Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].Cl.C(N(CC)CC)C>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Cl)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1O

Procedure:
To a solution of 100 grams of 2 amino-4-chlorophenol (0.70 mole) in 1 liter of tetrahydrofuran is added 71 grams of triethylamine (0.70 mole). The resulting solution is cooled with an ice bath. To the solution is then slowly added 55 grams of acetyl chloride (0.70 mole) in 200 ml. of tetrahydrofuran. A precipitate forms (triethylamine hydrochloride). The solution is then filtered and the filtrate evaporated under reduced pressure, yielding a dark solid residue. Recrystallization of the residue from methylene chloride and petroleum ether (1:1) yields 4-chloro-2-acetamidophenol.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:23])[N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].Cl>C(O)C.C1(C)C=CC=CC=1.CC(=O)OCC.C(Cl)Cl.CO>[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[C:6]2[C:7](=[O:23])[N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: COc1cnccc1B(O)O
Reactant: O=c1c2c(Br)csc2ccn1CCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cnccc1-c1csc2ccn(CCc3ccc4ccccc4n3)c(=O)c12
Temperature: 130 °C
Yield: 29.8 %

Procedure:
A reaction tube was charged with a solution of 3-bromo-5-[2-(quinolin-2-yl)ethyl]thieno[3,2-c]pyridin-4(5H)-on (100 mg, 0.260 mmol) in 1.5 mL of ethanol and 1.5 mL of toluene under argon. To this suspension, 3-methoxypyridin-4-ylboronic acid (39.7 mg, 0.260 mmol) and a 2M solution of Na2CO3 (41.3 mg, 0.389 mmol) were added. Then, tetrakis(triphenylphoshine)palladium (30.0 mg, 0.026 mmol) was added. The reaction mixture was heated in a Biotage microwave at about 130° C. for about 30 min. The reaction was monitored by TLC (DCM/methanol=9:1). After completion of the reaction, EA was added followed by the addition of 1 N HCl. The mixture was extracted twice with EtOAc. The organic layer was basified with NaHCO3 and extracted with brine. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in isopropanol. Isopropanol containing HCl was added. The precipitate was sucked off and recrystallized from hot ethyl acetate to give a white solid (32 mg, 29.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl.[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[N:16][NH:15][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: COc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 5-methoxy-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344-8) and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ3.80 (s, 3H), 6.87 (s, 2H), 7.20 (s, 1H), 7.28 (s, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 10.93 (s, 1H), 12.85 (s, 1H); APCI−MS m/z 344.9 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]([CH3:46])[C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1.CS(C)(=O)=O>>[CH3:39][N:40]([CH3:46])[C@@H:41]1[CH2:45][CH2:44][N:43]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:42]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Product: CN(C)[C@@H]1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)C1

Procedure:
A solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, dimethyl-(R)-pyrrolidin-3-yl-amine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 486.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[C:22]([CH3:29])[CH:21]=1>O1CCOCC1.CN1C(=O)N(C)CC1.CS(C)=O.C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:1][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[NH:4][N:3]=2)=[S:28])=[C:22]([CH3:29])[CH:21]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cc(Cl)ccc1NC(=S)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 202 mg (1.1 mmol) of 4-chloro-2-methyl-phenyl isothiocyanate (Maybridge) are added and the reaction mixture is stirred overnight at RT and finally for 16 hours at 60° C. Working-up analogously to Example 66 and stirring in DMSO/ethyl acetate yield 3-[(4-chloro-2-methyl-phenyl-amino)-thiocarbonyl-amino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100)=12.2; FAB-MS: (M+H)+=444.
Reaction SMILES: I(O)(=O)(=O)=O.[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:15])[F:14])[C:8]=1[CH:16]=[O:17].[Cr](Cl)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:14])[F:15])[C:8]=1[C:16]([OH:19])=[O:17]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: Cn1nc(C(F)F)c(C=O)c1F
Agent: [O-][I+3]([O-])([O-])O
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Reaction time: 0.5 h

Procedure:
A suspension of 79.7 g (350 mmol) of periodic acid in 640 ml absolute acetonitrile was stirred for 30 min. To this was added 56.6 g (318 mmol) of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde at 0° C. and a solution of 1.4 g (6 mmol) of pyridinium chlorochromate in 130 ml dry acetonitrile. The reaction mixture was stirred for 2.5 hours at room temperature. 1600 ml of ethyl acetate was added to the reaction mixture and the separated organic phase was washed consecutively with brine/water(1:1), saturated sodium metabisulfite and brine. Then the organic phase was dried with sodium sulphate, and evaporated under vacuum to give the expected product as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16]>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and 1-dimethylamino-2-methylamino-ethane
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](OCC)=[O:14])[CH:7]=[CH:6]2.COC1C=C2C(=CC=1)C=C(C#N)C=C2.BrC(C)(C)C(OCC)=O.[BH4-].[Na+]>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2
Reactant: CCOC(=O)c1ccc2cc(OC)ccc2c1
Agent: CCOC(=O)C(C)(C)Br
Agent: COc1ccc2cc(C#N)ccc2c1
Agent: [BH4-]
Solvent: CCO
Product: COc1ccc2cc(C=O)ccc2c1

