Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:13]([F:12])=[C:14]([C:15]2[N:17]=[C:4]([OH:5])[C:3]3[CH:7]=[CH:8][C:9]([F:11])=[N:10][C:2]=3[N:16]=2)[CH:18]=1
Reactant: O=C(Cl)c1ccc(F)nc1F
Reactant: N=C(N)c1cc(Cl)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2nc(F)ccc12
Temperature: 25 °C

Procedure:
To a mixture of 2,6-difluoronicotinic acid chloride (6.4 g), dissolved in acetonitrile (200 mL) was added 2-fluoro-5-chlorobenzamidine (6.73 g) and diisopropyl ethyl amine (24 mL). The mixture was heated to reflux for 2 h and cooled to room temperature. The mixture was concentrated under reduced pressure. The precipitate was filtered and washed with ether and dried under reduced pressure to afford the 2-(5-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[2,3-d]pyrimidin-4-ol that was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:21][OH:22])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O>[Cl:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[N:4]=[C:3]([CH2:2][Cl:1])[N+:21]([O-:22])=[C:12]2[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(O)cc1)c1cc(Cl)ccc1NC(CCl)=NO
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: [O-][n+]1c(CCl)nc2ccc(Cl)cc2c1-c1ccc(O)cc1
Reaction time: 5 h
Yield: 55.3 %

Procedure:
A solution of 40.5 g (0.12 mole) 2,4'-dichloro-2'-(4-hydroxybenzoyl)-acetanilide oxime and 40.5 mg (0.329 mole) of boron trifluoride etherate was heated to reflux. After 5 hr, it was cooled and 200 ml of water was added. The dioxane was removed by distillation and the reaction mixture was made basic with a 5% sodium bicarbonate solution. The solid was collected, heated in methanol at reflux for a few minutes, cooled and collected to give, in two crops, 21.3 g (56%) of product. An analytical sample which was recrystallized from methanol melted at 226°-227° dec.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:17]O>CCCCCC.C(OCC)(=O)C>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: Cc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccccc1C
Yield: 98 %

Procedure:
30.0 g of o-tolylacetic acid (0.2 mol) was dissolved in 100 ml of methanol, 5 ml of concentrated sulfuric acid was added thereto and the resulting solution was stirred with heating for 6 to 12 hours. The resulting solution was cooled and the solvent was removed under a reduced pressure to obtain a residue. The residue was washed twice with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure. The residue thus obtained was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (4:1) as an eluent to obtain 32.15 g (yield 98%) of the title compound as a colorless liquid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A solution containing the product from Example 2C (1.09 g, 2.05 mmol) in THF (20 mL) was treated with the product from Example 70A (0.71 g, 2.45 mmol), DEPBT (1.0 g, 3.34 mmol), and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 1% methanol in ethyl acetate to give the title compound (1.197g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.56 (m, 2 H), 2.33 (q, J=9.2 Hz, 1 H), 2.58 (dd, J=13.6, 8.8 Hz, 1H), 2.67 (m, 2H), 2.78 (dd, J=13.6, 3.3 Hz, 1H), 2.84 (m, 1 H), 2.94 (q, J=9.2 Hz, 1 H), 3.19 (m, 1 H), 3.50 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.09 (s, 1 H), 4.19 (m, 2 H), 4.31 (s, 2 H), 4.55 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 7.07 (m, 5 H), 7.22 (d, J=8.5 Hz, 2 H), 7.29 (m, 4 H), 7.36 (m, 2 H), 7.47 (d, J=9.56 Hz, 1 H), 7.85 (m, 3H), 7.89 (d, J=8.5 Hz, 2 H ), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)C>ClCCl>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:14]
Reactant: Clc1ccccc1
Reactant: O=C(Cl)CCCCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CCCCCCCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 74 h

