Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[N:5]([CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C(=O)N([Br:23])C(=O)C1>ClCCCl>[Br:23][C:6]1[N:5]([CH3:14])[C:4](=[O:15])[C:3]([O:2][CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: CCOC(=O)c1ccn(C)c(=O)c1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: CCOC(=O)c1cc(Br)n(C)c(=O)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of Intermediate 1 (109 mg, 0.516 mmol) in DCE (2.0 mL) was added NBS (110 mg, 0.619 mmol). The reaction mixture was stirred at rt overnight and then was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in a small amount of DCM and charged to a 12 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 18 (138 mg, 0.476 mmol, 69% yield) as a white solid. HPLC/MS (Method D) RT=1.4 min, [M+1]+ 291.9; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29 (1H, s), 4.42 (2H, q, J=7.28 Hz), 3.99 (3H, s), 3.55 (3H, s), 1.39 (3H, t, J=7.15 Hz).
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Cl:10][C:11]1[N:12]=[C:13]([CH:16]([C:22]2[NH:23][C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)=[C:25]3[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=23)[CH:17]([CH2:20]O)[CH2:18]O)[S:14][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][S:6]([O:5][CH2:20][C:17]([CH:16]([C:13]1[S:14][CH:15]=[C:11]([Cl:10])[N:12]=1)[C:22]1[NH:23][C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:25]2[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=12)=[CH2:18])(=[O:7])=[O:8]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(c3nc(Cl)cs3)C(CO)CO)c2n(C)c1=O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(COS(C)(=O)=O)C(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic anhydride (1699 mg, 9.75 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)-3-hydroxy-2-(hydroxymethyl)propyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (934 mg, 1.950 mmol) and triethylamine (1.631 mL, 11.70 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 16 hours. Further portions of triethylamine (1.631 mL, 11.70 mmol) and methanesulfonic anhydride (1699 mg, 9.75 mmol) were added as necessary to allow the reaction to run to completion. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:11])([CH3:10])[CH2:12][C:13]([OH:21])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C2C(=O)OC(C)(C)OC2=O)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(C)(C)CC(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 107.8 %

Procedure:
The 5-(2-(3-methoxyphenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione 85.C (0.313 g, 1.1 mmol) was dissolved in DMF (1.50 mL, 19 mmol). To the solution was added water (0.15 mL, 8.3 mmol). The resulting solution was then heated to 100° C. and stirred for four hours. The reaction was cooled to room temperature and then diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were then washed with 1N lithium chloride solution (1×20 mL) and brine (1×20 mL) and dried over magnesium sulfate. The filtrate was then concentrated to give crude 3-(3-methoxyphenyl)-3-methylbutanoic acid 85.D (0.247 g, 111% yield) that was used directly in the following reaction. MS ESI (pos.) m/e: 226.1 (M+H2O)+.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][C:10]([CH2:12][C@H:13]2[N:16]([C:17](=O)[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[C:15](=[O:32])[C@@H:14]2[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH3:34])=[O:11])[CH2:6][N:5]1[C:49](=[N:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=1)=[O:53])[CH3:50])(=[O:3])[NH2:2].[P:65]([O:74][CH:75]([CH3:77])[CH3:76])([O:70][CH:71]([CH3:73])[CH3:72])[O:66][CH:67]([CH3:69])[CH3:68]>C1(C)C=CC=CC=1>[C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][C:10]([CH2:12][C@H:13]2[N:16]([C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[P:65]([O:70][CH:71]([CH3:73])[CH3:72])([O:74][CH:75]([CH3:77])[CH3:76])[O:66][CH:67]([CH3:69])[CH3:68])[C:15](=[O:32])[C@@H:14]2[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH3:34])=[O:11])[CH2:6][N:5]1[C:49](=[N:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=1)=[O:53])[CH3:50])(=[O:3])[NH2:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(=O)C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@H]1C(N)=O
Solvent: Cc1ccccc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(OC(C)C)(OC(C)C)OC(C)C)C[C@H]1C(N)=O
Temperature: 90 °C
Yield: 60 %

