Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[N:5]([CH2:6][C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4](=[O:14])[CH2:3]1.C(N(CC)CC)C>C(OCC)C.C(Cl)Cl.C(OCC)(=O)C>[C:9](/[CH:8]=[C:7]1/[CH2:6][N:5]2[CH:2]([O:13]/1)[CH2:3][C:4]2=[O:14])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)CN1C(=O)CC1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C1/CN2C(=O)CC2O1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38.2 %

Procedure:
Methyl 4-(4-chloro-2-oxoazetidin-1-yl)-3-oxobutyrate (1.1 g, 5 mmole) was dissolved in a mixture of diethyl ether (20 ml) and methylene dichloride (30 ml). The solution was stirred at -30° C. with exclusion of moisture while triethylamine (510 mg, 5 mmole) in diethyl ether (5 ml) was added dropwise over 3 minutes. The mixture was then warmed to 0° C. and stirred for a further 40 minutes. The mixture was diluted with ethyl acetate (100 ml) and the solution was washed twice with 5% sodium chloride solution. The solution was dried (magnesium sulphate) and the solvent was evaporated to yield a yellow gum (350 mg). The gum was chromatographed on silica gel (30 g) using ethyl acetate/petroleum ether to give, in order of elution, (Z)-carbmethoxychloromethylene-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (5 mg), (E)-carbmethoxymethylene-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (73 mg) and (Z)-carbmethoxymethylene-4-oxa- 1-azabicyclo[3.2.0]heptan-7-one (65 mg). The latter compound was obtained as colourless prisms, m.p. 168°-169° C., from ethyl acetate/petroleum ether (b.p. 60°-80° C.). (Found: M+, 183.05334. C8H9NO4 requires 183.05315).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([OH:21])[N:16]=3)[CH2:11][CH:10]=2)[O:3]1.Cl[CH2:24][C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:22])([CH3:1])[O:3][B:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:24][C:25]4[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[C:17](=[O:21])[N:16]=3)[CH2:11][CH:10]=2)[O:5]1
Reactant: FC(F)(F)c1ccc(CCl)s1
Reactant: CC1(C)OB(C2=CCN(c3ncnc(O)n3)CC2)OC1(C)C
Product: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(C(F)(F)F)s4)c(=O)n3)CC2)OC1(C)C
Yield: 46 %

Procedure:
4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2-ol (3.32 g, 10.9 mmol) synthesized in Reference Synthesis Example 345 and 2-(chloromethyl)-5-(trifluoromethyl)thiophene were used to obtain the title compound (2.36 g, yield 46%) by synthesis in a similar manner to Reference Synthesis Example 16.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Product: Cc1cccc([N+](=O)[O-])c1NCCN1CCOCC1
Yield: 60.3 %

Procedure:
A solution of 2-chloro-3-nitrotoluene (180 mg, 1.0 mmol), 4-(2-aminoethyl)morpholine (0.54 mL, 4.1 mmol) and triethylamine (0.43 mL, 3.1 mmol) was heated to 180° C. by microwave for 20 min. The resultant mixture was purified by column chromatography on silica gel eluting with hexane/ethyl acetate(8/1-3/1) to afford 160 mg (59%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:5]2[C:6]([C:16]([O:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(OCC)(=O)C.Cl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:5]=3[C:6]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC(C)C)cc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Methyl 6-amino-2-(4-fluorophenyl)-5-isopropoxybenzofuran-3-carboxylate (0.6 g, 1.75 mmol) was dissolved in dichloromethane. Pyridine (0.71 mL, 8.74 mmol) and methanesulfonyl chloride (0.27 mL, 3.5 mmol) were added and the resulting yellow orange solution was stirred at room temperature 15 hours. The solvent was removed in vacuo leaving an oily residue. The oil was redissolved in 100 mL ethyl acetate and 25 mL 10% aqueous HCl. The layers were separated and the organic layer was washed with 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride, dried over anhydrous sodium sulfate(s), filtered and the solvent was removed in vacuo leaving an off-white solid, 0.65 g, 88%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C@@H:20]2[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@H:31]([O:32][C@H:33]3[O:50][C@H:49]([CH2:51][O:52][C:53](=[O:55])[CH3:54])[C@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:63][O:64][C:65](=[O:67])[CH3:66])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[OH-].[Na+]>C[O-].[Na+].O.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C@@H:20]2[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@H:31]([O:32][C@H:33]3[O:50][C@H:49]([CH2:51][O:52][C:53](=[O:55])[CH3:54])[C@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:63][O:64][C:65](=[O:67])[CH3:66])[O:11][C@H:6]1[O:7][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](O[C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]3COC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@@H]2O[C@H](COC(C)=O)[C@H](O[C@H]3O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 63 %

