Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][NH2:6].C(N(C(C)C)C(C)C)C.[Br:20][CH:21]([CH2:25][CH2:26][Br:27])[C:22](Cl)=[O:23]>ClCCl>[Br:20][CH:21]([CH2:25][CH2:26][Br:27])[C:22]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([F:1])[CH:3]=1)=[O:23]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: Cc1ccc(CN)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)C(Br)CCBr)cc1F
Temperature: 0 °C
Yield: 87.6 %

Procedure:
To a stirring 0° C. solution of 3-fluoro-4-methylbenzyl amine (2.0 g, 14 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.5 mL, 20 mmol) in dichloromethane (30 mL) was added dropwise a solution of 2,4-dibromobutanoyl chloride (3.98 g, 15 mmol) in dichloromethane (5 mL). After completion of the addition, the reaction was stirred in the ice bath until all of the ice had melted, then it was partitioned between ethyl acetate and water. The layers were separated, the organic layer was washed with brine, and it was then dried over magnesium sulfate. The drying agent was filtered off, the solvent was evaporated, and the residue was dissolved in ethyl acetate and subjected to silica gel chromatography in 10→25→100% ethyl acetate/hexane, collecting the main component to yield 4.5 g (85%) 2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide. LCMS (method CZ-1): RT 1.21 min, m/z 367.9 (MH+); 1H NMR (500 MHz, chloroform-d) δ 7.17 (t, J=7.7 Hz, 1H), 7.01-6.91 (m, 2H), 6.70 (br. s., 1H), 4.59 (dd, J=9.0, 4.9 Hz, 1H), 4.51-4.37 (m, 2H), 3.64-3.51 (m, 2H), 2.71 (dddd, J=15.0, 8.5, 6.1, 4.9 Hz, 1H), 2.51 (ddt, J=15.0, 9.2, 5.5 Hz, 1H), 2.27 (d, J=1.4 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:37]=[CH:36][C:7]([NH:8][C:9]([N:11]([CH3:35])[C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]([N:11]([CH3:35])[C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:36][CH:37]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(N(C)C(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(N(C)C(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
After adding methanol (20 ml) and 2N aqueous sodium hydroxide (5 ml) to methyl 4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate (1.042 g, 2.19 mmol), the mixture was stirred at room temperature for 3 hours. 2N Hydrochloric acid was added to the reaction solution for neutralization, and then the methanol was distilled off under reduced pressure and the precipitated white crystals were filtered out and dried at 70° C. to obtain the title compound (1.01 g, 2.19 mmol, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.[OH-].[Na+].[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)(=O)C>[C:14]([CH2:15][CH2:16][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:17]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#CCCNc1cccc(C(=O)O)c1
Temperature: 5 °C

Procedure:
200.0 g of 3-aminobenzoic acid in 2 1 of water were admixed with 53.2 g of sodium hydroxide. At 30° C., 126.6 g of acrylonitrile were added dropwise, and the mixture was then heated under reflux for 22 hours. The mixture was then cooled to 5° C. and acetic acid was added (pH=5) and the precipitate which had formed was filtered off with suction and washed with water.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31](O)=[O:32]>>[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2ccnc(C)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-methyl-isonicotinic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[Na].[CH2:10]([OH:13])[CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:13][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: OCCO
Reactant: ClCc1cnccn1
Agent: [Na]
Product: OCCOCc1cnccn1

Procedure:
2-Chloromethylpyrazine is reacted with the sodium salt of ethylene glycol to give 2-(2-hydroxyethoxymethyl)pyrazine which is treated with thionyl chloride to give 2-(2-chloroethoxymethyl)pyrazine. Using this intermediate in place of 4-(3-chloropropoxy)methylimidazole in the procedure of Example 22 gives the title compound.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CS(C)=O>[NH2:1][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cnc(F)c(-c4ncccn4)c3)cc2)[C@H]1c1ccccc1
Reactant: N
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(-c4ncccn4)c3)cc2)[C@H]1c1ccccc1
Temperature: 100 °C

