Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:16][CH:15]=3)=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH:32]([CH2:36]CO)[CH2:33]CO.O>CN(C)C=O>[CH3:33][N:32]([CH3:36])[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:16][CH:15]=3)=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCCNCCO
Reactant: Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cc(-c2cn(C)nc2-c2ccc(OCc3ccc4ccccc4n3)cc2)ccn1
Temperature: 130 °C

Procedure:
To a solution of 2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline (100 mg) in dimethyl formamide (1 ml) was added diethanolamine (0.035 ml) and the reaction mixture heated at 130° C. for 72 h. The reaction mixture was poured into water and extracted with ethyl ether, dried magnesium sulfate, filtered and concentrated. Prep TLC eluting with 60% ethyl acetate/hexane provided the title compound as a Free base. The product was stirred in ethyl acetate and 1 eq. of succinic acid was added. After 18 h, the white precipitate was filtered to provide the succinate salt (24 mg). 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.3 Hz, 1 H), 8.03 (s, 1 H), 7.98 (m, 2 H), 7.90 (d, J=5.4 Hz, 1 H), 7.77 (m, 1H), 7.65 (d, J=8.3 Hz, 1 H), 7.59 (m, 1 H), 7.31 (d, J=6.6 Hz, 2H), 7.04 (d, J=9.1 Hz, 2 H), 6.37 (m, 2 H), 5.35 (s, 2H), 3.84 (s, 3H), 2.80 (s, 6H) 2.37 (s, 4H); MS: M+H m/z=436.0).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O[C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[S:44]([C:47]1[N:51]2[C@:52]([CH3:77])([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([C:71]4[CH:72]=[N:73][CH:74]=[N:75][CH:76]=4)=[CH:67][CH:66]=3)[C:53](=[O:63])[N:54]([C:55]3[CH:60]=[C:59]([Cl:61])[CH:58]=[C:57]([Cl:62])[CH:56]=3)[C:50]2=[N:49][CH:48]=1)(=[O:46])=[O:45])=[O:38])(C)(C)C.[CH3:78][O:79][CH2:80][CH2:81][NH2:82].Cl>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[CH3:78][O:79][CH2:80][CH2:81][NH:82][C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[S:44]([C:47]1[N:51]2[C@:52]([CH3:77])([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([C:71]4[CH:76]=[N:75][CH:74]=[N:73][CH:72]=4)=[CH:67][CH:66]=3)[C:53](=[O:63])[N:54]([C:55]3[CH:56]=[C:57]([Cl:62])[CH:58]=[C:59]([Cl:61])[CH:60]=3)[C:50]2=[N:49][CH:48]=1)(=[O:45])=[O:46])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 44.9 %

Procedure:
TBTU (0.077 g), DIPEA (0.090 mL) and (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (Example 14) (0.10 g) were combined in 5% DMF-CH2Cl2 (4.2 mL) at room temperature. 2-Methoxyethylamine (0.036 g) was then added and the reaction solution was stirred overnight. The reaction was diluted with CH2Cl2, poured into 1N HCl, and extracted with CH2Cl2. The organic layers were subsequently extracted with CH2Cl2 from saturated aqueous NaHCO3 followed by brine. The combined organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography to afford 0.045 g of the title compound (684.2, M+1) as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[Cl:19])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CCOC(C)=O.CN(C)C=O>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([Cl:19])[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:22])=[CH2:25]
Reactant: C=COCCON
Reactant: Cn1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10ff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.010 mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL, 0.077 mmol), and EDCI (19 mg, 0.10 mmol) are dissolved into dimethylformamide (1.0 mL) and allowed to stir under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture is diluted with EtOAc, washed with water (3×), 10% potassium carbonate (2×), saturated ammonium chloride, brine, dried (Na2SO4), and concentrated under reduced pressure to give 39 mg of 85% pure material. MS APCI (−) m/z 497, 501 (M−, Br pattern) detected.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:17]([NH2:21])([NH2:20])(=[O:19])=[O:18].Cl>C(O)C>[C:1]1([C:7]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:21][S:17](=[O:19])(=[O:18])[N:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=S1(=O)N=C(c2ccccc2)C(c2ccccc2)=N1
Reaction time: 8 h

Procedure:
