Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[CH:5]([NH:8]C(C)C)(C)[CH3:6].C(#N)C.[CH2:15]([O:22][C:23]1[CH:30]=[C:29]2[C:26]([CH2:27][C:28]2([S:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24]=1[O:40][CH3:41])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C.O1CCCC1>[NH2:32][C:31]([C:28]1([S:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:27][C:26]2[C:29]1=[CH:30][C:23]([O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:24]([O:40][CH3:41])[CH:25]=2)=[CH:6][C:5]#[N:8]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C#N)(Sc1ccccc1)C2
Reactant: CC(C)NC(C)C
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc2c(cc1OCc1ccccc1)C(Sc1ccccc1)(C(N)=CC#N)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a stirred solution of ethylmagnesium bromide (3.0 mL of a 3M solution in diethyl ether, 9.0 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. under nitrogen is added diisopropylamine (2.5 mL, 17.8 mmol). The mixture is stirred at 0° C. for 1 hour and acetonitrile (0.25 mL, 4.8 mmol) and a solution of 4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (0.83 g, 2.2 mmol) in anhydrous tetrahydrofuran (3 mL) are added successively, and the resulting mixture is stirred for an additional hour. The reaction is quenched with aqueous ammonium chloride and the product is extracted with ethyl acetate. The extract is washed with brine, dried over anhydrous sodium sulfate and evaporated to yield a solid. The crude product is purified by silica gel chromatography, utilizing a 9:1 to 4:1 gradient of hexane/ethyl acetate to yield 0.527 g of 3-amino-3-(4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-trien-7-yl)acrylonitrile as a white solid, mp 122-125° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-methyl-2-nitrophenol (2.0 g, 13.06 mmol) in acetic acid (40 mL) was added bromine (0.70 mL, 13.71 mmol) and the mixture was stirred at RT for 5 h. The reaction was poured in to ice water and the yellow precipitate formed was filtered and washed with water and dried in vacuo to yield 4-bromo-3-methyl-2-nitrophenol. 1H NMR (400 MHz, CDCl3) δ=2.61 (s, 3H), 2.62 (s, 5H), 6.92 (d, J=8.84 Hz, 1H), 7.66 (d, J=9.09 Hz, 1H) and 9.28 (s, 1H); MS (ES+): m/z 215.00 [M-17].
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[OH-].[Na+]>[Br:1][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[OH:3])[C:11](=[O:14])[NH:10][N:9]=[CH:8]2
Reactant: BrBr
Reactant: O=c1[nH]ncc2ccc(O)cc12
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]ncc2cc(Br)c(O)cc12
Reaction time: 2 h

Procedure:
Bromine (20 g, 0.25 mole) was added to a stirred solution of 7-hydroxy-1(2H)phthalazinone (10g, 0.062 mole) in aqueous sodium hydroxide (2N, 140 ml), and the stirring was continued for two hours. An excess of sodium metabisulphite was added to the reaction mixture, and the precipitate was filtered off, washed with water and dried. This solid was suspended in acetic anhydride (17 ml) and was heated on a steam-bath for 30 minutes, and the solution was treated with charcoal, filtered and allowed to cool. The cooled mixture was filtered to give 7-acetoxy-6-bromophthalazone, which had m.p. 200°-201° after recrystallisation from ethanol. 7-Acetoxy-6-bromophthalazone was heated with 5% aqueous sodium hydroxide until a clear solution was obtained. The cooled solution was neutralised and the precipitate was filtered off to give 6-bromo-7-hydroxy-1(2H)-phthalazinone, m.p. > 320° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:20])[N:11]([CH2:18][OH:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[P:21](Cl)(=[O:32])([O:30][CH3:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[P:21]([O:30][CH3:31])([O:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:20])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reactant: COP(=O)(Cl)OCc1ccccc1
Product: COP(=O)(OCc1ccccc1)OCN1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21