Procedure:
6-methoxy-2-naphthaldehyde (substrate IIA) was synthesized from 6-methoxy-2-carbethoxynaphthalene, prepared from 6-methoxy-2-naphthonitrile, ethyl 2-bromoisobutyrate, and zinc dust as described by Horeau et al., 1947, Bull. Soc. Chim. Fr. 14:53-59. The keto-ester intermediate, mp 74°-76° C. (lit. 72.5-73.5° C.) was reduced to the corresponding secondary alcohol ester with sodium borohydride in ethanol at 4° C. and then thermally decomposed (Horeau et al. 1953, Compt. Rend. 236:826-8) to afford the final compound. The aldehyde was 25 purified either by zone sublimation or via the bisulfite adduct; mp 80°-81.5° C.; (lit. 79° C. Horeau et al., 1953, supra: lit. 81°-82° C. Gandhi et al., 1955 J. Chem. Soc., 2530).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[C:70]([NH:74][C:75](=[O:83])[C:76]1[CH:81]=[C:80](Cl)[CH:79]=[CH:78][N:77]=1)([CH3:73])([CH3:72])[CH3:71].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:70]([NH:74][C:75]([C:76]1[CH:81]=[C:80]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)[CH:79]=[CH:78][N:77]=1)=[O:83])([CH3:73])([CH3:71])[CH3:72]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)NC(=O)c1cc(Cl)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(C(=O)NC(C)(C)C)c3)cn2)cc1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
Bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (81 mg), palladium acetate (1.7 mg), S-Phos (6.2 mg), 4-chloropicolinic acid t-butylamide (64 mg) and potassium phosphate (64 mg) were stirred in dimethylformamide (1.5 ml) under an argon atmosphere at 100° C. for 2 days. The reaction mixture was cooled to room temperature, and subsequently diluted with water (20 ml), followed by extraction with ethyl acetate (10 ml). The organic layer was washed with brine, and dried over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/0 to 3/1), to obtain 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridine-2-carboxylic acid tert-butylamide as a pale yellow solid (44 mg, 41%). The above compound was dissolved in trifluoroacetic acid (3 ml), and refluxed for 5 hours in the presence of N-acetylcysteine (33 mg, 3.3 equivalents). The reaction mixture was concentrated under reduced pressure, and water (2 ml) was added to the resulting residue, followed by neutralization with saturated sodium bicarbonate water. The resulting precipitate was filtered and dried, and purified by amino silica gel column chromatography (dichloromethane), to obtain a colorless powder (17 mg, 58%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[C:56]1([CH2:62][CH:63]=O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:63][CH2:62][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: O=CCc1ccccc1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CCc5ccccc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 39.7 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with phenylacetaldehyde (22.5 mg, 1.5 eq) to provide the title barbituric acid (45.0 mg, 40%). MS found: (M+H)+=564.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Yield: 95.6 %

Procedure:
A solution of 31.8 g (0.11 m) of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone of Example 2B and 15.29 g (0.22 m) of hydroxylamine hydrochloride in 150 ml of pyridine is refluxed 64 hours. The pyridine is evaporated in vacuo, 5% HCl added, extracted with ethyl acetate, dried (Na2SO4) and evaporated to give 32 g (96%) of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime. An analytical sample is recrystallized from ethanol/H2O, m.p. 168°-175° C. TLC indicates the product is a mixture of isomers.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22].Cl>C1COCC1>[CH:7]([CH:4]1[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2][CH:3]1[O:10][C:21](=[O:22])[CH2:20][Br:19])([CH3:8])[CH3:9]
Reactant: O=C(Br)CBr
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OC(=O)CBr)C1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (−) Menthol (2.75 mmoles) in anhydrous THF (5 ml), Et3N (2.75 mmoles) is added under stirring. The solution temperature is lowered to 0° C. and bromo-acetylbromide (2.5 mmoles) added. The solution temperature is then allowed to raise to room temperature and the reaction mixture is stirred for 2 hours. An HCl 1N (2 ml) aqueous solution is added and the organic phase is extracted with ethyl acetate (3×5 ml). The pooled organic phases are washed with a saturated aqueous NaCl solution (1×15 ml), dehydrated on Na2SO4 and filtered. The solvent is evaporated under a reduced pressure and the crude product is purified by flash chromatography in n-hexane/ethyl acetate 97/3 volume/volume. 388 mg of 2-isopropyl-5-methyl-cyclohexyl ester of the bromo acetic acid (51% yield) are recovered.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH2:14]Br>CN(C=O)C>[Br:12][CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CCc1ccc(C(Br)CBr)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.67 g (0.0055 mol) p-hydroxy benzaldehyde and 0.237 g (0.0098 mol) sodium hydride in 10 mL DMF, 1 g (0.0034 mol) 2-bromo-[5-ethyl-2-pyridyl]-ethyl bromide dissolved in 10 mL of DMF was added at 10-15° C. Reaction mixture was stirred for 1 hr at 25-30° C. and further warmed at 75-80° C. for 24 hr. After subsequent work-up crude product was obtained which on purification gave titled compound. Yield of the product was 0.068 g (6%). The product obtained was characterized by satisfactory mass.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](B(CC)CC)[CH3:27].S(=O)(=O)(O)O>CN(C=O)C.C(Cl)Cl.O>[CH2:26]([C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1)[CH3:27]
Reactant: CCOC(=O)C1(C)CC(c2cc(F)cc(Br)c2)=NO1
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(C)CC(c2cc(F)cc(CC)c2)=NO1
Temperature: 150 °C
Yield: 82.8 %