Benzil (10 g, 48 mmol) and sulfamide (4.6 g, 48 mmol) were combined in anhydrous, denatured ethanol (100 mL) and dry hydrogen chloride gas was bubbled into the reaction mixture until the temperature reached 55° C. The mixture was heated at reflux for 2 hrs, allowed to equilibrate and proceed overnight at room temperature. Concentration of the mixture gave a light yellow solid which was triturated first with water then with ether yielding 10.74 g (83%) of a white solid. The solids may be recrystallized if necessary from acetone to give white crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]1SC=CN=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(S(OC)(=O)=[O:38])(F)F.[BH4-].[Na+].O>CC#N.[Hg](Cl)Cl>[Si:1]([O:8][C@H:9]([CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])[C@@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:11][OH:38])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nccs1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: COS(=O)(=O)C(F)(F)F
Agent: Cl[Hg]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CO)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
A solution of tert-butyl (1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propylcarbamate (6.150 g, 12.2 mmol) in 120 mL MeCN was treated with 4 A mol. sieves and was allowed to stir at room temperature for 10 minutes. Methyl trifluoromethylsulfonate (1.62 ml, 14.7 mmol) was added, and the reaction mixture was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo. The crude residue was dissolved in 100 mL MeOH, cooled to 0° C., and treated with NaBH4 (1.39 g, 36.7 mmol). The reaction mixture was allowed to warm to RT and stir for an additional 20 minutes. The reaction mixture was then concentrated, diluted with EtOAc, filtered through celite and again concentrated in vacuo. The residue was dissolved in 100 mL ACN and 20 mL water and was treated with mercury(II)chloride (3.32 g, 12.2 mmol). After stirring for 30 minutes, an additional portion of NaBH4 (1.39 g, 36.7 mmol) was added, and the reaction mixture was allowed to stir for another 30 minutes. The reaction mixture was quenched with saturated NaHCO3 solution and diluted with EtOAc. The crude reaction mixture was then washed with water then brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude residue was forced through a short plug of silica eluting with ether. The filtrate was again concentrated in vacuo yielding tert-butyl (2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-hydroxybutan-2-ylcarbamate (5.33 g, 96.9% yield) with minor impurities.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[CH2:21][CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CC2CCNCC2)cc1Cl
Yield: 100.5 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperidine (24 g, 69.7 mmol) in methylene chloride (150 ml) and the reaction mixture was stirred for lh. The solvent was removed under reduced pressure, followed by addition of ethyl acetate (200 ml), and the resulting mixture was made basic with 1N aqueous sodium hydroxide. The organic layer was separated, dried over magnesium sulfate and the solvent was removed under reduced pressure to give 4-(3,4-dichlorobenzyl)piperidine (17.1 g) as light brown solid.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:21]([C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:22].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+]>O1CCOCC1.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]>[Cl:20][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Cl:19])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:29][C:25]3[CH:24]=[C:23]([CH2:21][CH3:22])[N:28]=[CH:27][N:26]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1)[C:15]#[N:16]
Reactant: CCc1cc(N)ncn1
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Br)c3s2)c(Cl)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: CCc1cc(Nc2nccc3nc(-c4c(Cl)cc(C#N)cc4Cl)sc23)ncn1
Temperature: 70 °C
Yield: 30.5 %

Procedure:
