Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[C:18]1([CH2:17][S:24][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccnc1SCc1ccccc1
Yield: 49.07 %

Procedure:
In a stirred suspension of 96.37 gm potassium carbonate in 700 gm dimethyl sulphoxide, 100 gm 2-chloro nicotinic acid was charged. A solution of 82.38 gm benzyl mercaptan in 300 gm dimethyl sulphoxide was added in a period of two hours maintaining reaction temperature 80-90 deg. c. The temperature of the reaction was raised up to 140 deg. c. and then maintained for another three hours. 500 gm water was added after completion of the reaction and solvent recovery. Product precipitation achieved by lowering the pH of the reaction mass by using dilute HCl. Product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid precipitated completely till pH 4.5. After filtration and washing, cake was dried to get 75.5 gm white to off white solid product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid with 49.07% yield (Assay by HPLC 99.16%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.S(O)(O)(=O)=O.[NH2:25][OH:26]>CO>[CH3:1][NH:2][C:3](=[O:19])/[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:25]/[OH:26]
Reactant: CNC(=O)C(=O)c1ccccc1Oc1ccccc1
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: CO
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 95.5 %

Procedure:
N-Methyl-2-(2-phenoxyphenyl)-2-oxoacetamide (2.55 g, 10 mmol) was dissolved in methyl alcohol (10 ml). Hydroxylamine sulfate (0.99 g, 12 mmol) was added, followed by heating under reflux for 3 hours. After completion of the reaction, methyl alcohol was evaporated under reduced pressure. Toluene (10 ml) and conc. hydrochloric acid (1.04 g) were added to the resulting residue (E/Z=41/59), and the mixture was stirred at room temperature for 20.5 hours. After completion of the reaction, water (300 ml) was added. The mixture was extracted with ethyl acetate (300 ml), washed with brine twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E)-N-methyl-2-(2-phenoxyphenyl)-2-hydroxyiminoacetamide (2.58 g, Yield: 95.6%, E/Z=96/4).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:37]=[C:1]([Br:5])[Br:2])=[CH:39][CH:40]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
43 g of carbon tetrabromide was dissolved in 100 ml of dichloromethane, and then 69 g of triphenylphosphine was added to the solution while cooling in an ice bath, followed by stirring at 0° C. for ten minutes. Then, to the resulting solution, a solution of 7.0 g of 4-benzyloxybenzaldehyde dissolved in 100 ml of dichloromethane was added dropwise, followed by stirring at 0° C. for further twenty minutes. 30 ml of a saturated sodium bicarbonate aqueous solution was added slowly to the reaction solution, followed by adding 100 ml of water. The reaction solution was extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Ether was added to the residue, and insoluble substance was removed by filtration and the filtrate was evaporated. The residue was subject to column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:20) was collected, to afford 6.4 g of the titled compound(a) as a white solid.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:28][C:29]1[N:30]=[CH:31][N:32]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 4 h

Procedure:
A mixture of trityl chloride (17 g), triethylamine (8.5 ml), 4-methylimidazole (5 g) and toluene (40 ml) was stirred at 80° for 4 h and filtered, and the solid material was washed with toluene. It was then partitioned between water and chloroform, and the chloroform solution was separated, dried and combined with the dried toluene filtrate. The combined organic solutions were evaporated to dryness under reduced pressure, and the residue was triturated with diethyl ether to give 4-methyl-1-tritylimidazole, m.p. 214°-216°.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:2]([CH3:4])[CH3:3])=[CH:8][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2-Bromopropane (701 μl) was added to a suspension of 2-bromo-5-hydroxypyridine (1.0 g) and potassium carbonate (2.38 g) in N,N-dimethylformamide (19 ml), and stirred at 80° C. for four hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (1.05 g) as a yellow oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:27](=[O:28])[CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
48.1 ml (77 mmole) of butyllithium (as a 1.6M solution in hexane) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 12.41 g (70 mmole) of (4S)-(-)-4-benzyl-2-oxazolidinone in 200 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 13.0 g (77 mmole) of 3-phenylpropionyl chloride in 100 ml of anhydrous tetrahydrofuran was slowly added dropwise to the mixture, and the mixture was stirred for 1 hour. The mixture was then mixed with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced-pressure. The residue was purified by column chromatography through silica gel (using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent) to afford 16.8 g (yield 78%) of the title compound as white crystals, melting at 92°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:13])([O-])C.[K+].C1(Br)CC1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:13]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Sc1ccc(Br)cc1
Agent: BrC1CC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc(SC2CC2)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Dissolve 4-bromo-benzenethiol (2.00 g, 10.6 mmol) in dry DMSO (50 mL) under a nitrogen atmosphere. Add potassium tert-butoxide (1.30 g, 11.7 mmol) and stir until dissolved. Add cyclopropyl bromide (2.6 mL, 31.8 mmol) and heat the reaction to 80° C. for 2 days. Cool to room temperature and pour the reaction into water (500 mL). Extract the aqueous layer with Et2O (2×200 mL) and wash the combined organic layers with water (100 mL). Dry over sodium sulfate and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the material with hexanes to give 1.73 g of 1-bromo-4-cyclopropylsulfanyl-benzene (72%).
Reaction SMILES: [C:1]1([P:7]([CH2:14][SH:15])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CSNC(=O)C.[C:24]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:26])[CH3:25]>CN(C=O)C>[NH:27]([C:24]([CH3:25])=[O:26])[C@H:28]([C:36]([S:15][CH2:14][P:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: SCP(c1ccccc1)c1ccccc1
Agent: CSNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)SCP(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 92 %