Procedure:
The title compound was prepared from (3Z)-3-[(3,5-Dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one and benzyl methyl phosphorochloridate (modification of procedure used to prepare {3(Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}methyl acetate).
Reaction SMILES: [C:1]12([O:16][CH2:15][CH2:14][O:13]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=O)[CH2:2]2.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C=CC=CC=1>C(Cl)Cl>[C:1]12([O:16][CH2:15][CH2:14][O:13]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:2]2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Solvent: ClCCl
Product: CCOC(=O)C=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To the stirred solution of (R)-3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carbaldehyde (4.1 g, 18.79 mmol) in DCM (10 mL), ethyl 2-(triphenyl phosphoranylidene)acetate (7.85 g, 22.54 mmol) was added and reaction mixture was stirred at RT for 16 h. After completion of reaction, reaction mixture was concentrated under vacuum to get 5.5 g of crude compound. This crude compound was further purified by flash chromatography (Biotage) using eluent hexane/ethyl acetate 80:20 to get the title compound (2.5 g, 46.2% yield); m/z 288.34
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2c3ccccc3CNc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of 5,11-dihydro-10H-dibenz [b,e][1,4]diazepine 1.9 g of 4-[(2-methylbenzoyl) amino]benzoyl chloride, 4 ml of triethylamine and 0.2 g of 4-(dimethylamino)pyridine in 60 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is poured into ice water and the separated organic layer washed with 50 ml each of water, 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and the solvent removed to give a residue. The residue is chromatographed on a silica gel column using 1:4 ethyl acetatehexane to give 1.8 g of the desired product as a solid, m.p. 68°-71° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(OCC)(=O)C>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (600 mg, 2.24 mmol) obtained in Example 81 was dissolved in pyridine (4.0 ml) and acetic anhydride (0.40 ml, 4.24 mmol) was added under ice-cooling and stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed with water and dried over magnesium sulfate. The solvent was distilled out under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:30) and recrystallized to yield the titled compound (574 mg, 82%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2([NH:18][C:19]([C:21]3([NH:24][C:25]([C:27]4[N:31]5[C@@:32]([CH2:45][C:46]6[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=6)([CH3:44])[C:33](=[O:43])[N:34]([C:35]6[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=6)[C:30]5=[N:29][CH:28]=4)=[O:26])[CH2:23][CH2:22]3)=[O:20])[CH2:17][CH2:16]2)[CH:10]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2([NH:18][C:19]([C:21]3([NH:24][C:25]([C:27]4[N:31]5[C@@:32]([CH2:45][C:46]6[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=6)([CH3:44])[C:33](=[O:43])[N:34]([C:35]6[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=6)[C:30]5=[N:29][CH:28]=4)=[O:26])[CH2:22][CH2:23]3)=[O:20])[CH2:16][CH2:17]2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C2(NC(=O)C3(NC(=O)c4cnc5n4[C@](C)(Cc4ccc(C#N)cc4)C(=O)N5c4cc(Cl)cc(Cl)c4)CC3)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN)ccn5)CC4)CC3)n21
Yield: 164.3 %

Procedure:
(2-{1-[(1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropyl}-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (45 mg, 0.06 mmol) was placed in RBF with CH2Cl2 and TFA was added. The reaction was diluted with 10 mL 10% MeOH/CH2Cl2 and washed with water (2×5 mL). The organic layer was separated, dried (MgSO4), and concentrated. Reverse Phase HPLC purification (30-100% CH3CN/H2O as gradient) yielded 66 mg of the title compound as a bis-TFA salt, m/z=669.5 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[O:8][CH:7]=1)=[O:5])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=[O:12])[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1coc(C=O)c1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
5-Hydroxymethyl-3-furancarboxylic acid ethyl ester (0.34 g, 2.0 mmol) was dissolved in dichloromethane (20 mL), manganese dioxide (1.4 g, 15.9 mmol) was added, and the mixture was stirred overnight. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound (0.26 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]2[C:8]=1[CH:14]=[CH:15][CH:17]=[N:7]2
Reactant: OCC(O)CO
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(Cl)c2cccnc12
Yield: 67 %

Procedure:
In a similar fashion using route 10 general procedure 20, 5-chloro-4-fluoro-2-nitroaniline (1.0 g, 5.2 mmol), glycerol (1.5 g, 16.2 mmol), 3-nitrobenzensulfonic acid sodium salt (1.52 g, 6.7 mmol) and H2SO4/H2O (6 ml, 7:5) gave the title compound (790 mg, 67%) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:10][N:11]=[C:12]([CH2:14][O:15][CH3:16])[N:13]=2)[CH:3]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].O>C(O)(=O)C>[Cl:17][CH2:18][C:19]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]1[NH:10][N:11]=[C:12]([CH2:14][O:15][CH3:16])[N:13]=1)=[O:20]
Reactant: COCc1n[nH]c(-c2cc(Cl)ccc2N)n1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Solvent: O
Product: COCc1n[nH]c(-c2cc(Cl)ccc2NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.9 %

