Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:24]1([C:27]2[C:28](F)=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25]1>CS(C)=O.CCOC(C)=O>[CH:24]1([C:27]2[C:28]([O:17][C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][CH:13]=3)=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CC2)c1
Temperature: 125 °C

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (1.17 g, 4.81 mmol) in DMSO (40 mL) was added cesium carbonate (1.88 g, 5.78 mmol) and 3-cyclopropyl-2-fluoropyridine (660 mg, 4.81 mmol). The resulting mixture was heated to 125° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-(4-(3-cyclopropylpyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as tan solid. MS (ESI, pos. ion) m/z: 360.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[S:4][N:3]=1.[ClH:20]>ClCCl.CCO>[ClH:20].[CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[S:4][N:3]=1
Reactant: Cc1nsc(C2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: Cc1nsc(C2CCCNC2)n1
Temperature: 35 °C

Procedure:
The Boc-protected intermediate 11a (0.87 g, 3.07 mmol) was stirred in dichloromethane (10 mL) and treated with 10 mL of a 2.53 M solution of HCl in EtOH. After warming to 35° C. for 2 hours, the mixture was concentrated under vacuum. The product was precipitated from IPA:MTBE (1:10). The product was recrystallized from IPA:MTBE three times to afford a high purity sample (42 mg) of white solid. MS (ESI) m/z 184 [M+1]+. 1H NMR (CDCl3) δ 1.68-1.91 (m, 3H), 2.13-2.20 (d, 1H), 2.58 (s, 3H), 2.87-2.95 (dt, 1H), 3.14 (t, 1H), 3.25-3.28 (d, 1H), 3.54-3.59 (d, 1H), 3.65-3.73 (m, 1H), 9.10 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CCOCC>C1COCC1>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][N:18]1[CH2:19][CH2:20][CH:15]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:16][CH2:17]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCN(C1CCNCC1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(C1CCN(CCNC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
A mixture of N-ethyl-4-methoxy-N-piperidin-4-yl-benzenesulfonamide (Example A4., 1.19 g, 4 mmol), (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.12 g, 5.0 mmol) and DIPEA (650 mg, 5 mmol) in THF (30 mL) is heated at reflux for 15 h. The solution is poured into Et2O (150 mL) and extracted with sat. aq. Na2CO3 (2×50 mL) and sat. aq. NaCl (30 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by reversed phase MPLC to provide the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].Cl[CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C[N-]C>[CH3:6][C:2](=[CH2:1])[C:3]([O:5][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:4]
Reactant: C[Si](C)(C)CCl
Reactant: C=C(C)C(=O)O
Agent: C[N-]C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)C(=O)OC[Si](C)(C)C
Temperature: 90 °C
Reaction time: 5 h

Procedure:
300 mmol of Methylacrylic acid (MAA) and 200 mmol of chloromethyl trimethylsilane were dissolved in 400 ml of dimethylamide. Potassium carbonate was added to the solution and heated to 90° C. and stirred for 5 hours. Next, the reaction solution was filtered. The filtrate was added to a sodium hydrogen carbonate solution, extracted with ether and pure water respectively, dried, filtered, and concentrated to obtain trimethylsilanylmethyl methylacrylate (TMSA) having the formula (i) below
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[C:9]2[C:4](=[N:5][C:6]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:7][CH:8]=2)[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[F:32][C:29]([F:30])([F:31])[C:28]1[C:23]([C:6]2[N:5]=[C:4]3[C:9]([C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=4)=[CH:11][CH:2]=[N:3]3)=[CH:8][CH:7]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(Nc2cc(Cl)nc3nc(-c4ncccc4C(F)(F)F)ccc23)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4ncccc4C(F)(F)F)ccc23)nc1

