Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])=[O:9])=C>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Solvent: CO
Solvent: ClCCl
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Yield: 29.9 %

Procedure:
8-(4-Bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (40 mg, 0.09 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue that was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (11 mg, 29%). LCMS (method A): RT=6.06 min, [M+H]+=409/411. 1H NMR (CD3OD): 8.27 (1 H, d, J=0.85 Hz), 7.79 (1 H, dd, J=7.39, 0.97 Hz), 7.42 (1 H, dd, J=10.00, 2.19 Hz), 7.31 (1 H, ddd, J=8.53, 2.20, 1.19 Hz), 7.12 (1 H, t, J=8.60 Hz), 6.79-6.73 (1 H, m), 6.65 (1 H, s), 3.97 (2 H, t, J=4.69 Hz), 3.73 (2 H, t, J=4.68 Hz).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](C)(C)O[SiH2]C(C)(C)C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28](COCC[Si](C)(C)C)[CH:29]=[C:30]([NH2:32])[CH:31]=1)=O)(C)(C)C.[C:42]1([C@@H:48]([N:50]2[CH:54]=[C:53]([C:55](Cl)=[O:56])[CH:52]=[N:51]2)[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[O:41]=[C:27]1[NH:28][CH:29]=[C:30]([NH:32][C:55]([C:53]2[CH:52]=[N:51][N:50]([C@H:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:49])[CH:54]=2)=[O:56])[CH:31]=[C:26]1[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([CH2:17][N:28]1[CH2:29][CH2:30][CH2:31][CH2:26][CH2:27]1)=[CH:14][CH:15]=2
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Reactant: C[C@@H](c1ccccc1)n1cc(C(=O)Cl)cn1
Product: C[C@@H](c1ccccc1)n1cc(C(=O)Nc2c[nH]c(=O)c(-c3cc4cc(CN5CCCCC5)ccc4[nH]3)c2)cn1

Procedure:
The title compound was prepared by the route outlined in Scheme 8, following the same experimental procedures as for Example 37, reacting intermediate (8d), 2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl with intermediate (6h), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride in the coupling step as described for Example 160.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:19]([N:22](C(C)C)CC)(C)C.[C:28]([C:30](=C)C#N)#N>CN(C=O)C>[CH2:2]([N:9]1[CH2:30][CH2:28][N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]([C:19]#[N:22])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CNCCNc2ccccc2)cc1
Reactant: C=C(C#N)C#N
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N#CC1CN(Cc2ccccc2)CCN1c1ccccc1

Procedure:
A solution of 3 (5.07 g, 17.0 mmol) and diisopropylethylamine (4.97 g, 38.4 mmol) in DMF (40 mL) was treated with a solution of 2-cyanoacrylonitrile (2.30 g, 26.3 mmol) in DMF (40 mL) at room temperature (14 d). The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with water, brine, and dried (Na2SO4). Concentrated in vacuo, the residue was recrystallized from ethanol to afford 4 as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[S:11](=O)(=[O:14])([OH:13])[OH:12]>>[OH2:8].[OH2:12].[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([S:11]([OH:14])(=[O:13])=[O:12])[CH:7]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: O=S(=O)(O)O
Product: COc1cc(C)c(Br)cc1S(=O)(=O)O
Product: O
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
4-Bromo-3-methylanisole (500 g, 2.5 moles) was cautiously added dropwise over a period of 20-25 minutes to 98% sulfuric acid (1,600 ml) at ambient temperature (exothermic, temperature rise to 42-43° C.) and the reaction stirred for 16 hours. The reaction mixture was cautiously quenched onto cooled (0-5° C.) deionised water (7.5 liter) over a 2 hour period at a rate that maintained the temperature below 20° C. The precipitated product was granulated for 3 hours, filtered and dried to give the crude sulphonic acid (980 g). The crude product was recrystallised from ethyl acetate (2.94 liters, 3 ml/g) to give the subtitle compound (680 g, 86% yield) as a white crystalline solid (mp=131-133° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:14][NH:15][C:16]([O:18]CC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][NH:15][C:16]2=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC=C(C(=O)OCC)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c(=O)c2cc(Cl)ccc12
Yield: 60.4 %

Procedure:
Then, 13.7 g of ethyl p-chlorophenyl-(α-ethoxycarbonylaminomethylene)acetate was added to 50 ml of diphenyl ether and the mixture was heated at reflux for 3 hours. After cooling, benzene and petroleum ether were added to the reaction mixture, and the precipitated crystals were filtered and recrystallized from a mixture of dimethylformamide and ethanol to obtain 7 g of 7-chloro-4-ethoxycarbonyl-1(2H)-isoquinolone having a melting point of 243° C. as colorless prisms.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[O:11]1[C:16]2([CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:24]=[C:25]([CH2:30][CH2:31][OH:32])[CH:26]=[C:27]([F:29])[CH:28]=3)[CH2:18][CH2:17]2)[CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:29][C:27]1[CH:26]=[C:25]([CH2:30][CH2:31][OH:32])[CH:24]=[C:23]([CH2:22][N:19]2[CH2:18][CH2:17][C:16]3([O:11][CH2:12][CH2:13][N:14]([S:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:9])=[O:8])[CH2:15]3)[CH2:21][CH2:20]2)[CH:28]=1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)s1
Reaction time: 1 h