Procedure:
4-Chloro-2-(5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-phenylamine (60.6 g, 239 mmol) was dissolved in acetic acid (1.2 L) and chloroacetic chloride (40.4 mL, 508 mmol) was added dropwise at 14-16° C. over a period of 30 min. The resulting reaction mixture was stirred for 22 h at ambient temperature. After addition of water (600 mL) and stirring for another 90 min, the solid was filtered off and washed with water (600 mL). Drying in vacuo afforded the title compound (66.2 g, 83%) which was obtained as a yellow solid. MS: m/e=314.9 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=2)[C:23]=1[CH3:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:40])[C:24]([C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1ncccc1-c1nc2cc(F)ccc2c(Cl)c1C
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ncccc1-c1nc2cc(F)ccc2c(N2CC3(CCOCC3)c3ccc(N4CCOCC4)cc32)c1C
Temperature: 100 °C

Procedure:
To a stirred solution of 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (86 mg, 0.31 mmol), 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (90 mg, 0.31 mmol) in toluene (1.7 mL) was added Pd2dba3 (43 mg, 0.047 mmol), XPhos (45 mg, 0.09 mmol) and sodium tert-butoxide (90 mg, 0.94 mmol) and the reaction was heated in the microwave for 1 h at 100° C. After this time the reaction was cooled to rt and treated with EtOAc (100 mL) and water (40 mL). The separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL), dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59-8.67 (1H, m), 7.84-7.94 (1H, m), 7.76-7.83 (1H, m), 7.59-7.69 (1H, m), 7.27-7.34 (2H, m), 7.11-7.18 (1H, m), 6.28-6.47 (1H, m), 5.48-5.70 (1H, m), 3.97-4.09 (2H, m), 3.85-3.94 (1H, m), 3.68-3.80 (4H, m), 3.48-3.63 (2H, m), 2.89-3.05 (4H, m), 2.36-2.44 (3H, m), 2.09-2.25 (2H, m), 2.05 (4H, dd, J=4.5, 2.3 Hz), 1.90 (1H, dt, J=13.7, 1.2 Hz), 1.72-1.81 (1H, m). Mass Spectrum (ESI) m/e=525 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][C:4]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:20][CH3:21])[CH2:3]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:26]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][C:4]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:20][CH3:21])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(O)ccc2S(=O)(=O)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(OCC(=O)OCC)ccc2S(=O)(=O)C1
Yield: 96.7 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051; 100 mg, 0.27 mmol), ethyl bromoacetate (50 mg, 0.30 mmol), sodium carbonate (100 mg, 0.94 mmol) and tetrabutylammonium bromide (10 mg 0.031 mmol) were added to MeCN (4 ml). The mixture was refluxed for 20 h and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel. The product was eluted with DCM: ethyl acetate (50:50). 120 mg (97%) of the title compound was obtained. NMR (300 MHz): 0.7-0.9 (m, 6H), 1.0-1.8 (m, 11H), 3.1-3.25 (m, 2H), 3.6-3.8 (m, 2H), 4.3 (q, 2H), 4.6 (s, 2H), 6.9-7.1 (m, 5H), 7.2-7.3 (m, 2H), 7.5 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1ccccc1S
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccccc2C)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 2-methylbenzenethiol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.94 (s, 3H) 2.32 (s, 3H) 6.79 (s, 1H) 7.58-7.68 (m, 3H) 7.76-7.88 (m, 3H) 7.92 (d, J=8.14 Hz, 1H) 8.18 (d, J=8.24 Hz, 1H) 10.38 (s, 1H) 13.10 (bs, 1H); ESI-MS: m/z calc'd for C20H17N3OS 347.11. found 348.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Li+]>O1CCCC1.CO.O>[OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1sccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1sccc1O
Temperature: 22 °C
Reaction time: 18 h

Procedure:
10.0 g of methyl 3-hydroxy-thiophene-2-carboxylate were dissolved in a mixture of 90 ml of tetrahydrofuran (THF) and 90 ml of methanol, and a solution of 25.2 g of lithium hydroxide in 25 ml of water was added. The reaction mixture was stirred at 22° C. for 18 h and then heated at 55° C. for 6 h. The reaction mixture was concentrated to 50 ml in a rotary evaporator, acidified to pH=1 with 2 molar hydrochloric acid and extracted 3 times with 50 ml of t-butyl methyl ether each time. The combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].[Br:14]Br.II>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][C:2]([C:11]([OH:13])=[O:12])=[CH:1]2
Reactant: BrBr
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: II
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(Br)cccc2c1
Yield: 53.4 %

