Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2]>C(#N)C.C(O)CCC=C>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7]([O:8][CH2:7][CH2:6][CH2:5][CH:10]=[CH2:9])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C=CCCCO
Solvent: CC#N
Product: C=CCCCO[C@@H]1C[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(C)=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.2 %

Procedure:
A solution of 3,4,6-tri-O-acetyl-D-galactal (3.6 g) in acetonitrile (40 ml) anhydrous lithium bromide (4.7 g), 4-pentene-1-ol (4 ml), molecular sieves 4 Å (4 g) and the activated resin prepared as in Example 1 (5.1 g) was stirred at room temperature for 30 min. The product was isolated as described in Example 1 and purified on a column of Silica Gel using ethyl acetate-hexane (1:6) as eluant and yielded the title compound (2.92 g) and minor β-glycoside (0.32 g). [α]D20 (α-anomer)=+126°±2° (c 1.03, CHCl3); [α]D20 (β-anomer)=-9.4°±2° (c 1.03, CHCl3) 1H NMR δ (α anomer): 5.81 (m, --CH=C), 5.33 (d, H-1), 5.28 (m, H-3), 4.94-5.06 (m, H-4, C=CH 2), 4.16-4.06 (H-6a,b, H-5), 3.65 and 3.40 (m, O-CH2 -), 2.1 (m, H-2eq), 1.86 (m, H-2ax) MS (calc. mass for C17H26O8 =358.17). Obs. m/e 571.33, 357.21, 299.19, 273.05, 213.11.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([P:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([SH:17])=[S:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([P:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([S:17][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: BrCc1ccccc1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Product: S=P(SCc1ccccc1)(C1CCCCC1)C1CCCCC1

Procedure:
Benzyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain benzyl dicyclohexylphosphinodithioate, m.p. 107°14 108° C, which on testing lasted 350 hours longer than the control. The total number of hours required to reach failure was 1.9 times that of the control.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[C:15](/[C:16](/O)=[CH:17]\[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[O:38]1[CH2:43][CH2:42][CH:41]([C:44](=[S:46])[NH2:45])[CH2:40][CH2:39]1>CC(N(C)C)=O.O>[Cl:9][C:10]1[C:15]([C:16]2[N:45]=[C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)[S:46][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: NC(=S)C1CCOCC1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Temperature: 25 °C
Yield: 50.1 %

Procedure:
Recrystallized NBS (1.56 g, 8.8 mmol) was added to a suspension of N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (4.02 g, 8.80 mmol) in DMA (15 mL) in an ice-bath. The reaction was immediately removed from the ice bath and allowed to warm to rt over 0.5 h. Tetrahydro-2H-pyran-4-carbothioamide (1.27 g, 8.80 mmol) was added and the reaction warmed in an oil bath (rt to 65° C.). The reaction was diluted with water (100 mL) which caused the precipitation of a yellow solid. The solid was then dissolved by the addition of EtOAc (100 mL) and the phases separated. The aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was filtered through Whatman 1 PS (phase separating) paper and concentrated under vacuum to a crude orange residue. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give the title compound of Step A as a bright yellow solid (2.56 g; 50.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 7.62-7.74 (m, 1H), 7.48-7.57 (m, 2H), 7.42-7.47 (m, 1H), 7.22 (t, J=9.1 Hz, 2H), 6.54 (d, J=5.3 Hz, 1H), 3.92 (d, J=11.0 Hz, 2H), 3.41-3.51 (m, 2H), 2.03 (br. s., 2H), 1.69-1.83 (m, J=12.1, 12.1, 11.9, 4.2 Hz, 2H).
Reaction SMILES: [C:1]([Si:5]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:6][CH2:7][CH:8]([CH3:33])[O:9][C:10]1[CH:11]=[C:12]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)([CH3:4])([CH3:3])[CH3:2].Cl.C[N:46](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>CCCCCC.C(OCC)(=O)C>[C:1]([Si:5]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:6][CH2:7][CH:8]([CH3:33])[O:9][C:10]1[CH:11]=[C:12]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:46])=[O:21])=[CH:15]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Reaction time: 9 h
Yield: 68.6 %

