Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:35][C:36]([F:48])([F:49])[C:37]1[CH:38]=[C:39]([NH:40][C:27]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3)c2cc1OC
Yield: 58 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 3,5-Bis(trifluoromethyl)aniline (116 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 54 mg of the title compound (yield: 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:28](=O)([O-])[O-].[Na+].[Na+].IC.O>CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[N:17]([CH3:28])[C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)C(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)S1
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)SC(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
5-[3-(3,5-Difluoro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione (Compound No. 58, 0.10 g, 0.21 mmol) was dissolved in 1.0 mL of anhydrous dimethylformamide. Sodium carbonate (26.50 mg, 0.25 mmol) was added under nitrogen atmosphere and iodomethane (20.00 μL, 0.32 mmol) was added 10 minutes later. The mixture was stirred for 2 hours at room temperature. Water was added after the reaction was completed. The resultant solid was washed with water (10 mL×3 times). The solid was dried to obtain 90.0 mg (87%) of the target product.
Reaction SMILES: [C:1]1(=[O:12])[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.[I:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[I:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:23]3[CH:32]=[N:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:8][CH2:7]2)[C:1]1=[O:12]
Reactant: BrCc1cccc(I)c1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C1NCCCC12CCNCC2
Product: O=C1N(Cc2cccc(I)c2)CCCC12CCN(c1cnc3ccccc3n1)CC2

Procedure:
The title compound was synthesized in analogy to method A from 2,9-diazaspiro[5.5]undecan-1-one (TFA salt) [1190586-22-1], 3-iodobenzyl bromide [49617-83-6] and 2-chloroquinoxaline [1448-87-9]. [LCMS RtF=1.99 min, [M+H]+=513.0].
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][N:11]=[C:5]2[N:4]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]1=[O:17].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:10]3[CH:9]=[C:6]4[C:5]([N:4]([CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:3](=[O:17])[N:2]([CH3:1])[C:7]4=[O:8])=[N:11]3)=[CH:21][CH:22]=2)[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: Cn1c(=O)c2c[nH]nc2n(CC(C)(C)C)c1=O
Reactant: BrCc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cn(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.1 %

Procedure:
5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (200 mg, 0.847 mmol), 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole (202 mg, 0.847 mmol) and K2CO3 (117 mg, 0.847 mmol) are suspended in 5 mL of anhydrous DMF. The reaction mixture is stirred at room temperature for 5 h, and then evaporated to dryness under reduced pressure. The residue is treated with water, and then extracted with dichloromethane three times. The combined organic phase is dried with anhydrous sodium sulfate, filtered, and then evaporated to dryness to give 337 mg of crude product, which is used in the next step without further purification. MS (ESI) m/z 394.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1.[Cu]I>[C:15]([CH:4]1[CH:5]=[CH:6][N:1]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]([CH3:8])=[C:3]1[CH3:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)[Mg]Cl
Reactant: Cc1cccnc1C
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOC(=O)N1C=CC(C(C)(C)C)C(C)=C1C

Procedure:
A solution of 45 ml of 2,3-lutidine (2,3-dimethylpyridine) and 4.3 g of copper(I) iodide in 500 ml of tetrahydrofuran is cooled to -20° and treated under argon with 31 ml of ethyl chloroformate. The reaction mixture is heated to 30° and treated dropwise within 30 minutes with 125 ml of t-butylmagnesium chloride (2.6 molar, in tetrahydrofuran). Whereby the reaction temperature amounts to 40°-45°. The ethyl 4-tert-butyl-2,3-dimethyl-1(4H)-pyridinecarboxylate obtained as the intermediate can be isolated as follows: the reaction mixture is cooled to -10° and treated with 300 ml of aqueous (20%) ammonium chloride solution, whereupon 500 ml of ether are added and the organic solution is washed several times with a 20% ammonium chloride/ammonia (1:1) solution. 2N hydrochloric acid and 10% sodium carbonate solution. The organic phase is dried and concentrated, and the residue is purified on a silica gel column. whereby the medium pressure flash chromatography method (solvent: n-hexane/ether [20:1]) is used and the pressure is produced with nitrogen gas. The ethyl 4-tert-butyl-2,3-dimethyl-1(4H)-pyridinecarboxylate (2.1 g) obtained is processed directly by heating it at 170° for 1.5 hours with 420 mg of sublimed sulphur. The reaction mixture is dissolved in 200 ml of ether, whereupon the solution is extracted with 2 N HCl and the aqueous solution is washed with ether, made alkaline with a 10% sodium carbonate solution and extracted with methylene chloride. The organic solution is dried and concentrated at normal pressure. The 4-tert-butyl-2,3-dimethylpyridine obtained is processed directly.
Reaction SMILES: Cl.[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19](I)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:30]1[CH2:34][CH2:33][O:32][CH:31]1[C:35]1[O:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][CH:36]=1>>[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19]([C:38]4[O:39][C:35]([CH:31]5[O:32][CH2:33][CH2:34][O:30]5)=[CH:36][CH:37]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(I)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Product: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(-c3ccc(C4OCCO4)o3)cc12

