Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[CH:5]2.[OH-].[K+].[I:14]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[I:14]
Reactant: Clc1cc2cn[nH]c2cc1Cl
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
To a solution of 5,6-dichloro-1H-indazole (0.50 g, 2.67 mmol) in DMF (8 ml) at room temperature was added powdered potassium hydroxide (450 mg, 8.02 mmol) and iodine (1.02 g, 4.01 mmol). The maroon reaction mixture was stirred at room temperature for 45 min then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated to afford 827 mg (99%) of 5,6-dichloro-3-iodo-1H-indazole as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 13.79 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([NH:29][C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[F:21])=[O:31])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)c1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (43.9 mg, 0.160 mmol) in CH2Cl2 (2 mL) was added 2-fluoro-5-methylphenyl isocyanate (0.23 μL, 0.176 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 139 as a colorless solid (53.2 mg, 78%). LCMS m/z (%)=426 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.98 (bs, 1H), 8.42 (bs, 1H), 7.96 (dd, J=7.89, 1.96 Hz, 1H), 7.45 (d, J=1.82 Hz, 1H), 7.44-7.38 (m, 2H), 7.13-7.06 (m, 2H), 6.82-6.75 (m, 1H), 6.24 (d, J=1.85 Hz, 1H), 3.98 (t, J=6.35 Hz, 2H), 3.66 (s, 3H), 2.25 (s, 3H), 2.19 (t, J=7.03 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH2:12][CH3:13])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[Cl:1][C:2]1[C:3]([O:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([OH:11])[CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(C(O)CC)sc2c(Cl)c1Cl
Reaction time: 3 h

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol and 200 ml of 2-butanone is added a mixture of 7.35 g of ethyl bromoacetate in 100 ml of 2-butanone, followed by 7.4 g of potassium carbonate and 3.3 ml of sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 3 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and the mixture is extracted with ethyl ether. The organic layers are washed, dried over anhydrous magnesium sulfate, filtered and the solvent removed to give an oil which solidifies on cooling. Recrystallization from ethyl ether and hexane gives 10 g of ethyl [(6,7-dichloro-2-(1-hydroxypropyl]benzo[b]thien-5-yl]oxy]acetate, mp 69°-70°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](C2C=CC=CC=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([S:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1Br
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2-[2-({4-[(E)-2-(2,4-Difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole was prepared according to the method of Example 135 Step 2 using 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (Step 1) in place of (S)-1-(2-iodophenyl)ethanol and Intermediate 2 in place of Intermediate 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]OC(=O)C1C=CC=C(Br)C=1C>CO>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: COC(=O)c1cccc(Br)c1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(Br)ccc1C

Procedure:
The crude 5-bromo-2-methylbenzoic acid (1) (60.8 g; 283 mmol) was stirred in methanol (400 mL) and concentrated sulfuric acid (6 mL) was added. The mixture was heated at gentle boiling for 20 hours. The solvent was evaporated and the residue was taken up into toluene and water. The solution was shaken and the phases were separated. The organic layer was washed with dilute aqueous NaHCO3, water, and brine. The solution was dried with MgSO4, filtered, and evaporated to get an orange oil. Fractional distillation at reduced pressure yields a mixture of the title compound and 3-bromo-2-methylbenzoic acid methyl ester (47.9 g; 74%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O:20]CC)=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+:27].[Na+]>C(O)C.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[Na+:27]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@H](COCC(C)C)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Yield: 148.1 %

Procedure:
Crude ethyl (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (15.29 g) synthesized according to the process (acid chloride method) similar to that described in Patent reference 1 was dissolved in ethanol (24 mL). While the solution was stirred at room temperature, sodium carbonate (2.44 g) dissolved in water (24 mL) was dropped. After the solution was stirred at room temperature for 1 hour, it was further stirred at 90° C. to 95° C. for 2 hours. The solvent was distilled off under reduced pressure, and water (50 mL) was added to the residue. The obtained solution was washed with two portions of ethyl acetate (50 mL), and water was distilled off under reduced pressure. Acetone (400 mL) was dropped to the residue, and the obtained solution was stirred overnight at room temperature. The precipitated crystalline product was collected by filtration, washed with a mixture of 3% water-acetone (30 mL), washed again with acetone (30 mL), and dried in air to obtain white solid sodium (2S,3S)-3[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (10.55 g, 70.3%). The NMR data of the solid product were the same as those in Example 9.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24]C)=[C:8]([CH3:30])[N:7]=1.[CH3:31]O.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([O:29][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=2[OH:24])=[C:8]([CH3:30])[N:7]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Reactant: CO
Agent: BrB(Br)Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of boron tribromide (2.51 ml, 1M in DCM) was added portionwise over 30 min to a stirred suspension of the product from example 83 step (iv) (300 mg) in DCM (5 mL) at 0° C. The suspension was allowed to warm to rt and stirred for 3 h. A further portion of boron tribromide (1.674 ml, 1M in DCM) was added and the mixture stirred at rt for a further 2 h. MeOH (2 mL) and 4M HCl in dioxane (2 mL) were added and the mixture stirred for 1 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC, to give the title compound as a white solid, 27 mg.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(=Cc2ccc(F)c([N+](=O)[O-])c2)c2ccccc21

