Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:12]([C:14]3[S:18][C:17]([C:19]4[O:23][C:22]5[CH:24]=[CH:25][C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:27][C:21]=5[N:20]=4)=[CH:16][CH:15]=3)=[N:13][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[S:32](=[O:36])(=[O:35])([OH:34])O>>[S:18]1[C:14]([C:12]2[O:11][C:8]3[C:9]([S:32]([OH:34])(=[O:36])=[O:35])=[CH:10][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][C:7]=3[N:13]=2)=[CH:15][CH:16]=[C:17]1[C:19]1[O:23][C:22]2[C:24]([S:32]([OH:36])(=[O:35])=[O:34])=[CH:25][C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:27][C:21]=2[N:20]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)c1ccc2oc(-c3ccc(-c4nc5cc(C(C)(C)C)ccc5o4)s3)nc2c1
Product: CC(C)(C)c1cc(S(=O)(=O)O)c2oc(-c3ccc(-c4nc5cc(C(C)(C)C)cc(S(=O)(=O)O)c5o4)s3)nc2c1

Procedure:
One hundred milliliters of 20% fuming sulfuric acid is charged into a 500 mL Erlenmeyer flask. With magnetic stirring, 60 g of BBOT is added in small portions. The reaction is exothermic. After the addition is complete, the reaction mixture is heated to 90°-100° C. for two hours. The reaction is then quenched by pouring the reaction mixture onto 500 g of crushed ice. A brown product precipitates as a fine powder. The product is collected on a fritted-glass Buchner funnel. The product is then washed by stirring it in 200 mL of 1N hydrochloric acid. Washing is prepared several times. The product is then dried in a vacuum oven at 60°-70° C. Typical yields are 75-80 g (89-93%).
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]>[Ni].C(O)(C)C.N>[NH2:2][CH2:1][C:3]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1(C#N)CCOCC1
Agent: [Ni]
Agent: N
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1(CN)CCOCC1
Reaction time: 36 h

Procedure:
A mixture of tert-butyl (4-cyanotetrahydro-2H-pyran-4-yl)carbamate (59 g, 260 mmol) and Raney Nickel (25 g) in isopropanol and ammonia (700 mL) was stirred under a hydrogen atmosphere. After 36 hours, the solids were filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from DCM (60 mL) to afford tert-butyl [4-(aminomethyl)tetrahydro-2H-pyran-4-yl]carbamate. MS ESI calc'd. for C11H23N2O3 [M+H]+ 231. found 231. 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 1H), 3.77 (d, J=11.6 Hz, 2H), 3.66-3.60 (m, 2H), 2.94 (s, 2H), 1.97-1.94 (d, J=13.6 Hz, 2H), 1.57 (m, 2H), 1.44 (s, 9H), 1.28 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][C:17]=3[F:27])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[F:27])=[CH:28][CH:29]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(F)c1
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-fluorophenyl)acetate (32 mg, 0.072 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.072 ml, 0.36 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-fluorophenyl)acetic acid (15 mg, 48% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.25 (d, 2H), 7.19 (m, 3H), 7.10 (m, 2H), 6.95 (d, 2H), 3.65 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][CH2:17][CH2:18][C:19]([CH3:24])([N+:21]([O-:23])=[O:22])[CH3:20])(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[K+].Cl>C(O)C.O>[C:1]([NH:4][CH:5]([CH2:16][CH2:17][CH2:18][C:19]([CH3:24])([N+:21]([O-:23])=[O:22])[CH3:20])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CCCC(C)(C)[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NC(CCCC(C)(C)[N+](=O)[O-])C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Diethyl 