A mixture of 4-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.095 g, 0.25 mmol), 6-ethylpyrimidin-4-ylamine (29 mg, 0.23 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), XantPhos (14 mg, 0.025 mmol) and cesium carbonate (0.201 g, 0.62 mmol) in dioxane (2.5 mL) was degassed with a stream of nitrogen. The reaction mixture was heated at 70° C. for 16 hours. After cooling to room temperature, the resultant mixture was diluted with water and filtered through Celite® washing with DCM. The aqueous phase was further extracted with DCM and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resultant residue was purified by silica gel flash C18 column chromatography eluting with 0-100% EtOAc in pentane followed by a 20-60% gradient MeOH in H2O+1M HCl (1.25 mL in each 25 mL of eluent). The product containing fractions were combined and concentrated under reduced pressure. The resultant solid was suspended in a mixture DCM/EtOAc/MeOH and washed with a saturated solution of NaHCO3, then dried and concentrated under reduced pressure. Further column chromatography purification on silica gel, eluting with 0-50% EtOAc in DCM, afforded the title compound as a pale yellow solid (30 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.70 (br s, 1H), 8.66 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.39 (s, 2H); 7.84 (d, J=5.6 Hz, 1H), 7.56 (s, 1H), 2.67 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H). LCMS (Method C): RT=3.81 min, m/z: 427 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26].[C:28](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
DMF (5 drops) was added to a suspension of 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (42.6 g, 97 mmol) in dichloromethane (500 mL) at 0° C. Oxalyl chloride (12.71 mL, 145 mmol) was added slowly. The mixture was stirred at 0° C. for 1 h. MeOH (30 mL) was added, and the resulting mixture was stirred at 0° C. for 2 h and allowed to warm to room temperature overnight. The solvent was removed under reduced pressure. The residue was diluted with water, treated with saturated aqueous NaHCO3, and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified via column chromatography (ISCO, 330 g silica, 40-100% methylene chloride/hexanes) to afford methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (29.8 g, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.96-8.01 (m, 2H), 7.89 (d, J=7.78 Hz, 1H), 7.77 (t, J=7.65 Hz, 1H), 7.65 (s, 1H), 4.08 (s, 3H), 4.03 (s, 3H), 2.34 (s, 3H); MS (m/z) 455.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.B([O-])([O-])O[C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.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>[CH3:27][S:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=3[CH:17]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: CSc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(SC)cc3)ccc2OCC1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (1.0 g), 4-methylthiophenyl borate (622 mg) and potassium carbonate (0.93 g) in toluene-ethanol-water (30-3-3 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenyl-phosphinepalladium (117 mg), and the mixture was refluxed for 16 hours. To the reaction mixture was added tetrakistriphenyl-phosphinepalladium (0.13 g), and the mixture was refluxed for 24 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:10) to give ethyl 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (442 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(Cl)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(Cl)cc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a mixture of methyl 2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.68 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2.8 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration, and dried with air to give crystals (0.63 g, 97%) of 2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromophenyl)-1H-imidazole (15.0 g, 67.2 mmol) in DMF (150 ml) at 0° C. was added NaH (60% dispersion in mineral oil, 3.90 g, 97.5 mmol). The mixture was stirred at 0° C. for 1 hour and (2-(chloromethoxy)ethyl)trimethylsilane (14.8 mL, 84.0 mmol) was added. The resulting solution was allowed to warm from 0° C. to ambient temperature while stirring over 24 hours. The reaction mixture was diluted with 1:1 brine:H2O (500 mL), extracted with EtOAc (3×200 mL), dried over sodium sulfate, filtered and concentrated to an oil. Purification of the oil by column chromatography, eluting with 10-50% EtOAc/Hexane, afforded 2-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a light orange oil, (17.1 g, 70%). LCMS (APCI+) m/z 353, 355 [M+H]+.
