Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:26]1([C:32]([S:34][CH2:35][C@@H:36]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]([OH:39])=O)=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.Cl.[CH3:49][O:50][C:51](=[O:66])[C@H:52]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[CH:57][CH:56]=1)[NH2:53].C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[CH3:49][O:50][C:51](=[O:66])[C@H:52]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[CH:59][CH:60]=1)[NH:53][C:37](=[O:39])[C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:35][S:34][C:32]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:33]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2nccs2)cc1
Reactant: O=C(SC[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](CSC(=O)c1ccccc1)Cc1ccccc1

Procedure:
A solution of hydroxybenzotriazole (0.54 g; 4 mmoles) in tetrahydrofuran (30 ml) and, subsequently, a solution of dicyclohexylcarbodiimide (0.825 g; 4 mmoles) in methylene chloride (15 ml) were added, at 0° C. under stirring, to a mixture of (2S)-3-phenylcarbonylthio-2-phenylmethylpropionic acid (1.2 g; 4 mmoles), 4-(2-thiazolyl)-L-phenylalanine methyl ester dihydrochloride (1.34 g; 4 mmoles), prepared as described in example 4, triethylamine (1.11 ml; 8 mmoles) in tetrahydrofuran (20 ml) and methylene chloride (30 ml).
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C:7]([CH2:14][CH3:15])([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:8]O>C(#N)C>[CH2:10]([C:7]1([CH2:14][CH3:15])[CH2:8][NH:6]1)[CH:11]=[CH:12][CH3:13]
Reactant: CC=CCC(N)(CC)CO
Agent: O=S(=O)(O)Cl
Solvent: CC#N
Product: CC=CCC1(CC)CN1
Temperature: 25 °C
Yield: 57 %

Procedure:
Chlorosulphonic acid (18 mL) was added to a solution of the product from step (e) (32.3 g) in acetonitrile (100 ml) at least 9° C. When addition was complete, the mixture was warmed to room temperature. The resulting crystals were filtered off, washed with acetonitrile/pet. ether, dried, taken up in a mixture of 50% w/v aqu. KOH (100 mL) and water (55 mL) and distilled over KOH to give the desired product as a colourless oil (16.1 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1>O1CCCC1>[CH3:8][C:7]1[C:2]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Solvent: C1CCOC1
Product: Cc1cccnc1-c1ccccn1
Reaction time: 24 h

Procedure:
To a flask were added 1.0 g 2-bromo-3-methylpyridine and 10 ml of dry tetrahydrofuran. The solution was purged with nitrogen and 34 mg tetrakis(triphenylphosphine)palladium was added followed by 17.4 ml of a 0.5M solution of 2-pyridylzinc bromide in tetrahydrofuran. The mixture was stirred at 22 C for 24 hours, then 40 C for 72 hours. The mixture was poured into a solution of 5 g EDTA, 2 g sodium carbonate and 40 ml water. The product was extracted twice with diethylether, washed with water and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 48% ethyl acetate, 48% hexane and 4% methanol. A slightly yellow oil remained 0.38 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[CH:36][C:35]=2[C:45]2[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=2[O:53][CH3:54])=[CH:30][C:29]=1O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[N:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[CH:36][C:35]=2[C:45]2[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=2[O:53][CH3:54])=[CH:32][C:33]=1[O:7][CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1
Reactant: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(O)c2)n1
Reactant: CN1CCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(OC3CCN(C)C3)c2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