2-acetylamino-2-(4-methyl-4-nitropentyl)malonate (193.5 g, 558.5 mmol) was dissolved in ethanol (270 ml), and potassium hydroxide (51 g, 781.9 mmol) was dissolved in water (250 ml) and added. The mixture was stirred at 90° C. for 1 h, and potassium hydroxide (51 g, 781.9 mmol) was dissolved in water (250 ml) and added. The mixture was stirred at the same temperature for 2 h. The mixture was cooled to 40° C. and concentrated hydrochloric acid was added to adjust the solution to pH 1.5, which solution was stirred overnight at 80° C. Ethanol was evaporated by concentration under reduced pressure and the residue was ice-cooled. The precipitated crystals were separated, and the obtained slurry was washed with ethyl acetate (200 ml) and dried under reduced pressure to give the objective compound (99.6 g, yield 72%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:31][C:32]([NH:34][C:35](=[O:39])[O:36][CH2:37][CH3:38])=C)=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[C:27]5[CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23][C:22]=5[N:21]=[CH:20][N:19]=4)[CH2:13][C:12]=3[CH:30]=2)[CH:7]=1>O1CCCC1.[Hg]=O>[CH3:28][C:25]1([CH3:29])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:14]3[CH2:13][C:12]4[CH:30]=[C:8]([C:6]5[CH:7]=[C:2]6[NH:1][C:32]([NH:34][C:35](=[O:39])[O:36][CH2:37][CH3:38])=[N:31][C:3]6=[N:4][CH:5]=5)[CH:9]=[CH:10][C:11]=4[O:17][CH2:16][CH2:15]3)[C:27]=2[CH2:26]1
Reactant: C=C(NC(=O)OCC)Nc1ncc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cc1N
Agent: O=[Hg]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1
Temperature: 70 °C
Reaction time: 24 h
Yield: 7.8 %

Procedure:
A mixture of ethyl [1-({3-amino-5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2-yl}amino)ethenyl]carbamate (82 mg, 0.15 mmol) and mercury(II) oxide (33 mg, 0.15 mmol) in tetrahydrofuran (8 mL) was stirred at 70° C. for 24 h. On cooling to room temperature, the mixture filtered then concentrated and the residue purified by preparative reverse phase HPLC to afford the title Compound (6 mg, 3% yield over 2 steps) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 8.51 (s, 1H), 8.49 (d, 1H), 8.22 (d, 1H), 7.72 (d, 1H), 7.66 (dd, 1H), 7.09 (d, 1H), 5.17 (s, 2H), 4.48 (m, 2H), 4.36 (q, 2H), 4.33 (m, 2H), 2.85 (m, 2H), 2.60 (s, 2H), 1.69 (m, 2H), 1.38 (t, 3H), 0.95 (s, 6H); MS (EI) for C28H31N7O3: 514 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]3[C:12](=[C:13]([NH2:15])[N:14]=[C:5]2[CH:4]=1)[N:11]=[CH:10][CH:9]=[CH:8]3)=[CH2:2]>CCO.C(Cl)Cl.[Pd]>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]3[C:12](=[C:13]([NH2:15])[N:14]=[C:5]2[CH:4]=1)[N:11]=[CH:10][CH:9]=[CH:8]3)[CH3:2]
Reactant: C=Cc1ccc2c(c1)nc(N)c1ncccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCc1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-vinylbenzo[f][1,7]naphthyridin-5-amine (1.0 eq) (from Example 91) and Pd/C (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The Pd/C was filtered off through celite, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-60% EtOAc/Hexanes to give 8-ethylbenzo[f][1,7]naphthyridin-5-amine as a white foam: 1H NMR (acetone-d6): δ 8.98 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.82 (dd, 1H), 7.46 (d, 1H), 7.22 (dd, 1H), 6.63 (br s, 2H), 2.78 (q, 2H), 1.30 (t, 3H). LRMS [M+H]=224.1.