Procedure:
Stir a mixture of 2-chloro-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl) pyridin-2-yl]-[1,8]naphthyridin-4-amine (40 mg), ammonium formate (31 mg), 10% palladium on carbon (10 mg) in methanol (2 mL) at 50° C. for 2 hours. Cool, filter through Celite and evaporate to dryness. Purify by preparative thin layer chromatography, eluting with dichloromethane/methanol/ammonium hydroxide mixture to give the title compound. MS 436 (M+1). 1H NMR δ (CDCl3) 8.99 (1H, s), 8.84 (1H, d), 8.63 (1H, d), 8.61 (1H, s), 8.32 (1H, brs), 8.14 (1H, d), 8.05 (1H, brs), 7.79-7.85 (2H, m), 7.51 (1H, dd), 7.22 (1H,d).
Reaction SMILES: CC(C)(C)C(NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)=O.[C:23]([O:27][C:28]([NH:30][C:31]1[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]2[C:34]([C:35]3([CH3:48])[C:45](Br)(Br)[CH:36]3[CH2:37][O:38]2)=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([NH:30][C:31]1[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]2[C:34]([C:35]3([CH3:48])[CH2:45][CH:36]3[CH2:37][O:38]2)=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc2c1OCC1C(Br)(Br)C21C
Agent: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1CC21
Product: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc2c1OCC1CC21C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 43, starting from methyl (1aRS,7bSR)-5-(tert-butoxycarbonylamino)-1,1-dibromo-7b-methyl-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylate (Intermediate 52).
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][C:10]#[CH:11])[C:5]([OH:7])=[O:6].CI.Cl.O1CC[CH2:23][CH2:22]1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[O:3]=[C:4]([C:8]([CH2:22][CH3:23])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][C:10]#[CH:11])[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: C#CCC(C(=O)C(=O)O)c1ccccc1
Reactant: C1CCOC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CI
Product: C#CCC(CC)(C(=O)C(=O)[O-])c1ccccc1
Yield: 41 %

Procedure:
A 3N aqueous solution (0.61 ml) of sodium hydroxide and 2.0 ml of tetrahydrofuran were added to 0.15 g (0.71 mmole) of 2-oxo-3-phenyl-5-hexynoic acid, and the mixture was stirred until a completely uniform solution formed. Then, 0.091 ml (1.47 mmoles) of methyl iodide and 19 mg (0.083 mmole) of triethylbenzylammonium chloride were added, and the mixture was reacted at 40° C. for 16 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ether. The ether layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated. The NMR spectral analysis of the resulting oily product led to the determination that 2-oxo-3-ethyl-3-phenyl-5-hexynoic acid formed in a yield of 62 %. Then, 0.35 ml of a 1N aqueous solution of sodium hydroxide was added, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated white solid was isolated by filtration to give 0.066 g (0.302 mmole) of sodium 2-oxo-3-ethyl-3-phenyl-5-hexynoate in a yield of 41 %.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([NH:20][C@H:21]([C:31]([C:33]([O:35][CH3:36])=[O:34])=[O:32])[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:31]([C:33]([O:35][CH3:36])=[O:34])=[O:32])[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.[F:47][C:46]([C:44]([OH:50])=[O:45])([F:49])[F:48]
Reactant: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Boc-Tyr(OBn)-Ser(OBn)-CO2Me (from Step 1 above, 2.64 g, 4.69 mmol) was dissolved in CH2Cl2 (15 mL), cooled to 0° C. and TFA (5 mL) was added. The solution was warmed to room temperature and stirred for 4 hours. The solution was concentrated, taken up in CH2Cl2 and reconcentrated twice. The resulting oil was triturated with ether to provide 2.7 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)[C:20](=[O:24])[CH:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:26])[F:27]
Reactant: O=c1cc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: ClCc1cncnc1
Product: O=c1cc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1cncnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyridinone and 5-(chloromethyl)pyrimidine. LC-MS (ESI): m/z 502 [M+H]+; 3.68 min (ret time).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH3:19])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21