Procedure:
A mixture of 7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (2.0 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.19 g), 1-hydroxybenzotriazole ammonium salt (943 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 9 hr. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with aqueous citric acid solution, water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio) to give the title compound (1.37 g, yield 69%) as an orange oil. MS 643 (MH+).
Reaction SMILES: O=O.[C:3]1([CH:9]([OH:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pt].O>[C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(O)c1ccccc1
Agent: [Pt]
Agent: O=O
Solvent: O
Product: CC(=O)c1ccccc1
Yield: 82 %

Procedure:
In an ambient pressure oxygen atmosphere, 121 μl of 1-phenyl ethanol and 173.7 mg of the platinum catalyst obtained in Example 1 were agitated for twenty-four hours at 60° C. in 10 ml of water. The reaction mixture was subsequently extracted using ethyl acetate, and the organic layer was dried using magnesium sulfate and filtered to obtain 98.9 mg (82% yield) of acetophenone. The reaction equation and the analytical results of the product are shown below.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:36]([CH3:37])=[CH:35][C:12]([C:13]([NH:15][CH2:16][C:17](OCC)([O:29]CC)[C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:19]=2)=[O:14])=[CH:11][C:10]=1[CH2:38][CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.Cl>[CH2:1]([O:8][C:9]1[C:36]([CH3:37])=[CH:35][C:12]([C:13]([NH:15][CH2:16][C:17]([C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:19]=2)=[O:29])=[O:14])=[CH:11][C:10]=1[CH2:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CNC(=O)c1cc(C)c(OCc2ccccc2)c(CC)c1)(OCC)c1cc(C)nc(NC(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)NCC(=O)c2cc(C)nc(NC(C)C)n2)cc(C)c1OCc1ccccc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 108.6 %

Procedure:
To a solution of 4-benzyloxy-N-[2,2-diethoxy-2-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethyl]-3-ethyl-5-methyl-benzamide (346 mg, 0.65 mmol) in THF (8 mL), 25% aq. HCl (500 μL) is added and the mixture is stirred at 65° C. for 18 h. The mixture is cooled to 0° C., neutralized by adding 1 N aq. NaOH solution and extracted twice with EtOAc. The combined org. extracts are dried over Na2SO4, filtered and concentrated to give crude 4-benzyloxy-3-ethyl-N-[2-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-2-oxo-ethyl]-5-methyl-benzamide (325 mg) as a yellow oil; LC-MS: tR=0.94 min, [M+H]+=461.13.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7](=[S:9])[NH2:8].[CH2:10]([O:12][C:13](=[O:22])[CH:14](Cl)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13]([C:14]1[S:9][C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:22])[CH3:11]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=S)c1ncccn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ncccn2)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 2-pyrimidinecarbothioamide (2 g) and 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (3.2 g) in 10 mL of DMF is heated at 110° C. with stirring overnight. The mixture is concentrated under vacuum, and purified on silica gel column to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@@:13]3([CH3:45])[O:14]C(=O)C3C=CC=CC=3)[N:9]=[C:10]([I:11])[C:3]=12>N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@@:13]3([CH3:45])[OH:14])[N:9]=[C:10]([I:11])[C:3]=12
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1nc(I)c2c(N)ncnc21
Agent: N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1nc(I)c2c(N)ncnc21
Yield: 79.9 %