Add 88 mg (0.87 mmol) of 1-methyl-3-hydroxypyrrolidine, 246 mg (1.09 mmol) of triphenylphosphine and 0.01 mL (0.07 mmol) of TEA to a solution of 300 mg (0.72 mmol) of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in 2.5 mL of anhydrous THF cooled to 0° C. and placed under argon. After dissolution, add dropwise, at 0° C., a solution of 0.24 mL (1.09 mmol) of DIAD in 2.5 mL of anhydrous THF. Bring the reaction mixture to RT, stir for 18 h, then take up in 50 mL of EtOAc. Wash the organic phase successively with 20 mL of a saturated aqueous solution of sodium bicarbonate (NaHCO3) then 20 mL of water. After drying over Na2SO4 and concentration under reduced pressure, purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 20% of methanol. After concentration under reduced pressure, we obtain 250 mg of ethyl 6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [NH2:1][CH:2]([CH:8]=[C:9]([CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:10][CH:11]([OH:13])[CH3:12])[C:3]([O:5]CC)=[O:4]>O>[NH2:1][CH:2]([CH:8]=[C:9]([CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:10][CH:11]([OH:13])[CH3:12])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(N)C=C(CC(C)O)CP(=O)(O)O
Solvent: O
Product: CC(O)CC(=CC(N)C(=O)O)CP(=O)(O)O
Reaction time: 12 h

Procedure:
2.5 g (8.89 mmol) of ethyl 2-amino-6-hydroxy-4-phosphonomethyl-hept-3-enoate are dissolved in 17 ml of H2O and the solution is heated to reflux. The reaction solution is kept for 12 hours at reflux temperature. The reaction solution is then treated with 0.3 g of activated carbon, stirred for 10 minutes and filtered over Hyflo®. The filtrate is concentrated by evaporation and the residue is crystallised from water/ethanol and dried, giving white crystals of 2-amino-6-hydroxy-4-phosphonomethyl-hept-3-enoic acid. Melting point: 210° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:12](=[O:17])[NH:13][CH2:14][CH2:15][N:16]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:19]1[S:20][C:21]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:26]([C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:25]([CH3:46])=[CH:24][C:22]=2[N:23]=1.COCCOCCN(CCOCCOC)CCOCCOC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]Cl>[C:42]([O:41][C@@H:35]([C:26]1[C:25]([CH3:46])=[CH:24][C:22]2[N:23]=[C:19]([N:13]3[CH2:14][CH2:15][N:16]=[C:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[N:3]=[CH:4]5)[C:12]3=[O:17])[S:20][C:21]=2[C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])([CH3:43])([CH3:44])[CH3:45]
Reactant: Cn1ncc2cc(C3=NCCNC3=O)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN=C(c4ccc5c(cnn5C)c4)C3=O)sc2c1-c1ccc(Cl)cc1
Temperature: 140 °C

Procedure:
The mixture of 3-(1-methyl-1H-indazol-5-yl)-5,6-dihydropyrazin-2(1H)-one (160 mg, 0.70 mmol), (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (500 mg, 1.05 mmol), tris(2-(2-methoxyethoxy)ethyl)amine (60 μL, 0.2 mmol), potassium carbonate (320 mg, 2.3 mmol), and copper(I) chloride (69 mg, 0.70 mmol) in xylene (16 mL) was degassed with nitrogen, and was heated at 140° C. for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The mixture was filtered through a pad of celite and washed with ethyl acetate. The organic solution was washed with water and brine, and was dried over sodium sulfate. Concentration and purification with flash column chromatography (hexanes/EtOAc) gave (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-5,6-dihydropyrazin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C34H34ClN5O4S: 644.2 (M+H+); Found: 644.3 (M+H+); and (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyrazin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate (40 mg). LCMS-ESI+: calc'd for C34H33ClN5O4S: 642.2 (M+H+); Found: 642.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2([CH3:25])[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:30]=2[N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2([CH3:25])[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:34]3[CH:33]=[CH:32][C:30]4[N:31]=[C:27]([CH3:26])[O:28][C:29]=4[CH:35]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Reactant: CC1(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5(C)CCC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-(1-methylcyclobutoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1.1 equiv) and tripotassium phosphate trihydrorate (3.0 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.45 M) was added palladium 1,1-bis(diphenylphosphion)-ferrocene dicholoride (0.1 equiv). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in petroleum ether) to afford the title compound (49% yield) as a yellow solid. MS (ESI) m/z 499.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH2:17][CH3:18]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Cl