Procedure:
A solution of 5-methylthiophene-2-sulfonyl chloride (0.15 g) in DCM (3 mL) was added dropwise to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g) and N-ethyl-N-isopropylpropan-2-amine (0.14 mL) in DCM (20 mL). The resulting mixture was stirred for 1 h and the solvent evaporated. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogen carbonate solution (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 47.5:47.5:5 ethyl acetate:isohexane:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow gum. Yield 0.21 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15]([OH:17])=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].N[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1.CC[N:31](C(C)C)C(C)C.CO.C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:15](=[O:17])[NH:31][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:23]=2[CH:22]=[CH:21][N:20]=[CH:19]3)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nccc2ccccc12
Reactant: CCOC(=O)C1(C(=O)O)Cc2ccccc2C1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1(C(=O)Nc2cccc3cnccc23)Cc2ccccc2C1
Reaction time: 0.08 h

Procedure:
A 25 mL reaction vial which contains a stirring bar is charged with indane-2-carboxylic acid ethyl ester (205, 1.0 g, 4.27 mmol) and dry DCM (15 mL). Stirring is initiated. After dissolution is complete, the HTBU (1.62 g, 4.27 mmol) is added. After 5 min, the 5,-aminoisoquinoline. (616 mg, 4.27 mmol) is added followed by DIPEA (1.72 mL, 9.8 mmol). The reaction is allowed to stir for 63 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting acid. The contents of the reaction flask are transferred to a reparatory funnel and diluted with EtOAc (40 mL). The organic phase is washed consecutively with dilute aqueous HCl (3%, 20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and evaporated in vacuo to provide 3.13 g of light orange solid. This material is dissolved in 15 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAC in heptanes over 4 column volumes followed by a linear gradient to 90% EtOAc over 12 column volumes. 17 mL fractions of eluent are collected. Fractions 17 through 31 are combined and evaporated in vacuo. This gives white solid (1.39 g, 90%).
Reaction SMILES: [C:1]([Si:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[C:31]([C:36]([O:38][CH3:39])=[O:37])[C:32]([O:34][CH3:35])=[O:33])=[N-]>C(Cl)(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH3:35][O:34][C:32]([C:31]1([C:36]([O:38][CH3:39])=[O:37])[CH2:10][C:9]1([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:33]
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: C=C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccccc1
Temperature: 100 °C
Yield: 69.1 %

Procedure:
To a mixture of t-butyldiphenyl-(3-phenyl-3-butenyloxy)-silane (3.0 g, 7.0 mmol) and dimethyl diazomalonate (1.1 g, 7.0 mmol), which was synthesized by the method described in Synth. Commun. (1987, 17, 1709-1716), was added rhodium (II) acetate dimmer (62 mg, 0.14 mmol) under argon atmosphere, and the mixture was heated at 100° C. for 10 min. After cooling to room temperature, the mixture was diluted with chloroform (4 mL), separated and purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 4:1) to give the title compound (2.5 g, yield 70%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[H][H].[Br-].[C:6]([CH2:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:8])=[O:7].O[CH:33]1[CH:41]2[CH:36]([CH:37]3[CH2:42][CH:40]2[CH2:39][CH2:38]3)[CH2:35][O:34]1>CS(C)=O.O>[OH:34][CH2:35][CH:36]1[CH:37]2[CH2:42][CH:40]([CH2:39][CH2:38]2)[CH:41]1[CH:33]=[CH:12][CH2:11][CH2:10][CH2:9][C:6]([OH:8])=[O:7]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Reactant: OC1OCC2C3CCC(C3)C12
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCC=CC1C2CCC(C2)C1CO
Reaction time: 0.17 h
Yield: 129.7 %