Procedure:
Method A (transthioesterification). Phosphinothiol 20 (500 mg, 2.2 mmol) was dissolved in dry TBF (5 mL). The solution was deoxygenated by bubbling Ar(g) for 0.5 h. To this solution was added NaH (51.6 mg, 2.2 mmol). The mixture formed a slurry to which was added DMF (2 mL0 to dissolve any precipitate. The N-methylmercaptoacetamide (NMA) thioester of N-acetylphenylalanine (63 mg, 0.22 mmol) was added, and the reaction mixture was stirred for 8 h. Unreacted Phosphinothiol 20 was removed by adding Merrifield resin (1.5 g, 1.26 mmol/g), stirring for 6 h, and removing the resin by filtration. The residue was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes). AcPheSCH2PPh2 was isolated as a white solid in 92% yield.
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1>C1CCCCC1.O1CCCC1>[Li:5][N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:15])[CH3:6]
Reactant: [Li]CCCC
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: [Li]N1C(C)(C)CCCC1(C)C
Yield: 100 %

Procedure:
A solution of 0.17 mole of lithium 2,2,6,6-tetramethyl piperidide is prepared by the addition of 0.17 mole of n-butyllithium (2.3 moles) in 74 ml of cyclohexane to 0.17 mole (28.7 ml) of 2,2,6,6-tetramethylpiperidine in 120 ml of tetrahydrofuran at a temperature below -20° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C=Cc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a 250 ml single neck flask was charged 12.1 g (100 mmoles,1.0 eq) of p-tolualdehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.5 g of 4-(p-tolyl)-3-buten-2-one as a faintly yellow oil in 84.3% yield.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)=[N:5][N:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>ClCCl.CO>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[N:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Clc1nnc(Cc2ccncn2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Clc1ccc(Nc2nnc(Cc3ccncn3)c3ccccc23)cc1

Procedure:
A mixture of 100 mg (0.45 mmol) 1-chloro-4-(4-pyrimidinylmethyl)phthalazine hydrochloride and 149 mg (1.17 mmol) 4-chloroaniline is heated for 1.5 h to 100° C. The reaction mixture is distributed between dichloromethane/CH3OH, 19:1 and sat. NaHCO3 solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4), and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH, 19:1) and crystallization from ethyl acetate/ether yield the title compound: m.p.: 174-176° C.; FAB MS (M+H)+=348. The starting material is prepared as follows:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16].IC>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([CH3:1])[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N,N-Diisopropylamine (1.18 mL, 8.35 mmol) was added dropwise to a 2M solution of “butyllithium (4.18 mL, 8.4 mmol) at −78° C. under nitrogen. After 15 min at this temperature the solution was raised to and held at 0° C. for 15 min prior to re-cooling to −78° C. and treatment with a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.62 g, 3.34 mmol) in THF (8 mL). After 30 min., iodomethane (0.31 mL, 5 mmol) was added dropwise and the mixture was allowed to warm to rt over 2 hr. The mixture was cooled to at 0° C., quenched with 2 N HCl (10 mL) then was extracted with EtOAc (2×10 mL), washed with brine (3×15 mL), and dried over anhydrous magnesium sulfate. Concentration of the combined organic extracts afforded a yellow solid. NMR (CDCl3) consistent with crude, desired product.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)CCC>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CCCCO
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 67.7 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and n-butanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 9.9 g of p-cyanobenzamide (yield 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.C([O-])(O)=O.[Na+].F[C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]1[CH:25]=[CH:24][S:23][CH:22]=1>O.C(Cl)Cl>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2c(O)nccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2c(O)nccc2c1)c1ccsc1
Reaction time: 4 h

