Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:4][C:3]=2[O:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[C:6]3[C:5](=[CH:4][C:3]4[O:2][CH2:1][O:9][C:8]=4[CH:7]=3)[CH2:10][C:11](=[O:12])[NH:13]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NC(=O)Cc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1Cc2cc3c(cc2C(c2ccc(Cl)cc2)N1)OCO3
Temperature: 100 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A flask containing polyphosphoric ester (90 g) was held at 100° C. (oil bath temperature). A mixture of 3,4-methylenedioxyphenylacetamide (22 g, 123 mmol) and parachlorobenzaldehyde (17.1 g, 122 mmol) was added in three portions over half an hour, with stirring. The solution (dark red) was heated at 100° C. for 5 h and poured onto ice (400 ml). A 10% solution (aqueous) of sodium carbonate (2 liters) was added and the mixture was left overnight. The resulting oily gum was extracted with chloroform (2×500 ml) and the chloroform extracts washed with brine (50 ml) and dried over sodium sulphate. The chloroform solution was filtered and the solvent was removed under reduced pressure. The solid so formed was triturated with ethanol (2×30 ml) to give 1-(4-chlorophenyl)-6,7-methylenedioxy-1,4-dihydroisoquinol-3-one (7 g). The combined ethanol layers were evaporated under reduced pressure and the residue chromatographed (Silica gel (300 g), chloroform as eluent) to give a further 8 g of product. Total yield (15 g, 41%), m.p. 200°-202° C. (ethanol).
Reaction SMILES: ICI.[CH3:4][Si:5]([CH3:14])([CH3:13])[O:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[CH2:15]([Zn]CC)C.[NH4+].[Cl-]>CCCCCC>[CH3:4][Si:5]([CH3:14])([CH3:13])[O:6][C:7]12[CH2:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: CC[Zn]CC
Reactant: C[Si](C)(C)OC1=CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ICI
Product: C[Si](C)(C)OC12CCCCC1C2
Temperature: 0 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
Diiodomethane(120 μl, 1.5 mmol) was added slowly to perfluorohexanes (FC-72, 3 mL) in a test tube (14 mm×105 mm) and then trimethylsiloxycyclohexene (180 mg, 1.05 mmol) in hexane (3.5 mL) was slowly poured into the test tube. A hexane solution of diethylzinc (1.0 M, 1.5 mmol, 1.5 mmol) was added to the hexane layer, and the diiodomethane layer on the bottom was stirred gently so as not to mix the three phases. After 10 h at room temperature, additional diidomethane (40 μl, 0.5 mmol) was added to the bottom layer of the test tube by using a syringe. After 14 h, the reaction mixture was cooled to 0° C., and saturated NH4Cl (10 mL) was added. The hexane layer was decanted, washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by short column chromatography (17 mm×20 mm of florisil layer over 50 mm of silica gel layer) with benzene/hexane: ¼ to give 1-trimethylsiloxybicyclo[4.1.0]heptane in 63% yield (123 mg).
Reaction SMILES: [OH:1][CH:2]([PH:5](=[O:7])[OH:6])[CH2:3][Cl:4].[CH2:8](O)[CH2:9][CH2:10][CH3:11].O>C1C=CC=CC=1>[OH:1][CH:2]([PH:5](=[O:6])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][Cl:4]
Reactant: O=[PH](O)C(O)CCl
Reactant: CCCCO
Solvent: c1ccccc1
Solvent: O
Product: CCCCO[PH](=O)C(O)CCl
Yield: 64.6 %