Procedure:
A solution of 59 (0.52 g, 0.5 mmol) in methanolic sodium methoxide (0.007M, 40 ml) was left at room temperature for 2 h and sodium hydroxide (95 mg) in water (2 ml) was added. The mixture was hydrogenated (atm. pressure, Pd/C, 10%, 100 mg) for 100 min, filtered, neutralized with M hydrochloric acid and the solvent was removed. The residue was acetylated (acetic anhydride-pyridine 1:1, 100 ml) for 17 h at room temperature and then co-concentrated with toluene. The residue wa partitioned between dichloromethane (100 ml) and water (25 ml) and the organic phase was dried (Na2SO4) and concentrated. Column (5×18 cm) chromatography (SiO2, ethyl acetate:isooctane 2:1) gave amorphous 67 (300 mg, 62%) with [α]D21 +41° (c 1.0 chloroform). 1H-NMR (CDCl3, Me4Si) δ 5.91 (d, 1H, J=3 Hz, H4"), 5.40 (dd, 1H, J=11 and 3 Hz, H3"), 5.21 (t, 1H, J=9 Hz, H3), 5.18 (dd, 1H, J=11 and 3.5 Hz, H2"), 5.11 (dd, 1H, J=11 and 8 Hz, H2'), 4.99 (d, 1H, J=3.5 Hz, H1"), 4.88 (dd, 1H, J=9 and 8 Hz, H2), 4.73 (dd, 1H, J=11 and 2.5 Hz, H3'), 4.56-4.38 (5H, inter alia H1 and H1'), 4.23-4.03 (4H), 4.02 (d, 1H, J=2.5 Hz, H4'), 3.98-3.70 (3H), 3.69-3.46 (2H), 2.14-1.98 (MeCO), 1.19 (t, 3H, J=7 Hz, CH3--CH2). 13C-NMR (CDCl3, Me4Si) δ 170.4, 170.3 (4C), 169.9, 169.6, 169.5, 169.4, 168.7, 100.9, 100.1 (2d, J=160 and 164 Hz, Cl, Cl'), 99.4 (d, J=172 Hz, Cl"), 76.8, 76.3, 73.0, 72.6, 72.3, 71.6, (2C), 68.8, 68.6, 67.7, 66.9, 66.9, 65.4 (CH2), 62.1 (CH2), 61.2 (CH2), 60.1 (CH2), 20.8, 20.7, 20.54 (3C), 20.5 (2C), 20.46, 20.4, 20.3, 14.9.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:42]=[CH:41][C:26]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]4)=[CH:25][CH:24]=3)[N:13]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].C(N(CC)CC)C>CN(C=O)C.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]3)=[CH:41][CH:42]=2)[N:13]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc(C(N)=O)c4)n3)cc2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Yield: 63 %

Procedure:
A suspension of tert-butyl 4-(4-((4-((3-carbamoylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I145) (105 mg, 0.18 mmol) and Pd/C (75 mg) was stirred in DMF (5 mL) and triethylamine (0.15 mL) at 30° C. under hydrogen for 18 hours. After filtration the volatiles were evaporated under reduced pressure and the residue chromatographed (Biotage Isolera: 4 g silica cartridge, 0-2% methanol/ethyl acetate) to give the title compound (I146) (66.6 mg, 63% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 8.67 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.74-7.50 (m, 8H), 7.40-7.35 (m, 2H), 7.33 (s, 1H), 7.24 (d, J=8.6 Hz, 2H), 3.43 (s, 2H), 3.17-3.04 (m, 4H), 2.36-2.23 (m, 4H), 1.38 (s, 9H). LCMS Method C: rt 5.05 min; m/z 585.2 [M+H]+; m/z 583.2 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][CH:9]=1)([O-])=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][CH2+:33]1SC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][C:33]1=[N:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][CH:9]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)Nc1ccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)cn1

