Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([NH2:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=2)[NH:16][CH:15]=1)[CH3:9].[CH2:26]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:27]#[C:28][CH3:29]>O.O1CCOCC1>[CH2:8]([O:10][C:11](=[O:25])[CH:12]([NH:24][S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:26][C:27]#[C:28][CH3:29])=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=2)[NH:16][CH:15]=1)[CH3:9]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(N)Cc1c[nH]c2ccc(Br)cc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(Br)cc23)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.4 %

Procedure:
Triethylamine (4.81 mL, 34.5 mmol) was added to a mixture of 2-amino-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (4.00 g, 11.51 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (3.10 g, 12.66 mmol) in H2O-dioxane (40 mL/60 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was concentrated and diluted with ethyl acetate. The organic solution was washed with H2O and brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica, 40% ethyl acetate in hexanes) to give 3.67 g of the title compound as a pale yellow solid. 1H NMR (DMSO-d6): 400 MHz δ 11.05 (s, 1H), 8.31 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.45 (d, J=1.6 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.14 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.80 (q, J=2.4 Hz, 2H), 3.88 (q, J=7.6 Hz, 1H), 3.75 (q, J=7.2 Hz, 2H), 3.00 (dd J=14.4, 7.2 Hz, 1H), 2.88 (dd J=14.4, 7.6 Hz, 1H), 1.82 (t, J=2.4 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H); HRMS: calcd for C23H24BrN2O5S (ESI+, Br79, [M+H]1+), 519.0584; found 519.0589.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)=[CH:19][C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O.O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([CH3:32])[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)=[CH:19][C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: COc1cc(Cl)ccc1NC(=O)C1CCCn2c1nc(-c1ccncn1)cc2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(Cl)ccc1NC(=O)C1(C)CCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a suspension of 0.100 g (0.24 mmol) of 4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic acid N-(4-chloro-2-methoxy-phenyl)-amide (example 1) in 1.00 mL of dimethylformamide was added 0.010 g (0.24 mmol) of sodium hydride at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. 0.020 mL (0.24 mmol) of methyl iodide was added and the mixture was stirred at room temperature for 1 hour. The mixture was dissolved in water and dichloromethane. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (cyclohexane/ethyl acetate in proportions of 80/20 to 70/30) to afford 0.053 g (51%) of a solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20])[OH:4].Br[CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=1.[H-].[Na+].O>CN(C)C=O>[F:33][C:27]1[CH:26]=[C:25]([CH2:24][O:4][CH:3]([C:5]2[S:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH3:20])[C:2]([F:1])([F:21])[F:22])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
1.30 g 2,2,2-Trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol and 815 mg 4-Bromomethyl-2-fluoro-benzonitrile were dissolved in 40 ml dimethylformamide. 192 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 15 ml water were added and the mixture extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reversed phase HPLC to obtain 840 mg 2-Fluoro-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile as an oil.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])#[N:2].C(N(CC)CC)C.[C:22]([O:26][C:27](OC([O-])=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3](=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: N#CC(=Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Oc1ccc(C=C(C#N)C(=O)O)cc1

Procedure:
5.6 g (30 mmol) of 2-cyano-3-(4-hydroxyphenyl) acrylic acid dissolved in 40 ml acetonitrile were stirred with 4.6 ml (33 mmol) of triethylamine until a clear solution was obtained. 0.2 g (4 mmol) 4-dimethylaminopyridine and 7.3 g (33 mmol) tert-butylpyrocarbonate were then added to the clear solution. After 2 hours reaction (the solution is at that point colourless), the solution was reduced to its half volume and washed with 200 ml of a cold 5% citric acid solution.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:25]1[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]1
Reactant: CC1CCNCC1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Reaction time: 6.5 h
Yield: 2.7 %

Procedure:
In a 100 ml flask were placed 7 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 10.2 g of 4-methylpiperidine and 60 ml of hexamethylphosphoric triamide and the mixture was stirred at 160° C. in nitrogen gas atmosphere. After 6.5 hours, disappearance of the starting materials was confirmed by thin layer chromatography, and hexamethylphosphoric triamide was removed using a vacuum pump. To the residue was added several drops of concentrated hydrochloric acid and then ethyl acetate to separate oily substances from crystals. The crystals were collected by filtration and recrystallized from dimethylformamide-water to give 200 mg of 9-fluoro-8-(4-methyl-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 266° to 268° C., white rhombic crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Br)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Br