Procedure:
To a stirring suspension of aluminium chloride (33.6 g) in dry dichloromethane (474 ml) was added 8-bromo-n-octanoyl chloride (67.8 g) over 10 min. Chlorobenzene (123 ml) was then added over 10 min and the mixture allowed to stir at 25° C. for 74 h and stood for 64 h. The mixture was poured into ice/water (540 ml) and diethyl ether (1.3 L). The organic layer was removed and was washed with water (540 ml), saturated sodium hydrogen carbonate (540 ml), water (400 ml) and brine (400 ml) and dried over magnesium sulfate. Removal of the organic layer under reduced pressure and chromatography of the residue on silica gel using 5% ethyl acetate in hexane gave 8-bromo-1-(4-chlorophenyl)octan-1-one (35.5 g). 1H-NMR (CDCl3) δ 1.2-1.6 (6H, m), 1.6-1.95 (4H, m), 2.95 (2H, t), 3,42 (2H, t), 7.43 (2H, m) and 7.90 (2H, m).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH2:6]1.[N+]([O-])(O)=O.C(Cl)Cl.[NH4+].[OH-]>C(Cl)Cl>[N+:1]([C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][O:5][CH2:6]2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:18])[CH3:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C2COC2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2COC2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The organic phase (upper phase) was isolated and the process was repeated with an additional 20 ml CH2Cl2. The organic extracts were combined, it was assumed the organic phase contained about 5 g (−80 mmol) of anhydrous HNO3. Using a 50 fold excess, this required about 25 ml of solution. The nitric acid solution was cooled in a ice bath. The N-(4-oxetan-3-ylphenyl)acetamide (21.0 mg, 0.70 mmol) was treated with 25 ml of the chilled HNO3/CH2Cl2 solution and was allowed to stir about 30 minutes. The reaction mixture was carefully poured into 45 ml 10% NH4OH solution and carefully shaken. The phases were separated and the aqueous phase was washed with 20 ml CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3,4-dichlorophenyl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([N+]([O-])=O)[CH:7]=1.[Cl:13]Cl>[Fe]>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([Cl:13])[CH:7]=1
Reactant: ClCl
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Agent: [Fe]
Product: Fc1cc(F)c(Cl)cc1Cl
Temperature: 200 °C
Reaction time: 5 h

Procedure:
3 kg (15.5 mol) of iron-free, dry 5-chloro-2,4-difluoronitrobenzene are introduced into a 2 l four-necked flask with stirrer, dropping funnel and gas inlet tube and, on top, a column with reflux condenser. After heating the reaction solution to 200° C., chlorine is passed through the solution at a rate of 15 l/h. After 4-6 hours, the solution begins to boil, and after a further 2-4 hours the 1,3-dichloro-4,6-difluorobenzene which is formed can be taken off at the head of the column. At the same time, fresh 5-chloro-2,4-difluoronitrobenzene is added to the reaction in accordance with the quantity of product removed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]1[NH:33][C:32](=[O:34])[N:31]2[C:35]([CH3:41])=[N:36][C:37]([CH2:38][CH2:39][CH3:40])=[C:30]2[N:29]=1)[CH3:16]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:14])[S:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[C:19]([C:28]3[NH:33][C:32](=[O:34])[N:31]4[C:35]([CH3:41])=[N:36][C:37]([CH2:38][CH2:39][CH3:40])=[C:30]4[N:29]=3)[CH:20]=2)(=[O:25])=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N(C)CCc4ccc(OC)c(OC)c4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
143 mg (0.73 mmol) of N-(3,4-dimethoxyphenylethyl)-N-methylamine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 138 mg (98%) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-4-ethoxy-N-methyl-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzene-sulfonamide are obtained.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[N:7]=[CH:6][C:5]=1[C:19](O)=[O:20])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:58]([O:62][C:63]([NH:65][C:66]([NH2:68])=[NH:67])=[O:64])([CH3:61])([CH3:60])[CH3:59]>CN(C)C=O>[C:58]([O:62][C:63]([NH:65][C:66]([NH:68][C:19]([C:5]1[CH:6]=[N:7][N:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:20])=[NH:67])=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: CC(C)c1c(C(=O)O)cnn1-c1ccc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NC(=N)NC(=O)OC(C)(C)C)cnn1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.5 %