Reaction SMILES: C1(C)C=CC([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=CC=1.[OH-].[Na+].[C:21]1(C)C=CC=CC=1>C(OC(=O)C)C>[CH3:21][N:9]1[N:8]=[CH:7][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1ncc2ccccc2c1=O
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-p-toluyl-phthalazin-1-(2H)-one [compound 2D] (2.36 g, 10 mMol) in toluene (50 mL) were added 2:5 N aqueous NaOH (4 mL) and Triton B (1 mL) followed by 2-(4'-bromomethylbiphenyl)-t-butylsulfonamide [prepared according to the procedure described in U.S. Pat. No. 5,126,342] (4.2 g, 11 mMol). The mixture was stirred at 85° C. for 12 h and then cooled to room temperature. The reaction was diluted with ethylacetate (100 mL), and the organic phase was washed with water (3×50 mL), and then dried over MgSO4. The ethylacetate layer was filtered and concentrated in vacuo to a small volume (~10 mL). Dry ether (100 mL) was added and the precipitate formed was filtered and dried. The crude product was then recrystallized from hot ethylacetate to give the desired product 4-p-toluyl-2-(2'-t-butylaminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one as white crystalline solid (4.3 g).
Reaction SMILES: [C:1]1(=O)OC(=O)C2=CC=CC=C12.[Al+3].[Cl-].[Cl-].[Cl-].C(B(CC)CC)C.[C:23]([C:28]1[CH:44]=[CH:43][C:31]([C:32]([C:34]2[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=2[C:36]([OH:38])=[O:37])=[O:33])=[CH:30][CH:29]=1)([CH2:26][CH3:27])([CH3:25])C>C(C1C=CC=CC=1)(CC)(C)C>[CH:23]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:34]2[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=2[C:36]([OH:38])=[O:37])=[O:33])=[CH:43][CH:44]=1)([CH:26]([CH3:1])[CH3:27])[CH3:25]
Reactant: CCC(C)(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CCB(CC)CC
Agent: CCC(C)(C)c1ccccc1
Agent: [Al+3]
Product: CC(C)C(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
74 g (0.5 mole) of phthalic anhydride and 134 g (1.10 moles) of AlCl3 were reacted with 20 g (0.2 mole) of triethylboron in 74 g of tert-amylbenzene for 8 hours, as described in Example 1. After the mixture had been worked up in a conventional manner, 127 g (86% of theory) of a mixture of 2-(4'-tert-amylbenzoyl)-benzoic acid and 2-(4'-sec-isoamylbenzoyl)-benzoic acid (tertiary/secondary ratio=60:40) were obtained.
Reaction SMILES: [F:1][C:2]([F:17])([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:16])[NH:14][CH3:15])[CH2:9][CH2:8]1)[C:3]([OH:5])=O.[NH2:18][CH2:19][C:20]([N:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][O:32][C:33]2[C:41]3[N:40]=[C:39]([O:42][CH3:43])[N:38]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:37]=3[CH:36]=[CH:35][CH:34]=2)[C:25]=1[Cl:51])[CH3:23])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:51][C:25]1[C:26]([CH2:31][O:32][C:33]2[C:41]3[N:40]=[C:39]([O:42][CH3:43])[N:38]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:37]=3[CH:36]=[CH:35][CH:34]=2)=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[N:22]([CH3:23])[C:20](=[O:21])[CH2:19][NH:18][C:3](=[O:5])[C:2]([F:1])([F:17])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([NH:14][CH3:15])=[O:16])[CH2:9][CH2:8]1
Reactant: CNC(=O)N1CCN(CC(F)(F)C(=O)O)CC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Agent: F[B-](F)(F)F
Product: CNC(=O)N1CCN(CC(F)(F)C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CC1

Procedure:
2,2-difluoro-3-(4-(methylcarbamoyl)piperazin-1-yl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide are coupling using TBTU as described for compound 1 to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-2,2-difluoro-3-oxopropyl)-N-methylpiperazine-1-carboxamide. LCMS (APCI) 733 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[NH:9][CH:5]([C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=32)[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2>[Si]([O-])([O-])([O-])[O-].[Ag+].[Ag+].[Ag+].[Ag+].C1C=CC=CC=1>[NH:9]1[CH:8]2[C:2](=[O:1])[C:3]3[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=3[CH:5]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=12
Reactant: OC1c2ccccc2C2NC1c1ccccc12