Procedure:
A solution of compound 1.4 (540 mg, 0.75 mmol) in MeOHic NH3 (120 mL, saturated at 0° C.) was stirred in a bomb at 45° C. for 16 hr. The mixture was evaporated to dryness and then the residue co-evaporated with additional MeOH. Purification by silica gel column chromatography using 6-14% MeOH in dicholoromethane as eluent gave the desired compound 1.5 (244 mg) as an off-white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26]C)[CH:19]=2)(=[O:17])=[O:16])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9]C>C(Cl)Cl.B(Br)(Br)Br>[OH:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:26])[CH:19]=2)(=[O:17])=[O:16])(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: CCCCCCN(S(=O)(=O)c1ccc(OC)c(OC)c1)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCN(S(=O)(=O)c1ccc(O)c(O)c1)S(=O)(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a 0° C. solution of N-(3,4-dimethoxyphenylsulfonyl)-N-hexyl-3,4-dimethoxybenzenesulfonamide (0.080 g, 0.181 mmol) in 1.81 mL of CH2Cl2, boron tribromide (1.81 mL, 1M in CH2Cl2) was added dropwise under a nitrogen atmosphere. The resulting solution was allowed to stir overnight and warm to room temperature. Upon quenching with a few drops of water, a precipitate formed and was filtered. The solid was triturated with ethyl acetate and the filtrate was evaporated, affording 0.046 g (65%) of N-(3,4-dihydroxyphenylsulfonyl)-N-hexyl-3,4-dihydroxybenzenesulfonamide as white solid. 1H NMR (acetone-d6, 400 MHz) δ 7.43 (d, J=2.3 Hz, 2H), 7.34 (dd, J=2.3, 8.2 Hz, 2H), 6.97 (d, J=8.2 Hz, 2H), 3.58 (m, 2H), 1.61 (m, 2H), 1.22 (m, 6H), 0.81 (t, J=6.9 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 150.61, 145.17, 131.03, 121.33, 115.07, 115.06, 49.01, 31.10, 26.05, 22.30, 13.42; HRMS, ES calcd. for C18H23NO8S2Na[M+Na]+468.0763, found: 468.0755.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14][OH:15].C1(C)C=CC(S(NN)(=O)=O)=CC=1.O.O.O.C([O-])(=O)C.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCC=Cc1ccc2ccccc2c1Br
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCc1ccc2ccccc2c1Br
Yield: 74.9 %

Procedure:
A solution of Example 3C (3.82 g, 14.5 mmol) in DMF and para-toluene- sulfonhydrazide (27 g, 145 mmol) was heated to reflux and treated with sodium acetate trihydrate (32.8 g, 241 mmol) in water (380 mL) over 3 hours. The mixture was allowed to stir at reflux for 2 hours, cooled, partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4), filtered, concentrated and purified on silica gel with a gradient of CH2Cl2 to 2% methanol/CH2Cl2 to provide 2.88 g (75%) of the desired compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:18][CH2:19][S:20][CH3:21])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].[OH:22]O>CO>[OH:1][CH:2]([CH2:18][CH2:19][S:20]([CH3:21])=[O:22])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CCCCCCCCCCCCOC(=O)C(O)CCSC
Reactant: OO
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of dodecyl 2-hydroxy-4-(methylthio)butanoate (20 g, 62.8 mmol) in methanol (100 mL) was added 30% hydrogen peroxide (20.0 mL, 176 mmol) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for about 3 hrs. The reaction was mildly exothermic. Analysis indicated the reaction was completed within two hours. Water (400 mL) was added to the mixture. The mixture was extracted with EtOAc (2×100 mL). The extracts were combined and washed with a 10% sodium bisulfite solution (100 mL). The organic phase was dried with anhydrous magnesium sulfate and the solvent was evaporated with a rotary evaporator. A colorless viscous liquid was obtained which solidified upon standing to give a white solid (20.6 g, 98%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=6.83 Hz, 3 H) 1.20-1.34 (m, 18 H) 1.53-1.62 (m, 2 H) 1.81-1.92 (m, 1 H) 1.98-2.07 (m, 1 H) 2.53 (d, J=4.13 Hz, 3 H) 2.60-2.90 (m, 2 H) 3.99-4.11 (m, 2 H) 4.12-4.19 (m, 1 H) 5.63 (dd, J=5.88, 2.38 Hz, 1 H). m/z 335 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[S:22][CH3:21])[CH2:34][CH2:33]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CSc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2ccccc2SC)CC1
Yield: 61.4 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=O)[O:9]C(=O)[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][NH2:15]>O>[NH2:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]([NH:15][CH3:14])=[O:9]
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: CN
Solvent: O
Product: CNC(=O)c1c(N)cccc1F
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A round-bottomed flask was charged with 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (500 mg, 2.8 mmol) and 30 mL water. The reaction was stirred for 15 min and then methylamine was added. The reaction was then stirred for 2 h. It was then extracted three times with ethyl acetate. Organic layers were combined and dried over sodium sulfate, then concentrated. The product was identified as 2-amino-6-fluoro-N-methylbenzamide (365 mg, 2.4 mmol, 86% yield). MS: M(C8H9FN2O)=168.17, (M+H)+=169.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([OH:31])=O)[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH3:68])=[O:74])=[O:31])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)O)c4)c3)cc2)c1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic acid (Example 123) (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46 mg, 0.33 mmol). The mixture was stirred for another 10 minutes, and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoate as off-white solid. Yield: 115 mg, 97%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23](=[O:35])[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](=[O:34])[NH2:33])[CH3:21].N1C=CC=CC=1>ClCCl.CN(C=O)C.C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:25]([CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:35])[C:26]2[C:27]([C:32](=[O:34])[N:33]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2
Reactant: O=C(O)CCc1cccc(F)c1F
Reactant: CCOC(=O)CNc1ccccc1C(N)=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 3-(2,3-difluorophenyl)-propionic acid (Int. A1) (5 g, 26.9 mmol) in anhydrous dichloromethane (50 ml) containing a few drops of DMF was added oxalyl chloride (4.7 ml, 53.8 mmol) at 0° C. under argon. The solution was then stirred at ambient temperature for 2 h and the solvent removed in vacuo. The residue which contained the acid chloride (Int. A54) was dissoved in toluene (50 ml) and added to a slurry of (2-carbamoylphenylamino)-acetic acid ethyl ester (5.0 g, 22.5 mmol) in toluene (50 ml) containing pyridine (1 ml) and 4-dimethylaminopyridine (DMAP) (100 mg). After 16 h at 90° C. the solvent was evaporated and the solid residue washed with water, aqueous ammonia and ether to give the title compound (6.9 g, 82%) as a cream solid. 1H-NMR (DMSO) δ 1.24 (3H, t), 3.13 (2H, t), 3.34 (2H, m), 4.24 (2H, q), 5.48 (2H, s), 7.19 (1H, m), 7.29-7.35 (2H, m), 7.60-7.72 (2H, m), 7.94 (1H, t), 8.19 (1H, d); MS (APCI+) found (M+1)=373; C20H18F2N2O3 requires 372.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[Na+:26].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([O-:13])(=[O:12])=[O:11].[Na+:26]
Reactant: OB(O)c1cccs1
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1c(-c2cccs2)cc(Br)cc1S(=O)(=O)[O-]
Temperature: 0 °C