Procedure:
To a solution of 5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid (336.7 mg, 1.2 mmol) in 5 ml dimethylformamide was added N,N-diisopropylethylamine (0.42 ml, 2.39 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (582 mg, 1.32 mmol) and tert-butoxycarbonylguanidine (210 mg, 1.32 mmol). The resulting solution was stirred at room temperature for 2 h, then heated to 60° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated to dryness in vacuo. The solid residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (sodium sulfate) and concentrated to dryness in vacuo. The solid residue was triturated with methanol (1.5 ml), filtered, washed with diethyl ether and dried to yield the title compound as a white solid (114.3 mg, 22.5% yield).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCCC3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclohexanecarbonyl chloride (48 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H39N3O3+H: 490, observed: 490.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:16][C:17]=3[C:18]32[N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)=[C:9]([F:34])[CH:8]=1)(=O)=O.BrC1C=C2[C:51]3([N:56]=[C:55](N)[CH2:54][O:53][CH2:52]3)C3C=C(Cl)N=CC=3OC2=CC=1.N1CCOCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:34][C:9]1[C:10]2[O:11][C:12]3[C:17](=[CH:16][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][CH:13]=3)[C:18]3([N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)[C:19]=2[CH:20]=[C:7]([N:56]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)[CH:8]=1
Reactant: NC1=NC2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(N3CCOCC3)cc12
Temperature: 25 °C
Yield: 550 %

Procedure:
A re-sealable vial was charged with 5-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (200 mg, 0.379 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) 1 (27.6 mg, 0.038 mmol) and 0.5 ml of THF. The mixture was stirred at RT until all solids were dissolved. Morpholine (66.1 μL, 0.758 mmol) and LiHMDS (1M in THF) (1138 pt, 1.138 mmol) were added and the vial was sealed and stirred at RT for 20 minutes. The reaction was quenched by addition of water (1 ml) and diluted with EtOAc (2 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×2 ml). The combined organic fractions were concentrated and purified by chromatography (10-80% DCM/MeOH/NH4OH in DCM) to provide racemic 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (97 mg, 0.209 mmol, 55.1% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[Br:21]Br>C(O)(=O)C>[Br:21][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: BrBr
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c(Br)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
The method of Siegel, J. S. et al. (Org. Lett., 2006, 8, 4989-4992) was used. 3-Nitro-2′-trifluoromethyl-biphenyl-4-ylamine (302 mg, 1.07 mmol, as prepared in Example 6, step A) was placed in an 8 mL vial equipped with a magnetic stir bar, and glacial acetic acid (2 mL) was added via pipette. The solid was allowed to dissolve, and bromine (1.07 eq., 59.0 μL, 1.14 mmol) was added dropwise via microsyringe. The reaction was tightly capped and stirred at RT for 30 min, during which time a precipitate formed. The reaction was poured into crushed ice, and the precipitate was isolated by filtration. The precipitate was washed with water (50 mL), dissolved in DCM (40 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure. The crude material was chromatographed on a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 20 min, yielding 341 mg (88%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.14 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.70 (br. s., 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1[CH:17]=O)[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29].N1CCCCC1>CCO>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1/[CH:17]=[C:22]1\[C:21](=[O:29])[NH:20][C:28]2[C:23]\1=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c2c1C(=O)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)CCc1c(/C=C2\C(=O)Nc3ccccc32)[nH]c2c1C(=O)CCC2

