Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1.Cl>O1CCOCC1>[F:35][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(F)F)sc3cc(O)ccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccccc3C(F)F)sc3cc(O)ccc23)cc1
Temperature: 50 °C
Yield: 18.3 %

Procedure:
To a solution of afford (E)-tert-butyl 3-(4-((2-(2-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100 mg, 0.202 mmol) in 1,4-dioxane (3.0 mL) was added 4.0M aq. HCl (0.202 mL, 0.809 mmol). The resulting mixture was warmed to 50° C. and stirred at that temperature for 2 b after which time the reaction was quenched by addition of sat. aq. NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the resulting crude material was purified by reverse phase HPLC (basic conditions, 0.1% NH4OH in CH3CN/H2O) to afford (E)-3-(4-((2-(2-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (16.7 mg, 0.037 mmol, 19% yield). 1H NMR (400 MHz, CD3OD) δ ppm=7.72-7.64 (m, 1H), 7.54-7.42 (m, 4H), 7.39 (d, J=8.7 Hz, 2H), 7.33-7.24 (m, 2H), 7.00 (d, J=55.2 Hz, 1H), 6.88 (dd, J=8.7, 2.2 Hz, 1H), 6.81 (d, J=8.9 Hz, 2H), 6.30 (d, J=16.0 Hz, 1H). HRMS (m/z, MH+): 439.0776.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23].O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([F:15])[CH:17]=2)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1F
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cc1F
Temperature: 100 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.6 mmol) and [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (0.85 g, 4.3 mmol) in 1,4-dioxane (12 mL) and 10% sodium carbonate in water (5.73 mL, 5.40 mmol) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (166 mg, 0.144 mmol) was added, the mixture was bubbled with N2 for 5 min. more and heated at 100° C. overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude product.
Reaction SMILES: [CH2:1]([C:3]([CH3:32])([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C>[CH2:1]([C:3]([CH3:32])([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)(CC)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)O

