 2H), 2.94 (t, J=8.2, 1.5 Hz, 1H), 1.66-1.33 (m, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 167.9, 161.6, 161.2, 142.7, 136.4, 132.6, 129.6, 129.1, 128.1, 126.6, 124.1, 123.5, 120.9, 120.3, 109.8, 92.9, 80.5, 72.6, 65.4, 57.4, 47.9, 42.3, 41.4, 28.8, 26.4, 25.7, 24.4, 15.6; MS (ES+) m/z 481.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:18](=[O:19])[C:7]2[CH:8]=[N:9][C:10]3[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5](CC2C=CC(OC)=CC=2)[C:4]1=[O:29])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:18](=[O:19])[C:7]2[CH:8]=[N:9][C:10]3[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5][C:4]1=[O:29])[CH3:2]
Reactant: CCn1c(=O)c2cnc3c(OC)cccc3c2n(Cc2ccc(OC)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(=O)[nH]c2c(cnc3c(OC)cccc32)c1=O
Yield: 83.8 %

Procedure:
3-Ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 3-ethyl-7-methoxy-1-(4-methoxy-benzyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (50 mg, 0.11 mmol) via treatment of trifluoroacetic acid in DCM (1 mL). LCMS: m/z 272 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]3[CH:11]=[CH:10][C:5]4[NH:6][C:7](=[O:9])[S:8][C:4]=4[CH:3]=3)[CH2:17][CH2:18]2)=[CH:24][CH:25]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)sc2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 6-amino-3H-benzothiazol-2-one and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 149-155° C. (diethylether)
Reaction SMILES: [H-].[Na+].C1(C)C(S)=CC=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33]C)[CH2:16][O:17][CH2:18][C:19]([N:27]([CH3:29])[CH3:28])([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:20][CH3:21].Cl>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C>[OH:33][C:32]1[C:31]([O:35][CH3:36])=[CH:30][C:15]([CH2:16][O:17][CH2:18][C:19]([N:27]([CH3:28])[CH3:29])([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:20][CH3:21])=[CH:14][C:13]=1[O:12][CH3:11]
Reactant: CCC(COCc1cc(OC)c(OC)c(OC)c1)(c1cccs1)N(C)C
Agent: Cc1ccccc1S
Agent: Cl
Agent: [H-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCC(COCc1cc(OC)c(O)c(OC)c1)(c1cccs1)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Sodium hydride (63.5% oil dispersion, 0.66 g) is added to a solution of thiocresol (2.2 g) in toluene (40 ml) under ice-cooling and the mixture is stirred at room temperature for 30 minutes. A solution of 1-(3,4,5-trimethoxybenzyloxymethyl)-1-(2-thienyl)-N,N-dimethylpropylamine (2.2 g) in toluene (20 ml) is added to the mixture under ice-cooling and hexamethylphosphoric triamide (3 ml) is added thereto. The mixture is refluxed in nitrogen atmosphere for 5 hours. After cooling, 10% hydrochloric acid is added to the mixture and the aqueous layer is collected therefrom. The aqueous layer is washed with ether and adjusted to pH 8 with sodium bicarbonate and then extracted with ether. The extract is dried and concentrated under reduced pressure to remove solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:ethanol=100:1). The resulting product is recrystallized from a mixture of ethyl acetate and n-hexane, whereby 1-(4-hydroxy-3,5- dimethoxybenzyloxymethyl)-1-(2-thienyl)-N,N-dimethylpropylamine (2 g) is obtained as colorless pillars.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:30]=[N:29]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+].Cl>C1COCC1>[CH3:26][C:23]1[C:22]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:30]=[N:29]2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(-c5ccccc5)cn4)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Cn1cc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-pyrazol-1-ylmethyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.051 g, 0.101 mmol) was dissolved in THF (1 mL) then MeOH (0.5 mL) and NaOH (3N aq., 0.5 mL) was added and the reaction stirred at room temperature. After 8 hours the reaction was acidified with 1N aq. HCl then submitted to standard workup procedures to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7](=[O:19])[CH2:8][C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH2:27]([O:29][C:30](=[O:33])[CH2:31]Cl)[CH3:28].[H-].[Na+]>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:33])[CH2:31][CH:8]1[C:7](=[O:19])[N:6]([CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]1=[O:18])[CH3:28]
Reactant: CC(C)(C)CN1C(=O)CC(=O)N(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1C(=O)N(CC(C)(C)C)c2ccc(Cl)cc2N(c2ccccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-5-(2-chlorophenyl)-2,4-dioxo-1-neopentyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.3 g) and chloroacetic acid ethyl ester (0.11 ml) in dimethylformamide (2 ml) was added sodium hydride (60% oil, 40 mg), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture were further added sodium hydride (40 mg×3) and chloroacetic acid ethyl ester (0.11 ml), which was stirred for 3 hours. To the mixture was then added acetic acid ethyl ester (50 ml), which was washed with water. The solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=4:1 v/v as an eluent) to give 0.25 g of colorless crystals, m.p. 152°-153° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23].Cl.C([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])C.C(N(CC)CC)C.O.N>C(#N)C>[C:28]([CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23])[CH3:31])([OH:32])=[O:27]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCBr
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCN(C)CC(=O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone (1.9 g) was dissolved in 50 ml of acetonitrile, then 2 g of N-methylglycine ethyl ester hydrochloride and 5 ml of triethylamine were added thereto, and stirred at 80° C. for 4 hours. The reaction mixture was extracted with ethyl acetate, the extract was washed with an aqueous solution saturated with sodium bicarbonate, next with water, then concentrated under reduced pressure. Thus obtained oily residual product was subjected to purification by means of a silica gel column chromatography, then dissolved in 10 ml of methanol and 10 ml of 1N-sodium hydroxide aqueous solution, and stirred at 70° C. for 1 hour. After the reaction mixture was cooled, the mixture was acidified by adding hydrochloric acid, further the acidified reaction mixture was made basic by adding 25% ammonia water. This reaction mixture was concentrated under reduced pressure to dryness, thus obtained solid residual product was subjected to extraction by means of Soxhlet's extractor with chloroform as the solvent. The chloroform extract was concentrated under reduced pressure to dryness, and recrystallized from acetone, there was obtained 1-[4-(N-carboxymethyl-N-methyl-amino)butyl ]-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.