Procedure:
A 2-mL glass microwave reaction vessel was charged with ammonia (2 M solution in 2-propanol) (123 μL, 5.68 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and (S)-3-(4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (25 mg, 0.057 mmol) in DMSO (568 μL). The reaction mixture was stirred and heated at 100° C. in a heating block overnight. LC-MS indicated clean and complete conversion to the desired product. The material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(6-amino-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J=5.02 Hz, 2H), 8.84 (d, J=2.46 Hz, 1H), 8.42 (d, J=2.56 Hz, 1H), 7.56 (s, 4H), 7.43 (t, J=4.81 Hz, 1H), 7.34-7.41 (m, 2H), 7.25-7.34 (m, 3H), 5.48 (s, 1H), 1.65 (s, 3H), 0.91 (s, 3H). m/z (ESI) 438.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:22]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:6]=1[NH2:22])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Temperature: 70 °C
Yield: 86.9 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (Intermediate 7, 0.9 g, 2 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (1.04 g, 6 mmol) in water (2.5 mL). The reaction mixture was stirred at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-3,4-difluoro-N2-(2-fluoro-4-iodo-phenyl)-benzene-1,2-diamine as a brown solid (730 mg). 1H-NMR (400 MHz, CDCl3): δ 3.86 (2H, bs), 4.54 (2H, d, J=5.2), 5.34 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 5.66 (1H, bs), 6.02-6.09 (1H, m), 6.20 (1H, d, J=8.4), 6.62-6.66 (1H, m), 7.33 (1H, dd, J=2, 8.4), 7.63 (1H, d, J=2).
Reaction SMILES: [Cl:1][C:2]([Cl:39])([Cl:38])[CH2:3][O:4][C:5](=[O:37])[N:6]([CH:16]1[CH2:20][CH:19]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH2:25][CH2:24]2)=[O:22])[NH:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15].[F:40][C:41]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:42]=1[CH:43]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:39][C:2]([Cl:1])([Cl:38])[CH2:3][O:4][C:5](=[O:37])[N:6]([CH:16]1[CH2:20][CH:19]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH2:25][CH2:24]2)=[O:22])[N:18]([CH2:43][C:42]2[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:41]=2[F:40])[CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15]
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccc(F)cc3F)C(=O)OCC(Cl)(Cl)Cl)CN2)CC1
Reactant: O=Cc1cccc(F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccc(F)cc3F)C(=O)OCC(Cl)(Cl)Cl)CN2Cc2cccc(F)c2F)CC1
Reaction time: 0.33 h

Procedure:
A mixture of {5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidin-3-yl}-(2,4-difluoro-benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.078 g, 0.13 mmol), 2,3-difluorobenzaldehyde and acetic acid (cat.) in DCM (5 ml) was stirred for 20 min, and then NaBH(OAc)3 (0.041 g, 0.13 mmol) was carefully added. The reaction mixture was stirred overnight, and was concentrated to give crude product which was directly used for next step.
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.Br[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27].F[B-](F)(F)F>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:24][C:22]1[CH:23]=[CH:18][C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20]([C:9]#[C:8][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:21]=1
Reactant: C#C[Si](CC)(CC)CC
Reactant: COC(=O)Cc1ccc(C)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1cc(C)ccc1CC(=O)OC)(CC)CC
Temperature: 70 °C