Procedure:
A mixture of compound 5 (0.50 mmol) and indolin-2-one (0.50 mmol) was added with EtOH (5.0 mL) and piperidine (0.1 mL). The reaction was heated at reflux for 12 h. The resultant precipitate was filtered and washed with EtOH to provide the diresed product. 1H NMR (CDCl3) δ 7.93 (s, 1 H), 7.61 (s, 1 H), 7.59 (d, 1 H, ArH), 7.19 (dd, 1 H), 7.09 (dd, 1 H), 6.89 (d, 1 H), 4.07 (q, 2 H), 3.27 (t, 2 H), 2.91 (t, 2 H), 2.74 (t, 2 H), 2.52 (t, 2 H), 2.14-2.19 (m, 2 H), 1.18 (t, 3 H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][N:3]2[C:7](=[O:12])[NH:8][C:9](=[O:11])[CH:10]=[C:2]12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:8]1[C:9](=[O:11])[CH:10]=[C:2]2[S:1][CH2:6][CH2:5][CH2:4][N:3]2[C:7]1=[O:12]
Reactant: ClCCCCBr
Reactant: O=c1cc2n(c(=O)[nH]1)CCCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc2n(c(=O)n1CCCCCl)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.76 g (15 mmol) of 3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 3.32 g (24 mmol) of potassium carbonate in 50 ml of N,N-dimethyl-formamide, 3.46 ml (30 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1→1/4) to yield 1.92 g (46.6%, white powder) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([S:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][S:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: COc1ccc2c(c1)C(=O)CCS2
Reactant: CCOC(OCC)N(C)C
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CS2

Procedure:
The 3,4-dihydro-2-dimethylaminomethylene-7-methoxy-4-thia-1(2H)-naphthalenone starting material was prepared from 3,4-dihydro-7-methoxy-4-thia-1(2H)naphthalenone (1.0 g, 5.2 mmol [Degani, I. et al, Boll. Sci. Fac. Chim. Ind. Bologna (1966), 24(2-3) 75-91], and N,N-dimethyl-formamide diethyl acetal (2.7 ml, 15.6 mmol) to give the product as a mustard yellow solid (1.06 g). δH (CDCl3) 7.63 (1H, J 2.9 Hz), 7.60 (1H, s), 7.17 (1H, d, J 8. Hz), 6.90 (1H, dd, J 2.9, 8.4 Hz), 3.98 (2H, s), 3.83 (3H, s) and 3.15 (6H, s). MS(EI+) 249 (M+, 66%), 205 (13%), 177 (59%), 82 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.[O:42]([NH2:44])[CH3:43].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:44][O:42][CH3:43])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A vessel was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]benzoic acid (1.0 g, 3.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (677 mg, 3.53 mmol) and hydroxybenzotriazole (HOBT) (541 mg, 3.53 mmol) in N,N-dimethylformamide (DMF, 7.0 mL) and was stirred at room temperature for 30 min. To this solution methoxylamine hydrochloride (0.3 g, 3.53 mmol) was added and reaction mixture was stirred for another 10 min. The reaction mixture was cooled to 0° C. by using an ice bath. To this reaction mixture diisopropylethylamine (1.2 mL, 7.06 mmol) was added and the mixture was stirred at room temperature overnight. After concentrating under vacuum, the residue was worked up by using a saturated aqueous solution of NaHCO3 and CH2Cl2. The organic phase was washed with brine then dried over MgSO4 and filtered. The CH2Cl2 was removed by rotary evaporation. The crude material was loaded on silica gel column and eluted by MeOH in CH2Cl2 with NH4OH 0.1%, which gave the desired product 2-[(2, 5-dichloro-4-pyridinyl) amino]-N-(methyloxy)benzamide (850 mg, 2.72 mmol, 77% yield) MS: M(C13H11C12N3O2)=312.15, (M+H)+=312, 314; 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 9.57 (br. s., 1 H) 8.72 (s, 1 H) 8.22 (s, 1 H) 7.51 - 7.67 (m, 3H) 7.25 (s, 1 H) 7.07 - 7.21 (m, 1 H) 3.92 (s, 3 H).