Procedure:
12 g (0.4 mole) of 80% strength NaH are added to 240 ml of absolute dimethylsulphoxide under an inert gas, and the mixture is warmed at 60° to 70° C. until the evolution of hydrogen has ended. Thereafter, 88.4 g (0.2 mole) of 4-carboxybutyl-triphenyl-phosphonium bromide in 200 ml of absolute dimethylsulphoxide are added at 15° to 16° C. After the mixture has been subsequently stirred for 10 minutes, 15.4 g (0.1 mole) of 1-hydroxyoctahydro-4,7-methano-iso-benzofuran in 50 ml of absolute dimethylsulphoxide are allowed to run in and the mixture is stirred at 20° C. for 3 hours. 20 ml of water are then added, the solvent is distilled off in vacuo and the evaporation residue is partitioned between 200 ml of water and 4×400 ml of diethyl ether. The aqueous phase is brought to pH 3.5 with 5N hydrochloric acid and the precipitate which deposits is separated off and washed 3, times with 200 ml of diethyl ether. The aqueous phase which remains is saturated with sodium chloride and extracted 5 times with 200 ml of diethyl ether. After the combined ethereal extracts have been dried, the solvent is evaporated off in vacuo and the residue is chromatographed on silica gel using methylene chloride/tetrahydrofuran/acetic acid (10:1:0.5). 30.9 g of 6-(3-hydroxymethylbicyclo[2.2.1]-hept-2-yl)-hex-5-enoic acid are obtained in this manner (65% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(Cl)cccc1Br
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
To a solution 2-bromo-6-chlorobenzoic acid (9.5 g, 0.041 mol) and potassium carbonate (8.6 g, 0.061 mol) in N,N-dimethylformamide (50 mL) was added methyl iodide (11.2 g, 0.081 mol) dropwise over a 10 minute period. The reaction mixture was stirred at RT for 3.5 hours and was subsequently diluted with water (500 mL). The aqueous phase was back-extracted with EtOAc (3×300 mL). The organic layers were combined, washed with 1M HCl aq (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (10.0 g, 99.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.413 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.137 (t, J=8 Hz, 1H), 3.9 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:28]1[N:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]2=[N:30][C:29]=1[CH:37]=O>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:23][CH2:24]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:37][C:29]3[N:30]=[C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]4[N:28]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Reactant: O=Cc1nc2ncccn2n1
Solvent: CO
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)C(Cc4nc5ncccn5n4)C(=O)O3)cc2F)CC1
Reaction time: 1 h

Procedure:
A solution of 1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with [1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (296 mg, 2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at room temperature. The reaction was stirred for 1 hour and then was concentrated to an oil. The oil was purified by flash chromatography (50 g SiO2, 70% ethyl acetate, 6% methanol, 0.5% acetic acid, 23.5% hexanes) to give the desired product as an oil. It was further purified by crystallization from ethyl acetate/hexanes to give a white powder (142 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 1.11–1.18 (m, 2 H), 1.31–1.52 (m, 10 H), 1.75–1.80 (m, 2 H), 2.16 (t, J=8.84 Hz, 1 H), 2.34 (d, J=17.68 Hz, 1 H), 2.46 (t, J=7.83 Hz, 2 H), 2.59 (d, J=17.94 Hz, 1 H), 3.94 (d, J=3.79 Hz, 2 H), 6.62–6.70 (m, 2 H), 6.97 (t, J=7.83 Hz, 1 H), 7.02–7.04 (m, 1 H), 6.82–6.85 (m, 2 H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[CH:1][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran was condensed with 5-chloro-2-oxindole to give 0.25 g of 5-Chloro-3-(2,3-dihydro-benzofuran-5-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O.C(O)(=O)C>[CH3:8][C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1c(C)cccc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Yield: 94 %