Procedure:
The procedure in Example 6 is followed but using ethyl 2-ethyl-2-methyl-6-[(4,6-diphenyl-2-pyridyl)oxy]hexanoate (3.6 g), potassium hydroxide pellets (0.95 g) dissolved in distilled water (20 cc) and ethanol (50 cc). The reaction mixture is refluxed for 120 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 75-25) and then by recrystallisation in an n-hexane-ethyl acetate (2-1) mixture (40 cc), white crystals (m.p.=119°-120° C.)
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][CH:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[N:3]1[C:4]=23.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:12]=[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2](=[O:1])[N:3]3[CH:14]([CH2:15][N:16]4[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]4)[CH2:13][N:5]1[C:4]=23
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A mixture of 1,1-dimethylethyl {1-[(4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl)methyl]-4-piperidinyl}carbamate (2:1 mixture of R:S) (1.83 g, 4.55 mmol) and DDQ (1.6 g, 6.83 mmol) in 1,4-dioxane (100 ml) was stirred at 60° C. under argon overnight. More DDQ (1.6 g, 6.83 mmol) was added and the reaction was stirred at 60° C. for another 1 h. The reaction was cooled to room temperature, treated with 5% aqueous solution of potassium carbonate (600 ml) and extracted with 20% methanol/dichloromethane (3×500 ml). The combined organic extracts were dried over magnesium sulphate, filtered and evaporated to afford the crude as a brown oil. LCMS showed that there was still ˜8% of starting material left so the oil was combined with more starting material (220 mg) recovered from the aqueous in the previous step and was dissolved in 1,4-dioxane (100 ml), treated with 1 eq. of DDQ and heated at 60° C. for 1 h. LCMS showed that the reaction was not complete so 0.5 g of DDQ was added and the reaction was stirred at 60° C. for 0.5 h. A small work-up showed that the reaction was complete so the reaction was treated with 5% aqueous solution of potassium carbonate (500 ml) and extracted with 20% methanol/dichloromethane (2×500 ml). The combined organic extracts were dried over magnesium sulphate, filtered and evaporated to afford the product as a light brown foam (1 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[OH-:16].[Na+:17]>O>[OH2:13].[OH2:16].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1.[Na+:17]
Reactant: [OH-]
Reactant: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 211.3 g (1.95 mol) of 1,4-phenylenediamine and 3900 ml of tetrahydrofuran. A solution prepared by dissolving 127.2 g (1.30 mol) of maleic anhydride in 600 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 3.3 hours, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was isolated by filtration, washed twice with 280 ml of tetrahydrofuran, and dried to obtain 259.2 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid as a yellow-orange powder. To 259.2 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid was added 520 ml of water and the mixture was cooled to 0 to 10° C., and 237 ml of a 5N sodium hydroxide aqueous solution was dropped, then, 6.5 ml of a 1N sodium hydroxide aqueous solution was dropped. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 200 ml of 2-propanol was added, and the solvent was distilled off under reduced pressure again. To the resultant yellow-brown solid was added 800 ml of tetrahydrofuran and the mixture was stirred at room temperature overnight, the solid was isolated by filtration, and washed four times with 100 ml of tetrahydrofuran and dried at 45° C. for 5 hours, to obtain 297.7 g of sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate di-hydrate as a yellow powder. Yield: 86.7%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>C(O)C>[CH3:15][C:14]1[CH:13]=[C:12]([CH3:16])[NH:11][C:10]=1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:19][N:18]=1
Reactant: NN
Reactant: Cc1cc(C)c(C(=O)c2cccnc2Cl)[nH]1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2n[nH]c3ncccc23)[nH]1
Yield: 46 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone (240 mg, 1 mmol) and hydrazine hydrate (0.7 mL) in ethanol (2 mL) was heated at 100–110° C. for overnight. The reaction was concentrated and purified on a silica gel column to give 97 mg (46%) of the titled compound as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:12]([C:14]2[CH:42]=[CH:41][C:17]([O:18][C@@H:19]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:29]([F:40])[CH:28]=4)[N:23]=3)[CH2:20][CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([C:12]([C:14]2[CH:42]=[CH:41][C:17]([O:18][C@@H:19]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:39]=[CH:38][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:40])[CH:28]=4)[N:23]=3)[CH2:20][CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:11][CH2:10][CH2:9]1
Reactant: CC[C@@H](Oc1ccc(C(=O)C2CCC2)cc1)c1nc(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](Oc1ccc(C(=O)C2CCC2)cc1)c1nc(-c2ccc(C(=O)O)c(F)c2)no1
Reaction time: 1 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a dichloromethane (5 mL) solution of the obtained tert-butyl 4-(5-{(1R)-1-[4-(cyclobutylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluorobenzoate at room temperature, and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the resulting residue was solidified by using hexane:ethyl acetate (5:1, v/v). Thus, the title compound (531 mg, yield: 56%) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])(=[O:12])=[O:11].O[Li].O.Cl>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:11])=[O:12]
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (125 mg, 0.29 mmol) in THF (3 ml) was added a solution of LiOH.H2O (25 mg, 0.59 mmol) in H2O (1 ml). The reaction was stirred at room temperature for 1 hour, acidified with 1M HCl, and was extracted with EtOAc.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CS[C:24]#[N:25].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCCl>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:24]#[N:25])[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CSC#N
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCCCCc1ccc(-c2ccc(O)c(C#N)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(4-n-octylphenyl)phenol (2.82 g) in 1,2-dichloroethane (40 ml) is added a 2M borone trichloride - 1,2-dichloroethane solution (6 ml) under ice cooling, and thereto are further added methyl thiocyanate (0.82 ml) and aluminum chloride (1.33 g). The mixture is stirred at room temperature until aluminum chloride is dissolved, and is further stirred at 80° C. for 3 hours. After cooling, 4N aqueous sodium hydroxide solution (33 ml) is added to the reaction mixture, and the mixture is stirred at 75°-80° C. for 30 minutes. After cooling, the reaction mixture is washed with methylene chloride, and the aqueous layer is adjusted to pH 2 with 6N hydrochloric acid and then extracted with ether. The extract is dried and then ether is distilled off under reduced pressure. The crude crystal thus obtained is purified by silica gel column chromatography to give 4-(4-n-octylphenyl)-2-cyanophenol (2.03 g) of the following formula: ##STR32##
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>[OH-].[Na+]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccccc1Cl
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccccc3Cl)nc2n1
Temperature: 120 °C
Yield: 76.1 %

