Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]12[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:18]=[C:19]([NH2:23])[C:20]([CH3:22])=[CH:21][C:4]2=1)[CH3:2].[C:24]([O-:27])(=O)[CH3:25].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[N:54](OCCC(C)C)=O>C(Cl)(Cl)Cl>[CH2:1]([C@:3]12[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][C@H:9]1[CH2:8][CH2:7][O:6][C:5]1[C:4]2=[CH:21][C:20]2[CH:22]=[N:54][N:23]([C:24](=[O:27])[CH3:25])[C:19]=2[CH:18]=1)[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCC12CCC3(CC1CCOc1cc(N)c(C)cc12)OCCO3
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC[C@]12CCC3(C[C@H]1CCOc1cc4c(cnn4C(C)=O)cc12)OCCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
A solution of rac-(7 aR,11 aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (88, R2=Ethyl) (6.40 g, 20.2 mmol) in chloroform (202 mL) was treated with potassium acetate (3.96 g, 40.3 mmol) and acetic anhydride (5.71 mL, 60.5 mmol) and the mixture was stirred at rt for about 10 min. 18-crown-6 (0.266 g, 1.01 mmol) and isoamyl nitrite (6.79 mL, 50.4 mmol) were each added sequentially in one portion and the reaction mixture was heated at reflux for about 68 h. The reaction was allowed to cool to rt and then the mixture was partitioned between DCM (100 mL) and a mixture of sat. aq. NaHCO3 and water (100 mL each). After separating the layers, the organic phase was washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The sample was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in Heptane). Collection and concentration of the appropriate fractions gave rac-1-((4aR,12bS)-12b-ethyl-1,4,4a,5,6,12b-hexahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolan]-9(2H)-yl)ethanone (89, R2=Ethyl) (3.02 g, 40.4%). LC/MS, method 3, 2.51 min, MS m/z 371 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.04-7.98 (m, 2H), 7.54 (s, 1H), 4.36-4.24 (m, 1H), 4.00-3.84 (m, 4H), 3.77-3.66 (m, 1H), 2.76 (s, 3H), 2.48-2.38 (m, 1H), 2.35-2.20 (m, 2H), 2.02-1.92 (m, 1H), 1.88-1.79 (m, 1H), 1.75-1.46 (m, 5H), 1.39-1.30 (m, 1H), (t, J=7.4 Hz, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([OH:21])([CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19])[C:14]#[N:15].Cl>C(Cl)Cl>[OH:9][CH2:19][C:18]1([CH3:20])[O:21][C:13]([CH3:12])([C:14]#[N:15])[CH2:16][CH2:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CCC(C)(O)C#N
Agent: Cl
Solvent: ClCCl
Product: CC1(C#N)CCC(C)(CO)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a cooled (ice bath) and stirred mixture of 139.52 g 86% m-chloroperbenzoic acid in 2 liters methylene chloride was added 87.98 g of crude 2,5-dimethyl-2-hydroxy-5-hexenenitrile. After 30 minutes at 3° C., the mixture was allowed to warm to room temperature (ca 25° C.) The resulting mixture, which contained the intermediate epoxy cyanohydrin, was then treated with 790 ml of 0.12N hydrochloric acid to effect cyclization. After stirring vigorously for an additional 2 hours at ca 25° C., the organic phase was separated, washed with 10% aqueous sodium carbonate and dried (MgSO4). Evaporation of solvent and distillation of the residue afforded 62.87 g product with bp 100°-105° C. (0.3 torr).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][N:9]2[CH:20]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:40]([F:43])([F:42])[F:41])=[C:35]([CH:39]=1)[C:36](Cl)=[O:37]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:36](=[O:37])[C:35]4[CH:39]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=4[C:40]([F:43])([F:41])[F:42])[CH2:16][CH2:15]3)=[N:10][N:9]2[CH:20]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: CCOC(=O)c1cn2nc(N3CCNCC3)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 6-piperazin-1-ylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1.016 g, 3.69 mmol) and diisopropylethylamine (1.29 mL, 7.38 mmol) in anhydrous dichloromethane (20 mL) was added 5-fluoro-2-trifluoromethylbenzoyl chloride dropwise at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, then diluted with dichloromethane and washed with water. The organic layer was dried and concentrated in vacuo. The title compound was obtained in 82% yield (1.365 g) after purification by column chromatography.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH3:17][NH2:18]>C1COCC1>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:18][CH3:17])=[CH:4][CH:5]=1)#[N:16]
Reactant: CN
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C

