Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:22])=[O:23])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/c3ccc(Cl)cc3)c2c1
Yield: 65.8 %

Procedure:
N-{3-[(E)-2-(4-Chlorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 631 mg of trans-2-(4-chlorophenyl) vinylboronic acid, 28 ml of dimethylformamide, 3.25 ml of a saturated aqueous sodium hydrogencarbonate solution and 48 mg of tetrakis(triphenylphosphine)-palladium[0]. 556 mg of N-{3-[(E)-2-(4-chlorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 247° C. (analysis C22H18ClN3O4S2 % calculated C, 54.15; H, 3.72; Cl, 7.27; N, 8.61; O, 13.11; S, 13.14. % found C, 54.32; H, 4.40; Cl, 5.65; N, 7.83; S, 11.93).
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([N:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:19]1[C:20]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:29][C:21]=2[S:22][C:23]=1[C:24]([O:26]CC)=[O:25])S(C)(=O)=O)(=[O:6])=[O:5].C(O)(=O)C>CO.O>[CH3:3][S:4]([NH:7][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:19]1[C:20]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:29][C:21]=2[S:22][C:23]=1[C:24]([OH:26])=[O:25])(=[O:5])=[O:6]
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccccc1Sc1c(C(=O)O)sc2cc(OCc3cccnc3)ccc12
Yield: 67.6 %

Procedure:
Sodium hydroxide (1 ml of 1M in water) was added to a solution of ethyl 3-[2-(N,N-dimethylsulfonylamino)phenyl]sulfanyl-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 16--185 mg, 0.31 mmol) in methanol (5 ml), and the solution was heated at reflux for 40 minutes. The hot solution was acidified by dropwise addition of acetic acid, diluted with water (5 ml), and cooled. The solid precipitate was isolated by filtration and dried under vacuo to give the title compound as a colourless solid (102 mg).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.[CH2:14]1[O:16][CH2:15]1>CCOCC.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:14][CH2:15][OH:16])=[CH:9][N:8]=1
Reactant: C1CO1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.2 %

Procedure:
BuLi (32.2 ml of a 1.6 M solution in hexanes, 52 mmol) added dropwise to a stirred solution of 2,5-dibromopyridine (11.09 g, 46.8 mmol) in Et2O (400 ml) at −78° C. under nitrogen. Upon complete addition the reaction mixture was stirred for 45 min and then a solution of ethylene oxide (6.74 g, 0.14 mol) in THF (70 ml) was added. The reaction mixture was warmed to room temperature, stirred for 1 h and then quenched by addition of NH4Cl solution (sat., 150 ml). The organics were extracted with EtOAc (3×100 ml), washed with brine (100 ml) and dried (MgSO4). The material was concentrated under reduced pressure, whilst simultaneously dry-loading onto silica. The material was purified by column chromatography on silica eluting with Et2O and then EtOAc to give the pure alcohol (3.8 g, 40%).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]([CH:18]=[CH2:19])[C:5]([N:7]1[C@H:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[O:9][C:8]1=[O:17])=[O:6])[CH3:3].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:1][C@@H:2]([C@@H:4]([CH:18]=[CH2:19])[C:5]([N:7]1[C@H:11]([CH:12]([CH3:13])[CH3:14])[C:10]([CH3:16])([CH3:15])[O:9][C:8]1=[O:17])=[O:6])[CH3:3])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=C[C@@H](C(=O)N1C(=O)OC(C)(C)[C@H]1C(C)C)[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C[C@@H](C(=O)N1C(=O)OC(C)(C)[C@H]1C(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