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
3-Chloro-4-methylphenol (2.00 g) was dissolved in N,N-dimethylformamide (10.0 ml), and potassium carbonate (2.91 g) and 1-propyl iodide (2.62 g) were added. The mixture was stirred at room temperature for 20 hr, and the reaction mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted with AcOEt. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with hexane:ethyl acetate=5:1. The objective fraction was concentrated under reduced pressure to give 2-chloro-4-(1-propoxy)toluene (2.18 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[NH2:10][C:11]1[CH:38]=[CH:37][C:14]([C:15]([C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:20]([NH:22][CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[O:21])=[O:16])=[C:13]([Cl:39])[CH:12]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O>[Cl:39][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[CH3:9])[CH:38]=[CH:37][C:14]=1[C:15]([C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])=[O:16]
Reactant: Cc1ccc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cc1C(=O)c1ccc(N)cc1Cl
Reactant: Cc1cc(F)ccc1Br
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(C(=O)NCCO)ccc2C)c(Cl)c1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
2-Bromo-5-fluorotoluene (8 μL, 0.11 mmol) was dissolved in 1 mL dry 1,4-dioxane in a vial under an argon atmosphere. Compound 430 (42 mg, 0.09 mmol) was added and dissolved in the solvent. Rac-BINAP (2.1 mg, 0.003 mmol), Pd2(dba)3 (2.0 mg, 0.002 mmol) and Cs2CO3 (41 mg, 0.13 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 100° C. for 72 h. The reaction mixture was filtered and then dissolved in THF (1.00 mL). Tetrabutylammonium fluoride trihydrate (37 mg, 0.12 mmol) was added to the solution and the mixture was stirred at 60° C. for 45 min. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with Na2CO3 (aq.), water, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography eluting EtOAc to afford the title compound as yellow/brown oil. 13C NMR (CDCl3) δ 195.6, 167.8, 160.6, 150.4, 141.2, 140.2, 136.5, 135.7, 134.3, 133.6, 131.5, 131.4, 128.8, 127.4, 127.4, 126.9, 117.8, 115.2, 113.9, 111.7, 77.2, 62.2, 42.9, 20.2, 18.1.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[CH:9][C:10]#[N:11])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: COc1cccc(C(=O)c2cc(OC)cc(OC)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.18 ml, 7.49 mmol) in anhydrous THF (10 ml) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 7.49 ml, 7.49 mmol) slowly. The mixture was stirred in rt for 40 min, before a solution of (3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanone (1.02 g, 3.75 mmol) in anhydrous THF (20 ml) was added. The mixture was refluxed overnight. The solution was poured into ice water (20 ml) and the two phases were separated. The THF phase was evaporated and combined with the aqueous phase, which were then extracted with CH2Cl2 (2×40 ml), washed with water (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography to give 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile as an off-white solid (1.06 g, 96%): mp, 81-83° C.; 1HNMR (DMSO-d6) δ 7.46-7.30 (m, 2H, Ar), 7.11-6.85 (m, 6H, Ar), 6.66-6.62 (m, 2H, Ar), 6.47 (t, J=1 Hz, 4H, Ar), 6.39 (s, 1H, double bond proton of one isomer), 6.38 (s, 1H, double bond proton of the other isomer), 3.78-3.73 (multiple singlets, 18H, 6OCH3), isomer ratio based on 1HNMR close to 48%:52%; 13C NMR (CDCl3) δ 163.0, 163.0, 160.9, 160.8, 159.8, 159.6, 141.0, 140.1, 138.8, 138.2, 129.8, 129.7, 122.1, 121.0, 117.8, 117.8, 116.1, 115.9, 115.0, 114.3, 107.8, 107.0, 102.3, 122.1, 122.1, 121.0, 117.8, 117.8, 116.1, 115.9, 115.0, 114.3, 107.8, 107.0, 102.3, 102.2, 95.4, 95.4, 55.6, 55.6, 55.5; Anal. Calcd. For C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.10; H, 5.72; N, 4.68.