Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[N:24]#[C:25]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl.O.[Cl-].[Na+].O>[NH2:24][C:25]1[O:20][C:19]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[CH3:23])=[C:17]([F:18])[C:13]3[N:14]=[CH:15][NH:16][C:12]=3[CH:11]=2)=[N:21][N:22]=1
Reactant: Cc1cc(Br)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Br)ccc1Nc1c(-c2nnc(N)o2)cc2[nH]cnc2c1F
Reaction time: 16 h
Yield: 55 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20a (0.041 g, 0.109 mmol) is suspended in 1,4-dioxane (1.5 mL) and 36 μL of a 3 M solution of cyanogen bromide in methylene chloride is added. NaHCO3 (9 mg, 0.109 mmol) in water (1.5 mL) is then added. After 16 hours, the reaction mixture is diluted with water and brine and extracted with THF. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Purification by FCC eluted with 98:2 ethyl acetate:MeOH provides 24 mg (55%) of pure desired product as a yellow solid: LC/MS ESI (+) m/z 403, 405 (M+ Br pattern) detected; 1H-NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.42 (s, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.36 (s, 2H), 7.33 (d, 1H), 7.15 (d, 1H), 6.40 (bs, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([NH:7][C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:21])=[C:15]([O:18]CC)[CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24]CC)=[O:23])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH2:2].[OH:18][C:15]1[CH:16]=[C:17]2[C:12](=[N:13][C:14]=1[CH3:21])[N:11]=[CH:10][C:9]([C:22]([OH:24])=[O:23])=[C:8]2[NH:7][C:6]1[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1.[OH:18][C:15]1[CH:16]=[C:17]2[C:12](=[N:13][C:14]=1[CH3:21])[N:11]=[CH:10][C:9]([C:22]([OH:24])=[O:23])=[C:8]2[NH:7][C:6]1[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(Nc2c(C(=O)O)cnc3nc(C)c(O)cc23)cc1
Product: O
Temperature: 0 °C

Procedure:
A mixture of ethyl 4-(4-methoxyanilino)-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.9 g) in dichloromethane (45 ml) was added rapidly to a suspension of powdered anhydrous aluminium chloride (12.8 g) in dichloromethane (115 ml) with stirring. The mixture was stirred for 24 hours at ambient temperature and then poured into ice/water. The mixture was stirred for 30 minutes then filtered. The residue was basified and partitioned between dichloromethane and water. The aqueous layer was evaporated to dryness. The residue was dissolved in propan-2-ol (150 ml) and then purified by column chromatography to give 6-hydroxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylic acid hemihydrate, m.p. 267°-268° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](I)[CH:19]=[CH2:20].O>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]([CH2:20][CH:19]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: C=CCI
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)C(C)(C)C)c1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(3-bromo-6-chloro-2-pyridinyl)-2,2-dimethylpropanamide (2.305 g, 7.907 mmol) in DMF (40 ml) at 0° C. under argon was treated with sodium hydride (0.696 g, 17.395 mmol) and then allowed warm to rt over 0.25 h, stirred at rt for 0.25 h and then treated with allyl iodide (1.61 ml, 17.395 mmol) and stirred at rt for 1 h. The reaction was then treated with water (10 ml), concentrated to approximately 5 ml, treated with more water (200 ml) and extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), filtered, evaporated and the residue chromatographed (0-20% ethyl acetate:Hexane) to give the product as a yellow oil which solidified to an off white solid (5.324 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[CH2:18]([CH2:22][C:23](=O)[CH3:24])[C:19]([CH3:21])=O.CCOC(C)=O>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:24][C:23]1[N:1]([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=3[F:14])[N:5]=[C:4]([CH3:15])[C:3]=2[C:16]#[N:17])[C:19]([CH3:21])=[CH:18][CH:22]=1
Reactant: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccc(O)cc2F)c(-n2c(C)ccc2C)c1C#N
Yield: 98.9 %

Procedure:
A solution of 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (100 mg, 0.43 mmol) and acetonylacetone (507 μL, 4.31 mmol) in glacial acetic (3 mL) acid was heated at 140° C. in the micro for 30 min. The mixture was transferred to a round bottom flask using EtOAc and evaporated, toluene was added and again evaporated, CH2Cl2 and silica was finally added and the mixture was evaporated to dryness. Purification using silica chromatography (short plug) gave 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (132 mg, 99%) as a 1:1 mixture with the starting material acetonylacetone. The product was used as such in the next step.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:72][C@@H:73]1[C:76](=[O:77])[NH:75][C@@H:74]1[CH2:78][N:79]1[N:83]=[C:82]([CH2:84][NH:85][C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[CH:81]=[N:80]1>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[C:88]([O:87][C:86]([NH:85][CH2:84][C:82]1[CH:81]=[N:80][N:79]([CH2:78][C@@H:74]2[C@H:73]([NH:72][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:19][CH2:18]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[S:29][CH:30]=3)[C:76](=[O:77])[NH:75]2)[N:83]=1)=[O:92])([CH3:91])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCc1cnn(C[C@H]2NC(=O)[C@H]2N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (prepared according to Yamawaki et al. Bioorg. Med. Chem. Lett. 2007, 15, 6716-6732) (1.50 g, 2.79 mmol) in DCM (15 mL) at 0° C. was added DIPEA (1.22 mL, 6.98 mmol) and HATU (1.11 g, 2.93 mmol). After warming to rt, a solution of tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)carbamate (827 mg, 2.79 mmol) in DCM:DMF (1.7:1, 12.7 mL). After 1 h of stirring it was diluted with DCM and washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-90%), to afford the title compound (1.92 g, 84%) as a purple oil. LCMS: Rt=1.08 min, m/z=816.5 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[C:30]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.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:30]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:39][CH:38]=1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1N1CCOCC1
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: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Bring a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-(1-morpholin-4-yl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl ester (0.19 g, 0.4 mmol), 4-t-butyloxycarbonylphenylboronic acid (0.106 g, 0.48 mmol), sodium carbonate (0.127 g, 1.2 mmol) in THF (10 mL) and water (3 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.023 g, 0.02 mmol) and then raise reaction temperature to 80° C. and stir for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and then purify on silica gel column with 40% ethyl acetate in hexanes to afford 0.15 g (74%) of the titled product. MS (m/z): 461 (M+).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br-].C(C1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)(O)=O.C(C1C=CC=CC=1CC[CH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][CH:65]=1)CC1C=CC=CC=1>>[CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][CH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][CH:65]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1CCc1ccccc1
Reactant: COC(=O)c1ccc(CCCc2ccccc2CCc2ccccc2)cc1
Agent: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: COC(=O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1

Procedure:
Methyl 4-[2-(phenethyl)phenethyl]benzoate was prepared from 2-phenethylbenzaldehyde and 4-carboxybenzyltriphenylphosphonium bromide using a similar method to the described in Example 24 for the preparation of methyl 4-[3-(2-(phenethyl)phenyl)propyl]benzoate.
Reaction SMILES: Cl.[NH2:2][C:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)([CH3:6])[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[S:9]1[CH:10]=[CH:11][C:7]([C:3]([NH:2][S:20]([CH3:19])(=[O:22])=[O:21])([CH3:6])[C:4]#[N:5])=[CH:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)(C#N)c1ccsc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C#N)(NS(C)(=O)=O)c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2.7 g (0.0143 mole) 2-amino-2-(3-thienyl)-propionitrile hydrochloride (the product of Example 8) in 50 ml methylene chloride, 3.6 g (5 ml [0.036 mole]) triethylamine were added, followed by 2 g (1.4 ml [0.018 mole]) methanesulfonyl chloride. The reaction mixture was stirred at room temperature for three hours. The reaction mixture was then washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and stripped to give the above-identified product which was used in Example 10 without further purification.