Procedure:
In a manner similar to Example 30, intermediate N-(5-nitropyridin-2-yl)acetamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (DMSO-d6): δ 10.45 (1H, s), 8.07 (1H, d), 7.97 (1H, d), 7.75 (1H, d), 7.33-7.46 (7H, m), 7.29 (1H, m), 7.22 (1H, m), 5.06 (2H, s), 3.79 (3H, s), 2.09 (3H, s); MS(ESI): 488 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)cc3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 4-chlorophenylboronic acid (116 mg, 0.74 mmol). Yield 150 mg (79%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Br)ccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 110 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of 4-bromo-2-methoxybenzonitrile (2.08 g, 9.81 mmol) and 4-(trifluoromethyl)phenylboronic acid (2.80 g, 14.7 mmol), potassium fluoride (1.71 g, 29.4 mmol) and Pd(PPh3)4 (1.13 g, 0.98 mmol) in toluene (40 mL) added water (10 mL). The mixture was stirred at 110° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography gave 3-methoxy-4′-(trifluoromethyl)biphenyl-4-carbonitrile (2.66 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.4 Hz, 2H), 7.63-7.56 (m, 3H), 7.15 (dd, J=8.0, 1.2 Hz, 1H), 7.06 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[N+:14]([O-])=O)[C:2]([CH3:4])=O>C(O)C.[Ni]>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]2[NH:14][CH:2]([CH3:4])[CH2:1][O:5][C:6]=2[C:11]=1[F:12]
Reactant: CC(=O)COc1c([N+](=O)[O-])ccc(Cl)c1F
Agent: [Ni]
Solvent: CCO
Product: CC1COc2c(ccc(Cl)c2F)N1
Yield: 75.3 %

Procedure:
2.3 g (7.9 mmols) of 2-acetonyloxy-4-chloro-3-fluoronitrobenzene was dissolved in 30 ml of ethanol and catalytically reduced in the presence of 2 g of Raney nickel. After completion of the reduction, the catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel (20 g) column chromatography using chloroform as an eluant to provide 1.2 g (75.5% yield) of 7-chloro-8-fluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[N:17](C(OC(C)(C)C)=O)[CH2:16][C@H:15]([CH3:25])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.CCO>C(Cl)(Cl)Cl>[CH3:25][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[NH:17][CH2:16]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3c(N)nc4ccccc4c3n21
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@H]1CNc2nc3c(N)nc4ccccc4c3n21
Yield: 60 %

Procedure:
tert-Butyl (10S)-6-amino-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate (130 mg, 0.383 mmol) was treated with 10 mL of 3.0 M HCl/EtOH and heated up to reflux for about 20 minutes. The volatiles were then removed under reduced pressure, and the resulting residue was partitioned between CH2Cl2 and H2O. The layers were separated, and the aqueous one was extracted again with CH2Cl2, and the combined organic layers were discarded. The aqueous layer was then treated with concentrated ammonium hydroxide solution until the pH ˜11. The layer was extracted with CH2Cl2 (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid. Chromatography (SiO2, 20-40% CMA/CHCl3) afforded (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine (55 mg) as an off white solid, m.p. 265-273° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.[C:27](O)(=[O:29])[CH3:28]>S(=O)(=O)(O)O.ClCCl>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:21][CH2:22][CH:23]([O:26][C:27](=[O:29])[CH3:28])[CH2:24][CH2:25]1
Reactant: CC(=O)O
Reactant: CC1CCc2c(N3CCC(O)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Reaction time: 5 h
Yield: 31.2 %