Procedure:
454 mg (0.5 mmole) of (3S,4R)-4-{[(2S,4S)-2-carbamoyl-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-4-ylthio]carbonylmethyl}-3-[1(R)-(p-nitrobenzyloxycarbonyloxy)ethyl]-1-(p-nitrobenzyloxyoxalyl)-2-azetidinone and 520 mg (2.5 mmole) of triisopropyl phosphite were dissolved in 10 ml of toluene. The solution was heated in a stream of a nitrogen gas at 90° C. for 2 hours. The solvent was then distilled off under reduced pressure. The residue was subjected to chromatography using a Lobar column eluted with a 30:10:1 by volume mixture of ethyl acetate, chloroform and methanol, to afford 330 mg (yield 60%) of the title product as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:9]=2[CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([S:69]([NH:72][CH3:73])(=[O:71])=[O:70])=[CH:65][CH:64]=1>CN(C=O)C>[CH3:73][NH:72][S:69]([C:66]1[CH:67]=[CH:68][C:63]([CH2:62][NH:61][C:18]([C:4]2[C:5]3[CH:6]=[N:7][N:8]([C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[C:9]=3[CH:10]=[C:2]([Br:1])[CH:3]=2)=[O:20])=[CH:64][CH:65]=1)(=[O:70])=[O:71]
Reactant: O=C(O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Reactant: CNS(=O)(=O)c1ccc(CN)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2cnn3-c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred room temperature solution of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.25 g, 0.70 mmol) in DMF (15 mL) was added PyBOP (0.45 g, 0.90 mmol) and triethylamine (0.20 g, 1.6 mmol). After 15 minutes, 4-aminomethyl-N-methyl-benzenesulfonamide (0.15 g, 0.7 mmol) was added. After 5 hours, the reaction was quenched with water (30 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 30-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2].[Br:21]Br>CC(O)=O.O.C([O-])(O)=O.[Na+]>[C:1]([C:4]1[C:9](=[O:10])[C:8]([Br:21])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 3-acetyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.00 g, 3.54 mmol) in AcOH (3.5 mL) was added Br2 (0.181 mL, 3.54 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and NaHCO3 aqueous solution, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (332 mg, 26% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.57 (3H, s), 7.79-7.91 (2H, m), 8.09-8:17 (1H, m), 8.22 (1H, s), 9.58 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]([CH2:19][C:20]([OH:22])=[O:21])[CH2:3]1.[Li+].[OH-].[CH3:25][CH2:26]OC(C)=O>O1CCOCC1.CO>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]([CH2:19][C:20]([O:22][CH2:25][CH3:26])=[O:21])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)CC2CC(=O)O)cc1
Reactant: CCOC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)CC1CC(=O)NCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
A solution of the product of step A (1.34 g, 5.44 mmol) was stirred in THF (30 ml) at 0*C. Bu3SnOTf (90%, 2.73 g, 5.60 mmol) in THF 8.0 ml was added dropwise over 6 min, and the mixture was heated to reflux for 22 h. The reaction was cooled to 0° C., and triethylamine (1.52 ml, 10.9 mmol) and dimethylaminopyridine (0.135 g, 1.11 mmol) were added followed by p-toluenesulfonyl chloride (2.09 g, 11.0 mmol) in THF 4.0 ml. The reaction was allowed to r.t. and after 4 h concentrated under reduced pressure. AcOEt (100 ml) was added to the residue and washed with 0.1 N HCl aq. (100 ml×2), sat'd NaHCO3 aq. (100 ml×2) and sat'd NaCl aq. (100 ml×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (AcOEt→AcOEt/-MeOH=80/1) to yield the title compound. MS:355.2 C. 2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (3) To a solution of the product of step B (0.416 g, 1.17 mmol) in 1,4-dioxane (24 ml) and MeOH (24 ml), 0.13 N LiOH (28 ml, 3.6 mmol) was added, and the mixture was heated to reflux for overnight. The reaction was cooled to r.t. and AcOEt (400 ml) was added and washed with sat'd NaCl (400 ml×5), dried over Na2SO4 and concentrated under reduced pressure to yield the title compound. MS: 327.1 D. (R)-2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide. To a mixture of 2-(7-oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (0.115 g, 0.352 mmol), (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (0.0945 g, 0.387 mmol) and HOBt (<5% H2O, ˜0.398 mmol) in DMF (3.0 ml) was added EDCI*HCl (0.0805 g, 0.420 mmol), and stirred overnight under N2. AcOEt (60 ml) was added and washed with sat'd NaHCO3 aq. (60 ml×3) and sat'd NaCl aq. (60 ml×3), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (CH2Cl2/MeOH with 2N NH3=10/1) to yield the title compound. MS: 553.1
Reaction SMILES: [N:1]([CH:4]1[CH2:33][C:8]2=[CH:9][N:10]([S:15]([C:18]3[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]([CH3:29])[CH3:28])=[CH:20][C:19]=3[CH:30]([CH3:32])[CH3:31])(=[O:17])=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[C:5]1=[O:34])=[N+]=[N-].[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1.[Pd]>[C:35]([NH:1][CH:4]1[CH2:33][C:8]2=[CH:9][N:10]([S:15]([C:18]3[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]([CH3:29])[CH3:28])=[CH:20][C:19]=3[CH:30]([CH3:32])[CH3:31])(=[O:17])=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[C:5]1=[O:34])(=[O:37])[CH3:36]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(=O)C(N=[N+]=[N-])C3)c(C(C)C)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)NC1Cc2cn(S(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c3cccc(c23)C1=O
Yield: 90.8 %