A cooled (0° C.) solution of (R)-3-[(R)-2-((R)-1-hydroxy-ethyl)-but-3-enoyl]-4-isopropyl-5,5-dimethyl-oxazolidin-2-one (654 mg, 2.43 mmol, prepared as described in Tetrahedron 2009, 65, 7837-7851) and imidazole (727 mg, 10.68 mmol) in N,N-dimethylformamide (5 mL) was treated with tert-butyldimethylsilyl chloride (474 mg, 3.16 mmol). After stirring for 5 h at room temperature, the reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted with diethyl ether (2×20 mL). The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (800 mg, 86%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 3H), 0.09 (s, 3H), 0.84 (s, 9H), 0.92 (d, J=6.7 Hz, 3H), 1.01 (d, J=7.1 Hz, 3H), 1.16 (d, J=6.2 Hz, 3H), 1.40 (s, 3H), 1.50 (s, 3H), 2.05-2.20 (m, 1H), 4.17 (d, J=3.3 Hz, 1H), 4.25-4.40 (m, 1H), 4.67 (t, J=9.1 Hz, 1H), 5.25 (dd, J=10.3, 1.6 Hz, 1H), 5.46 (dd, J=17.2, 1.3 Hz, 1H), 5.65-5.79 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([N+:12]([O-:14])=[O:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)sc(Cl)c1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 55.8-g (0.22 mol) sample of 2,5-dichloro-3-thienylsulfonyl chloride was added in small portions to a stirred solution of 150 ml concentrated nitric acid and 150 ml concentrated sulfuric acid. After the addition was completed, the reaction mixture was stirred at about 25° C overnight. The reaction mixture was then diluted with ice water and filtered to give the crude 2,5-dichloro-4-nitro-3-thienylsulfonyl chloride product. The product was washed with water and dried. Recrystallization from methylene chloride gave the product as a brown solid, m.p. 89°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.[N:10]([O-])=O.[Na+].CC([O-])=O.[Na+].[Cl:19][CH:20](C(C)=O)[C:21]([O:23][CH3:24])=[O:22]>CO>[CH3:24][O:23][C:21](=[O:22])[C:20](=[N:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[Cl:19]
Reactant: O=N[O-]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cl)=NNc1ccc(F)cc1
Temperature: 0 °C
Yield: 94 %

Procedure:
(Reference: Tetrahedron Asymmetry 1999, 4447-4454): To a solution of 4-fluoroaniline (10.0 g, 90.0 mmol; commercially available from Sigma Aldrich) in MeOH (80 mL) was added 6 N HCl (80 mL) and the solution was cooled to 0° C. NaNO2 (12.4 g, 180 mmol) was then slowly added as a solid. The reaction was stirred for 15 min at 0° C. after which time NaOAc was added as a solid to adjust the reaction to pH 5. Subsequently, a solution of methyl 2-chloroacetoacetate (10.96 mL, 90.0 mmol; commercially available from Sigma Aldrich) in MeOH (40 mL) was slowly added at 0° C. The reaction was then allowed to warm to 25° C. and stirred for 12 hr after which time the MeOH was removed under reduced pressure and ether (300 mL) was added. The organic layer was separated and washed with saturated NaHCO3 and water prior to drying over Na2SO4. The organic layer was concentrated to afford [(4-fluoro-phenyl)-hydrazono]-chloroacetic acid methyl ester (19.42 g, 94%) that was utilized without further purification: H-NMR (CDCl3) δ 8.37 (bs, 1 H), 7.22-7.12 (m, 2 H), 7.00-6.96 (m, 2 H), 3.87 (s, 3 H).