Procedure:
A solution of α-hydroxy-β-chloroethylphosphinic acid (2.9 g) and 1-butanol (10.0 g) in benzene (30 ml) was heated for 3 hours with removal of water through a Dean-Stark apparatus. The same work-up as in Example 6 gave 2.60 g (64.8%) of n-butyl α-hydroxy-β-chloroethylphosphinate (Compound No. 82).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(N3CCCC3)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=547.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: COCCN
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: COCCNC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-methoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=504.97 (M+H+); retention time=0.74 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[F:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>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.CN(C=O)C>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH:16]=[N:15][CH:14]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(-c2cncc(F)c2)cncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 73.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (790 mg, 3.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LXX) (1.01 g, 4.35 mmol), K3PO4 (1.15 g, 5.44 mmol), water (10 mL) and DMF (10 mL) was degassed with argon thrice. Pd(PPh3)4 (209 mg, 0.18 mmol) was added to the reaction and the solution was heated at 90° C. for 4 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→1.5:98.5 MeOH[7N NH3]:CHCl3) to give 5′-fluoro-5-nitro-3,3′-bipyridin-4-amine (LXXI) as a yellow solid (626 mg, 2.67 mmol, 74% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.62 (brs, 2H), 7.86-7.89 (m, 1H), 8.15 (s, 1H), 8.47-8.48 (m, 1H), 8.67 (d, J=2.7 Hz, 1H), 9.07 (s, 1H); ESIMS found C10H7FN4O2 m/z 235 (M+H).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.[C-:21]#[N:22].[Na+]>>[OH:20][C:17]1([C:21]#[N:22])[CH2:18][CH2:19][N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[CH:12][CH:11]=2)[CH2:15][CH2:16]1
Reactant: [C-]#N
Reactant: Cn1nnc(-c2ccc(CN3CCC(=O)CC3)cc2)n1
Agent: [Na+]
Product: Cn1nnc(-c2ccc(CN3CCC(O)(C#N)CC3)cc2)n1

Procedure:
In a first step as depicted in Scheme 2, an appropriately substituted phenyl derivative, for example, the known compound 2-methyl-5-(4-methylphenyl)-1,2,3,4-tetrazole, is brominated with, for example N-bromosuccinimide and light, to afford the corresponding 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole (A1). Intermediate (A1) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one (B1). Intermediate (B1) is then reacted under acidic conditions with, for example sodium cyanide, to afford the corresponding nitrile compound, 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile (C1). Intermediate (C1) is esterified under acidic conditions with, for example ethanol, to afford the corresponding ethyl 4-hydroxy-1-{[4-(2-methyl-(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carboxylate (D1). The Grignard of an appropriately substituted halophenyl derivative, for example 4-trifluoromethoxybromobenzene, is reacted with intermediate (D1) to provide compounds of formula I-B, wherein X and Y are, for example hydroxyl. Example 2, set forth below, provides detailed methods to how compounds of formula I (-B) shown in Scheme 2 were prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Yield: 133.4 %

Procedure:
A mixture of 2-chloro-4-nitrotoluene (0.20 g, 1.17 mmol), N-bromosuccinimide (0.228 g, 1.28 mmol) and benzoyl peroxide (0.014 g, 0.058 mmol) in tetrachloromethane (7 mL) was irradiated (500 W lamp) at reflux overnight. The reaction mixture was concentrated to give a yellow oil/solid (0.391 g) which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][CH:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[CH:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:38]([O:40][C:41]([CH3:43])=[CH2:42])=[O:39]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:38]([O:40][C:41]([CH3:43])=[CH2:42])=[O:39])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Reactant: C=C(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)OC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To (1S,4aS,5S,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 144, 50 mg, 0.096 mmol) and 4-dimethylaminopyridine (35 mg, 0.29 mmol) in dichloromethane (5 ml) at 0° C. under nitrogen was added isopropenyl chloroformate (17.4 mg, 0.144 mmol) and the resulting mixture stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (25 ml) and washed with citric acid solution (3×15 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (5 g) eluting with hexane:ethyl acetate (1:1). The pure fractions were combined and concentrated in vacuo to give the title product (56 mg, 96%).
Reaction SMILES: S(Br)([Br:3])=O.[F:5][C:6]1[N:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1.CC(OO)=O>C(Cl)Cl>[Br:3][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([F:5])=[N:11][CH:10]=1)[CH3:13]
Reactant: O=S(Br)Br
Reactant: CC(O)c1ccc(F)nc1
Agent: CC(=O)OO
Solvent: ClCCl
Product: CC(Br)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
Thionyl bromide (11.60 mL, 149 mmol) was added (dropwise over 15 min; gas evolution) to a solution of 1-(6-fluoropyridin-3-yl)ethanol (10.55 g, 74.7 mmol) in DCM (300 mL) at 25° C., and the resulting orange solution was stirred at 25° C. for 3 h. Excess SOBr2 was then carefully quenched with water (150 mL) at 0° C. with vigorous stirring, and 5.0 N aqueous NaOH (100 mL) was then carefully added at 0° C. (over about 10 min) to neutralize HBr and SO2 (Yellow mixture results; final pH about 9; adjust with saturated aqueous NaHCO3,to a pH of about 9 as necessary.) The resulting mixture was vigorously stirred at 0° C. for 5 min to ensure complete quench of acidic species, and the resulting mixture was then partitioned between DCM (200 mL) and half saturated aqueous NaHCO3 to a pH of about 9 (600 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (300 mL). The combined organic extracts were sequentially washed with saturated aqueous NaHCO3 (500 mL) and brine (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-bromoethyl)-2-fluoropyridine (14.58 g, 96% yield) as a yellow oil (71% LCAP; m/z (ESI, +ve) 204.0 (M+H)+), which was used directly in Step 3.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][Si:6](C)([O:9][CH3:10])[O:7][CH3:8].C1(C)C=CC=CC=1.C([Si](C=C)(C)O[Si](C)(C)C)=C>C(O)(=O)C>[Cl:4][CH2:1][CH2:2][CH2:3][Si:6]([CH3:5])([O:9][CH3:10])[O:7][CH3:8]
Reactant: C=CCCl
Reactant: CO[Si](C)(C)OC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CO[Si](C)(CCCCl)OC
Temperature: 50 °C
Yield: 40 %