Procedure:
A solution of 4-azido-3,4-dihydro-1-(2,4,6-triisopropylphenylsulfonyl)benz[cd]indol-5(1H)-one (5.36 g, 11.2 mmol), acetic anhydride (2.29 g, 22.4 mmol) and 10% Pd-C (1.7 g in THF (60 ml) was stirred for 4 hours at 4 hours under 4 atmospheres pressure under hydrogen atmosphere. After completion of the reaction, the catalyst was filtered off. The filtrate was concentrated under reduced pressure. To the concentrate was added isopropyl ether to give 5.03 g (91%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1)=[O:7].C1COCC1.Cl>O>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reaction time: 2 h

Procedure:
To a one liter three neck flask was charged the product of Example 73C (50 g, 0.153 mol), lithium hydroxide monohydrate,(13 g, 0.310 mol), 200 ml THF and 190 ml water. This hazy solution was stirred for 2 hours. The reaction was quenched with a solution of conc. HCl (32.4 g, 0.329 mol) in 65 mL water, the THF was removed under vacuum and the product extracted into methylene chloride (3×210 ml). (NOTE: If necessary, the pH of the aqueous layer should be adjusted to maintain pH 1-4 during the extractions.) The combined organics were then dried with 50 g sodium sulfate, filtered with a 150 ml methylene chloride rinse of the sodium sulfate, and the solvent was removed under vacuum. The product was dissolved in 450 ml THF and again the solvent was removed. Next the product was dissolved in 475 ml THF containing 0.12 g butylated hydroxytoluene (BHT) for storage. If desired, the solvent can be removed under vacuum and the residual syrup dried in a vacuum oven at 55° C. to provide a glassy solid.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([N:26]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH2:27][CH3:28])=[CH:24][CH:23]=[C:22]([C:42]([CH3:44])=[CH2:43])[N:21]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Pd].CCOC(C)=O>[F:46][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([N:26]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH2:27][CH3:28])=[CH:24][CH:23]=[C:22]([CH:42]([CH3:44])[CH3:43])[N:21]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C=C(C)c1ccc(N(CC)C[C@H]2CC[C@H](CC(=O)OCC)CC2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(C)C)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Reaction time: 4 h

Procedure:
A suspension of 10% palladium on carbon (2.0 mg) in a solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropenylpyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate (19.0 mg, 0.0284 mmol) in EtOAc (5 mL) was stirred under H2 (double balloon pressure) for 4 h. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate as a colorless oil. LCMS calc.=672.3; found=672.3 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 7.87 (s, 1 H); 7.78 (s, 2 H); 7.36 (d, J=7.6 Hz, 1 H); 7.03 (d, J=7.8 Hz, 1 H); 5.77 (d, J=8.2 Hz, 1 H); 4.95 (d, J=16.6 Hz, 1 H); 4.41-4.35 (m, 2 H); 4.08 (q, J—7.1 Hz, 2 H); 3.01 (s, 1 H); 2.90 (s, 2 H); 2.79-2.71 (m, 2 H); 2.12 (d, J=6.5 Hz, 2 H); 1.84-1.65 (m, 5H); 1.30-1.20 (m, 10 H); 0.98-0.86 (m, 7 H); 0.71 (d, J=6.3 Hz, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19](C(OC(C)(C)C)=O)[N:18]=2)=[O:15])[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:30]1[CH:35]=[C:34](F)[C:33]([F:37])=[CH:32][C:31]=1[S:38]([CH:41]1[CH2:45][CH2:44][O:43]C1=O)(=[O:40])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:37][C:33]1[C:34]([O:1][C:2]2[CH:3]=[C:4]([CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=2)[C:14]([NH:16][C:17]2[CH:21]=[CH:20][NH:19][N:18]=2)=[O:15])=[CH:35][C:30]2[O:43][CH2:44][CH2:45][CH2:41][S:38](=[O:40])(=[O:39])[C:31]=2[CH:32]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reactant: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)S(=O)(=O)CCCO3)cc(C(=O)Nc2cc[nH]n2)c1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
1,1-Dimethylethyl 3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl) carbonyl]amino}-1H-pyrazole-1-carboxylate (145 mg, 0.5 mmol), 3-[(2,4,5-trifluorophenyl)sulfonyl]dihydrofuran-2(3H)-one (140 mg, 0.5 mmol) and potassium carbonate (138 mg, 2 mmol) in acetonitrile (4 mL) were heated at 130° C. for 1 hour then 160° C. for a further 1 hour in a microwave reactor. Water was added to the reaction mixture and the phases separated. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organics washed with 1M hydrochloric acid, a saturated sodium bicarbonate solution, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on alumina, eluting with 0-10% methanol in DCM, to give the desired compound as a white solid (58 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:41]I>C1C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][I:41])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1