Procedure:
A mixture of 36 g (95.3 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 12.2 g (95.3 mmol) of 2-thienylboronic acid in 140 ml of 1,2-dimethoxyethane in the presence of 5.5 g of tetrakis(triphenylphosphine)palladium (0) and 30.3 g of sodium carbonate is heated at 70°-75° C. for 8.5 hours. The solvent is evaporated off under vacuum, the mixture is cooled to 0° C. and washed with water to pH=7, and the residue is then taken up in an ether/ethanol mixture (95:5).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.O.NN>C(O)C>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:2]1[C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccccc1-c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCOc1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-[6-(2-biphenyloxy)hexyl]phthalimide (15.1 g), ethanol (400 ml) and hydrazine hydrate (30 ml) was heated at reflux for 4 hours, cooled to room temperature, filtered, and evaporated to dryness. The material that remained was stirred with dichloromethane (500 ml), filtered and evaporated to yield 1-amino-6-(2-biphenyloxy) as an oil, which was converted to the hydrochloride salt, (m.p. 86°-88° CC.) according to the method of Example IV.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([Cl:13])[C:5]=1[N+:14]([O-])=O)([O-])=O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:14][C:5]1[C:6]([Cl:13])=[C:7]([Cl:12])[C:8]([Cl:11])=[C:9]([Cl:10])[C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(N)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
1,2-Diamino-3,4,5,6-tetrachlorobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 1,2-dinitro-3,4,5,6-tetrachlorobenzene (1.00 g, 3.27 mmol) and SnCl2 ·2H2O (3.69 g, 16.4 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 80° C. for 1 h. The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was adding (foaming ) to bring the pH to 6. The thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a brown solid 569 mg (71%). 1H NMR (CDCl3) δ3.96 (br s, 2(NH2)). 13C NMR (CDCl3) δ118.2, 127.0, 132.0.
Reaction SMILES: [C:1]1([C:7]2[O:8]C3C=C(C(O)=O)C=CC=3N=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2OC3C=C(C(OC)=O)C=CC=3N=2)C=CC=CC=1.[Li+].[OH-].[ClH:40]>C1COCC1.CO.O>[C:7]([Cl:40])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: O=C(O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Phenyl-benzooxazole-6-carboxylic acid, 1v. A mixture of methyl 2-phenyl-benzooxazole-6-carboxylate 1u (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1t (0.34 g).