Procedure:
N-(2,6-dimethylphenyl)acetamide (10 g, 60 mmol, 1.0 eq) was dissolved in a mixture of H2SO4 (40 mL) and acetic acid (20 mL) at 0° C. A mixture of HNO3 (10 mL) and H2SO4 (8 mL) was added dropwise with stirring. The reaction was allowed to warm to room temperature and stirred for a further 1 h. The reaction was quenched by pouring into ice water, and the solid that formed collected by filtration to give the title compound as a yellow solid (12 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].[H-].[Na+]>CN(C=O)C.O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH2:13]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(C(=O)OC)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (2.0 g, 7.2 mmol) is dissolved in DMF (25 ml) in a dry flask under nitrogen. Allyl bromide (0.65 ml, 7.55 mmol) is added drop-wise, followed by the careful addition of 60% NaH (303 mg, 7.55 mmol). The reaction is stirred overnight at RT and then is diluted with H2O (30 ml). The mixture is extracted with EtOAc (3×30 ml), and the combined organics are washed with 50% saturated NaCl (4×25 ml), dried (MgSO4), filtered, and concentrated under high vacuum to an oil that solidified upon standing. The volatiles are removed in vacuo to obtain 2.28 g (100%) of methyl 3-(allyloxy)-4-iodobenzoate as a tan solid. HRMS (FAB) calcd for C11H11IO3+H: 318.9833, found 318.9831 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH:3]=[CH2:4].C[N+]1([O-])CC[O:20]CC1.[OH2:24]>C1COCC1.[Os](=O)(=O)(=O)=O>[OH:24][CH:3]([CH2:4][OH:20])[CH2:2][CH2:1][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC(O)CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(but-3-enyl)isoindoline-1,3-dione (5.20 g, 25.8 mmol) in THF (86 mL) was added 4-methylmorpholine 4-oxide (4.54 g, 38.8 mmol) followed by osmium(VIII) oxide in water (3.16 mL, 0.517 mmol) dropwise. The reaction mixture was stirred at rt for 6 h. A saturated Na2S2SO3 solution was added to the reaction mixture and stirred for another 10 min. The aqueous layer was separated and extracted with EtOAc three times, and the combined organic layers were washed with water, brine and dried over Na2SO4. The solids were filtered off, and the filtrate was concentrated in vacuo to get 2-(3,4-dihydroxybutyl)isoindoline-1,3-dione which was used as-is in the next step. LC-MS (M+Na)+=258.1. 1H NMR (500 MHz, methanol-d4) δ 7.92-7.85 (m, 2H), 7.85-7.75 (m, 2H), 3.91-3.75 (m, 2H), 3.65 (dtd, J=9.1, 5.5, 3.7 Hz, 1H), 3.55-3.43 (m, 2H), 1.95-1.85 (m, 1H), 1.80-1.65 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Brc1cnc2ccc(NC[C@@H]3CCCN3)nn12
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of (S)-3-bromo-N-(pyrrolidin-2-ylmethyl)imidazo[1,2-b]pyridazin-6-amine (400 mg, 1.2 mmol) and triethylamine (0.5 mL, 3.5 mmol) in DCM (10 mL) was added t-butyl isocyanate (0.2 mL, 1.75 mmol) dropwise. After stirring at it for 2 h, the reaction mixture was concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give (S)-2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)-N-(tert-butyl)pyrrolidine-1-carboxamide (360 mg, 76% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.58 (d, J=9.60 Hz, 1H), 7.42 (s, 1H), 6.72 (d, J=9.85 Hz, 1H), 5.07 (s, 1H), 4.26 (dd, J=6.57, 1.77 Hz, 1H), 3.35-3.48 (m, 4H), 2.09-2.20 (m, 1H), 1.90-2.05 (m, 3H), 1.26 (s, 9H); LRMS (ESI) m/e 395.2 [(M+H)+, calcd for C16H24BrN6O 396.3].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1B(O)O.[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([F:8])[C:2]=2[F:1])=[CH:24][CH:23]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc(I)cc1
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: COCCOC
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)c(F)c1F

Procedure:
A solution of 2,3-difluro-4-octoxyphenylboronic acid (5) (8.29 g, 0.029 mol) in dimethoxyethane (40 ml) was added to a solution of 4-bromoiodobenzene (6.80 g, 0.024 mol) and tetrakis(triphenylphosphine)palladium (0) (1.4 8 g. 1.29 mmol) in dimethoxyethane (40 ml) under nitrogen. To this, 2M sodium carbonate (60 ml) was added. The stirred mixture was refluxed gently. Progress of the reaction was carefully monitored using tic until the 4-bromoiodobenzene had reacted completely (usually 4-5hr). The layers were separated and the aqueous layer once more extracted with ether. The combined organic layers were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel/petroleum fraction (bp 40°-60° C.) - ethyl acetate, 9:1) to give a white solid which was recrystallised from pentane (-20° C.) to yield colourless crystals.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=[O:23])C1C=CC=CC=1.[CH2:24]([Al](CC(C)C)CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:23][CH:11]1[CH2:12][CH:13]([CH2:14][OH:15])[CH:10]1[CH2:9][OH:8].[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:24]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: OCC1CC(O)C1CO
Product: c1ccc(COCc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of (2S-trans) -2,3-bis [(benzyloxy) -methyl]cyclobutanone (0.2 g., 0.645 mmole) in toluene (4 ml.) was added dropwise over 10 minutes to a solution of triisobutylaluminum (0.91M in hexane, 0.9 ml., 0.816 mmole) in toluene (2 ml. ) at -40° C. The mixture was stirred at -50° C. for 4 hours and at -40° C for one hour. A solution of triisobutylaluminum (1 ml., 0.91 mmole) was added to the reaction mixture. After stirring for 30 minutes the reaction was quenched by adding 10% hydrochloric acid (2 ml.) at -40° C. The organic phase was washed with brine, dried (magnesium sulfate), and the solvent was evaporated to give [1S-(1α, 2β, 3β)]-3-hydroxy-2-cyclobutane-dimethanol, dibenzyl ether; TLC (30% ethyl acetate/hexane) Rf =0.3. The product contained about 5% of the isomeric compound; TLC (30% ethyl acetate/hexane) Rf =0.2.