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.CC(C)=O.C(=O)=O.[C:16]([F:20])([F:19])(Br)[Br:17]>CCCCCC.CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[N:6][N:7]([C:16]([Br:17])([F:20])[F:19])[CH:8]=1
Reactant: FC(F)(Br)Br
Reactant: Brc1cn[nH]c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(Br)n1cc(Br)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 108.5 %

Procedure:
60% suspension of NaH in oil (19.2 g, 0.48 mol) was washed with hexane (3×150 mL), suspended in DMF (200 mL) and cooled to 0° C. under N2. Then, a solution of bromide 4 (61.7 g, 0.42 mol) in DMF (80 mL) was added dropwise over a period of 30 min while maintaining the temperature of the mixture below 0° C. (acetone-dry ice bath at −10° C.). The mixture was stirred at 0° C. for 5 min and a solution of CBr2F2 (47.4 mL, 0.515 mol) in DMF (60 mL) was added dropwise at <0° C. over a period of 30 min. Cooling bath was removed and the mixture was stirred for 2 h at RT. Reaction mixture was carefully poured into water (1 L) and extracted with ether (4×400 mL). Combined organic extracts were washed with water (3×200 mL), dried (MgSO4), and concentrated to afford crude 5 (125.68 g) as an orange liquid. A portion of this product (122.73 g) was distilled under reduced pressure to afford 5 (72.68 g, 64%) as colourless liquid b.p. 84-90° C./30 mm Hg. 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.88 (s, 1H). Some (about 9% mol) contaminants giving rise to signals at δ 7.60 and 7.68 were also present.
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH2:10]([CH2:12][NH2:13])[OH:11].C(OC(=O)C)C>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:5]([CH:4]=[C:3]1[NH:13][CH2:12][CH2:10][O:11]1)([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCO1
Temperature: 25 °C
Yield: 259.8 %

Procedure:
p-Toluene sulfonic acid (0.5 g) was added to a boiling solution of 1,1-bis-methylsulfanyl-2-nitro-ethene (I-1b: 20 g, 12.13 mol) in ethanol (200 mL). This was followed by the addition of ethanolamine (7.4 g, 12.13 mmol) and the resulting mixture was heated to reflux for 12 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated, 300 mL of water added and resultant filtered. The filtrate was further concentrated and was followed by the addition of acetone. The reaction mixture was refluxed for 1 hour, cooled to room temperature, and filtered. The acetone layer was concentrated to afford 4.1 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][CH:3]([CH3:11])[CH:4]=[CH:5][N:6]1CCCC1.[CH2:12]([O:14][C:15](=[O:27])[C:16](=[CH:23]OCC)[C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH3:13].C([O-])(=O)C.[NH4+]>C(#N)C>[CH2:12]([O:14][C:15](=[O:27])[C:16]1[CH:23]=[C:4]([CH:3]([S:2][CH3:1])[CH3:11])[CH:5]=[N:6][C:17]=1[C:18]([F:19])([F:20])[F:21])[CH3:13]
Reactant: CSC(C)C=CN1CCCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C(C)SC)cnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a dry 50 mL round bottom flask equipped with magnetic stirrer, nitrogen inlet, addition funnel, and thermometer, was charged the 1-(3-methylthiobut-1-enyl)pyrrolidine (5.0 g, 0.0291 mol) and 100 mL of dry acetonitrile. The 2-[1-ethoxymethylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (7.0 g, 0.0291 mol) was added dropwise, and the reaction was stirred at room temperature for 1 hour. An aliquot was analyzed by gas chromatography (GC) which indicated that no starting material remained