Procedure:
A solution of triethylsilyl acetylene (0.27 mL, 1.5 mmol) in degassed DMF (4 mL) and Et3N (2.0 mL, 15 mmol) was added to a mixture of methyl 2-(2-bromo-4-methylphenyl)acetate (A84) (0.30 g, 1.2 mmol), PdCl2(PPh3)2 (0.043 g, 0.062 mmol), CuI (0.012 g, 0.062 mmol) and t-Bu3PH.BF4 (0.018 g, 0.062 mmol) in degassed DMF (10 mL). The resulting mixture was heated at 70° C. for 17 hours then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (150 mL). The filtrate was concentrated under reduced pressure and adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-15% EtOAc in petroleum spirits) to yield the title compound A85 as a yellow oil (0.326 g, 72% purity contaminated with starting material); 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.12-7.08 (m, 1H), 3.82 (s, 2H), 3.68 (s, 3H), 2.31 (s, 3H), 1.05 (t, J=7.9 Hz, 9H), 0.72-0.64 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[C:9]2=[O:18])=[C:4]([Cl:19])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([C:60](O)=[O:61])[N:55]=1>CN(C=O)C.O>[Cl:19][C:4]1[CH:3]=[C:2]([NH:1][C:60](=[O:61])[C:56]2[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[N:55]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[C:16](=[O:17])[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:18]
Reactant: O=C(O)c1cccc(F)n1
Reactant: Nc1ccc(N2C(=O)C3CCCCN3C2=O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2C(=O)C3CCCCN3C2=O)c(Cl)c1)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 2-(4-amino-2-chlorophenyl)tetrahydroimidazo[1,5-α]pyridine-1,3(2H,5H)-dione (0.03 g, 0.107 mmol), HATU (0.045 g, 0.119 mmol), DIEA (0.041 mL, 0.236 mmol) in DMF (1 mL) was added 2-fluoro-6-pyridine carboxylic acid (0.017 g, 0.118 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was diluted with water (4 mL) and extracted with ethyl acetate (2×3 mL). The organic extracts were combined and concentrated. The residue was purified by reverse phase HPLC to give N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-6-fluoropicolinamide (TFA), 1.3.4.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(Cl)(Cl)Cl.CO>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:26](=[O:28])[CH3:27])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CC(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (110 μL, 0.82 mmol) in methylene chloride (25 mL) was added acetyl chloride (31 μL, 0.43 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to reach room temperature and then washed with water. The phases were separated, the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica get column using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 110 mg (90%) of the title compound as an oil. Crystallization from ethyl acetate/hexane gave 52 mg (44% yield) of white crystals: mp 152-154° C.; [α]21D +66° (c 0.13, chloroform); EIMS (70 eV) m/z (relative intensity) 287 (9, M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:9]=2)[N:5]=[C:4]([C:22]([NH2:24])=[O:23])[CH:3]=1.[CH:25](B1OC(C)(C)C(C)(C)O1)=[CH2:26].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:10]2[CH:9]=[C:8]([C:6]3[N:5]=[C:4]([C:22]([NH2:24])=[O:23])[CH:3]=[C:2]([CH:25]=[CH2:26])[CH:7]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: NC(=O)c1cc(Cl)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=Cc1cc(C(N)=O)nc(-c2cccc(Oc3ccc(F)cc3)c2)c1
Temperature: 120 °C
Yield: 49.8 %

Procedure:
A 5 ml sealed microwave tube was charged with 4-chloro-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid amide (0.267 g, 0.78 mmol), vinyl boronic acid pinacol ester (0.180 g, 1.17 mmol, Aldrich) in three equivalents of TBAF/THF. The mixture was heated to 120° C. by microwave for 45 minutes. The mixture was chromatographed without workup by combiflash using a 40-gram silica column with a gradient of methanol (30% max) in chloroform to provide 0.130 g of 6-[3-(4-fluoro-phenoxy)-phenyl]-4-vinyl-pyridine-2-carboxylic acid amide as a clear oil in good purity (50% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH4+:12].[OH-].O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:12])=[O:8]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5,6-dichloro-nicotinoyl chloride from step (a) above (1.73 g, 8.22 mmol)) in CH2Cl2 (50 mL) was added to a mixture of 28% aq. NH4OH (20 mL), water (20 mL) and CH2Cl2 (50 mL), and vigorously stirred at room temperature for 2 h. The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 191 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:19][C:12]3[NH:13][C:14](=[S:18])[NH:15][C:16](=[O:17])[C:11]=3[CH2:10][C:9]=2[CH:20]=1)=[O:4].[OH-].[Na+]>>[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:19][C:12]3[NH:13][C:14](=[S:18])[NH:15][C:16](=[O:17])[C:11]=3[CH2:10][C:9]=2[CH:20]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
Warm a suspension of 7-methoxycarbonyl-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (5 g.) in 1 N-sodium hydroxide (25 ml.) until a clear solution is formed and continue the warming for an additional 1/2 hour. Filter the solution and acidify the filtrate with 2 N sulfuric acid. Filter and wash the solids with water, isopropanol and then ether. Dry the washed solid to obtain. 7-carboxy-2,4-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][Br:20])=[CH:17][CH:18]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CBr)cc1

