Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8]1.C(N(CC)CC)C.O>C1COCC1>[CH3:16][C:9]1([CH3:17])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(N)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(NS(C)(=O)=O)c2ccccc21
Reaction time: 2 h
Yield: 88.6 %

Procedure:
with ice-cooling, 4.0 g (34.7 mmol) of methanesulfonyl chloride were added dropwise to a solution of 5.1 g (31.6 mmol) of 1-amino-3,3-dimethylindan and 12.8 g (126.4 mmol) of triethylamine in 100 ml of THF. After 2 h at RT, 100 ml of water were added, the reaction mixture was concentrated to about 50 ml and admixed with 100 ml of water and the precipitate was filtered off with suction, rinsed with water and dried under reduced pressure. This procedure gave 6.7 g of 3,3-dimethyl-1-methylsulfonylaminoindan; m.p. 117-119° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.[H-].[Na+].Cl.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-:26])[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1
Reactant: [O-][n+]1ccccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 2.66 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine followed by addition of 1.02 g of sodium hydride (60% in oil) and the mixture was stirred at room temperature for 30 minutes. Then, 2.77 g of 2-bromopyridine N-oxide hydrochloride was added with ice-cooling and, after the evolution of heat had subsided, the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured in water and extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on a silica gel column using chloroform as the eluent to give crude 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: [NH2:1][C:2]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:30][CH2:31][C:32](Br)=[O:33].CCN(CC)CC>C(Cl)Cl>[Br:30][CH2:31][C:32]([NH:1][C:2]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])([CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:33]
Reactant: CC(C)(C)OC(=O)CCC(N)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of di-tert-butyl 4-amino-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (5.00 g, 12.0 mmol) and 2-bromoacetyl bromide (1.46 mL, 3.40 g, 16.80 mmol) in DCM (60 mL) was added Et3N (2.5 mL) at room temperature. The reaction mixtures were stirred at room temperature for overnight. The reaction mixtures were diluted with DCM (300 mL), washed with 1N HCl solution, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 10% EtOC in hexanes to 100% EtOAc to afford di-tert-butyl 4-(2-bromoacetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (2.58 g, 40%). 1H NMR (400 MHz, CDCl3) 6.43 (s, 1H), 3.76 (s, 2H), 2.20 (t, J=8.0 Hz, 2H), 1.98 (t, J=8.0 Hz, 6H), 1.43 (s, 27H); MS (ESI), 558, 560 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[C:10]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])=[N:11][C:12]([Cl:16])=[N:13][C:14]=1[CH3:15]>CN(C)C=O>[ClH:16].[CH3:8][C:9]1[C:10]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])=[N:11][C:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][C:14]=1[CH3:15]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccccc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 22.1 %

Procedure:
After aniline(0.53 ml, 5.5 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.72 g, 2.5 mmol) and dimethylformamide(5 ml), 0.21 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH2:1]([C:4]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:21]1[C:22]2[C:29]([CH3:30])=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>C(Cl)Cl>[CH2:1]([C:4]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[O:11])[CH2:9][CH2:8][N:7]([C:21]2[C:22]3[C:29]([CH3:30])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCNCC1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 120 °C
Yield: 61 %

Procedure:
4-Allyl-N-(3-chlorophenyl)piperidine-4-carboxamide from step B (0.142 g, 0.453 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, 0.453 mmol), N,N-diisopropylethylamine (0.236 mL, 1.35 mmol), and isopropanol (5 mL) were combined and heated at 120° C. overnight in a pressure vessel. The crude reaction was dissolved in CH2Cl2, washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (MeOH:CH2Cl2 gradient) to give the title compound in 61% yield.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.CS(O[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29](/[CH:32]=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:30][CH:31]=2)=[CH:21][CH:20]=1)(=O)=O>>[C:34]1(/[CH:33]=[CH:32]/[C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:25][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:1]4[C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=[CH:2]4)=[CH:24][CH:23]=3)[N:28]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCCn3cnc4ccccc43)cc2)co1)\c1ccccc1
Yield: 36 %

Procedure:
In substantially the same manner as in Working Example 8, benzimidazole was allowed to react with 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate to give 1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]benzimidazole. The yield was 36%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 148-149° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](=O)[CH3:10])=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CO>[C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](=[N:14][OH:15])[CH3:10])=[CH:3][CH:2]=1
Reactant: CC(=O)C=Cc1ccc(C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1ccc(C)cc1)=NO
Yield: 60.9 %

