Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]>C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCOC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of diisopropylamine (8.00 mL, 57.1 mmol) in THF (300 mL) cooled to 0° C. was added n-BuLi (24.60 mL, 61.5 mmol) dropwise. The mixture was stirred at 0° C. for 1 h. Then to the mixture cooled to −30° C. was added a solution of ethyl isobutyrate (6.12 g, 52.7 mmol) in THF (2 mL). The mixture was stirred at −30° C. for 1 h. To the mixture was added a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (10.5 g, 43.9 mmol) in THF (5 mL) at −30° C. The whole mixture was stirred at −30° C. for 3 h and then stirred at 25° C. for 12 h. The mixture was quenched with aqueous NH4Cl and extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=200:1). All fractions found to contain product by TLC (PE/EA=10:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of ethyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate (10 g, 35.3 mmol, 80.0% yield): 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J=8.0 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.18 (s, 6H); ES-LCMS m/z 275 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:38]([N:37]([CH3:36])[C:28]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:8][C:2]=1[Cl:1])=[O:34])[CH2:39][CH2:40][CH3:41]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCCCNC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCN(C)C(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline 80 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (72 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 15 min. Next, N-methylbutylamine (43 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol. The solvent was removed by distillation, and the resultant crystal was washed with hexane to give 26 mg (yield 24%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[OH:31])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: C1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(C2CCCCC2O)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 100 °C

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, cyclohexene oxide (12 mg, 0.12 mmol) and K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 100° C. for 3 hours. After this time the solution was cool to RT and diluted with ethyl acetate. The resultant solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-hydroxycyclohexyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-(24.1 mg, 48%) as yellow solid. MS M+H=455; 1H NMR (CDCl3) δ 8.17 (1H), 7.33 (6H), 7.08 (2H), 4.26 (1H), 3.98 (1H), 2.17 (1H), 1.99 (1H), 1.82 (3H), 1.50-1.30 (3H).
Reaction SMILES: O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[CH3:12][C:13]1[N:14]=[C:15]2[C:20]([O:21][CH2:22][CH2:23][CH:24]([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]([CH3:33])=[CH:17][N:16]2[C:34]=1[C:35]([O:37]CC)=[O:36].Cl>CO.O>[CH3:12][C:13]1[N:14]=[C:15]2[C:20]([O:21][CH2:22][CH2:23][CH:24]([C:25]([F:28])([F:26])[F:27])[C:29]([F:30])([F:31])[F:32])=[CH:19][C:18]([CH3:33])=[CH:17][N:16]2[C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.28 g (10.4 mmol) of barium hydroxide octahydrate were added to 1.95 g (4.73 mmol) of ethyl 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]pyridine-3-carboxylate Example 258A in 30 ml of methanol, and the mixture was stirred at RT for 3 days. The suspension was diluted with 30 ml of water and adjusted to pH 6 with 1 M hydrochloric acid. The solid was filtered off, washed with 50 ml of water and dried under reduced pressure at 70° C. for 2 h. This gave 1.64 g of the target compound (90% pure, 81% of theory).
Reaction SMILES: [OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:35]=1[CH2:36][NH2:37])=[O:31])([CH3:28])([CH3:27])[CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1CCOCC1.CN(C)C=O>[OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([NH:37][CH2:36][C:35]2[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:34]=2[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])=[O:20])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
A solution of 9-hydroxy-9-fluorenylcarbonyl-L-proline (1.8 g, 5.6 mmol) from step 2 above, 2-tert-butoxycarbonylaminomethyl-5-chlorobenzylamine (1.8 g, 6.8 mmol), N-methylmorpholine (12 drops), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (3.0 g, 6.7 mmol) in N,N-dimethylformamide (25 mL) was stirred at ambient temperature for 24 hours, concentrated in vacuo, and purified on silica gel (ethyl acetate-hexane, 1:2) to give 1-((9-hydroxy-9H-fluoren-9-yl)carbonyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide. HPLC=99%, R.T.=3.69 min, method A; M+1=576.2.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([NH2:8])=[O:7])[CH2:3][CH2:2]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br.O>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:8][C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(N(CC2CC2)C(N)=O)cc1
Agent: Br
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(c1ccccc1)NC(=O)N2CC1CC1
Yield: 79.8 %

