Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCCOCc1ccccc1
Reactant: Cc1ccccc1C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1C1(OCCCCOCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
1 g (3.79 mmol) of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate dissolved in 5 ml of N,N-dimethylformamide is added dropwise to a suspension of 455 mg (11.4 mmol) of 60% sodium hydride in oil, precooled to 20° C. After stirring for 15 minutes, 2.77 g (11.4 mmol) of 4-benzyloxybutyl bromide are added and stirring is continued for 15 hours at room temperature. The reaction medium is hydrolysed with water and then extracted with ethyl acetate. The organic phase is washed three times with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue obtained is purified by chromatography on silica gel eluted with a heptane/ethyl acetate mixture, the polarity being increased from 100/0 to 90/00. 1.43 g of tert-butyl 3-(4-benzyloxybutoxy)-3-o-tolylazetidine-1-carboxylate are obtained in the form of a colourless oil in a yield of 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (6.37 g, 24.5 mmol) was dissolved in dichloromethane (100 mL) at -78° C. and treated with 4-methylmorpholine (5.5 mL, 50 mmol, 2.0 eq.) and benzoyl chloride (3.0 mL, 25.8 mmol, 1.05 eq. ). The solution was allowed to warm to 0° C. and stir for 2 hours. The reaction mixture was washed with 1N HCl and 5% NaHCO3, and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (300 g) with a gradient from ethyl acetate to 10% methanol in dichloromethane to give 6.32 g (71%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[F:68][CH:69]1[CH2:74][CH2:73][N:72]([CH2:75][CH2:76][NH2:77])[CH2:71][CH2:70]1>CN(C=O)C>[F:68][CH:69]1[CH2:74][CH2:73][N:72]([CH2:75][CH2:76][NH:77][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:71][CH2:70]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCCN1CCC(F)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (151 mg, 0.3 mmol), triethylamine (0.084 mL, 0.6 mmol) and BOP reagent (199 mg, 0.45 mmol) in DMF (0.5 mL) was added 2-(4-fluoro-piperidin-1-yl)-ethylamine (48 mg, 0.32 mmol) in DMF (0.5 mL). The mixture was stirred at rt for overnight. After the usual workup, the residue was purified on a silica gel column to give 90 mg (47%) of the titled compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.O.[CH2:36]([OH:40])[CH2:37][CH2:38][CH3:39]>>[CH2:36]([O:40][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCO
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Temperature: 50 °C

Procedure:
A suspension of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (525 g) in n-butanol (5.25 L) was treated with potassium carbonate (210 g) at 20±5° C. The mixture was heated to 50±5° C. overnight until the reaction was complete by HPLC. Acetic acid (1.57 L) was added dropwise, to control any gas evolution, keeping the temperature at 50±5° C. Water (3.67 L) was then added over 30 min keeping the temperature at 50±5° C. to allow full crystallisation to occur. The slurry was then cooled to 20-25° C. and aged for at least 1 hour. The resulting product was then filtered under vacuum and washed with a mixture of n-butanol (787 mL), acetic acid (236 mL), and water (551 mL) followed by water (2×1.57 L). The product was then dried at up to ca50° C. under vacuum to yield the title compound. Yield, 457 g, 88.4% of theory. The title compound was found to be identical to that of Example 10.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][O:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCC1CCCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCOC1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:31]1([CH2:36][CH2:37][C:38](Cl)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:38](=[O:39])[CH2:37][CH2:36][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Reactant: O=C(Cl)CCC1CCCC1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)CCC3CCCC3)ccc2O1

Procedure:
The titled compound was prepared following the procedure B using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride as a white foam (80%). 1H NMR (CDCl3, 300 MHz) δ 7.67 (m, 1H), 7.42 (m, 4H), 7.31 (m, 2H), 7.17 (d, J=7.9 Hz, 2H), 7.06 (m, 1H), 6.89 (d, J=8.7 Hz, 1H), 4.86 (s, 2H), 2.06 (m, 2H), 1.73 (s, 6H), 1.66-1.39 (m, 9H), 0.95 (m, 2H). M+ (ESI): 542.1. HPLC, Rt: 5.83 min (Purity: 97.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.[N+:18]([O-])([OH:20])=[O:19].[OH-].[NH4+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,2,3,4-Tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.0 g) is dissolved in a mixture of concentrated sulfuric acid (3 ml) and water (2 ml). The resulting solution is cooled in an ice bath and concentrated nitric acid (1 ml) is added. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is poured over ice and made basic with aqueous ammonium hydroxide solution. The product is filtered off and washed with water. Recrystallization from ethanol gave the product (535 mg), mp 200°-205° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].C(O)=O>>[OH:21][C:20]1[N:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:28])=[CH:24][N:23]=2)[N:18]=[CH:17][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][C:12]=1[CH3:31]
Reactant: CN1CCNCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-methylpiperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (22 mg, 0.055 mmol, 43.8%) as a white solid. MS: 403 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 2.43 (s, 3H) 3.28-3.70 (m, 8H) 7.62 (d, J=8.1 Hz, 1H) 7.68 (s, 1H) 7.90 (d, J=8.1 Hz, 1H) 8.02 (dd, J=8.6, 2.3 Hz, 1H) 8.08 (s, 1H) 8.43 (d, J=8.6 Hz, 1H) 8.52 (d, J=2.0 Hz, 1H) 12.74 (br. s., 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([CH:8]2[O:14][CH2:13][CH2:12][O:9]2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C2OCCO2)cc1
Reaction time: 2 h