Procedure:
Prepared according to Procedure B from (4-benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ1H NMR (400 MHz, DMSO-d6) 10.49 (s, 1H), 8.88 (d, 1H), 8.63 (s, 1H), 8.1 (d, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 6.97 (m, 1H), 6.75 (d, 1H), 6.01 (s, 1H), 4.09 (m, 2H), 3.97 (m, 2H). ESI-MS m/z 516 (M−1).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:17]4[CH2:24][CH2:23][CH2:22][C:18]=4[N:19]([CH3:21])[N:20]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:17]4[CH2:24][CH2:23][CH2:22][C:18]=4[N:19]([CH3:21])[N:20]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC4)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CCC4)nc12
Reaction time: 15 h
Yield: 92666.7 %

Procedure:
To a solution of N-isopropyl-2-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (68 mg, 150 μmol) in dichloromethane (5 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol) and the reaction mixture stirred for 15 h then concentrated. The residue was re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated and purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane). The pure product was suspended in dichloromethane and cyclohexane added to promote solid formation, which was separated by decantation and dried under high vacuum to give N-isopropyl-2-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 139 mmol, 93%) as a white solid. MS (M+H)+=325; 1H NMR (DMSO-d6) δ: 12.68 (br. s., 1H), 8.87 (s, 1H), 8.31 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 4.02-4.46 (m, 1H), 3.79 (s, 3H), 2.92 (t, J=6.4 Hz, 2H), 2.73 (t, J=6.4 Hz, 2H), 2.60 (t, J=6.4 Hz, 2H), 1.24 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.C(ON=O)(C)(C)C.[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1N.Cl>CS(C)=O>[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1[C:4]#[N:5]
Reactant: N#C[Cu]C#N
Reactant: Nc1ccc(Br)cc1Br
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1ccc(Br)cc1Br
Temperature: 45 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Copper cyanide (2.32 g, 25.9 mmol) is added to stirred anhydrous dimethylsulfoxide (50 mL) at 60° C. to form a clear solution, followed by the addition of tert-butylnitrite (7.1 mL, 59.7 mmol) all at once. A solution of 2,4-dibromoaniline 21 (5.0 g, 19.9 mmol) in anhydrous dimethylsulfoxide (30 mL) is added dropwise, via cannula, to the mixture. After the addition is complete, the reaction mixture is allowed to stir for 1 hr. After being cooled to 45° C., the mixture is slowly treated with 5N hydrochloric acid (50 mL). Five minutes later, the reaction mixture is cooled to ambient temperature before being extracted with ethyl acetate/hexane (1:1; 2×300 mL). The combined organic layers are washed with water (100 mL) and brine (100 mL), dried, concentrated in vacuo, and then chromatographed on silica (0–5% ethyl acetate in hexane) to give the title compound (1.61 g, 31% yield). FD(+)MS m/z 259, (M+) consistent with 2 Br.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20]>C(=S)=S>[Cl:5][CH2:6][C:7]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:20])[C:11]2([CH3:21])[CH3:10])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)C(=O)Nc2ccc(C(=O)CCl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.1 %