Procedure:
306 mg Of allyl chloride, 530 mol of dimethyldimethoxysilane, and 77 mg of toluene were placed in a glass reaction tube and 0.01 ml of acetic acid was added to this mixture. Then, 0.005 mol of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed and heated for 2 hours in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of allyl chloride was 100% and γ-chloropropylmethyldimethoxysilane was produced at a yield of 40%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cccnc2)c1
Yield: 68.7 %

Procedure:
A mixture of 3-bromo-4-chloronitrobenzene (5.17 g, 21.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (4.27 g, 26.2 mmol) in ethanol (30 ml) and toluene (30 ml) together with 2 N Na2CO3 solution (13.9 ml) was degassed with a stream of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) was added and the reaction was heated at reflux for over 24 h. The mixture was concentrated under reduced pressure to remove the organic solvents and water (100 ml) was added. This was extracted with ethyl acetate (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography (silica gel, 50% Et2O/CH2Cl2), to yield the title compound (3.53 g, 69%): 1H NMR (360 MHz, CDCl3) δ 7.42-7.48 (1H, m), 7.70 (1H, d, J 8.7 Hz), 7.81 (1H, dt, J 8.0, 1.8 Hz), 8.17-8.27 (2H, m), 8.68-8.77 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=C.C1C[O:41]CC1.O.I([O-])(=O)(=O)=O.[Na+]>CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:41]
Reactant: C1CCOC1
Reactant: C=Cc1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(C=O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 50 %