Procedure:
To a suspension of 28.6 g (0.13 mole) of N-cyclopropylmethyl-N-(p-methoxyphenyl) urea in 140 g of toluene were added 13.8 g (0.13 mole) of benzaldehyde and 0.55 g (0.0033 mole) of a 48% hydrobromic acid. The resulting mixture was heated under relux for 10 hours with stirring using a water separator. Thereafter the solvent was removed under reduced pressure and the residue was suspended in a mixture of 80 ml of methanol and 40 g of a 2% hydrochloric acid. The mixture was cooled with ice with stirring. The precipitated crystals were collected by filtration, washed with a mixture of methanol-2% hydrochloric acid (2:1) and then with water, and dried to give 32.0 g (80%) of 1-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinone, m.p. 133° C.
Reaction SMILES: [Si]([O:8][CH:9]([C:24]1[O:25][C:26]([I:29])=[CH:27][N:28]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[I:29][C:26]1[O:25][C:24]([CH:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:28][CH:27]=1
Reactant: COc1cccc(CCCCCCC(O[Si](C)(C)C(C)(C)C)c2ncc(I)o2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(CCCCCCC(O)c2ncc(I)o2)c1
Yield: 88 %

Procedure:
2-(1-(tert-Butyl dimethylsilyloxy)-7-(3-methoxyphenyl)heptyl)-5-iodooxazole (0.088 g, 0.166 mmol) was dissolved in tetrahydrofuran (2 mL) under an atmosphere of argon with stirring and 1 M tetrabutylammonium fluoride (in tetrahydrofuran) (0.199 mL, 0.199 mmol) was added. The reaction was allowed to proceed over 90 minutes before dilution with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the desired product was purified as an oily white solid in 88% yield (0.061 g) using flash column chromatography with silica (0-30% ethyl acetate:hexanes gradient mobile phase): 1H NMR (500 MHz, CDCl3) δ 7.17-7.20 (m, 1H), 7.07 (s, 1H), 6.76 (d, J=7.5 Hz), 6.72 (m, 2H), 4.77 (q, 1H), 3.79 (s, 3H), 3.24 (bs, 1H), 2.57 (t, 2H), 1.80-1.93 (m, 2H), 1.58-1.62 (m, 2H), 1.43-1.48 (m, 1H), 1.30-1.42 (m, 5H); 13C NMR (150 MHz, CDCl3) δ 170.52, 159.48, 144.32, 135.05, 129.11, 120.79, 114.13, 110.80, 110.74, 86.84, 67.48, 55.07, 35.89, 35.21, 31.16, 29.03 (2 C), 24.84; HRMS (ES+) mile calc'd for [M+H]+ C17H23INO3: 416.0717. found 416.0699.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][NH:35][C:16]([C@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccccc1
Product: CON=C1C[C@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 94% purity by HPLC. MS(ESI+): m/z=472.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[F:11][C:12]1[CH:25]=[CH:24][C:15]2[S:16][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:18]([CH3:19])[C:14]=2[CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:20]([C:17]2[S:16][C:15]3[CH:24]=[CH:25][C:12]([F:11])=[CH:13][C:14]=3[C:18]=2[CH3:19])(=[O:22])=[O:21])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Solvent: c1ccncc1
Product: CCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 46.6 %

Procedure:
This compound was prepared in analogy to Example 1, starting from 4-bromo-2-ethylaniline (CAS:45762-41-2, 2.0 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.265 g) in pyridine (2.0 ml) for 4 h to obtain the desired compound (0.20 g) as a colorless solid. MS (ISP): 445.0, 447.0 (M+NH4)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH2:32]([O:34][C:35](=[O:48])[C@@H:36]([O:45][CH2:46][CH3:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:48])[C@@H:36]([O:45][CH2:46][CH3:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:11][CH2:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:40][CH:39]=1)[CH3:33]
Reactant: Cc1ccc(C(=CCO)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(C)cc2)c2ccc(C)cc2)cc1)OCC
Yield: 39.5 %