Reaction SMILES: [CH3:1][C@H:2]1[C@:7]2([OH:30])[C@:8]34[O:28][C@H:27]5[C@@:16]6([C@@H:23]([OH:29])[C:24]([O:26]5)=[O:25])[C@H:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][C@H:12]([C@@:13]36[C@@H:14]([OH:15])[C@@H:6]2[O:5][C:3]1=[O:4])[O:11][C:9]4=[O:10].[C:31]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:1][C@H:2]1[C@:7]2([OH:30])[C:8]34[O:28][CH:27]5[C@@:16]6([C@@H:23]([O:29][CH3:31])[C:24]([O:26]5)=[O:25])[C@H:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][C@H:12]([C@:13]36[C@H:14]([OH:15])[CH:6]2[O:5][C:3]1=[O:4])[O:11][C:9]4=[O:10]
Reactant: C[C@@H]1C(=O)O[C@H]2[C@H](O)[C@@]34[C@H]5C[C@@H](C(C)(C)C)[C@]36[C@@H](OC(=O)[C@@H]6O)O[C@@]4(C(=O)O5)[C@@]12O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CO[C@H]1C(=O)OC2OC34C(=O)O[C@@H]5C[C@@H](C(C)(C)C)[C@@]21[C@]53[C@H](O)C1OC(=O)[C@@H](C)[C@@]14O
Yield: 54.6 %

Procedure:
To a suspension of ginkgolide B (0.030 g, 0.071 mmol) and K2CO3 (0.030 g, 0.212 mmol) in acetonitrile (0.5 mL) was added iodomethane (0.020 g, 0.141 mmol). The reaction mixture was heated under reflux for 30 min. This reaction resulted in a mixture of 10-methoxy-ginkgolide B and 1-methoxy ginkgolide B in a ratio of 4 to 1. 10-Methoxy-ginkgolide B was separated using an HPLC semi-preparative C18 column (7.8 mm×30 cmL) with a mobile phase of MeOH/H2O (40:60) at a flow of 2 mL/min to give the final product as a white solid (0.017 g, 56%). 1H NMR (400 MHz, CD3OD): δ1.14 (s, tert-butyl), 1.24 (d, J=7.1, CH3), 1.90 (dd, J=14.2, 4.6, 8-H), 2.06 (td, J=13.9, 4.3, 7α-H), 2.25 (dd, J=13.6, 4.6, 7β-H), 3.05 (q, J=7.1, 14-H), 3.80 (s, OCH3), 4.24 (d, J=7.4, 1-H), 4.57 (d, J=7.4, 2-H), 4.93 (s, 10-H), 5.43 (d, J=4.1, 6-H), 6.10 (s, 12-H). 13C NMR (75 MHz, CD3OD): δ7.6, 7.0, 29.6 (3 C), 32.9, 37.6, 41.8, 48.8, 68.6, 70.5, 71.5, 74.4, 80.4, 82.2, 84.8, 90.9, 98.2, 110.3, 171.1, 173.0, 175.4. [Hu, L., Chen, Z., Xie, Y., Jiang, Y., & Zhen, H. (2000) Bioorg. Med. Chem. 8, 1515-1521]
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([Cl:16])([Cl:15])=[O:14]>CC(=O)CC>[Cl-:15].[CH3:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:13]([Cl:16])=[O:14])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Solvent: CCC(C)=O
Product: C[NH+]1C(C)(C)CC(OC(=O)Cl)CC1(C)C
Product: [Cl-]
Temperature: 53 °C
Yield: 94.4 %

Procedure:
Into a 2 liter round bottom flask equipped with an oil bath, reflux condenser, and nitrogen atmosphere sparger were charged 1,2,2,6,6-pentamethyl-4-piperidinol (51.2 g, 0.3 mole) and 1 liter of 2-butanone. Freshly distilled phosgene (35 ml, 0.45 mole) was evaporated into the reactor in a stream of nitrogen; a solid precipitate formed immediately. The resulting slurry was heated to reflux which initially was 53° C. but rose gradually over 25 minutes to 77° C. during which time the initially formed solid dissolved. After an additional 25 minutes of reflux at 77° C., the reaction mixture was cooled while being purged of excess phosgene and hydrogen chloride with a nitrogen stream. The ketone solvent was stripped from the product using an aspirator vacuum. The solid obtained was isolated and washed with 300 ml of 1,1,1-trichloroethane; then it was washed a second time with 200 ml of 1,1,1-trichloroethane. The resulting white crystalline solid was dried under high vacuum to give 76.5 g of the chloroformate hydrochloride having an assay of 99.7% (by analysis of hydrolyzable chloride: theoretical 26.24%, found 26.17%) and a corrected yield of 94.4%.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:9]2([OH:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CC2(O)CCNCC2)cc1
Reaction time: 12 h

Procedure:
137 mL (0.983 mol) of triethylamine is added to a solution of 41.5 g (0.410 mol) of 4-hydroxypiperidine in 500 mL of dichloromethane. Then 56.28 g (0.328 mol) of 4-nitrobenzylchloride is slowly added. The reaction mixture is boiled for 12 hours. The solid formed is suction filtered, the filtrate is washed twice with water and dried over magnesium sulfate. The solvent is evaporated down. Yield: 66.45 g (86% of theory); C12H16N2O3 (M=236.27); calc.: molecular ion peak (M+H)+: 237; found: molecular ion peak (M+H)+: 237.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:1]([O-:4])=[O:2])[C:7]=1[OH:12]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1F