Procedure:
To a 50 ml round bottom flask is added 4-(4-methylphenyl)butyl tert-butyldimethylsilyl ether (0.25 g, 0.89 mmol), N-bromosuccinimide (0.158 g, 0.89 mmol), benzoyl peroxide (2.17 mg, 0.0089 mmol) and 10 ml carbon tetrachloride. This mixture is refluxed overnight after which it is cooled and filtered. The filtrate is concentrated and the resulting crude residue is purified by flash chromatography in ethyl acetate-hexanes to afford the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([C:20]#[N:21])=[CH:17][NH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([N:18]2[CH:19]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]([C:20]#[N:21])=[CH:17]2)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23]
Reactant: N#Cc1c[nH]cc1-c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(F)cc1OCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCc3ccccc3)c2)cc1OCOC
Temperature: 65 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a solution of 4-(2-benzyloxyphenyl)-1H-pyrrole-3-carbonitrile (1.5 g), 4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (1.4 g) in N,N-dimethylformamide (25 mL) was added cesium carbonate, and this mixture was stirred at 65° C. for 15 hours. This reaction mixture was poured into water, the precipitated solid was collected by filtration, and washed with water and n-hexane, dried under reduced pressure at 50° C. to give the title compound (2.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].[C:26]1(=O)[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.O>C1(C)C(C)=CC=CC=1>[CH3:25][O:24][C:4]1[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:6]2[C:11](=[C:2]([N:1]3[C:29](=[O:30])[C:28]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]4[C:26]3=[O:31])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc(N2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Yield: 99.3 %

Procedure:
A mixture of 8-amino-6-methoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline (I) (6.96 g, 20 mmol) and phthalic anhydride (3.25 g, 22 mmol) in xylene (100 mL) was refluxed with water removal via a Dean-Stark trap for 24 hours. After cooling, filtration gave 9.5 g (100%) of the title compound, mp 228°-30° C. Recrystallization from ethanol raised the mp to 228°-31° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[N:12]([O-])=O.[Na+].Cl.NN.[OH-].[Na+]>Cl.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cccc(NN)c1

Procedure:
To a solution of 3-methanesulphonyl-phenylamine (2.5 g) in 6 mL HCl was added a solution of NaNO2 in 5 mL of H2O at −5° to 0° C. After stirring for 30 min the resulted diazonium salt was poured into a cold solution (−10° to −15° C.) of stannous chloride in 6 ml HCl. The mixture of resulted hydrazine hydrochloride in HCl was stored in the refrigerator overnight. The solution was basified to pH 10, by addition of a 6N solution of NaOH, and extracted with THF. The organic layer was washed, dried over MgSO4, and evaporated to yield 2 g of a light brown solid (3-methanesulfonyl-phenyl)-hydrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(Cl)=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:14][C:15](=[O:16])[O:9][C:7](=[O:8])[C:6]2=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Product: COc1cc(OC)c2c(=O)oc(=O)[nH]c2c1

Procedure:
4,6-Dimethoxyisatoic anhydride is prepared from 4,6-dimethoxyanthranilic acid (H. Newman & R. Anzier, J. Org. Chem. 34, 3484 (1969) and phosgene according to the method of E. C. Wagner and M. F. Fegley, Org. Synthesis 27, 45 (1947).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11](=[O:17])[NH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:23]([O-])([O-:25])=[O:24].[K+].[OH-].[NH4+]>C(O)(=O)C>[N+:23]([C:3]1[CH:2]=[C:1]([C:7]2[N:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11](=[O:17])[NH:12]3)[CH:6]=[CH:5][CH:4]=1)([O-:25])=[O:24]
Reactant: O=c1ccc2c(-c3ccccc3)nccc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1ccc2c(-c3cccc([N+](=O)[O-])c3)nccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To a mixture containing 16.7 g of 5-phenyl-1,6-naphthyridin-2(1H)-one and 250 ml of concentrated sulfuric acid was added portionwise 7.6 g of potassium nitrate with stirring, keeping the mixture in an ice bath. The addition was completed within 15 minutes and the temperature of the reaction mixture was kept below 10° C. during addition. The reaction mixture was then stirred in the ice bath for 40 minutes, allowed to warm up to room temperature and then stirred at room temperature for 5 and 1/2 hours. The reaction mixture was poured over ice and the resulting mixture was made basic using concentrated ammonium hydroxide solution. The mixture was made slightly acidic using glacial acetic acid and chilled. The separated solid was collected and dried. The solid was recrystallized from boiling dimethylformamide using decolorizing charcoal, the hot mixture filtered and the filtrate chilled. The separated solid was collected, washed with ethanol and dried in a vacuum oven at 90° C. to yield 12.2 g of 5-(3-nitrophenyl)-1,6-naphthyridin-2 (1H)-one, m.p. >300° C.