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:33]>O1CCCC1.O1CCOCC1>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:33])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a cooled (0°) and stirred solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-hydroxyacetate (3.79 g., 10.7 mmole) in tetrahydrofuran (40 ml.) and dioxane (40 ml.) was added pyridine (0.97 ml., 12 mmole) followed by SOCl2 (1.43 g., 0.88 ml., 12 mmole). The mixture was stirred 30 minutes at 0°, the precipitate was removed and washed with toluene, and the combined filtrates were concentrated on a rotary evaporator to leave a yellow oil. Partial purification was achieved by filtering the residue over a silica gel pad and washing with chloroform. δ(ppm, CDCl3): 8.2 (2H, m, aromatic), 7.55 (2H, m, aromatic), 6.12 (1H, s, CHCl), 5.65 (1H, m, H-4), 5.35 (2H, two s, benzylic H), 3.62 (1H, dd, J3-3 =16, J3-4 cis =6, H-3), 3.08 (1H, m, H-3), 2.35 (3H, two s, CH3). The product was obtained as a mixture of two epimers.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.N1CCCCC1.[C:14]1([C:20]2[CH:21]=[C:22]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[CH:34]=[C:33](C=O)[CH:32]=[CH:31]4)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[S:40]1[CH2:44][C:43](=[O:45])[NH:42][C:41]1=[O:46]>C(O)(=O)C>[C:14]1([C:20]2[CH:21]=[C:22]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[CH:34]=[C:33]([N:42]3[C:43](=[O:45])[C:44](=[CH2:1])[S:40][C:41]3=[O:46])[CH:32]=[CH:31]4)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1-c1ccccc1
Reactant: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=C1SC(=O)N(c2ccc3cc(-c4ccc(OC)c(-c5ccccc5)c4)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
A mixture of toluene (2.5 mL), piperidine (0.003 mL), acetic acid (0.004 mL), 6-[3-phenyl-4-methoxyphenyl]-2-naphthaldehyde (0.124 g, 0.37 mmol) and 2,4-thiazolidinedione (0.043 mg, 0.37 mmol) was heated at reflux for 20 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in EtOH. After 3 hours, the solid was filtered and dried under high vacuum to afford 0.023 g (14%) of 6-(3-phenyl-4-methoxyphenyl)-naphthalen-2-yl-methylene-2,4-thiazolidinedione, mp 221–224° C. 1H NMR (300 MHz, DMSO-d6): δ 3.85 (s, 3H), 7.28 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.46 (t, J=7.0 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.20 (s, 1H), 8.32 (s, 1H), 12.66 (brs, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([CH:18]=[CH2:19])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:41]C)C=C4)N(CC2)C1.[O-]S([O-])=O.[Na+].[Na+].[OH2:84]>C(O)(C)(C)C>[C:1]1([C:7]2[C:16]([CH3:17])=[CH:15][C:14]3[C:9](=[C:10]([C@H:18]([OH:41])[CH2:19][OH:84])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1cccc2cc(C)c(-c3ccccc3)nc12
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1cc2cccc([C@H](O)CO)c2nc1-c1ccccc1
Reaction time: 16 h
Yield: 69 %

Procedure:
8.6 g (35 mmol) of 2-phenyl-3-methyl-8-vinylquinoline are added, at 0° C., to a suspension of 52 g of AD-mix-α in a mixture of 200 ml of distilled water and 200 ml of tert-butanol. The reaction mixture is then vigorously stirred for 16 hours at this same temperature using a mechanical stirrer. 2 g of Na2SO3 are then added. The reaction mixture is stirred for one hour and is then taken up in 200 ml of water and extracted with 3×200 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane 3/7) to provide 6.65 g of 2-phenyl-3-methyl-8-(1-(S),2-dihydroxyethyl)quinoline in the form of an orange-colored solid; M.p.=117° C. (Yield: 69%)
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27]CC)=[O:26].[CH:30](/B(O)O)=[CH:31]\[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(COC)OC.[Li+].[OH-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[C:15]1([O:14][CH2:13][CH2:12][CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:3]2[C:25]([OH:27])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1CCCOc1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1c(/C=C/c2ccccc2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 31C (100 mg), (E)-styrylboronic acid (39 mg), and bis(triphenylphosphine)palladium(II) dichloride (8 mg) in 7:3:3 dimethoxyethane:ethanol: 1N aqueous LiOH (2 mL) was heated under microwave conditions (CEM Discover) at 130° C. for 30 minutes The mixture was quenched with 1 NHCl and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (br, 1H), 8.24 (m, 1H), 8.15 (d, 1H), 7.94 (m, 1H), 7.87 (m, 1H), 7.69 (d, 1H), 7.59 (m, 2H), 7.53 (m, 2H), 7.46 (m, 1H), 7.40 (m, 3H), 7.28 (m, 3H), 7.21 (m 1H), 6.87 (d, 1H), 4.87 (t, 2H), 4.17 (t, 2H), 2.34 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.CON(C)C(=O)CCC>CC(C)=O.O>[S:4]1[CH:5]=[CH:6][C:2]([C:9](=[O:10])[CH2:8][CH2:7][CH3:11])=[CH:3]1