Procedure:
2-11 (10.42 g, 0.048 mol) was dissolved in 400 ml benzene, imidazole (4.66 g, 0.068 mol), triphenylphosphine (15.24 g, 0.05 mol) and iodine (0.048 mol) were added at room temperature. After 6 hours the reaction mixture was filtered and the filtrate was evaporated to give a dark residue. This was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes to give 2-12 as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[I:19]I.O>C1COCC1>[I:19][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(I)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 1.00 g (4.22 mmol, Aldrich) of 6-bromo-2-methoxynaphthalene in 10 ml of dry THF at -78° was added dropwise 4.5 ml (1.4M in pentane, 6.3 mmol, Aldrich) of t-butyllithium solution over 10 minutes. The reaction mixture was stirred at -78° for 30 minutes then at 0° for 15 minutes. The resulting yellow solution was re-cooled to -78° then 1.20 g (4.72 mmol, Aldrich) of iodine was added in one portion. The reaction mixture was warmed to room temperature, stirred for 1 hour then added to 50 ml of H2O and extracted with 50 ml of ethyl acetate. The organic extract was washed with an additional 50 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was recrystallized (EtOAc/petroleum ether) to afford 805 mg (67%) of title compound as pale yellow flakes, m.p. 142°-143°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[CH2:12](I)[CH3:13]>>[CH2:12]([C:10]1[O:9][C:8]2=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=1)[CH3:13]
Reactant: COc1nccc2ccoc12
Reactant: CCI
Product: CCc1cc2ccnc(OC)c2o1

Procedure:
Starting from 7-methoxyfuro[2,3-c]pyridine (4.5 g) and ethyl iodide (4.0 ml). Purification by column chromatography on silica eluting with 70% hexane in ethyl acetate gave the title compound (30 g) as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[C:12]1(/[CH:18]=[CH:19]/B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CC#N.O.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].C(Cl)Cl>[CH3:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2](/[CH:19]=[CH:18]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)O)cc(/C=C/c2ccccc2)n1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A suspension of 2-chloro-6-methyl-isonicotinic acid (171.6 mg, 1 mmol), (E)-2-phenyl-etheneboronic acid (180.0 mg, 1.2 mmol), K2CO3 (414 mg), Pd(dppf)Cl2-CH2Cl2 (27 mg) in CH3CN—H2O (3:1, 10 mL) is stirred under argon at 90° C. for 15 h. The solution is cooled to r.t. and aq. hydrochloric acid (2 M, 1.5 mL) is added to adjust the pH at 3. The mixture is evaporated to dryness and purified by reversed phase MPLC to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][S:9][C:8]=2[CH:21]=1)([O-])=O.O.NN>CO.[Ni]>[N:15]1([CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][S:9][C:8]3[CH:21]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]2=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCN1CCCCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)SCCN2CCN1CCCCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A mixture of 7-nitro-4-(2-(piperidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.9 g, 2.93 mmol) in methanol (10 mL) under an argon atmosphere was treated first with hydrazine hydrate (1.424 mL, 29.3 mmol) and then with Raney-Nickel (˜0.172 g, 2.93 mmol). The reaction was transferred to oil bath pre-heated to 65° C. After one hour, the reaction mixture was poured over a pad of Celite. The pad of Celite was then rinsed with methanol (25 mL). The purple filtrate was concentrated and subjected to a short column on silica gel (1:9 (2M NH3 in MeOH):CH2Cl2). The fractions were concentrated, and the residue was carried on to the next step. 1H-NMR (DMSO-d6) δ 6.49 (d, J=8.7 Hz, 1H), 6.26-6.23 (m, 2H), 4.41 (s, 2H), 3.38-3.35 (m, 2H), 3.20 (t, J=7.2 Hz, 2H), 2.98-2.94 (m, 2H), 2.40-2.34 (m, 6H), 1.50-1.46 (m, 4H), 1.38-1.36 (m, 2H); ESI-MS (m/z, %): 278 (MH+, 100).
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.Cl>[OH-].[Na+].CCOCC>[CH3:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:1][C:2]#[N:3])=[O:10])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84908.4 %

Procedure:
To a solution of cyanamide (1.05 g, 0.025 mmol) in 25 ml of sodium hydroxide (10%) was added slowly to a solution of 4-methylbenzoyl chloride (3.3 ml, 0.025 mmol) in ether (8 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture then was cooled in ice bath and acidified with hydrochloric acid (10%) to pH 2. The white solid separated was filtered, washed with water, later hexanes and dried under high vacuum to give the N-(4-methylbenzoyl)cyanamide (3.4 g); m.p. 140–142° C. (lit m.p. 149–150° C.); purity 88% HPLC; 1H-NMR (CD3OD) δ 2.42 (s, 3H, CH3), 7.38 (d, 2H, ArH), 7.78 (d, 2H, ArH).