Procedure:
To a boiling solution of 2-naphthoic acid (10.00 g, 58.14 mmol) in acetic acid (50 mL) is added dropwise bromine (3 mL) containing iodine (0.25 g). After the addition is complete, the solution is refluxed for 0.5 hr. A white precipitate forms during cooling and is isolated by filtration, washed with acetic acid and then water. The solid is triturated in methanol (100 mL) and 7.01 g (53.4% yield) of the desired product is obtained as a white solid. m.p. 248-250° C. 1H NMR (300 MHz, CD3OD): δ 8.94 (d, J=1.8 Hz, 1H), 8.52-8.42 (m, 3H), 8.27 (dd, J=1.8, 7.5 Hz, 1H), 7.79 (t, J=8.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=O)[NH:10][CH:11]=[C:12]([C:15]([NH2:17])=O)[C:13]=3[S:14][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:21].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([Cl:21])=[N:10][CH:11]=[C:12]([C:15]#[N:17])[C:13]=3[S:14][C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1c[nH]c(=O)c2c1sc1cc(Br)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1cnc(Cl)c2c1sc1cc(Br)ccc12

Procedure:
A mixture of 7-bromo-1-oxo-1,2-dihydro[1]benzothieno[3,2-c]pyridine-4-carboxamide and POCl3 (29 equiv) was heated to refluxed for 8 h. The mixture was poured onto ice, neutralized with NaHCO3, filtered, washed with H2O and dried to give a yellow solid. The crude product was heated to reflux with 20% EtOAc in hexanes, cooled and filtered to give the title compound.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:23]=[C:22]([CH3:37])[CH:21]=3)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)C.C1COCC1.Cl>CO>[CH3:37][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:38])=[O:5])=[CH:8][CH:9]=3)=[N:15][CH:16]=2)[CH:25]=[C:24]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][N:28]=2)[CH:23]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(Oc3ccc(C(=O)O)cc3)nc2)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
Sodium hydroxide (1 M in water, 1.41 mL, 1.41 mmol) was added to a solution of ethyl-4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]oxy}benzoate (349 mg, 0.706 mmol) in methanol (3.53 mL) and stirred at 60° C. for 16 hours. THF (5 mL) was added to the reaction mixture and heated at 60° C. for 6 hours. The reaction was cooled to room temperature and acidified with aqueous 1N HCl. The aqueous layer was extracted with 3:1 CHCl3:isopropanol (3×). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]oxy}benzoic acid (114 mg, 0.244 mmol) as a white solid. MS ESI calc'd for C24H18F3N4O3 [M+H]+ 467. found 467.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14]SCCC(OCC)=O)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14][OH:28])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCSCc1nnsc1SCCC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)CCSc1snnc1CO
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(2-ethoxycarbonylethyl)thio]-4-[(2-ethoxycarbonylethyl)thiomethyl]-1,2,3-thiadiazole (1.0 g, 3.0 mmol) in dichloromethane (40 mL) was added m-chloroperoxybenzoic acid in several portions at 0 ° C. until the starting material was disappeared. The mixture was then sequentially washed with saturated aqueous sodium thiosulfate, cold aqueous 1% sodium hydroxide and brine, and was concentrated to dryness. The oxidized product was treated with trifluoroacetic anhydride (2 mL) for 30 min at room temperature. After removal of trifluoroacetic anhydride under the reduced pressure, the mixture was stirred in ethyl acetate/1% sodium hydroxide (30 ml/30 mL) for 30 min. The ethyl acetate layer was concentrated to a volume of 5 mL and methanol (10 mL) was added. Excess sodium borohydride (200 mg) was added in portions at 0° C. while stirring. After 30 min, the reaction was quenched with diluted hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (1% methanol/dichloromethane) to provide 225 mg of 5-[(2-ethoxycarbonylethyl)thio]-4-hydroxymethyl-1,2,3-thiadiazole. 1H NMR (CDCl3) δ 1.27 (t, 3H, J=8), 2.71 (t, 2H, J=7), 3.27 (t, 2H, J=7), 4.16 (q, 2H, J=8), 5.03 (s, 2H).