Procedure:
To ice-cooled carbon disulfide (77 ml) were added anhydrous aluminum chloride (61.2 g) and chloroacetyl chloride (36.5 g), and then 2,3-dihydro-3,3-dimethylindol-2-one (24.6 g) was added thereto. The mixture was stirred for 10 minutes at ambient temperature and for 4 hours at 35° to 40° C. The solvent was removed by decantation and to the residue was added ice-water. The resulting crystal was collected, washed with water and dried to give 5-chloroacetyl-2,3-dihydro-3,3-dimethylindol-2-one (37.39 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]1[NH:20][C@@H:19]([C:21]([OH:23])=[O:22])[C:18]([CH3:25])([CH3:24])[S:17]1>O>[C:1]([N:20]1[C@@H:19]([C:21]([OH:23])=[O:22])[C:18]([CH3:25])([CH3:24])[S:17][C@H:16]1[C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[Cl:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)SC(c2ccc(Cl)cc2Cl)N[C@H]1C(=O)O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
5.56 ml of acetic anhydride are given to a hot suspension containing 2-(2,4-dichlorophenyl)-5,5-dimethylthiazolidine-4(S)-carboxylic acid in 5.56 ml of water. The mixture is heated at 100° C. for 6 minutes, then cooled down and diluted with 10 ml of water. The crystalline precipitate is filtered to give the title compound in a yield of 2.57 g (73.8%). After recrystallization from a mixture of methanol and water, this acid melts at 233°-235° C., [α]d22 =-142.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH:26](=O)[CH3:27].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH2:26][CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC=O
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
4-[1-(3-Amino-2-pyridyl)piperazin-4-yl-carbonyl]benzoic acid methyl ester (4 g) was dissolved in methanol (80 ml) and then, acetaldehyde (1.7 ml) and acetic acid (4 ml) were added at 0° C. The solution was stirred at 0° C. for 30 minutes. Then, with the addition of sodium cyanoborohydride (2.2 g), the solution was stirred at 0~5° C. for 2 hours. Excess of water was added gradually, and the solution was neutralized (pH=~8) by addition of aqueous 3N-sodium hydroxide. The mixture was stirred for 1 hour and filtered, and the crude solid was recrystallized using methanol and ether to give 3.51 g (yield: 81%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].[CH2:14]([S:16][CH2:17][CH2:18]Br)[CH3:15]>C(O)C>[CH2:14]([S:16][CH2:17][CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:15]
Reactant: CCSCCBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSCCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A solution of 4-amino-3-nitrophenol (17.5 g.) in ethanol (300 ml.) was treated with solid potassium hydroxide (6.38 g.). The mixture was treated with a solution of 2 -bromoethyl ethyl thioether (21.2 g.) in ethanol (100 ml.), and stirred at room temperature for 4 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in chloroform (200 ml.). The chloroform solution was washed with aqueous sodium bicarbonate solution (10% w/v; 200 ml.), dried over magnesium sulphate and evaporated to give 4-[2-(ethylthio)ethoxy]-2-nitroaniline (23.4 g.) in the form of a dark red oil, which was used in the next stage without further purification being necessary.
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[NH:11]2)=[C:7]([NH2:16])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:7]([NH2:16])[N:6]=1
Reactant: CCC(C)COc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 2-[(2-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine (109 mg) in dry DMF (1.86 mL) was added potassium carbonate (165 mg) and the mixture was stirred at 60° C. for 90 mins. The mixture was cooled to room temperature and 4-(bromomethyl)tetrahydro-2H-pyran (59 mg) was added. The reaction was stirred at 50° C. overnight and was cooled to room temperature. The mixture was taken up in EtOAc (15 mL) and washed with water (2×10 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give a yellow viscous oil. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a yellow oil (41 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([Cl:10])[CH:3]=1.CC(C[AlH]CC(C)C)C.C[OH:21].Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:21])=[C:4]([Cl:10])[CH:3]=1
Reactant: CO
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Br)cc1Cl
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To 4-bromo-2-chlorobenzonitrile (2.0 g, 9.2 mmol) in toluene (50 mL) at −78° C. under argon was added DIBAL (1M solution in toluene, 13.9 mL, 13.9 mmol). The mixture was allowed to warm to −50° C. over 4 h. MeOH (4.5 mL) and water (4.5 mL) were added and the mixture stirred for 10 min at −50° C. The mixture was allowed to warm to rt, acidified with 2N HCl (pH<7) and extracted with EtOAc (200 mL) and water (100 mL). The aqueous was further extracted with EtOAc (2×50 mL), the combined organics were then washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (25% DCM: Iso-hexane) to give 4-bromo-2-chlorobenzaldehyde. To a solution of 4-bromo-2-chlorobenzaldehyde (750 mg, 3.4 mmol) in DME (22 mL) and EtOH (15 mL) was added 3-carboxamidobenzene boronic acid (676 mg, 4.1 mmol) and 2M Na2CO3 solution (15 mL). Argon was bubbled through the mixture for 15 min. Bis(triphenylphosphino) palladium dichloride (120 mg, 0.17 mmol) was added and the reaction heated to 75° C. for 6.5 h before cooling to rt. The mixture was partitioned between water (200 mL) and EtOAc (200 mL), the aqueous was extracted with EtOAc (2×50 mL) and the combined organics dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (50% EtOAc: Iso-hexane to 100% EtOAc) to give the title compound: RT=3.19 min; m/z (ES+)=301.0 [M+H+MeCN]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30]([C:36]#[C:35][CH2:34][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C3CC3)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a degassed solution of the above ester (392 mg, 0.707 mmol), N-propargylmorpholine (176 mg, 1.41 mmol) and diisopropyl amine (0.466 mL, 3.3 mmol) in anhydrous tetrahydrofuran (11 mL), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) and copper(I) iodide (12.0 mg, 0.063 mmol) were added. The reaction mixture was stirred at ambient temperature for 7 h under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5) yielding methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][CH:16]=[C:17]([CH3:20])[CH2:18][OH:19])=[C:4]([O:13][CH3:14])[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.Br[CH2:22][P:23](=[O:32])([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26].CC(C)([O-])C.[Li+]>CN(C=O)C>[CH:29]([O:28][P:23]([CH2:22][O:19][CH2:18][C:17]([CH3:20])=[CH:16][CH2:15][C:3]1[C:2]([OH:1])=[C:10]2[C:6](=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])[CH2:7][O:8][C:9]2=[O:11])(=[O:32])[O:24][CH:25]([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CO)C(=O)OC2
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(OC(C)C)OC(C)C)C(=O)OC2
Temperature: 70 °C
Yield: 30.4 %