Procedure:
The title compound was prepared using 0.30 g of 6-(2-bromo-6-chloro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 104 and 0.105 mL of tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with 1:1 CHCl3 :EtOAc; mp 314° C. (dec); MS(CI).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]#[C:16][CH2:17][CH2:18][CH3:19]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:15]#[C:16][CH2:17][CH2:18][CH3:19])[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C#CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (0.70 g), bis(triphenylphosphine) palladium chloride (0.12 g), and 1-pentyne (2 mL) in triethylamine (12 mL) was placed in a sealed tube. The mixture was heated to 75° C. and stirred 18 h. The reaction mixture was cooled, filtered, and concentrated in vacuo. The resulting brown residue was chromatographed on silica gel with hexane/ethyl acetate 9/1 to obtain the product. NMR (300 MHz, CDCl3) δ 8.61 (1H, d, J=2 Hz), 8.16 (1H, m), 7.64 (1H, m), 3.96 (3H, s), 2.49 (2H, t, J=7 Hz), 1.66 (2H, m, J=7 Hz), 1.06 (3H, t, J=7 Hz).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)([OH:10])[C:7]([OH:9])=[O:8].[CH3:21]I.O>C(O)C.C(OCC)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)([OH:10])[C:7]([O:9][CH3:21])=[O:8]
Reactant: O=C(O)C(O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CI
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
From 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, a sodium ethoxide solution is prepared to which 26.6 g (0.0855 mol) of 3,3′-dichlorobenzilic acid in 50 ml of ethanol are added dropwise. The mixture is then stirred for 4 h at ambient temperature. After the solvent has been distilled off the residue is dissolved in 150 ml DMF and 24.27 g (0.171 mol) of methyl iodide are added dropwise, then stirred for another 24 h. While cooling with ice, 300 ml of water and 200 ml of diethylether are added dropwise, the phases are separated, the aqueous phase is extracted with diethylether, then the organic phases are washed with Na2CO3 solution and shaken with water till neutral. After drying over Na2SO4 the mixture is evaporated to dryness. Yield: 22.91 g of yellow oil (=82% of theory).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>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.CN(C=O)C.CCN(CC)CC>[OH:7][C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[C:4][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-pentyn-3-ol (75 mg, 0.75 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (25 mg) and Cul (12 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 66 mg, 31%).
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[C:13]1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>[Rh].C1CCC=CCCC=1>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: [Rh]
Solvent: C1=CCCC=CCC1
Product: C=C(C=O)CCOC(C)=O
Yield: 50545.7 %