Procedure:
A stirred solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (20 g, 0.083 mol) and 4-fluoro-3-nitrobenzaldehyde (13.97 g, 0.083 mol) in tetrahydrofuran (120 ml) was cooled to 15° C. and triethylamine (11.5 ml, 0.083 mol) was added dropwise at <25° C. The mixture thickened at this point, so further tetrahydrofuran (50 ml) was added to aid stirring. The mixture was stirred at ambient temperature for 65 hours and the resulting solid was collected by filtration. The filtrate was concentrated in vacuo, the residue was triturated with water (30 ml) and the resulting solid was collected by filtration. The two crops of solid were combined and suspended in water (120 ml). The mixture was stirred at ambient temperature for 30 minutes and the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-fluoro-3-nitrobenzylidene)-3H-isobenzofuran-1-one, still slightly wet with water, which was used directly in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11]([Cl:35])=[O:12])=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccc(OC)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)Cl)OCc1ccc(OC)cc1
Temperature: -10 °C

Procedure:
To a solution of acid 34 (500 mg, 1.37 mmol) in DCM (5 mL) was added dimethylformamide (DMF) (100 mg, 1.37 mmol), and the resulting mixture was cooled to −10° C. Oxalyl chloride (174 mg, 1.37 mmol) in DCM (5 mL) was added dropwise. The solution was allowed to warm to room temperature over 1 h. After TLC analysis showed no acid present, the mixture was concentrated in vacuo and used without further purification.
Reaction SMILES: [Na+].[I-].CC(C)=[O:5].Br[C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1=[C:18]1[CH:25]3[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]4)[CH2:24]3)[CH2:15]2>O.O1CCOCC1>[OH:5][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1=[C:18]1[CH:25]3[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]4)[CH2:24]3)[CH2:15]2
Reactant: BrC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2
Reactant: CC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2

Procedure:
The 4-eq.-bromoadamantylidene adamantane has bee found to have particularly advantageous and unexpected properties. Thus, unlike the corresponding 4-eq.-chloroadamantylidene adamantane, this compound permits carrying out substitution reactions by means of solvolysis without requiring an adjuvant such as an Ag+ salt. It has moreover been found that certain substituents can be introduced in one step where this had not been possible before. The 4-eq.-bromoadamantylidene adamantane reacts with primary and secondary alcohols to form ethers, with carboxylic acids to form esters, with primary amines to form secondary amines, and with nitriles to form N-adamantylidene adamantyl amides. Furthermore it has been found to be possible to carry out halogen exchange reactions with this compound, for example, in a reaction with NaI/acetone. Reaction of 4-eq.-bromoadamantylidene adamantane with H2O/dioxane gives a quantitative yield of 4-eq.-hydroxyadamantylidene adamantane. The solvolysis reactions are carried out in the pure reagent as the solvent or together with dioxane or DMF as a co-solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[F:10][C:11]1[CH:12]=[C:13]([C:17]#[CH:18])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Ca+2]>C(NCC)C.[Cu]I>[F:10][C:11]1[CH:12]=[C:13]([C:17]2[NH:7][C:6]3[C:5]([CH:18]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:8]=3)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(F)ccc1I
Reactant: C#Cc1cccc(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCNCC
Product: Fc1cccc(-c2cc3ccc(F)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
5-Fluoro-2-iodoaniline (30 g, 126 mmol) and 3-fluorophenylacetylene (20 g, 166 mmol) were dissolved in diethylamine (500 ml) and the mixture purged with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium (2 g) and copper(I) iodide (0.4 g) were added and the mixture stirred at room temperature for 15 h. The solvent was removed in vacuo and the residue partitioned between diethyl ether (500 ml) and water (500 ml), the organic layer was separated and washed with water (2×500 ml), saturated sodium chloride (200 ml), dried over MgSO4, filtered through a short plug of Florisil and evaporated in vacuo. The solid was dissolved in anhydrous DMF (500 ml), copper(I) iodide (12 g, 63 mmol) and calcium carbonate (12.6 g, 126 mmol) added and the mixture heated at 120° C. under an atmosphere of nitrogen for 48 h. The mixture was filtered through hyflo and the filtrate evaporated in vacuo. The residue was partitioned between ethyl acetate (500 ml) and water (500 ml), the organic layer was separated and washed with water (2×500 ml) and saturated sodium chloride (100 ml), dried over MgSO4 and evaporated in vacuo. The residue was triturated with a mixture of diethyl ether and hexane, the solid filtered and dried in vacuo to afford 25 g (109 mmol; 87%) of 2-(3-fluorophenyl)-6-fluoroindole as a brown solid. δH (360 MHz; CDCl3) 6.78 (1H, d, J 1.8, indole H3), 6.88 (1H, m, aromatic), 6.99 (1H, m, aromatic), 7.05 (1H, dd, J 9.5 and 2.2, aromatic), 7.29 (1H, dd, J 8.6 and 1.0, aromatic), 7.36 (2H, m, aromatics), 7.51 (1H, dd, J 8.6 and 5.3, indole H4), 8.37 (1H, br s, NH).
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[NH2:16][NH:17][C:18]([NH2:20])=[O:19]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[C:6]2=[O:14]
Reactant: NNC(N)=O
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Agent: Cl
Solvent: O
Product: NC(=O)NN=c1c(=O)c2ccc(O)cc2c1=O