Procedure:
2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (1.1 g) was mixed with MeI (850 mg, Aldrich), K2CO3 (1.38 g, Aldrich) and DMF (30 ml, Aldrich) at 40° C. for 48 h. The DMF was removed in vacuo and the residue was diluted with EtOAc (80 ml). The organic phase was washed with H2O (50 ml), aqueous Na2SO3 (50 ml) and brine (50 ml). The resulting solution was dried (MgSO4) and concentrated to provide the compound which was used as is for the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC(=O)Nc1ccc(Oc2ccncc2)c(F)c1)Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (31 mg, 0.10 mmol), copper(II) acetate (27 mg, 0.15 mmol), pyridin-4-ylboronic acid (25 mg, 0.20 mmol), and pyridine (16 μL, 0.20 mmol) were placed in a pressure tube in that order. The tube was charged with methylene chloride (0.5 mL) and sealed. The reaction was stirred at 120° C. for 5 h. The reaction mixture was filtered through silica gel using 5% methanol/ethyl acetate. After concentration, the crude product was purified by prep HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was treated with 4N HCl in dioxane and concentrated. Lyophilization with water gave the title compound (8 mg, 21%) as a yellow solid. 1H NMR (CD3OD) δ 8.31 (d, 2H, J=6.1 Hz), 7.72 (dd, 1H, J=12.7, 2.4 Hz), 7.49-7.46 (m, 2H), 7.27-7.25 (m, 1H), 7.15 (t, 1H, J=8.8 Hz), 6.97 (t, 2H, J=8.7 Hz), 6.85 (dd, 2H, J=5.1, 1.2 Hz), 3.46 (s, 2H); MS (ESI+) m/z 384.21 (M+H)+.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45](=[O:48])[NH:46][CH3:47])=[CH:41][CH:40]=3)[C:19](=[O:37])[N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]3[NH:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[NH2:17][CH:18]([C:19](=[O:37])[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[C:26]1[NH:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:30]=1)[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:46][CH3:47])=[O:48])=[CH:43][CH:44]=1
Reactant: CNC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccc(CC(N)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.1 %

Procedure:
To a solution of 148 mg (0.21 mmol) of the product from step C in 2 mL of chloroform was added 2 ml of piperidine. The resulting mixture was allowed to stir at room temperature under argon for 3.5 hours. The reaction mixture was then concentrated and the residue purified on a Gilson prep LC system. The product was lophilized to obtain 47 mg (0.08 mmol, 48% yield) of the desired product as a white powder assumed to be a TFA salt. 1H NMR (300 MHz, CD3OD): δ 1.20-1.45 (2H, m), 1.50-1.80 (4H, m), 1.90-2.40 (2H, m), 2.90 (3H, d), 2.95-3.21 (2H, m), 3.78 (1H, m), 4.54 (1H, d), 5.12 (1H, s), 5.92 (1H, t), 7.28 (1H, d), 7.33-7.88 (10H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]OS(C)(=O)=O)[CH:7]=1)[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:30]=[N+:31]=[N-:32])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2COS(C)(=O)=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN=[N+]=[N-])c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
[3-(2-Methanesulfonyloxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (1.0 mmol) and sodium azide (0.195 g, 3.0 mmol) were combined in DMF (10 mL) and stirred at 80° C. for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer was separated and extracted twice with EtOAc, and the combined organic layers were washed three times with H2O, and then dried and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>ClCCl.CN(C)C1C=CN=CC=1>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:35](=[O:36])[C:34]5[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (40 mg, 0.123 mmol, 1.0 equivalent, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial, and triethylamine (0.051 mL, 0.37 mmol, 3.0 equivalents) was added. 3-(Trifluoromethyl)benzoyl chloride (33.4 mg, 0.160 mmol, 1.3 equivalents) was added as a solution in 0.1 mL of dichloromethane followed by 4-(dimethylamino)pyridine (1.50 mg, 0.012 mmol, 0.1 equivalent). The reaction was stirred for 30 minutes. The reaction solution was loaded directly onto a 4 g silica column and eluted with 50:50 to 100:0 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (31 mg, 54%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 8.07 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.91 (s, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 5.47 (t, J=4.4 Hz, 1H), 4.51 (s, 1H), 4.34 (dd, J=17.0, 9.1 Hz, 1H), 4.22 (d, J=13.6 Hz, 2H), 3.84-3.75 (m, 1H), 3.26 (dd, J=12.7, 11.1 Hz, 1H), 3.04 (dd, J=14.2, 9.5 Hz, 1H), 2.94-2.77 (m, 1H), 2.71 (dd, J=15.4, 4.9 Hz, 1H), 2.41 (dd, J=14.0, 6.7 Hz, 1H), 2.05-1.82 (m, 2H), 1.00 (dt, J=4.9, 2.9 Hz, 2H), 0.93-0.80 (m, 2H); MS (ESI+) m/z 461.1 (M+H)+; [α]D23.6=−0.09 (c=0.13, CH3OH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH2:19][CH:20]1[CH2:26][O:25]C(C)(C)[O:23][CH2:22][CH:21]1[OH:29].C(=O)([O-])[O-].[Na+].[Na+].CO>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:19][CH:20]([CH:21]([OH:29])[CH2:22][OH:23])[CH2:26][OH:25])=[O:8]
Reactant: CC1(C)OCC(N)C(O)CO1
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NC(CO)C(O)CO)c1I
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride (12.0 g, 19.8 mmol) was dissolved in dioxane (40 ml). 6-Amino-2,2-dimethyl-1,3-dioxepane-5-ol (3.20 g, 19.8 mmol) and sodium carbonate (2.10 g, 19.8 mmol) were added and the mixture heated to reflux for 10 h. The reaction mixture was cooled, methanol (100 ml) and water (50 ml) were added and the solution was neutralized with a strongly acidic ion exchange resin. The resin was filtered off and a aqueous solution of hydrochloric acid (2M, 20 ml) was added. The mixture was stirred at 60-70° C. for 30 min, and then evaporated to dryness, which gave a semisolid residue (13.6 g) which was used without further purification in the next steps.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[H-].[Na+].Br[CH2:16][C@@:17]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:19][CH:18]1[CH2:20]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:7]1([S:4]([C:3]2([S:2][CH3:1])[CH2:20][C@H:18]3[C@:17]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)([CH2:19]3)[CH2:16]2)(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCC1C[C@@]1(CBr)c1cccc2ccccc12
Reactant: CSCS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Temperature: 40 °C
Yield: 145.4 %