Procedure:
62.1 g (228 mmol) 4-bromomethyl-2'-cyanobiphenyl (prepared according to D. J. Carini et al., J. Med. Chem. 1992, 34, 2525) were dissolved in 3 l THF. After addition of 1.5 l of a 40% aqueous solution of methylamine the mixture was stirred over night at room temperature, and the THF distilled off in vacuo. The remaining aqueous layer was extracted with ethyl acetate, the extract dried by stirring over night with 0.4 nm mole sieve, and evaporated in vacuo. The title compound was obtained as a viscous oil, which was pure enough according to its 1H-NMR spectrum for further conversions,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].S(Cl)(Cl)(=O)=O>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]=[N+:14]=[N-:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 30 °C
Yield: 96 %

Procedure:
274 g (1.33 mole) of p-methoxybenzenesulfonyl chloride was dissolved in one liter ethanol in a two liter Erlenmeyer flask. The solution was stirred magnetically and warmed to 30° C. 112 g (1.72 mole) of sodium azide was dissolved in a minimum amount of water and the sodium azide solution was then added to the sulfonyl chloride solution. Sodium chloride precipitated over a 30 minute period. The reaction solution was then poured into a 4 liter Erlenmeyer flask containing 2 liters of ice water. The resultant white solid was removed by filtration and air dried in a vacuum oven overnight at room temperature; yield 281 g of p-methoxybenzenesulfonyl azide (99% of theory; mp 39°-42° C.). The sample was crystallized from methanol to yield a white solid in 96% yield, mp 48°-50° C., lit. value mp 52° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]>CC(O)=O.CO.[Zn]>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Compound 16a (2.12 g; 6.55 mmol) in AcOH (15 mL) and CH3OH (20 mL) was added Zn (2.57 g; 39.31 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature for 6 h. The solid was collected by filtration and washed with CH3OH. The filtrate was concentrated. The residue was quenched with aqueous NaOH (<1N) and adjusted to pH ˜7, and extracted with EtOAc (2×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16b. 1H NMR (300 MHz, CDCl3): δ 8.15 (d, 2H), 7.95 (s, 1H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 294.1 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2Cl)[C:11]([F:26])=[CH:10][C:9]=1[Cl:27].[C:30](OCC)(=[O:32])C.CCCCCC>CO>[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2[O:32][CH3:30])[C:11]([F:26])=[CH:10][C:9]=1[Cl:27]
Reactant: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)N(C)OC)c(Cl)cc1F
Reaction time: 0.17 h

Procedure:
A solution of 0.54 g of sodium methylate in 5 ml of methanol is added dropwise to a suspension of 4.14 g of N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide in 25 ml of methanol and the reaction mixture is stirred for 10 minutes. The mixture is then treated with 30 ml of ethyl acetate as well as 50 ml of n-hexane, filtered and the filtrate is evaporated. The resulting colourless, viscous crude product crystallizes from diethyl ether/n-hexane. There is obtained N-methoxy-N-methyl-2-chloro-4-fluoro-5-[2-methoxy-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-benzamide, m.p. 119° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[I:13]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([I:13])=[C:4]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[NH2:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)cc(Br)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)aniline (5.00 g) in acetic acid (40 mL) was added N-iodosuccinimide (5.16 g) at 0° C., and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.21 g). 1H NMR (300 MHz, CDCl3) δ 4.58 (2H, brs), 6.84 (1H, d, J=1.1 Hz), 7.23 (1H, d, J=1.1 Hz).
Reaction SMILES: [Br:1][CH:2](C)[CH2:3]O.N1C=CN=C1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].[Cl-].[Na+].CN(C)[CH:23]=[O:24]>>[Br:1][CH2:2][CH2:3][CH2:23][O:24][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(Br)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Separately, 7.0 g (corresponding to 50.4 mmol) of 2-bromopropanol and 6.86 g (corresponding to 101 mmol) of imidazole were dissolved in 50 mL of dimethylformamide, and cooled to 0° C. Then, 7.59 g (corresponding to 50.4 mmol) of t-butyldimethylchlorosilane was added thereto. After the reaction mixture was stirred at room temperature for 24 hours, it was supplemented with a saturated sodium chloride aqueous solution, and extracted three times with diethyl ether. The combined diethyl ether layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by vacuum distillation (100° C., 70 mmHg), to obtain 7.23 g (corresponding to 30.2 mmol) of 1-bromo-3-(t-butyldimethylsiloxy)propane (FIG. 10, Step 3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[N:28][C:29]3[N:30]([N:32]=[C:33]([CH3:35])[N:34]=3)[CH:31]=2)[CH:23]=[CH:24][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:36]3[CH:37]=[CH:38][C:39]([CH2:40][N:16]4[CH2:17][CH2:18][CH:13]([C:11]5[N:12]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=6)[NH:9][N:10]=5)[CH2:14][CH2:15]4)=[CH:42][CH:43]=3)=[N:28][C:29]3[N:30]([N:32]=[C:33]([CH3:35])[N:34]=3)[CH:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3cccc(F)c3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nc(C)nn6cc5-c5cccc(F)c5)cc4)CC3)n[nH]2)n1
Reaction time: 2 h