Reactant: Brc1ccsc1
Reactant: C1CCOC1
Agent: CCCC(=O)N(C)OC
Solvent: CC(C)=O
Solvent: O
Product: CCCC(=O)c1ccsc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
3-Bromothiophene (11 g, 67 mmol) dissolved in hexanes (110 ml) was cooled to −20 C in acetone/water bath, and n-Bu Li (28 ml, 71 mmol, 2.5 N solution in hexanes) was added slowly, over 10 min, then stirred 10 min at −20 C. THF was added (10 ml) over 5 min with rapid stirring. Precipitate formed after about 2/3 of addition. After adding all of the THF, the reaction mixture was stirred 20 min at −20 C, then 20 ml hexanes was added and the reaction mixture was allowed to warm to zero degrees C. N-Methoxy-N-methyl-butyramide (9.29 g, 71 mmol) dissolved in 20 ml hexanes was added via cannula over 5 minutes, and the reaction mixture was stirred at zero degrees C. for 1.5 hours. The reaction mixture was quenched with water, then 1 N HCl (75 ml), extracted twice with ether, washed 1 N HCl, brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure to give an oil, which was chromatographed by flash chromatography (5% EtOAc/hexanes) to give 6.7 g, 64% of 1-Thiophen-3-yl-butan-1-one as an oil.
Reaction SMILES: [OH:1][C:2]1([C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])[CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[F:25][C:26]1[C:27]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:28]([CH:32]=[CH:33][C:34]=1[F:35])[C:29](F)=[O:30]>ClCCl>[F:25][C:26]1[C:27]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:28]([C:29]([N:4]2[CH2:3][C:2]([C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])([OH:1])[CH2:5]2)=[O:30])[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (200 mg, 0.92 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (228 μL, 1.38 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (prepared according to the procedures described in Reference 1) (363 mg, 0.92 mmol). The mixture was stirred at rt for 16 h, after which the volatile materials were removed in vacuo. The residue was purified by column chromatography (50% hexanes:50% ethyl acetate) to provide 1,1-dimethylethyl {(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate as a colorless film (333 mg, 0.56 mmol, 61% yield). 1H NMR (400 MHz, CDCl3) δ 8.47 (br s, 1H), 7.40 (dd, 1H), 7.32 (d, 1H), 7.12 (m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.74 (br d, 1H), 4.22 (d, 1H), 4.15-4.07 (m, 2H), 3.96 (br s, 1H), 3.77 (m, 1H), 1.43 (s, 9H), 1.18 (d, 3H); MS (EI) for C23H25F3IN3O4: 536 (M-tert-butyl+H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.O>C1COCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N[C@H]1CCc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(Cl)nc(N[C@H]2CCc3ccccc32)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of cyanuric chloride (631 mg, 3.42 mmol) in THF (2.00 mL) at 0° C. was added (S)-(+)-1-aminoindan (0.385 mL, 3.00 mmol) and DIPEA (0.596 mL, 3.42 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction was then poured into H2O, extracted with DCM and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to afford the title compound as a yellow solid (738 mg, 87%). LC/MS: Rt=1.99 nm, ES+ 281 (FA standard).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]1[C:15]([O:17]C)=[O:16].[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(=O)O)ccc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Methyl 1-methyl-5-benzoylpyrrole-2-carboxylate (0.78 g.) was heated on a steam bath for 1 hour with 40 ml. of 1N sodium hydroxide and 20 ml. of methanol. The reaction mixture was cooled to room temperature, extracted with ether, made acid with conc. hydrochloric acid and 1-methyl-5-benzoylpyrrole-2-carboxylic acid recovered by filtration (0.47 g., m.p. 178°-181° C.). Recrystallization from acetone/hexane afforded product for analysis (0.34 g., m.p. 178°-180° C.).