Reaction SMILES: [NH2:1][C@@:2]1([CH2:18][OH:19])[C:15]2[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:8]3[C:3](=[CH:4][C:5]([I:17])=[CH:6][CH:7]=3)[C@:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH2:18][OH:19])[C:15]=2[CH:14]=1
Reactant: N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 14 h

Procedure:
The (S)-(9-amino-2-bromo-7-iodo-9H-xanthen-9-yl)methanol (3.84 g, 8.89 mmol) was dissolved in THF (200 mL). The solution was cooled to 0° C., and TEA (1.425 mL, 10.22 mmol) and 2-chloroacetyl chloride (0.707 mL, 9.07 mmol) were added. The reaction was allowed to warm naturally to RT. After 14 h, the reaction was concentrated. The residue was taken up in aqueous 1 M Na2CO3 (50 mL) and the aqueous phase was extracted with 7.5% MeOH-DCM (3×133 mL). The organics were combined, washed with aqueous 1 M Na2CO3 (30 mL), dried over sodium sulfate and concentrated. The residue was dissolved in THF (100 mL) and aqueous 1 M Na2CO3 (15 mL) was added. The reaction was concentrated. The residue was taken up in 5% MeOH-dcm (400 mL) and the organic phase was washed with dilute brine (40 mL), dried over sodium sulfate concentrated to afford crude (S)—N-(2-bromo-9-(hydroxymethyl)-7-iodo-9H-xanthen-9-yl)-2-chloroacetamide, which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:38])/[C:4](/[NH:16][C:17](=[O:37])[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])=[CH:20][C:19]=1[Cl:36])=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.O.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:36][C:19]1[CH:20]=[C:21]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:23]([CH3:24])[C:18]=1[C:17]([NH:16]/[C:4](=[CH:5]\[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)/[C:3]([OH:38])=[O:2])=[O:37]
Reactant: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N/C(=C\c1cnc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.1 %

Procedure:
A mixture of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (Example 211; 32 mg, 0.06 mmol) and lithium hydroxide monohydrate (11 mg, 0.262 mmol) in methanol/tetrahydrofuran/water (2:2:1; 0.25 mL) was stirred at room temperature for 48 h. An additional portion of lithium hydroxide monohydrate (6 mg, 0.14 mmol) was added and the solution was stirred for an additional 4 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of chloroform/methanol/water/acetic acid (150:30:10:6) and re-evaporated. A solution of the residual material in the same solvent mixture (1 mL) was applied to a silica gel column. The column was eluted with in turn with chloroform, chloroform/methanol/water/acetic acid (600:30:10:6), chloroform/methanol/water/acetic acid (300:30:10:6 and chloroform/methanol/water/acetic acid (150:30:10:6). The appropriate homogeneous fractions were combined, evaporated and then lyophilized to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid (18 mg, 58% yield).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1B(O)O)=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[Na+].[Cl-]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[CH3:19][O:18][C:14]1[N:13]=[C:12]([C:7]2[CH:6]=[CH:5][S:4][C:3]=2[CH:1]=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(Br)n1
Reactant: O=Cc1sccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2ccsc2C=O)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a 500 mL flask was added 2-formylthiophene-3-boronic acid (30A, 5.00 g, 32.1 mmol, 1.0 eq.), 2-bromo-6-methoxypyridine (30B, 6.03 g, 32.1 mmol, 1.0 eq.), toluene (100 mL), EtOH (100 mL), aqueous sodium carbonate (2N, 32 ml, 64 mmol, 2.0 eq.), and Pd(dppf)Cl2 (1.17 g, 1.6 mmol, 0.05 eq.). The reaction was stirred overnight at 90° C. The reaction was cooled and saturated aqueous NaCl (100 mL) was added and the mixture was stirred for 20 min. The reaction mixture was extracted with EtOAc (2×100 mL) and the resulting organic layers were combined and passed through a Celite pad to remove residual Pd. The organic phases were washed with a succession of H2O (100 mL) and saturated aqueous NaCl (100 mL) and then dried over anhydrous Na2SO4, filtered, and concentrated to give a bubbly brown solid that was used in the next step without further purification (6.2 g, 88%). ESI-MS: m/z 220.2 (M+H)+.