Procedure:
In a 25 ml flask were placed 0.43 g of 9-fluoro-8-(4-hydroxy-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 0.2 g of acetic acid and 5 ml of dichloromethane and the mixture was refluxed after adding 5 drops of concentrated sulfuric acid. During the reaction oily substance appeared on the bottom of the flask. After 5 hours the reaction was stopped, dichloromethane was removed and water was added to the product followed by filtration. Crystals thus obtained were washed with methanol to give 150 mg of 9-fluoro-8-(4-acetoxy-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 250°-253° C., pale yellow rhombic crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[N:14][C:9]3[O:10][CH2:11][CH2:12][NH:13][C:8]=3[CH:7]=2)=[CH:2]1.[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(N(CC)CC)C.O>ClCCl>[Br:16][C:17]1[CH:18]=[C:19]([C:20]([N:13]2[CH2:12][CH2:11][O:10][C:9]3[N:14]=[CH:15][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[CH:7][C:8]2=3)=[O:21])[CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1cc(-c2cnc3c(c2)NCCO3)co1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccoc4)cc32)cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
In a 5 ml flask, 7-furan-3-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (18 mg, 0.089 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (32.1 mg, 0.098 mmol) were dissolved in dichloromethane (1 ml). Triethylamine (0.037 ml, 0.267 mmol) was added thereto and then stirred at 0° C. for 3 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by preparative TLC eluting a solvent of dichloromethane:methanol=20:1. Silica gels containing the product were eluted with dichloromethane and the solvent was evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-(7-furan-3-yl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone as white solid (40 mg, 91%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([S:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([S:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)(=[O:36])=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(S(=O)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(S(=O)(=O)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(1-isopropylpiperidine-4-sulfinyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 242 (38 mg, 0.078 mmol) in DCM (4 mL) was added TFA (30 μL, 0.39 mmol) followed by a solution of m-CPBA (18 mg, 0.101 mmol) in DCM (1 mL). The resulting mixture was stirred for 3 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 3-15% MeOH in DCM) affording 244 as a white solid (31 mg, 81%). LCMS: RT 2.77 min [M+H]+ 499.1. 1H NMR (CD3OD, 400 MHz): δ 8.73 (1H, d, J=8.46 Hz), 7.84 (1H, s), 7.60 (1H, dd, J=8.47, 1.85 Hz), 7.55 (1H, d, J=1.82 Hz), 5.95-5.82 (1H, m), 4.65-4.57 (4H, m), 3.22-3.11 (1H, m), 2.99 (2H, bd, J=11.61 Hz), 2.77-2.64 (1H, m), 2.37 (3H, s), 2.20 (2H, t, J=11.89 Hz), 2.01 (2H, d, J=12.72 Hz), 1.73 (2H, td, J=12.41, 3.93 Hz), 1.55 (6H, d, J=6.65 Hz), 1.03 (6H, d, J=6.56 Hz)
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.09 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 65-(2); 21.5 mg, 0.0437 mmol) in methanol (0.6 mL) at room temperature, and the mixture was stirred at room temperature for three hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (20 mg, 91%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(Cl)CCl>ClCCl>[CH3:37][O:36][N:35]([CH3:34])[C:11](=[O:13])[CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])n1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a suspension of 250 mg (1.37 mmol) of (6-nitropyridin-2-yl) acetic acid in 6 mL of dichloromethane was added DIEA (0.72 mL, 4.12 mmol) which resulted in some exotherming (+5° C.) and the suspension becoming a solution. After 2 min cooling, HOBt (263 mg, 1.72 mmol), N,O-dimethylhydroxylamine HCl (167 mg, 1.72 mmol) was added to the solution followed by EDC (329 mg, 1.72 mmol) and the resulting mixture stirred at room temperature overnight under nitrogen atmosphere. The solution was transferred to a separatory funnel and washed with 1 M HCl which caused an emulsion. Methanol was added to break up the emulsion and the aqueous was partitioned off. The organics were dried over sodium sulfate, filtered and concentrated under vacuum. Purification via preparative TLC plate (2×1000 μM) eluting with 50% ethyl acetatehexane afforded the title compound (236 mg, 76%) as a white solid. LC-MS: C9H11N3O4 calculated 225.20 found m/z (ES) 226 (MH)+. 1HNMR (500 MHz, DMSO) δ:8.56 (d, J=2.0 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.04 (dd, J=2.0, 8.3 Hz, 1H), 4.02 (br s, 2H), 3.88 (s, 3H), 3.07 (s, 3H).