Procedure:
A solution of 1,4-diacetoxy-2-butene (170 g.), (1,5-cyclooctadiene) rhodium (acetylacetonate) (0.17 g.) and triphenylphosphite (0.51 g.) was heated to 75° C. in a 1 liter stainless steel autoclave under a pressure of 2,000 psig of synthesis gas. After a few hours, the reaction was complete. After cooling and venting, the resulting solution was distilled to remove benzene. P-toluenesulphonic acid (0.5 g.) was added and the mixture was distilled (115°-120° C./5 mmHg). The resulting distillate was fractionated to give 2-formyl-4-acetoxybutene (118.1 g., 89% yield).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][C:19]=1[CH3:44]>O1CCCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][C:19]=1[CH3:44]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(C(=C(C=CC=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)c(C)c1)c1ccc(F)c(C)c1)c1nnnn1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A solution of the dianion of ethyl acetoacetate (1.42 mL, 11.1 mmoles) in dry tetrahydrofuran (15 mL) was generated as described in Example 10 using 450 mg (11.3 mmoles) of NaH (60% in mineral oil) and 4.5 mL (11.1 mmoles) of 2.5M n-BuLi in hexane at 0° C. under argon. The orange dianion solution, after being chilled to -78° C., was transferred via a cannula into a tetrahydrofuran (15 mL) solution containing 5,5-bis(4-fluoro-3-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (2.12 g, 5.6 mmoles) at -78° C. The reaction mixture was stirred at -78° C. for 15 minutes. Analytical TLC eluted once with 50% (v/v) ethyl acetate in hexanes showed a major product at Rf =0.16. The reaction mixture was diluted with 20 mL of 1N HCl and the organic residues were extracted with ethyl acetate (30 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give a pale syrup. The crude product was chromatographed on a silica gel column eluted with 35% (v/v) ethyl acetate in hexanes to give 1.39 g (48.7%) of the title compound. MS (CI): m/e=511 for (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25](I)[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.[Cu]I.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>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25]([C:42]#[C:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(C#Cc4ccccc4)ncn3)[C@@H]2O1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-iodopyrimidin-4-amine (0.300 g, 0.594 mmol) in DMF (2.46 mL) was added CuI (0.0113 g, 0.0594 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.0292 g, 0.0415 mmol). The tube was sealed and flushed with argon. Et3N (0.165 mL, 1.19 mol) was added and the reaction was stirred for 1 h. Phenylacetylene (0.216 mL, 1.96 mmol) was added and the reaction was stirred overnight. The suspension was filtered and the filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography (10 to 40% EtOAc/hexanes) to afford the title compound as a yellow oil (0.238 g, 84%). LC/MS: Rt=2.47 min, ES+ 480 (FA standard).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[Cl:17][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Cl)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (6.2 g, 34.44 mmol, 1.00 equiv) in dichloromethane (50 mL), oxalyl dichloride (8.74 g, 69.37 mmol, 2.00 equiv), and N,N-dimethylformamide (cat.). The resulting solution was stirred for 1 h at 40° C. in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 6.6 g (87%) of methyl 3-(chlorocarbonyl)benzoate as brown oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[C:1]1([CH2:7][C:8](=[NH:9])[O:13][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
2-Phenylacetonitrile was dissolved in anhydrous ethanol (2 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2-phenylacetimidate hydrochloride (1.7 g, 99%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.35 (m, 5H), 4.39 (q, J=7.0 Hz, 2H), 3.99 (s, 2H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.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>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][CH:10]4[CH2:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:39]6[CH:38]=[CH:42][N:41]([CH:43]7[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]7)[N:40]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
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: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(C7CCN(C(=O)OC(C)(C)C)CC7)n6)cn5)C4)c3n2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (20 mg, 0.0434 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (20 mg, 0.053 mmol), Pd(PPh3)4 (2.6 mg, 0.0022 mmol), and Na2CO3 (17 mg, 0.13 mmol) were dissolved in THF (1 ml)+H2O (0.6 ml), and then the mixture was degassed with N2 (gas), followed by stirring at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:20), to give tert-butyl 4-(3-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (25 mg, 90%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]2=[O:21].[CH2:22]([NH:25][C:26]1[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=1)[CH:23]=[CH2:24]>>[O:21]=[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][N:25]([CH2:22][CH:23]=[CH2:24])[C:26]3[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=3)[CH:4]=2)[N:9]=[CH:8][N:7]1[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C=CCNc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Reactant: CC(C)(C)C(=O)OCn1cnc2ccc(CBr)cc2c1=O
Product: C=CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1

Procedure:
This was synthesised by reaction of the compound (4) and diethyl N-(4-(prop-2-enylamino)benzoyl)-L-glutamate Lit. T. R. Jones, A. H. Jackman, S. J. Brown, M. Jones and K. R. Harrap: Europ. J. Cancer, 17 11 (1981). For characterisation a portion was dried at 70° C./P2 05 /1 mm/10 hours to give a brittle glass.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH2:4][CH2:3]1.C1C=CC(C2C3NC(C(C4C=CC=CC=4)=C4C=CC(=C(C5C=CC=CC=5)C5C=CC(=C(C6C=CC=CC=6)C6C=CC=2N=6)N=5)N4)=CC=3)=CC=1.[O:66]=[O:67].FC(F)(F)C(O)=[O:71]>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C@:10]3([CH3:12])[O:66][O:67][C@:6]42[C@H:5]([C@@H:13]([CH3:14])[C:15]([O:17][C@@H:11]4[O:71]3)=[O:16])[CH2:4][CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1=C[C@H]2[C@@H](CC1)[C@H](C)CC[C@H]2[C@@H](C)C(=O)O
Reactant: O=O
Agent: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Solvent: Cc1ccccc1
Product: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Yield: 62 %

Procedure:
The feed was a solution of dihydroartemisinic acid at a concentration of 0.5 mol/L and the photosensitizer tetraphenylporphyrin at a concentration of 1 mmol/L in toluene (2.95 g dihydroartemisinic acid and 15 mg tetraphenylporphyrin, total volume 25 mL, volumetric flask). The feed was introduced at a flow rate of 1.25 mL/min and the oxygen flow adjusted to 5 mL/min. The solution of trifluoroacetic acid injected into the output stream of the photochemical reactor contains 1.93 mL trifluoroacetic acid filled up to 20 ml with toluene (1.25 M, volumetric flask). The output stream showed a conversion of 89% yielding 62% of the desired artemisinin with a selectivity of 70% (NMR of crude).