Procedure:
323 mg (1.02 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 8.8 mL NMP. After addition of 0.34 mL triethylamine the reaction mixture is stirred for two hours. 340 mg (1.02 mmol) 4-[6-(3-Fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-benzaldehyde and 0.1 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 251 mg (1.12 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 6 hours. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water and dried. After purification by preparative HPLC 13.2 mg (2.3%) of the desired product are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][S:16]([O-:18])=[O:17].[Na+]>CS(C)=O>[CH3:15][S:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 130 °C
Yield: 57.9 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzotrifluoride (2.09 g, 10 mmol) and sodium methanesulfinate (1,32 g, 11 mmol) in DMSO (20 mL) was heated at 130° C. for 17.5 hours. After cooling down to room temperature, the mixture was poured into ice-water. The whole was extracted with ethyl acetate (30 mL×2), the combined organic layer washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from hexane to give the subtitle compound (1.56 g, 57.8%, yield).
Reaction SMILES: [F:1][C:2]1([F:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[F:12][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:11].[C:15]([O-:17])(=[O:16])[CH3:14]
Reactant: O=C1Nc2ccccc2C1(F)F
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(=O)[O-]
Product: CC(C)(C)OC(=O)CN1C(=O)C(F)(F)c2ccccc21

Procedure:
The title compound was prepared from 3,3-difluoroindolin-2-one using protocol K except using tert-butyl 2-bromoacetate to give crude tert-butyl difluoro-2-oxoindolin-1-yl)acetate as a yellow oil. LCMS method [1] showed an M+Na peak of 306.1 with a retention time of 2.502 min.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21].Cl>O1CCCC1.CCCCC>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([CH:20]=[O:21])[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4]1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1c(C=O)c(C(F)(F)F)nn1C
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
Dissolve 4-bromo-1,5-dimethyl-3-trifluoromethyl-1H-pyrazole (0.30 g, 1.23 mmol) in tetrahydrofuran (14.7 mL). Cool to −78° C. and add 1.7 M t-butyllithium in pentane (2.9 mL) dropwise. Stir for 3 min. at −78° C. and then add dimethylformamide (669 μL, 8.64 mmol). Stir for thirty min. at −78° C., then warm to 0° C. over 2 hr. Add 2 N hydrochloric acid (12.3 mL) and stir at room temperature for one hr. Separate layers and extract aqueous layer 2 times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography eluting with 0:100 to 15:85 ethyl acetate:hexanes), to give the title preparation (79 mg, 33%). GC-MS: m/z=192 [M+].
Reaction SMILES: [F:1][C:2]1[C:3]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=2[F:42])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]3[CH2:21][N:20](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[C:3]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=2[F:42])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]3[CH2:21][NH:20][CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C2CNCCN2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 26.3 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol (139.4 mg, 0.19 mmol) in DMF (1 mL) was added potassium carbonate (79 mg, 0.57 mmol) and thiophenol (21 μL, 0.21 mmol). The mixture was stirred for 45 min at room temperature then quenched with water. The aqueous mixture was extracted twice with ethyl acetate, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by preparative reverse phase HPLC to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperazin-2-ylazetidin-3-ol as a white solid (26.8 mg, 0.05 mmol). 1H NMR. (400 MHz, CD3OD): 7.45 (dd, 1H), 7.36 (m, 1H), 7.32 (m, 1H), 7.03 (m, 1H), 6.62 (ddd, 1H), 4.51 (br dd, 1H), 4.31 (br dd, 1H), 4.17-3.92 (m, 4H), 3.73-3.56 (m, 3H), 3.46 (br m, 1H), 3.26 (m, 1H); MS (EI) for C20H20F3IN4O2: 533 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](I)[CH:27]=1>CO>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:31]=1
Reactant: Cc1ccc(Br)cc1I
Reactant: OB(O)c1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)cc1-c1c(O)cccc1Cl
Temperature: 105 °C
Yield: 80 %