Procedure:
A suspension of 6-(N-(3-chloro-4-vinylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (890 mg, 1.65 mmol) in 1:1 THF/water (36 mL) was treated with a solution of osmium tetroxide (2.5% in t-butanol, 0.415 mL, 0.033 mmol) and stirred for a few minutes. The resulting solution was treated with sodium periodate (883 mg, 4.13 mmol) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with EtOAc and washed with 1:1 water/brine (1×), then brine (1×). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane, filtered and the filtrate was purified by flash chromatography (silica gel, gradient of 0 to 50% EtOAc in hexanes) to afford the title compound (0.45 g, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.23 (s, 1H), 8.45-8.53 (m, 1H), 8.04 (s, 1H), 7.94-8.01 (m, 2H), 7.86 (d, 1H), 7.35-7.46 (m, 3H), 7.31 (dd, 1H), 7.24-7.29 (m, 1H), 3.57 (s, 3H), 2.84 (d, 3H), 1.89-1.98 (m, 1H), 0.68-1.02 (m, 3H), 0.42-0.58 (m, 1H). LCMS (m/z, ES+)=541 (M+H+).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]([C:27](O)([CH3:29])[CH3:28])[C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH:26]=1>O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:17][C:13]3[C:12]([C:27]([CH3:29])=[CH2:28])=[CH:11][C:10]([OH:9])=[CH:26][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(C(C)(C)O)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
Pyridine hydrochloride (400 mg) was heated to 190° C. To the melt was added 2-[5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole-7-yl] propan-2-ol (114 mg, 0.36 mmol) and the reaction was stirred for 2 h. The mixture was cooled to room temperature, dissolved in water and extracted with EtOAc. The organic layers were combined and washed with HCl (1N), water then brine and dried over MgSO4. Evaporation and purification by flash chromatography (50%–60% EtOAc/petroleum ether) gave (40 mg, 41% yield) of the product as a light red-brown solid, m.p. 225–228° C.; MS m/e 268 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:24]([CH2:25][NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])=[N:23][N:22]([CH2:39][C@@H:40]2[C@H:43]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42](=[O:55])[N:41]2[CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=2[O:65][CH3:66])[N:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:66][O:65][C:58]1[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:57]=1[CH2:56][N:41]1[C:42](=[O:55])[C@@H:43]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:40]1[CH2:39][N:22]1[N:21]=[C:20]([CH2:19][OH:18])[C:24]([CH2:25][NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:28])=[O:29])=[N:23]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CO)c(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])n2)c(OC)c1
Reaction time: 2.6 h
Yield: 87.8 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-((2-nitrophenylsulfonamido)methyl)-2H-1,2,3-triazol-2-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (252 mg, 0.270 mmol) in THF (2.8 mL) at 0° C. was added TBAF (1.0 M in THF, 270 μL, 0.270 mmol). After stirring for 2.6 h, the solution was diluted with EtOAc and partially concentrated in vacuo. Additional EtOAc was added along with KHSO4 (2%, aq) and water. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-100%), affording the title compound (165 mg, 88%) as a white solid. Rt=0.83 min, m/z=696.3 (M+1) Method 2m_acidic.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH2:12]O)[CH:11]=1)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=[CH:6]2.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:25][CH2:12][C:10]1[CH:11]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=[C:5]2[C:9]=1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=[CH:6]2
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CO)c21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CBr)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol (980 mg, 2.83 mmol) and carbon tetrabromide (1.41 g, 4.24 mmol) in tetrahydrofuran (10 mL) at 0° C. was added triphenylphosphine (1.11 g, 4.24 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (4%→8% EtOAc/Hex) to give 1.155 g (100%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.61 (d, J=1.2 Hz, 1H), 6.05 (s, 2H), 5.01 (s, 2H), 3.52 (m, 2H), 0.87 (m, 2H), −0.08 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 138.4, 135.1, 126.4, 125.7, 124.4 (q, J=33 Hz), 124.3 (q, J=273 Hz), 122.5, 120.1, 80.5, 66.6, 29.7, 17.9, −1.4.
Reaction SMILES: C([O:5][C:6](=[O:9])CI)(C)(C)C.CCOCC.C([O:19][C:20]([CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:33][CH:34](OCC)[CH2:35][C:36](=C=O)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH3:32])[C:24]1=[O:48])=[O:21])(C)(C)C>CCCCCC>[C:20]([CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:33][CH:34]([C:6]([OH:9])=[O:5])[CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:32])[C:24]1=[O:48])([OH:19])=[O:21]
Reactant: CC(C)(C)OC(=O)CI
Reactant: CCOC(CC(=C=O)c1ccccc1)NC1(C)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(NC(CCc2ccccc2)C(=O)O)C(=O)N(CC(=O)O)c2ccccc21

Procedure:
This above lactam was alkylated with t-butyliodoacetate as described in Example 1, Step B, to afford, after chromatography (silica, 2 ether: 1 hexane), 1-t-butyoxycarbonylmethyl 3-(1-ethoxy-carbonyl-3-phenylpropyl)amino-3-methyl-1,2-dihydro-2-oxo-3H-indole. NMR (CDCl3): δ1.1 (t, 3H); 1.5 (s, 9H); 1.55 (s, 3H); 1.8-3.2 (m, 6H); 3.9 (s, 2H); 4.4 (s, 2H); 7.1 (br.s., 9).