Procedure:
To a mixture of 4-nitrobenzaldehyde (7.55 g, 50 mmol) and ethyleneglycol (4.65 g, 75.0 mmol) in toluene (125 ml) was added 4-toluenesulphonic acid (100 mg, 0.5 mmol) and the mixture heated under reflux using a Dean-Stark water separator for 2 h. The solution was evaporated to dryness, the residue dissolved in EtOAc (125 ml), washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. The residue was dissolved in ethanol (200 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature. The catalyst was removed by filtration, the ethanol evaporated to yield the title compound which was used without further purification.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@@H:12]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1[O:34][CH3:35])(=O)C1C=CC=CC=1.N>CO>[CH3:35][O:34][C@@H:11]1[C@H:10]([OH:9])[C@@H:14]([CH2:15][OH:16])[O:13][C@H:12]1[N:25]1[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Agent: N
Solvent: CO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Yield: 97.7 %

Procedure:
3',5'-Di-O-benzoyl-2'-O-methyl-5-fluorouridine (9.6 g, 20 mmoles) was dissolved in methanol (350 ml) which had been previously saturated with ammonia at -20° C. The solution was sealed in a stainless steel bomb at room temperature for 17 hours and then concentrated to an oil under reduced pressure. The oil was chromatographed on silica gel (200 g) using ethyl acetate to give 5.4 g (98%) of 2'-O-methyl-5-fluorouridine as a white solid. A portion (0.5 g) was crystallized from ethyl acetate/toluene to yield 0.4 g of white needles as the analytical sample, mp 151°-152° C. (lit. M. J. Robins, et. al., J. Am. Chem. Soc., 89, 7381 (1976)., mp 144°-147° C.). 1H NMR (DMSO-d6): δ 3.39 (s, 3H, OCH3), 3.5-3.7 (m, 2H, H-5'), 3.7-3.9 (m, 2H, H-3',4'), 4.13 (m, 1H, H-2'), 5.18 (d, J=6 Hz, 1H, 3'--OH), 5.35 (br t, 1H, 5'--OH), 5.81 (dd, 1H, H-1'), 8.35 (d, J=7 Hz, 1H, H-6), 11.40 (br d, 1H, N--H). Anal. Calcd for C10H13N2O6 (276.22): C, 43.48; H, 4.74; N, 10.14. Found: C, 43.56; H, 4.63; N, 10.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[OH:13][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(O)CCC2
Reaction time: 2 h
Yield: 102.6 %

Procedure:
7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-one (5 g) was dissolved in methanol and sodium tetrahydroborate (1.3 g) was added thereto at 0° C. After reacting at room temperature for 2 hr, the reaction solution was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to give the title compound (5.19 g) as a colorless oil. (280-2) 1-(4-Acetylpiperazin-1-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:27]I>ClCCl.C(Cl)(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([N:18]2[CH:2]([CH2:3][I:27])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine (0.102 g, 0.27 mmol) (from Example 18, Step E, supra) in dichloromethane (20 mL) was added I2 (0.69 g, 2.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with chloroform (100 mL) and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated to give the desired 4-(3-chloro-4-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a yellow foam. (Yield 0.134 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:14][C:13]([C:6]1[O:7][C:8]([C:10]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)=[O:9])=[O:15]
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
To a solution of 6-chloro-4-phenylisocoumarin-3-carboxylic acid (9 g) in methanol (200 ml) was added sulfuric acid (20 ml) and the mixture was refluxed for 2 hrs. The reaction mixture was concentrated, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was crystallized from isopropyl ether to give the title compound (8.7 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][O:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12]I)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]1[C@@H:8]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1)=[O:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)COC(CI)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1COCc1ccccc1
Temperature: 25 °C

Procedure:
To [(S)-1-benzyloxymethyl-2-(2-iodo-1,1-diphenylethoxy)-ethyl]-carbamic acid tert-butyl ester (4.74 g, 8.07 mmol) in N,N-dimethylformamide (70 mL) at room temperature add sodium hydride (0.452 g, 11.3 mmol, 60% dispersion in mineral oil). Heat reaction mixture to 60° C. for 4 hours, cool to room temperature and dilute with ethyl acetate (˜400 mL). Wash with water and saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify on silica gel eluting with 0:100 to 20:80 ethyl acetate:hexanes to give the desired compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19].[OH-:20].[Na+].[OH-].[K+]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][C:11]([OH:19])=[O:20]
Reactant: O=C1Cc2ccccc2N1c1c(Cl)cc(O)cc1Cl
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cc(O)cc1Cl
Temperature: 0 °C