Agent: [Ag+]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C2NC1c1ccccc12
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
A mixture of 1.5 g of 11-hydroxy-10,11-dihydro-5,10-imino-[5H]-dibenzo (a,d) cycloheptene dl cis, 60 ml of benzene and 3 g of silver silicate was refluxed with stirring for 45 minutes and then 1.5 g of silver silicate were added and reflux was continued for another hour. The mixture was filtered hot and the filter was washed with methylene chloride. The combined filtrates were washed with 2N hydrochloric acid and the acid phase was made alkaline with sodium hydroxide. The mixture was extracted with methylene chloride and the organic phase was dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 95-5 mixture of chloroform-methanol to obtain 780 mg of 10,11-dihydro-5,10-imino-[5H]-dibenzo (a,d) cycloheptene-11-one dl melting at 100° C identical to that of Example 1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]2[O:10][CH2:9][NH:8][C:7](=[O:11])[C:6]=2[CH:12]=1.I[C:16]1[CH:17]=[C:18](C)[C:19]([NH2:22])=[N:20][CH:21]=1>>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([N:8]2[C:7](=[O:11])[C:6]3[CH:12]=[C:2]([F:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:17][CH:18]=1
Reactant: CNc1cc2c(cc1F)C(=O)NCO2
Reactant: Cc1cc(I)cnc1N
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Yield: 13.6 %

Procedure:
Analogous to the procedure described in Ex. 40, 6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.100 g, 0.51 mmol) and 5-iodo-3-methylpyridin-2-amine (0.119 g, 0.53 mmol) were coupled to yield pure 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.020 g, 13%) after reverse phase HPLC purification. ES-MS (M+H)+=303.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Nc1ccccc1

Procedure:
0.6 g (2.46 mmol) of 4,6-dichloro-3-nitro-quinoline (step c)) and 0.247 ml (2.71 mmol) of aniline in 4 ml of acetic acid are stirred at room temperature for 4 h (tlc-control). A precipitate is formed. The reaction mixture is poured into 150 ml of water. The solid is filtered off and washed with water and hexane. The filtrate is dissolved in ca. 50 ml of diethylether, filtered from insoluble material, and the solvent is evaporated. The residue (title compound, yellow crystals) is dried at 60° C. overnight. mp: 174-175° C.; ES-MS: m/e0=300.
Reaction SMILES: [CH3:1][C:2]([C:5]1O[C:7]([O:10]CC)=[CH:8][N:9]=1)([CH3:4])[CH3:3].[C:13](#[N:16])[CH:14]=[CH2:15]>>[C:13]([C:14]1[CH:15]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:9]=[CH:8][C:7]=1[OH:10])#[N:16]
Reactant: C=CC#N
Reactant: CCOc1cnc(C(C)(C)C)o1
Product: CC(C)(C)c1cc(C#N)c(O)cn1
Temperature: 20 °C
Yield: 36.9 %

Procedure:
A neat mixture of 2-(1,1-dimethylethyl)-5-ethoxyoxazole (17 g., 0.1 mole) and acrylonitrile (6.1 g., 0.11 mole) is stirred and heated at 70°-75° C. for 16 hours. The resulting dark reaction mixture is cooled to 20° C. and chromatographed on silica gel (600 g.). Elution with 1% methanol in chloroform (4.35 l.) yields recovered 2-(1,1-dimethylethyl)-5-ethoxyoxazole (10.7 g., 63% recovery). Continued elution with the same eluant (300 ml.) affords impure product (3.2 g.). Further elution with the same eluant (2.5 l.) gives the desired product as a solid (6.5 g., 37%), m.p. 185°-195° C. Two recrystallizations of the latter from methanol-water (1:1; v:v) provides an analytical sample of 4-cyano-6-(1,1-dimethylethyl)-3-pyridinol as colorless crystals (4.5 g., 26%), m.p. 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[O:19]CC.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[OH:19]
Reactant: CCOc1ccc(Sc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Sc2ccc(O)c(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the compound from Example 17 (10 g., 0.029 mole) in 400 ml. of methylene chloride was treated with 8.52 g. of AlCl3 all at once at 0°. The reaction mixture was stirred overnight at room temperature and an additional 3.87 g. of AlCl3 was added. Stirring was continued for an additional 3 hours at which time 3.87 g. of AlCl3 was again added. After stirring for 41/2 hours, the mixture was poured into 800 ml. of crushed ice and the precipitate filtered. The solid was washed with ethanol and dried to give 8.67 g. of product, m.p. 204°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH2:13]([O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[C:26](Cl)=[O:27])[CH3:14]>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:26]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[O:15][CH2:13][CH3:14])=[O:27])[CH:3]=1