Procedure:
Reaction of 3,3-di-(4-methylphenyl)-prop-2-en-1-ol (1.0 g, 4.20 mmol), tributylphosphine (1.27 g, 6.30 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1.10 g, 4.62 mmol) and azodicarboxylic dipiperidide (1.59 g, 6.30 mmol) in an identical manner to example 3 gave the title compound (0.76 g, 39%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.O(CC)CC.C([Li])CCC.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:26]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:16]=[CH:17][CH:18]=[CH:19]2)[OH:27]
Reactant: O=Cc1ccc2ncccc2c1
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc2ncccc2c1)c1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a stirred and cooled (-5/0° C.) solution of 5.4 parts of thiophene in 21.3 parts of 1,1'-oxybisethane were added portionwise 43.5 parts of a solution of n. butyllithium in hexanes 1.6M. After stirring for 20 min. at 0° C., there was added a solution of 5 parts of intermediate 16, namely 6-quinolinecarboxaldehyde, in 71.2 parts of tetrahydrofuran. Stirring at 0° C. was continued for 1 hour and then the reaction mixture was poured into 200 parts of ice-water. The product was extracted with 1,1'-oxybisethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 2.4 parts (31.1%) of α-(2-thienyl)-6-quinolinemethanol (interm. 17).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>CCCCC.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:29]#[N:30])=[O:7])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCC
Solvent: ClCCl
Product: N#CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
4-Fluorobenzoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.829 g of 4-fluorobenzoyl chloride (98%, Aldrich) (11.54 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.8 mL of trimethylsilyl cyanide (13 mmol) were added to a 100-mL round bottom flask. To this solution 0.29 mL of tin (IV) chloride (2.5 mmol) was added. On addition of the tin (IV) chloride, the color of the solution changed from clear to dark yellow and within 4 min the color of the solution was dark brown. The reaction mixture was stirred for 2 hr at room temperature, then quenched with 90 mL of ice-cold water, and finally extracted with two 90-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 90-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation. The dark brown residue which resulted was stirred with pentane. The pentane solution was decanted and the pentane removed by rotary evaporation to yield 0.911 g of 4-fluorobenzoyl cyanide as a yellow oil. The product was further purified by Kugelrohr vacuum distillation which afforded 0.666 g (39%) of 4-fluorobenzoyl cyanide as a colorless oil that solidified on standing in the freezer: IR (CCl4) (partial) 2220, 1685, 1600, 1505, 1410 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:11](C(O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C1C2C(=CC=CC=2)C=CC=1O.[H-].[Na+:27]>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O-:1].[Na+:27]
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Product: [O-]c1ccc2ccccc2c1

Procedure:
2-hydroxynaphthalene-3-carboxylic acid is important as an intermediate for pigments or dyes. Generally, the compound is synthesized by reacting β-naphthol with sodium hydride to give sodium β-naphtholate, reacting the resulting compound with carbon dioxide under pressure to give sodium 2-hydroxynaphthalene-3-carboxylate and then, isolating the desired compound by means of acid precipitation i.e. by adding a mineral acid to the salt.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1)[C:3]1[CH:4]=C([CH:8]=[CH:9][CH:10]=1)C#N.[OH-:17].[Na+].Cl.[CH2:20]([OH:22])[CH3:21]>CO.C(Cl)Cl>[CH3:1][N:2]([C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1)[C:3]1[CH:4]=[C:21]([CH:8]=[CH:9][CH:10]=1)[C:20]([OH:17])=[O:22]
Reactant: [OH-]
Reactant: CCO
Reactant: CN(c1cncnc1)c1cccc(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(c1cncnc1)c1cccc(C(=O)O)c1
Yield: 89 %