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, semicarbazide hydrochloride, reflux for 4 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1I)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)#[CH:19]>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[C:19]#[C:18][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Br)cc1I
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-bromo-2-iodo-phenoxy)-acetic acid tert-butyl ester (Intermediate 190) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]CC)=[O:15])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2.[OH-].[Na+].Cl.O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:12])(=[O:13])[N:6]=2
Reactant: CCOC(=O)C1=CC(C)=CN2CCS(=O)(=O)N=C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=CN2CCS(=O)(=O)N=C2C(C(=O)O)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of ethyl 7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylate 2,2-dioxide (106 mg) in methanol (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1.05 mL) and water (1 mL), and the resulting precipitate was collected by filtration, washed successively with water and a small amount of THF, and dried to give the title compound (79 mg) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:40])[CH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:15][O:16][C:17](=[O:40])[CH2:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9]4[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=4)=[CH:6][N:7]=3)=[CH:29][CH:30]=2)[CH2:23][CH2:24]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cn1ccc(Nc2ccc(Br)nc2)n1
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: [K+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccn(C)n4)cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of (6-bromo-pyridin-3-yl)-(1-methyl-1H-pyrazol-3-yl)-amine (0.15 g, 0.6 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.23 g, 0.7 mmol, 1.1 equiv) in 5 Ml DME was added 0.5 Ml saturated potassium carbonate solution followed by 5 mg Pd(PPh3)4 catalyst. The reaction was then heated to 80° C. for 2 h. Removal of volatiles in vacuo followed by silica gel chromatography (20% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.26 (m, 2 H) 1.54 (qd, J=12.59, 2.40 Hz, 2 H) 1.68 (br. S., 1 H) 1.87 (d, J=11.12 Hz, 5 H) 2.31 (d, J=6.57 Hz, 2 H) 3.66 (s, 3 H) 3.82 (s, 3 H) 5.86 (s, 1 H) 7.33 (d, J=8.34 Hz, 2 H) 7.59 (d, J=2.02 Hz, 1 H) 7.80 (d, J=8.84 Hz, 1 H) 7.93 (d, J=8.34 Hz, 2 H) 7.97 (dd, J=8.84, 2.78 Hz, 1H) 8.65 (d, J=2.27 Hz, 1 H) 8.83 (s, 1 H); (M+H)+ 405.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].BrC[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8]
Reactant: COC(=O)CCBr
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.32 g, 58 mmol) was added to a solution of 2-butyne-1,4-diol (5.0 g, 58 mmol) in THF (60 mL) at 0° C. under nitrogen. After 1 h at 0° C., methyl bromomethylacetate (5.5 mL, 58 mmol) was added and the reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with 1 N HCl (60 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (1×100 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→5% MeOH/CH2Cl2, gradient) afforded 3.2 g (35%) of (4-hydroxy-but-2-ynyloxy)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:39][C:34]=2[O:33][CH2:32]1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40]([N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[CH2:10][C@@H:9]([OH:18])[C@@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]3[C@H:29]4[C@H:25]([O:26][CH2:27][CH2:28]4)[O:24][CH2:23]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:41])=[O:42])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (0.100 g, 0.237 mmol), 1,3-benzodioxole-5-sulfonyl chloride (52 mg, 0.237 mmol), diisoproylethylamine (0.042 mL, 0.237 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous hydrochloric acid (1N). The organic phase was separated and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 97:3 dichloromethane:methanol. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate (114 mg, 80%) as a white solid. H1-NMR (chloroform-D3): 0.89 (m, 6H), 1.57 (m, 7H), 2.95 (m, 5H), 3.69 (m, 2H), 3.89 (m, 4H), 4.15 (m, 1H), 4.82 (d, 1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.10 (s, 2H), 6.90 (d, 1H), 7.23 (m, 6H), 7.39 (m, 1H). MS(ESI): 629(M+Na).