Procedure:
The 2-[(2,6-dichloro-4-methoxyphenyl)amino]phenylacetic acid (0.1 mol) from example 22 was added in portions to a melt of 200 g of pyridine hydrochloride (1.75 mol) at 170° C. The mixture was heated at 180° C. for 3 h and poured onto 2000 ml of ice water while hot. The precipitated product was filtered off, washed with water, and dissolved in 1000 ml of ethyl acetate. The organic phase was washed with 200 ml of 1N HCl in water (2×100 ml) and evaporated to give N-(2,6-dichloro-4-hydroxyphenyl) oxindole. To a solution of 8 g of N-(2,6-dichloro-4-hydroxyphenyl)-oxindole in 200 ml of n-butanol were added 7 g of NaOH and 1 g of KOH, and the reaction mixture was refluxed for 24 h and evaporated in vacuo. The residue was dissolved in 700 ml of water and the aqueous solution was extracted with ether (2×200 ml), cooled to 0° C., and acidified with concentrated HCl. The precipitate was taken up in 300 ml of ether. The organic phase was washed with 30 ml of water, 0.5N NaHCO3 (5×80 ml), and 80 ml of 2N KHCO3 solution. The combined NaHCO3 extracts were cooled to 0° C. and acidified with 2N HCl, and the precipitate was dissolved in 200 ml of ether. The organic layer was washed with 30 ml of water and evaporated to yield 2-[(2,6-dichloro-4-hydroxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][OH:7])[CH:8]=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: OCCc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 3-hydroxyphenethyl alcohol (6.0 g, 43.4 mmol) in 275 mL of CH2Cl2 was added 6.55 g (43.4 mmol) of TBDMS-Cl (tert-butyldimethylsilyl chloride), cooled to 0° C., then added 7.0 mL (86.8 mmol) of pyridine. The reaction mixture was stirred at ambient temperature overnight. Upon concentration, the crude mixture was purified by silica gel flash chromatography (eluted with hexane then 5% EtOAc/hexane) to provide 8.9 g of a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.04 (m, 1H), 6.60 (m, 3H), 3.73 (t, J=6.9 Hz, 2H), 2,65 (t, J=6.9 Hz, 2H), 0.83 (s, 9H), −0.03 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Br:8][C:5]1[N:4]=[N:3][C:2](/[N:1]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(Br)nn1
Product: CN(C)/C=N/c1ccc(Br)nn1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
3-Amino-6-bromopyridazine (5.0 g, 28.7 mmol) was heated and stirred with dimethylformamide dimethylacetal (5.36 g, 6.0 mL, 45.0 mmol) under nitrogen at 110° C. for 3 h. The brown homogeneous reaction mixture was cooled to room temperature. The resulting heterogeneous slurry was stirred in EtOAc/hexanes (1:1, 75 mL) and filtered. The filtered solid was suction dried to obtain apparently (E)-N′-(6-bromopyridazin-3-yl)-N,N-dimethylformimidamide (4.9 g) as a pale pink crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 3.11 (s, 3H), 3.00 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O: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]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A solution of 10.0 g (0.0383 mole) of 1-(methylthio)-4-(4-nitrophenoxy)benzene and 7.76 g (0.0383 mole) of 85% 3-chloroperbenzoic acid dissolved in 500 ml of CH2Cl2 was stirred at ambient temperature for 3 days. The reaction mixture was extracted with aqueous K2CO3, water and dried (Na2SO4). Removal of solvent in vacuo afforded 10.3 g (97.2% yield) of product. Recrystallization from 2-propanol yielded purified 1-(methylsulfinyl)-4-(4-nitrophenoxy)benzene, mp 76°-78° C.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][CH:7]([C:10]3[CH:19]=[C:18]4[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:16][N:17]4[CH:20]4[CH2:22][CH2:21]4)=[CH:12][C:11]=3[F:29])[CH2:6]2)[O:4]CC1>C(O)C.Cl>[O:4]=[C:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([OH:25])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:29])[CH2:6]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(C3CCC4(C3)OCCO4)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: O=C1CCC(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 191.9 %

Procedure:
A solution of 20 g (50 mmol) of 7-(1,4dioxaspiro[4.4]non-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, ethyl ester in 150 ml of ethanol and 100 ml of 6.0 M hydrochloric acid was heated at reflux for 6 hours. The solvent was removed in vacuo to give 31.6 g of the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.[CH3:13][C:14]1[N:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25]#[N:26])[C:18](=[O:24])[NH:19]2>O>[CH3:13][C:14]1[N:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25](=[N:2][OH:3])[NH2:26])[C:18](=[O:24])[NH:19]2
Reactant: NO
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nccc2[nH]c(=O)c(C(N)=NO)cc12
Yield: 96.3 %

Procedure:
To a solution of hydroxylamine hydrochloride (4.17 g) in water (50 ml) was added sodium carbonate (3.18 g) with stirring under ice cooling. To the solution were subsequently added ethanol (200 ml) and 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile (3.70 g), and the mixture was refluxed for 2 hours. After distilling off the solvent under reduced pressure, water was added to the residue, and the precipitated crystals were separated by filtration. The product was washed with water, isopropanol, diisopropyl ether in this order, and dried to give 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridin-3-amidoxime (4.2 g). This compound was used in the next reaction without being purified.