Procedure:
In a 250 ml single neck flask was charged 4.8 g (30.0 mmoles, 1.0 eq.) of 4-(p-tolyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.2 g of 4-(p-tolyl)-3-buten-2-one 2-oxime (E/Z mixture of isomers) as an oil in 60.9% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:17](C)=[CH:16][CH:15]=[CH:14][N:13]=1.Cl[C:20]1C=CC=C(C(OO)=O)C=1.[OH-:30].[Na+]>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:20])=[CH:14][N+:13]=1[O-:30]
Reactant: Cc1cccnc1-c1c(Cl)ccc2ccccc12
Reactant: [OH-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2c(Cl)ccc3ccccc23)[n+]([O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round-bottomed flask having a volume of 50 mL and equipped with a glass stopper and a three-way cock was dried, and 890 mg (3.51 mmol) of 2-(2-chloronaphthalen-1-yl)-3-methylpyridine and 20 mL of dichloromethane were introduced thereinto. This colorless solution was cooled to 0° C., and then 1.59 g (69-75%) of m-CPBA (meta-chloroperbenzoic acid) was each added thereto three times at intervals of 10 minutes. Next, the temperature was slowly increased to room temperature, and the colorless solution was stirred for 2 hours. Thereafter, the solution was cooled to 0° C. again, and 10 mL of an aqueous NaOH solution having a concentration of 1M was gradually added. Thereafter, an organic layer was washed with 10 mL of an aqueous NaOH solution having a concentration of 1M and 10 mL of salt water, then dried with 50 g of sodium sulfate, and subjected to dehydration and filtration steps, thereby obtaining 947 mg of yellow oily 2-(2-chloronaphthalen-1-yl)-5-methylpyridine-1-oxide.
Reaction SMILES: [CH:1]1[C:6](O)=CC=C(S(O)(=O)=O)[CH:2]=1.[C:12]([OH:29])(=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CO>CC(O)C>[CH3:1][O:28][C:12](=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH:1]([O:28][C:12](=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:6])[CH3:2]
Reactant: O=S(=O)(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Solvent: CO
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCC(=O)OC
Product: CCCCCCCCCCCCCCCC(=O)OC(C)C