Procedure:
1-((Methylthio)methylsulfonyl)benzene (6.54 g, 32.2 mmole) was dissolved in dry dimethylforamide (DMF, 40 mL). Sodium hydride (3.86 g, 80.5 mmol) was added portion wise under nitrogen atmosphere at 0° C. The reaction mass was gradually heated to 40° C. and maintained for 30 minutes at 40° C. (1S)-1,2-bis(bromomethyl)-1-(1-naphthyl)cyclopropane (5.7 g, 6.1 mmol) dissolved in DMF (15 mL) was added dropwise for 30 min at 0° C. The temperature of the reaction mass was gradually brought to room temperature and maintained for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (10:90)). The reaction mass was quenched with water. The aqueous layer was extracted with diethyl ether (2×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 12.0 g of crude oil that was purified by column chromatography (silica gel, ethyl acetate/hexane (4:96) to yield 3.5 g (53%) of product. 1H NMR δ(300 MHz,CDCl3): 1.93 (2H,m), 2.01 (1H,m), 2.07 (3H,s), 2.28 (2H,m), 2.44 (2H,m), 2.88 (1H, dd, J=15 Hz), 7.36 (1H,m), 7.47-7.68 (7H,m), 7.74 (1H,m), 7.91-7.97 (3H,m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14]>N1CCCC1.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.[Cu]I>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][CH2:11][OH:15])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: C#CCCO
Reactant: COc1cc(Cl)ccc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: COc1cc(Cl)ccc1C#CCCO
Temperature: 80 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a stirred solution of 2-bromo-5-chloroanisole (2 g, 9 mmol), Pd(PPh3)4 (520 mg, 0.45 mmol), and CuI (400 mg) in pyrrolidine (20 mL) was added a solution of 3-butyn-1-ol (1.26 g, 18 mmol) in pyrrolidine (30 mL). The reaction mixture was stirred at 80° C. for 6 h, and then concentrated in vacuo. The resulting residue was extracted with ethyl acetate and the organic phase was washed with 1N hydrochloric acid, followed by water, then brine, and dried over sodium sulfate. Upon removal of the solvent under reduced pressure, the crude product was subjected to column chromatography on silica gel (gradient elution with 0%-40% EtOAc/hexane) to give 4-(4-chloro-2-methoxy-phenyl)-but-3-yn-1-ol as a colorless oil (1.46 g, 76.7%). 1H NMR (300 MHz, CDCl3) δ ppm 7.29 (d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 1.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 3.87 (s, 3H), 3.82 (t, J=6.2 Hz, 2H), 2.73 (t, J=6.2 Hz, 2H), 1.92 (br. s, 1H).