Procedure:
A mixture composed of 2-amino-7-chloro-1,8-naphthyridine (17.9 g), 2-chlorophenol (51.4 g) and potassium hydroxide pellets (13.2 g; 85% purity) is heated for 4 hours at 120° C. The mixture produced is poured into 4N caustic soda (100 cc), and the precipitate formed is separated by filtration and washed with water until the pH =7. After being dried at 40°C. under reduced pressure (0.067 kPa), 2-amino-7-(2-chlorophenoxy)-1.8 naphthyridine (20.6 g) is produced, m.p. 166° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.Br[C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:19]1([CH2:18][CH2:17][O:16][C:15]2[CH:14]=[C:13]([NH:1][C:2]3[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cnc(N)nc1
Reactant: Brc1cccc(OCCN2CCCC2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2cccc(OCCN3CCCC3)c2)nc1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
Two 20 mL microwave vials were each charged with methyl 2-aminopyrimidine-5-carboxylate (460.0 mg, 3.0 mmol), 1-[2-(3-bromo-phenoxy)-ethyl]-pyrrolidine (811.0 mg, 3.0 mmol), Pd2(dba)3 (110.0 mg, 0.12 mmol), XantPhos (208.3 mg, 0.36 mmol), Cs2CO3 (1.95 g, 6.0 mmol) and anhydrous dioxane (20 mL). The mixture was purged with argon gas for 15 min, then sealed and irradiated in a microwave (Initiator, Biotage) at 180° C. for 60 min. After cooling to room temperature, the cap was removed and the reaction mixtures were combined and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL). Combined EtOAc solutions were washed with H2O (2×100 mL), brine (2×100 mL) and dried over anhydrous Na2SO4. The resulting solution was concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for further purification (80 g column, solid method, 0% to 20% MeOH gradient in DCM, 40 min method). Fractions, containing the product, were combined and concentrated in vacuo to give reddish oil. The oil was re-crystallized from 10 mL of CH3CN to give the title compound as a light-yellow solid (1.07 g, 35% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:2][C:1]2[CH:3]=[CH:4][CH:5]=[C:20]3[C:21]=2[N:16]=[CH:17][CH:18]=[CH:19]3)(=[O:11])=[O:10])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 46 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (0.60 g, 4.16 mmol), 4-cyano-2-nitro-benzenesulfonyl chloride (Intermediate 217) (1.33 g, 5.41 mmol), DMAP (cat), pyridine (5 ml) and DCM (3 ml) gave the title compound (0.65 g, 46%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:18])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])=[N+]=[N-].[ClH:19].[H][H]>[Pd].C(O)C>[ClH:19].[NH2:1][CH2:4][CH:5]([OH:18])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]
Reactant: [N-]=[N+]=NCC(O)CN1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCC(O)CN1C(=O)c2ccccc2C1=O
Reaction time: 6 h