Procedure:
(2-Chloro-6-hydroxyphenyl)boronic acid (250 mg, 1.450 mmol, 1 equiv), Pd(PPPh3)4 (168 mg, 0.145 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 1.8 ml, 3.63 mmol, 2.5 equiv) were mixed with toluene (2 mL) in a sealed microwave tube. 4-Bromo-2-iodo-1-methylbenzene (431 mg, 1.450 mmol, 1.0 equiv) in MeOH (1.00 mL) was to the above mixture. The mixture was heated at 105° C. overnight. Then, the crude reaction mixture was loaded on 12 g column and purified at 30% EtOAc/hexane to afford 5′-bromo-6-chloro-2′-methyl-[1,1′-biphenyl]-2-ol (345 mg, 80%). LCMS (M+1)=299.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[Br:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Br:18][C:19]1[C:24]([C:25]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Reactant: O=C(O)c1cccnc1Br
Product: Cc1nc(N2CC3CN(C(=O)c4cccnc4Br)CC3C2)nc(C)c1C

Procedure:
The title compound was prepared in a manner analogous to Example 1 utilizing Intermediate 42 and 2-bromopyridine-3-carboxylic acid. MS (ESI): mass calculated for C19H22BrN5O, 415.10; m/z found 416.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.44 (dd, J=4.7, 1.6, 1H), 7.33 (dd, J=7.6, 4.7, 1H), 6.38-6.24 (m, 1H), 3.94-3.90 (m, 2H), 3.88-3.84 (m, 1H), 3.74-3.50 (m, 4H), 3.31-3.01 (m, 3H), 2.40-2.23 (m, 6H), 2.12-2.06 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH2:7][C:8]([CH3:23])([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:9]2)=[CH:4][C:3]=1[OH:25].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:25][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[O:9][C:8]([CH3:23])([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH2:7][C:6]2=[O:24])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(O)c(Cl)cc2O1
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(cc1Cl)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O

Procedure:
A procedure similar to that described in Preparation 17 was repeated, except that 550 mg of 7-chloro-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 34), 1 ml of acetic anhydride and 10 ml of pyridine were reacted, to afford 580 mg of the title compound as a pale yellow glassy substance.
Reaction SMILES: BrC1SC([C:7]([O:9][CH3:10])=[O:8])=C(NC)C=1C.[CH3:14][O-].[Na+].[Br:17][C:18]1[S:22][C:21]([C:23]([O:25]C)=O)=[C:20]([N:27]([CH3:34])[C:28](=[O:33])[C:29](F)(F)F)[C:19]=1[CH3:35]>CO>[Br:17][C:18]1[S:22][C:21]2[C:23]([OH:25])=[C:29]([C:7]([O:9][CH2:10][CH3:14])=[O:8])[C:28](=[O:33])[N:27]([CH3:34])[C:20]=2[C:19]=1[CH3:35]
Reactant: CNc1c(C(=O)OC)sc(Br)c1C
Reactant: C[O-]
Reactant: COC(=O)c1sc(Br)c(C)c1N(C)C(=O)C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c(O)c2sc(Br)c(C)c2n(C)c1=O
Reaction time: 1 h

Procedure:
Methyl 5-bromo-4-methyl-3-(methylamino)thiophene-2-carboxylate. Sodium methanolate (3.9 mL, 1.9 mmol) was added to a suspension of methyl 5-bromo-4-methyl-3-(2,2,2-trifluoro-N-methylacetamido)thiophene-2-carboxylate (0.70 g, 1.9 mmol) in MeOH (5 mL) and stirred for 1 hour. The solvent was removed, and the residue was dissolved in CHCl3, washed with water, brine, dried over MgSO4, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give the title compound. MS (ESI) m/z: Calculated 264.1; Observed; 265.9. 1H NMR (300 MHz, CDCl3) δ ppm 6.85 (1H, br. s.), 3.79 (3H, s), 3.06 (3H, s), 2.28 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Br:18]Br>C(Cl)(Cl)Cl.[W]>[Br:18][CH:5]([C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([O:3][CH2:1][CH3:2])=[O:17]
Reactant: BrBr
Reactant: CCOC(=O)Cc1ccccc1C(=O)OCC
Agent: [W]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccccc1C(Br)C(=O)OCC
Temperature: 20 °C
Yield: 50.2 %

Procedure:
A solution of ethyl 2-[2-(ethyloxy)-2-oxoethyl]benzoate (4.15 g, 17.5 mmol) in chloroform (70 ml) was treated with bromine (1.3 ml, 25 mmol) and stirred at reflux, whilst irradiating with a 120 W tungsten bulb, for 5 hrs. The mixture was cooled to 20° C., evaporated and purified by automated flash silica-gel column chromatography (using a Biotage SP4), eluting with 0-10% gradient of ethyl acetate in hexane (10 column volumes), to give ethyl 2-[1-bromo-2-(ethyloxy)-2-oxoethyl]benzoate (2.77 g) as a pale yellow oil.