Procedure:
To 6-aminoisoquinolin-1-ol in H2O was added NaHCO3 followed by a solution of (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate in CH2Cl2. The solution was stirred for 4 hours, extracted with EtOAc and NH4Cl(sat)/HCl (1N) and then with NaHCO3 (0.05%), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH, CH2Cl2) gave pure (R)-tert-butyl 2-(1-hydroxyisoquinolin-6-ylamino)-2-oxo-1-(thiophen-3-yl)ethylcarbamate (95% ee by Chiracel OD-RH)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=2[CH3:23])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.70 g, 4.093 mmol, see preparation 1) in CH2Cl2 (6 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (0.74 g, 4.093 mmol, see preparation 12), and triethylamine (0.83 g, 8.187 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.60 g, 8.187 mmol) is added via syringe and stirred at ambient temperature. After 12 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (1.10 g, 81%). Mass spectrum (m/z): 333.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[Cl:17][C:18]1[C:19]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[C:29]3=[O:37])[C:20]=2[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1
Reactant: O=C1Nc2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Reactant: BrCc1ccccn1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 197-199° C.; 1H NMR (300 MHz, CDCl3) δ8.60 (d, J=2.1 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.25-7.15 (m, 3H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.79 (s, 1H), 5.35 (d, J=16.2 Hz, 1H), 5.00 (d, J=9.3 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.16-3.86 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.9, 155.8, 151.7, 149.5, 141.8, 138.6, 138.3, 136.7, 130.9, 128.9, 123.6, 123.4, 122.6, 121.4, 118.2, 116.8, 109.4, 106.8, 81.7, 64.5, 63.8, 57.7, 46.3; MS (ES+) m/z 421.2 (M+1), 423.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC.C(OC(C1C=CC2N(C(CC3C=C4C(=CC=3)N(C)N=C4)=CN=2)N=1)=C)C>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>[CH2:31]([O:30][C:28]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:29])[CH3:32]
Reactant: CC(c1ccc2c(cnn2C)c1)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Product: C=C(OCC)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 95.6 %

Procedure:
The title compound (415.0 mg, 86%, 90% purity) was synthesized from 6-chloro-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (390.0 mg, 1.25 mmol), tributyl(1-ethoxyvinyl)stannane (497.0 mg, 1.38 mmol) and Pd(PPh3)4 (145 mg, 0.13 mmol) using the same procedure as described in the synthesis of compound 13.3. LCMS (method A): [MH]+=348, tR=5.86 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].N1C=CN=C1.[CH3:16][Si:17]([CH3:23])([C:19]([CH3:22])([CH3:21])[CH3:20])Cl>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][Si:17]([CH3:23])([CH3:16])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: OCCCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Yield: 88 %

Procedure:
One operates as in preparation 13 starting with 3.97 g of 8-bromooctanol, 19 cm3 of dimethylformamide, 1.55 g of imidazole and 3.32 g of dimethyl tertbutyl chlorosilane. After chromatography on silica (eluant: cyclohexane-toluene 8-2), one obtains 5.4 g of the expected product.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]1([OH:10])[CH2:9][CH2:8]1>CC(O)C.O>[Br:1][CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5][CH2:4][Cl:3]
Reactant: BrBr
Reactant: OC1(CCCCl)CC1
Solvent: O
Solvent: CC(C)O
Product: O=C(CCBr)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (2.0 mL, 39 mmol) was added slowly to a solution of 1-(3-chloro-propyl)-cyclopropanol (5.0 g, 34 mmol) in i-PrOH (80% in water, 30 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hr then diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3×30 mL) and the organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude 1-bromo-6-chloro-hexan-3-one.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)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>[F:1][C:2]1[CH:8]=[C:7]([CH:10]=[CH2:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(N)c(F)c1
Temperature: 100 °C
Yield: 93 %

Procedure:
A solution of 2-fluoro-4-iodoaniline (2.37 g, 10 mmol) in toluene (50 mL) was treated with tetrakis(triphenylphosphine)palladium (0.578 g, 0.5 mmol), tributylvinyltin (3.5 mL, 12 mmol) and a catalytic amount of 2,6-di-tert-butyl-4-methylphenol. After being heated at 100° C. for 1 h, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:5) as eluant to afford 2-Fluoro-4-vinylaniline (20-1, LJO-324, 1.275 g, 93%) as a yellow oil.