Procedure:
To ethanol solution (240 ml) of N-(3-azido-2-hydroxypropyl)phthalimide 10 g (40.3 mol), 10% Pd—C (1 g) and concentrated hydrochloric acid solution 7.84 ml (80.6 mmol) were added sequentially. To the reaction mixture, hydrogen was introduced at 2 kgf/cm2 atm. and hydrogenated at room temperature for 6 hours. After removal of catalyst by filtration, catalyst was washed with EtOH/DMF (1:1) solution (300 ml) and then combined filtrate was evaporated to dryness. Addition of EtOH to the residue gave crystal of desired product as hydrogen chloride salt. Crystal was collected by filtration and dried under reduced pressure at 40° C. to afford 5.3 g of the product. The NMR spectra were consistent with the desired title intermediate.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:30][CH:31]([F:33])[F:32])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1)=[C:8]2[O:30][CH:31]([F:32])[F:33]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-methanesulfonylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.10 g), methanol (5.0 mL), water (1.0 mL) and saturated aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 45 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol removed under reduced pressured. The residue was diluted with water (2.0 mL) and the resulting precipitate collected by filtration, washed with water and dried to afford title compound as a white solid, 0.075 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([N:10]([CH2:18][CH2:19][OH:20])[C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:18][CH2:19][O:20][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=C(c1c(Cl)ncnc1Cl)N(CCO)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)ncnc2OCCN1c1ccc(I)cc1

Procedure:
A stirred slurry of 4,6-dichloro-N-(2-hydroxyethyl)-N-(4-iodophenyl)pyrimidine-5-carboxamide (543 mg, 1.24 mmol) and potassium carbonate (350 mg, 2.53 mmol) in DMF was heated at 80° C. for 2 hours. The reaction was cooled, filtered, solids washed with small portion of DMF and the combined filtrates were concentrated in vacuo. The residue was chromatographed (40 g of silica gel, 0-70% EtOAc:heptane) to afford 4-chloro-6-(4-iodophenyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one as a white solid, 427 mg. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.80 (d, 2H), 7.17 (d, 2H), 4.77 (m, 2H), 4.03 (m, 2H). m/z=402.0 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH3:16]>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH3:16]
Reactant: CCc1ccc([N+](=O)[O-])cc1CCl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc([N+](=O)[O-])cc1COC
Temperature: 3 °C

Procedure:
Sodium methoxide is added portionwise to a solution of 150.0 g of α-chloro-2-ethyl-5-nitrotoluene in 1.15 l. of methanol maintained between 18° C. and 30° C. The mixture is refluxed for 2 hours, cooled to 3° C., and filtered. The filtrate is concentrated under vacuum and the resulting slurry shaken with saturated aqueous sodium chloride and methylene chloride. The methylene chloride layer is washed, filtered through sodium sulfate, and stirred over magnesium sulfate. The filtered solution is concentrated under vacuum to yield 133.89 g of a dark brown liquid. The crude product is fractionated by vacuum distillation to yield a yellow liquid with boiling point 113° C. to 115° C. at 0.35 mm Hg which solidifies to light yellow prisms with mp 21.5° C. to 23.5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16](F)(F)F)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)([CH3:29])[CH3:28])=[CH:23][CH:22]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>>[CH2:15]([NH:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([NH:35][C:33]1[S:34][C:30]([C:27]([CH3:29])([C:24]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH3:28])=[N:31][N:32]=1)=[O:6])(=[O:13])=[O:12])[CH3:16]
Reactant: O=C(O)c1cc(S(=O)(=O)NCC(F)(F)F)ccc1F
Reactant: CC(C)(c1ccc(F)cc1)c1nnc(N)s1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1ccc(F)c(C(=O)Nc2nnc(C(C)(C)c3ccccc3)s2)c1
Yield: 5.8 %

Procedure:
To 2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]sulfonyl}benzoic acid (intermediate 25)(30.1 mg 0.1 mmol) and above 5-[1-(4-fluorophenyl)-1-methylethyl]-1,3,4-thiadiazol-2-amine (23.7 mg, 0.1 mmol) in 2.0 mL of mixed solvent (DCM:DMF=10:1) were added EDC (19.2 mg, 0.1 mmol) and HOAt (13.6 mg, 0.1 mmol). The resultant mixture was stirred at room temperature for overnight, and then concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-[(ethylamino)sulfonyl]-2-fluoro-N-[5-(1-methyl-1-phenylethyl)-1,3,4-thiadiazol-2-yl]benzamide (2.6 mg).