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Reactant: Brc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ccccc2c1C(=O)n1cc(Br)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
3-Bromo-7-azaindole (500 mg, 2.0 mmol) 3 was dissolved in N,N-dimethylformamide (50 mL) and sodium hydride (210 mg, 5.3 mmol, 60% dispersion in mineral oil) and 2-Ethoxy-naphthalene-1-carbonyl chloride (710 mg, 3.0 mmol) were added. The reaction mixture was stirred at ambient temperature for 30 min, cast into ice water (100 mL) and extracted into ethyl acetate. The organic portion was dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated. Purification via column chromatography (10% Ethyl acetate in hexanes) provided the desired product 85 (800 mg, 80%).
Reaction SMILES: Br.[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17](=N)[NH2:18].C(=O)([O-])[O-].[K+].[K+].O.C(S(C1[CH2:37][C:36]([CH3:39])([CH3:38])[O:35]N=1)(=O)=O)C>C(O)C.CN(C)C=O>[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17]1[CH2:37][C:36]([CH3:39])([CH3:38])[O:35][N:18]=1
Reactant: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 1.93 g (5.00 mmol) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrobromide in 10 ml of ethanol were added 0.83 g (6.00 mmol) of anhydrous potassium carbonate and 5 ml of water, followed by 30 minutes of stirring at room temperature. Thereto were added a solution of 0.95 g (5.00 mmol) of 3-ethanesulfonyl-5,5-dimethyl-2-isoxazoline in 5 ml of N,N-dimethylformamide and 0.83 g (6.00 mmol) of anhydrous potassium carbonate at room temperature, followed by further 3 hours of stirring at 50° C. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. The obtained residue was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1.55 g (yield: 86.1%) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline.
Reaction SMILES: [CH3:1][P:2]([CH:7]([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[CH3:8])(=[O:6])[O:3]CC.[OH-].[K+]>C(O)C.O>[CH3:1][P:2]([CH:7]([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[CH3:8])(=[O:3])[OH:6]
Reactant: CCOP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate (1.1 g) in ethanol (10 ml) is added potassium hydroxide (0.5 g) in water (15 ml). The mixture is stirred at RT for 4 hours. The ethanol is removed, and the aqueous solution is acidified and extracted with ether. The combined extracts are dried and evaporated to dryness to give P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-ethylphosphinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][C:17]\2=[O:18])=[N:9][N:8]=[N:7]1)=[O:4].[BH4-].[Na+]>>[CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:16][CH:17]\2[OH:18])=[N:9][N:8]=[N:7]1)=[O:4]
Reactant: COC(=O)Cn1nnnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)Cn1nnnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Yield: 67.9 %

Procedure:
Following a procedure similar to that described in Example 150-(d), (E)-3-{[1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (Example 150-(c), 2.2 g) was reduced with sodium borohydride. Purification gave the title compound (1.5 g, yield: 68%) as a pale yellow amorphous solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:38][CH2:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCC3CCOCC3)c2C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (350 mg, 0.65 mmol, example 1b) was dissolved in DMF (2 mL). 4-Aminomethyltetrahydropyran (74.4 mg, 0.65 mmol) was added and the reaction mixture was stirred at 80° C. for 6 h. The solvent was evaporated under reduced pressure and the crude was used in the next step as such. MS (ES+) m/z 507.3 (M+H)+