Procedure:
A mixture of 7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one 156A (50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem., 45, 703), diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithium t-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5 hours. The reaction was quenched with 1N HCl. The mixture was poured into 5% aqueous lithium chloride, extracted with ethyl acetate, and concentrated. The residue was purified by chromatography on silica gel, affording [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl ester 156B (25 mg, 32%); 1H NMR (300 MHz, CDCl3) 1.25 (m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (d, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t, J=6.6 Hz, 1H), 7.83 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C@@H:3]([O:5][C:6](=O)[O:7]C1C=CC([N+]([O-])=O)=CC=1)[CH3:4].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]3[CH2:38][C@H:37]([CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[O:36][C:33]3=[CH:34][N:35]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]([F:19])([F:18])[C@@H:3]([O:5][C:6]([N:42]1[CH2:43][CH2:44][CH:39]([C@@H:37]2[O:36][C:33]3=[CH:34][N:35]=[C:30]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:25][CH:26]=4)[CH:31]=[C:32]3[CH2:38]2)[CH2:40][CH2:41]1)=[O:7])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)cc1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](OC(=O)N1CCC([C@H]2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester (85 mg) is added to a solution of (R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (100 mg) and N,N-diisopropyl-ethylamine (60 μL) in tetrahydrofuran (2 mL) at room temperature. The solution is stirred at room temperature overnight and then washed with 1 N aqueous NaOH solution (3×), water, and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:3) to give the title compound. LC (method 1): tR=1.00 min; Mass spectrum (ESI+): m/z=499 [M+H]+.