Procedure:
The phenolsulfonic acid-functionalized on different solid supports were used as the catalysts in the liquid phase esterification of palmitic acid (PA) with MeOH and iPrOH to form methylpalmitate and iso-propylpalmitate as the products, respectively. The reactions were carried out at the reflux temperature of MeOH.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]5[CH2:22][CH2:23]5)(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[N:32][CH:33]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)C5CC5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (Example 39) following General Procedure B-3 was reacted with 2-aminopyridine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 123. (400 MHz, CDCl3): 0.91-0.94 (21 μm, CH2), 1.10-1.12 (2H, m, CH2), 2.20 (1H, m, CH), 2.58-2.60 (4H, m, CH2), 3.29-3.31 (4H, m, CH2), 3.79-3.82 (6H, m, CH2), 3.94-3.97 (4H, m, CH2), 4.55 (1H, b, NH2), 6.47 (1H, d (J=0.62), ar), 7.22 (1H, s, ar), 8.38 (1H, dd (J=8.89, 2.27), ar), 9.08 (1H, dd (J=2.20, 0.49), ar). (M+H)+ 516.37
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=2[C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([Cu])#[N:31].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:30]#[N:31])=[CH:17][C:16]=2[C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCc1nnc(-c2cc(I)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C#N)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-iodo-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C, 18 mg, 0.034 mmol), CuCN (15 mg, 0.17 mmol), and DMF (500 μL). The reaction was then heated to 100° C. and stirred for 48 hours. The solution was then diluted with EtOAc and washed with an aqueous solution of EDTA (5% wt/wt). The organic layer was then concentrated and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-cyano-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide as a white solid: MS (ES) M+H expected 424.2, found 424.4.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].BrBr.C(=O)(O)[O-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:23][C:22]=1[CH2:33][OH:34].C(N(CC)CC)C>CCOCC.CC(C)=O>[Cl:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][C:1]([C:4]3[O:5][C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]=3)=[O:3])[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:22]=1[CH2:33][OH:34]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: OCc1ccc(N2CCNCC2)cc1Cl
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CN1CCN(c2ccc(CO)c(Cl)c2)CC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-acetylbenzofuran (3.2 g. 0.02) in ether (50 ml) was treated with bromine (3.2 g., 0.02 mole) portionwise at room temperature. The mixture rapidly decolorized to a light yellow solution that was poured into cold aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ether. The combined ether extracts were dried (K2CO3) and the ether was removed in vacuo, keeping the mixture cold. The gummy, off-white solid was dissolved in acetone (50 ml) and quickly added to a solution of 2-chloro-4-(1-piperazinyl)benzenemethanol (4.0 g, 0.0176 mole) and triethylamine (2.0 g, 0.902 mole) in acetone (200 ml). The mixture was stirred at room temperature for one hour, then cooled in an ice bath. The solid was collected, washed with ether, and air dried. Recrystallization from acetone-ethanol gave 3.7 g (55%), mp 169°-172°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH:33]([Mg]Br)=[CH2:34].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH:33]=[CH2:34])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: C=C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A stirred suspension of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (75.4 mg, 0.168 mmol) in THF (1.6 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Vinylmagnesium bromide (1.6 ml, 1.600 mmol) was added to the reaction mixture slowly. The reaction mixture was stirred at 0° C. for 20 min, then at room temperature for 1.5 h. The reaction mixture was added via pipette to saturated aqueous NaHCO3 (20 ml) before being partitioned between EtOAc (40 ml) and water (20 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×20 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient, followed by a 100% acetonitrile+0.05% TFA. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C26H22ClN3O4 475.13 observed m/e: 476.18 (M+H)+ (Rt 1.21/2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[S:36][C:35]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1.O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][S:37]([C:35]2[S:36][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:33][CH:34]=2)(=[O:38])=[O:39])[CH2:10][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)(NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
The product of Example 2, Step (b) (0.2 g) was dissolved in acetone (4 ml). Potassium carbonate [0.130 g dissolved in H2O (1 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.171 g) and the reaction left to stir for 10 mins. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried, filtered and concentrated. Purification by reverse phase HPLC {with a gradient eluent system [30% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.135 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][O:1][C:2]2[CH:3]=[C:4]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=2[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(Oc1ccc(Cc2ccccc2)c(O)c1)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)ccc2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To 294 mg (0.787 mmol) of 2-chlorobenzenesulfonic acid 3-hydroxy-4-benzylphenyl ester, as prepared in the preceding step, in tetrahydrofuran (5 mL) containing 236 μL (1.10 mmol) of N-tert-butoxycarbonyl-4-piperidinemethanol, as prepared in step f of Example 1, 300 μL (2.72 mmol) of N-methylmorpholine, and 309 mg (1.18 mmol) of triphenylphosphine was added 185 μL (1.18 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred at ambient temperature for 1 h, quenched with saturated NaHCO3, and extracted into ether. The organic phase was dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (ethyl acetate/hexane (1:2)) gave 382 mg of the title compound as a colorless foam. 1H-NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J=1.5, 8 Hz), 7.55-7.64 (m, 2H), 7.35-7.40 (m, 1H), 7.08-7.26 (m, 5H), 6.93 (d, 2H, J=8 Hz), 6.65 (d, 2 Hz), 6.53 (dd, 1H, J=2, 8 Hz), 3.87 (s, 2H), 3.67 (d, 2H, 6 Hz), 2.69 (t, 2H, J=13 Hz), and 1.47 (s, 9H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C30H34ClNO6S: 594.2 (M+Na). Found: 594.0, 472.0 (M - (tert-butoxycarbonyl)+H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[C:21]([O:23][CH3:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 82, 0.090 g, 0.208 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 1.9 M solution of lithium hydroxide (1.5 mL, 2.8 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% methanol in ethyl acetate as the eluent to afford the title product as a white amorphous solid (0.062 g, 60%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:21])[CH:10]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[OH:11])=O)(C)(C)C.[CH3:22][Si](C)(C)[Cl:24].C(OC(C)C)(C)C>C(O)(C)C>[ClH:24].[NH2:8][C@@H:9]([CH2:21][CH3:22])[CH:10]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[OH:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Reactant: C[Si](C)(C)Cl
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: CC[C@H](N)C(O)c1nc2ccccc2o1
Product: Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
To a solution of 2(S)-(tert-butoxycarbonyl)amino-1-benzoxazol-2-ylpropan-1-ol (26.3 g, 86 mmol) in isopropanol (118 mL) at 20-25° C. was added trimethylchlorosilane (1.4 eq). The solution was stirred for 5 h at 50° C. Concentration of the reaction mixture to 52 mL followed by addition of isopropyl ether (210 mL), filtration and drying under vacuum afforded 2(S)-amino-1-benzoxazol-2-yl-butan-1-ol hydrochloride salt as a grey solid (16.4 g; yield=79%; mixture of diastereomers.