Procedure:
Ethyl 3-(3-bromo-5-fluorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylate (1000 mg, 3.03 mmol), potassium carbonate (1.67 g, 12.12 mmol) and tetrakis(triphenylphosphane)palladium (350 mg, 0.30 mmol) were suspended in DMF (10 ml). Triethylborane (1M in hexane, 4.24 ml, 4.24 mmol) was then added, and the reaction mixture was heated in a microwave oven at 150° C. for 30 min. After cooling, water (20 ml), sulfuric acid (1 M, 5 ml) and CH2Cl2 (20 ml) were added, and the mixture was shaken. The organic phase was then dried over Na2SO4, and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel using the mobile phase heptane/EtOAc gave 701 mg (83%) of ethyl 3-(3-ethyl-5-fluorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylate.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]#[N:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH3:27][N:29]1[C:10]2[C@@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]#[N:38]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(Nc1ccccc1C#N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1ccccc1C#N)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.2 %

Procedure:
Triethylamine (0.82 mL, 5.9 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 690 mg, 3.21 mmol) in 1,2-dichloroethane (6 mL) over 1 min. A solution of N′-(2-cyano-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (435 mg, 1.76 mmol) in 1,2-dichloroethane (10 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 1 h. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated in an oil bath at 50° C. for 30 min and then at 100° C. for 1 h and allowed to cool. Dichloromethane (150 mL) was added and the mixture was washed with 1:1 water/brine (30 mL), dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with methanol and then diethyl ether. The residue was dried under high vacuum at 70° C. to give 2-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-yl)-benzonitrile (55 mg, 10%) as an off-white solid. ES(+)-MS (M+H) 308.
Reaction SMILES: [C:1]([CH:3]([C:9](=[O:27])[C:10]1[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)C(OCC)=O)#[N:2].Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:2][C:1]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:11]2[C:10]([C:9](=[O:27])[CH:3]=1)=[CH:15][CH:14]=[CH:13][N:12]=2
Reactant: CCOC(=O)C(C#N)C(=O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc(=O)c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate (2.0 g, 5.3 mmol) was heated to 120° C. in a mixture of conc. HCl (4 mL) and glacial acetic acid (2 mL) for 3 h. The reaction mixture was cooled to room temperature, and neutralized by slow addition of NaOH pellets. The mixture was extracted with CH2Cl2 (3×). The combined organic extracts were washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150×20 mm I.D.; 30-70% CH3CN in water, 20 min.) to afford 2-Amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (880 mg, 55%): LCMS RT: 2.03 min, MH+: 306.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1.Cl.CN(C)[CH2:21][CH2:22][CH2:23][N:24]=[C:25]=NCC.N1CCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][C:2]1([CH3:1])[CH2:15][C:6]2=[C:7]([C:12]([N:24]3[CH2:25][CH2:21][CH2:22][CH2:23]3)=[O:14])[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CC(C)(C)C2
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)CC(C)(C)C2
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a stirred solution of 6,6-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylic acid (1.0 g, 3.7 mmol), 4-dimethylaminopyridine (0.75 g, 6.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol) in DCM (30 mL) was added pyrrolidine (0.34 mL, 4.1 mmol). The mixture was stirred for 18 h then the solution was evaporated and the residue partitioned between EtOAc (20 mL) and water (20 mL). The organic later was separated, washed with 1M HCl (2×20 mL) and sat. K2CO3 (20 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was titurated with hexane/ether to afford the title amide (905 mg, 76%) as a colourless solid. mp 153-155° C. C16H21NO2S2 requires: C, 59.41; H, 6.54; N, 4.33%. Found: C, 59.70; H, 6.73; N, 4.77%. 1H NMR (360 MHz, CDCl3) δ 1.05 (6H, s), 1.94-2.04 (4H, m), 2.40 (2H, s), 2.59 (3H, s), 2.84 (2H, s), 3.59-3.62 (4H, m). MS (ES+) 324 (M+1).