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(F)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Concentrated HNO3 (95%, 44 g, 0.62 mol) was added dropwise at 0-5° C. to the solution of 2-fluorophenol (64.6 g, 0.58 mol) in 1 L of DCM. The mixture was stirred at 0° C. for 1 hour before filtration. The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (DCM:PE=1:2) to afford 2-fluoro-6-nitrophenol.
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[C:7]([N:11]([C:16]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:19]3[C:20]([C:30]([O:32]CC)=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.CO.Cl>C1COCC1.O>[Br:4][C:5]1[CH:6]=[C:7]([N:11]([C:16]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:19]3[C:20]([C:30]([OH:32])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N(c1cccc(Br)c1)c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
Lithium hydroxide monohydrate (68.5 mg, 1.630 mmol) was added to a suspension of ethyl 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (311 mg, 0.543 mmol) in THF:MeOH:water/3:1:1 (10 mL). The mixture was stirred at room temperature overnight. The mixture was acidified with 2N aqueous HCl and the volatile solvents were evaporated. The residue was partitioned between EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate and concentrated to give 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylic acid (309 mg, quantitative) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.01-8.13 (m, 2H) 7.77 (s, 1H) 7.66 (s, 1H) 7.54 (t, J=1.95 Hz, 1H) 7.39 (dd, J=8.21, 1.37 Hz, 1H) 7.30-7.36 (m, 1H) 7.17-7.26 (m, 3H) 3.27 (s, 3H) 2.11 (s, 1H) 0.74-1.18 (m, 3H) 0.48-0.74 (m, 1H). LCMS (m/z, ES+)=544, 546 (M+H, M+2).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[CH2:15])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[CH2:15])[C:12]=3[N:30]3[CH2:31][CH2:32][C@H:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: C=Cc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=Cc1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 89.2 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-vinyl-1,3-benzoxazole-4-carbonitrile (I-180) (100 mg, 0.41 mmol) was dissolved in dimethyl sulfoxide (2 ml), then at room temperature, triethylamine (86 μl, 0.62 mmol) and (3S)-3-(dimethylamino)pyrrolidine (68 μl, 0.54 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 4.5 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain a roughly-purified product (123 mg, 89%) as a pale brown solid. This was recrystallized from diisopropyl ether and hexane to obtain the entitled compound (79 mg) as a white solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH2:19][C:20]([CH3:26])([CH3:25])[C:21](OC)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[CH:13]1([CH2:19][C:20]([CH3:26])([CH3:25])[C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C(C)(C)CC1CCCCC1
Reactant: COP(C)(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)CC1CCCCC1)OC
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of dimethyl methylphosphonate (6.6 ml, 60.5 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.59N, 38.1 ml, 60.5 mmol) at -78° C. under argon atmosphere, and the mixture was stirred for 30 minutes. Then, methyl 3-cyclohexyl-2,2-dimethylpropionate (5.00 g, 25.2 mmol) was added dropwise and the mixture was stirred at -78° C. for 20 minutes and then at room temperature for 2 hours. An aqueous saturated solution of ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 ml×4) and then the combined ethyl acetate layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate) to yield a pure product of dimethyl 4-cyclohexyl-3,3-dimethyl-2-oxobutylphosphonate (3.9491 g, 13.6 mmol, 54.0%). This compound was assigned the structure by the following data:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][OH:11])[C:7]([OH:9])=[O:8].CC(C)([O-])C.