Ammonium acetate (5.0 g, 0.058 mol) was added to the dark red solution and the reaction was heated at reflux for 30 minutes. Cooled and concentrated under vacuum on a rotary evaporator, the crude product was purified by silica gel column chromatography with a gradient of 5% ethyl acetate, 95% hexane to 50% ethyl acetate 50% hexane over 20 minutes to afford 2.5 g of the title compound as a pale yellow oil. 1H NMR (CDCl3): δ 1.42 (t, 3H), 1.62 (d, 3H), 1.96 (s, 3H), 3.94 (q, 1H), 4.43 (q, 2H), 8.08 (s, 1H), and 8.71 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[C:13]1[C:14](=[O:23])[CH:15]([CH2:20][C:21]#[CH:22])[CH2:16][C:17]=1[O:18]C>CC(C)=O.Cl.ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[CH:13]1[C:14](=[O:23])[CH:15]([CH2:20][C:21]#[CH:22])[CH2:16][C:17]1=[O:18]
Reactant: C#CCC1CC(OC)=C(c2c(Cl)cc(C#CC)cc2OC)C1=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C#CCC1CC(=O)C(c2c(Cl)cc(C#CC)cc2OC)C1=O
Temperature: 25 °C

Procedure:
A solution of 2-(2-chloro-6-methoxy-4-prop-1-ynyl-phenyl)-3-methoxy-5-prop-2-ynyl-cyclopent-2-en-1-one (0.042 g, 0.1277 mmol) in acetone (1.5 mL) and 2M aqueous HCl (0.5 mL) was heated under microwave irradiation at 100°C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then was diluted with dichloromethane (5 ml) and water (5 ml), and then was separated by elution through a phase separation cartridge, washing with more dichloromethane. The organic filtrate was evaporated to dryness under reduced pressure to give a yellow solid. The crude product was dissolved in dichloromethane and adsorbed onto silica and then purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired product as a mixture of atropisomers. 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 6.85 (s, 1H), 3.79 (s, 3H), 2.99-2.56 (m, 5H), 2.06 (s, 3H), 2.00 (s, 1H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C1C=CC=CN=1)C.N1C=CN=C1.[Si:52](Cl)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]>N1C=CC=CC=1>[Si:52]([O:4][C@@H:3]1[C@@H:5]([CH2:6][OH:7])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CN(C)c1ccccn1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of thymidine (10.00 g, 41 mmol) in pyridine (50 ml) was added triphenylmethyl chloride (13.81 g, 50 mmol) and dimethylaminopyridine (0.4 g, 3.0 mmol). The mixture was allowed to stir at 80° C. for 30 min. The pyridine was removed under reduced pressure and the residue dissolved in DMF (80 ml). Imidazole (6.14 g, 90 mmol) and t-butyldimethylsilyl chloride (6.18 g, 41 mmol) were added, and the mixture was allowed to stir overnight at room temperature. The DMF was removed under reduced pressure, and the residue was dissolved in 80% aqueous acetic acid (60 ml). The mixture was allowed to reflux for 30 min, cooled, and neutralized with NaOH. The mixture was lyophilized, and the residue was purified by chromatography (1:1 EtOAc: hexanes) to give 21 as a white solid (10.35 g, 71%): mp 60° C. (softens), 90° C. (melts); Rf 0.69 (1:9 MeOH:CH2Cl2); 1H NMR (CDCl3) 7.33(m, 1H), 6.13(t, 1H, J=6.75 Hz), 4.48(m, 1H), 3.90(m, 2H), 3.74(m, 1H), 2.32(m, 1H), 2.22(m, 1H), 1.89(s, 3H), 0.88(s, 9H), 0.07(s, 6H)ppm.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:14]1[CH2:19][C@@H:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH2:16][C@@H:15]1[CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH2:20]([C@H:18]1[CH2:19][N:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:15]([CH3:27])[CH2:16][N:17]1[C:29]([O:31][CH3:32])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Pyridine (0.57 ml, 7.0 mmol) was added to a stirring solution of (2S,5R)-1,5-dibenzyl-2-methylpiperazine (0.40 g, 1.2 mmol) and methyl chloroformate (0.20 ml, 2.5 mmol) in CH2Cl2 (14 ml). After stirring at ambient temperature for 2 h, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 3% MeOH in CH2Cl2) to afford pure product (0.28 g, 68% yield over the two steps). MS (ESI) 339 (M+H).