Procedure:
Compound 16 (0.735 g, 3.50 mmol, 1.00 eq) was dissolved in ethanol (15 mL) and 1N NaOH (7.5 mL) was added. The mixture was refluxed for 18 h and after cooling the reaction was neutralized with 1N HCl (7.5 mL) and the reaction was concentrated in vacuo. The crude reaction was dissolved in 10% MeOH/CH2Cl2 and the undissolved salt was filtered off and the solvents were removed in vacuo to afford 0.710 g (89%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.45 (s, 2H), 7.69-7.64 (m, 2H), 7.48 (t, J=8.3 Hz, 1H), 7.43-7.39 (m, 1H), 3.34 (s, 3H); [M+1]+: 230.2.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][C:8]2[N:9]=[C:10]([O:30][CH2:31][CH2:32][CH3:33])[C:11]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][CH:26]5[CH2:28][O:27]5)=[C:19]([CH3:29])[CH:18]=4)[O:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1>CO>[NH2:1][CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:20]1[C:19]([CH3:29])=[CH:18][C:17]([C:15]2[O:14][C:12]3[N:13]=[C:8]([CH2:7][C:6]4[CH:34]=[CH:35][C:3]([Cl:2])=[CH:4][CH:5]=4)[N:9]=[C:10]([O:30][CH2:31][CH2:32][CH3:33])[C:11]=3[N:16]=2)=[CH:22][C:21]=1[CH3:23]
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4CO4)c(C)c3)nc12
Reactant: N
Solvent: CO
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CN)c(C)c3)nc12
Temperature: 60 °C

Procedure:
5 ml of a 7 N solution of ammonia in methanol were added to 100 mg of crude 5-(4-chloro-benzyl)-2-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine. The mixture was heated to 60° C. for 6 h. Then the solvent was removed in vacuo and the residue was purified by silica gel chromatography (method SC1) to give 44 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][NH2:17])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[C:18](O)(=O)[CH3:19].[OH2:22]>C(O)C>[F:1][C:2]1[C:15]([NH:16][NH:17][CH:19]2[CH2:18][CH2:2][CH2:3][CH2:4][C:5]2=[N:6][OH:22])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Reactant: O
Reactant: CC(=O)O
Solvent: CCO
Product: C#CCN1C(=O)COc2cc(F)c(NNC3CCCCC3=NO)cc21

Procedure:
To a solution of 7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6-ylhydrazine (2.5 g) and enaminoxime (2.5 g) in ethanol (50 g), acetic acid (0.1 g) was added, and the resultant mixture was heated under reflux for 3 hours. After completion of the reaction, water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with ether to give 2-[2-(7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)hydrazino]cyclohexanone oxime (4.0 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:20])[C:8]=1[Br:21])(=O)=O.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:13]([N:10]1[CH:11]=[CH:12][C:7]([C:31]#[C:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:8]([Br:21])[C:9]1=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1c(Br)c(OS(=O)(=O)C(F)(F)F)ccn1Cc1ccccc1
Reactant: C#Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1c(Br)c(C#Cc2ccccc2)ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g) in DMF (5.0 mL) was added phenylacetylene (0.4 mL) and degassed using house vacuum. The reaction flask was then purged with argon, added diisopropylethylamine (0.53 mL), and PdCl2(PPh3)2 (0.35 g) were added. The resulting mixture was stirred at room temperature for 15 min and heated at 65° C. under an argon atmosphere for 3 h. The dark colored reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and 5% aqueous citric acid (25 mL). The organic extracts were washed with water, dried (Na2SO4), filtered, and concentrated to dryness. The resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent. The appropriate fractions were combined, concentrated under reduced pressure. 1H NMR (CDCl3) δ: 7.57 (m, 2H), 7.38 (m, 8H), 7.21 (d, 1H, J=6.8 Hz), 6.25 (d, 1H, J=6.8 Hz), and 5.16 (d, 2H), ES-MS: m/z=364 (MH+);
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[C@H:13]([OH:20])[CH2:12][N:11]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[Li+].[OH-].Cl>C1COCC1>[C:24]([O:23][C:21]([N:11]1[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C@H:13]([OH:20])[CH2:12]1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C(C(=O)O)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(2S,5S)-1-tert-butyl 4-methyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-5,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate 101, 4.22 g, 10.51 mmol) was dissolved in THF (64.0 mL) and water (32 mL) and then LiOH (0.277 g, 11.56 mmol) was added and stirred at rt overnight. The reaction mixture was acidified with 1N HCl, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated to obtain the desired product (4.07 g, 100%) as a transparent oil.