[K+].Br[C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>CS(C)=O>[C:23]([O:22][C:20]([C:19]([O:11][N:10]=[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([OH:9])=[O:8])([CH3:28])[CH3:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)C(=NO)c1ccco1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)O)c1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(fur-2-yl)-2-hydroxyiminoacetic acid (syn isomer) (14.1g) in dimethyl sulphoxide (100ml) was added all at once to a magnetically stirred solution of potassium t-butoxide (22.4g) in dimethyl sulphoxide (400ml), the reaction mixture being maintained under an atmosphere of dry nitrogen. A gel was formed which, on stirring, became a finely divided, yellow solid. Stirring was continued for one hour, and then a solution of t-butyl 2-bromo-2-methylpropionate (24.0g) in dimethyl sulphoxide (50ml) was added over one hour to the reaction mixture at room temperature. After addition was complete. the resulting solution was stirred for a further hour. The reaction was poured into ice-water (1.5 liters) and acidified under ether (500ml) to pH 1.8 with concentrated hydrochloric acid. The two layers were separated, and the aqueous layer was extracted with more ether. The combined ether extracts were washed once with water, then extracted with aqueous sodium bicarbonate solution. The combined alkaline extracts were acidified under ether to pH 1.8 with concentrated hydrochloric acid, and the acid solution was extracted further with ether. The combined ether extracts were washed (water, saturated brine), dried, and concentrated to a yellow oil, which crystallised under high vacuum (22.41g, 83%), λmax (EtOH) 272.5nm (ε15,400).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[NH:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([NH:20][C:21]3[N:26]=[C:25]([N:27](CC)[CH2:28][C:29]4C=CC(OC)=CC=4)[C:24]4=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:23]4[N:22]=3)[C:13]=2[Cl:44])[CH2:8][C@H:7]1[OH:45])[CH3:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:44][C:13]1[C:14]([NH:20][C:21]2[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]3=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:23]3[N:22]=2)=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][C@@H:6]([NH:5][C:4](=[O:46])[O:3][CH2:1][CH3:2])[C@H:7]([OH:45])[CH2:8]1
Reactant: CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(CC)Cc4ccc(OC)cc4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OCC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To ethyl((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (50 mg, 0.068 mmol), in DCE (0.8 mL) was added anisole (0.1 mL, 0.915 mmol) and TFA (0.5 mL, 6.49 mmol); the mixture stirred 2 h at 25° C. and solvent was removed. 2N NH3/MeOH (5 ml) was added and the mixture stirred for 30 min at 25° C. The solution was stored at −20° C. and a white precipitate formed. The material was collected by filtration, washed with 20 ml cold MeOH, 5 ml ether and dried under air-suction for 0.5 h to afford ethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (10 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][C@H:4]([O:9][C@H:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6].[I:30][CH3:31]>C(#N)C>[I-:30].[CH3:8][O:7][C:5]([C@@H:4]([O:9][C@H:10]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N+:19]([CH3:31])[CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:3][CH:2]([CH3:29])[CH3:1])=[O:6]
Reactant: CI
Reactant: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(-c2cccnc2)cc1
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(-c2ccc[n+](C)c2)cc1
Product: [I-]
Reaction time: 18 h

Procedure:
A solution of methyl (2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanoate from example 36 step 2 (881 mg, 2.26 mmol) and iodomethane (3.2 g, 22.6 mmol) in acetonitrile (22 mL) was heated in a pressure tube immersed in an oil bath at 120° C. for 18 hours. The solution was concentrated and the residue pumped on to obtain the pyridinium iodide salt as a foam.