Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH3:25])[N:9]=2)[CH:7]=1.I[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH2:28][CH3:29])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH3:25])[N:9]=2)[CH:7]=1
Reactant: CCI
Reactant: Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2cccnc12
Temperature: 45 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a solution of N-(3-(5-chloro-2-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (61.1 mg, 0.166 mmol) in 3.0 mL acetone was added iodoethane (26.0 μL, 0.325 mmol) and potassium carbonate (70.6 mg, 0.511 mmol) The reaction was stirred at 45° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 34.8 mg (54%) N-(3-(5-chloro-2-ethoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=397.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H), 8.73 (dd, J=4.2, 1.6, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 7.46 (dd, J=8.8, 2.7, 1H), 7.38 (d, J=2.7, 1H), 7.32-7.23 (m, 2H), 4.12 (q, J=6.9, 2H), 3.91 (s, 3H), 1.04 (t, J=6.9, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:26]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:26][C:10]1[N:9]=[C:8]([C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: Cc1nccn2c([C@@H]3CCN(C(=O)OCc4ccccc4)C3)ncc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn2c([C@@H]3CCN(C(=O)OCc4ccccc4)C3)nc(Br)c12
Yield: 96 %

Procedure:
To (R)-benzyl 3-(8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (1.332 mmol, 448 mg) in N,N-dimethylformamide (5 ml) was added N-bromosuccinimide (1.332 mmol, 237 mg). After stirring at room temperature for five minutes saturated aqueous sodium hydrogencarbonate solution was added, the organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane/methanol (gradient 0 to 10% methanol)) to give (R)-benzyl 3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (531 mg).
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:6]=[C:7]([CH3:15])[C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1>Cl.O1CCOCC1>[F:16][CH:2]([F:1])[CH2:3][O:4][C:5]1[N:6]=[C:7]([CH3:15])[C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1ncc(OCC(F)F)nc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(OCC(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of methyl 5-(2,2-difluoroethoxy)-3-methylpyrazine-2-carboxylate (63.8 mg, 0.275 mmol) in aqueous 2N HCl (1 mL) and Dioxane (2 mL) was stirred at ambient temperature for 20 hrs. The reaction was concentrated and the resulting solid was rinsed with acetonitrile. The filtrate was collected and concentrated in vacuo to give the title compound (60 mg, 0.275 mmol, 100%) as a white solid. MS m/z=219.1 (M+H).
Reaction SMILES: [C:1](OCC)(=[O:13])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C[AlH]CC(C)C)C.C(OCC)C>CCCCCCC.[Cl-].[Na+].O>[CH2:1]([OH:13])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC/C=C/C=C/C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: CCOCC
Product: CCCCCCC/C=C/C=C/CO
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Under nitrogen atmosphere, (2E,4E)-ethyl dodeca-2,4-dienoate (6.1 g) was dissolved in n-heptane (120 ml) and cooled to −70° C. DIBAL-H in hexanes (82 ml) was added dropwise and the mixture was stirred at −70° C. for 45 min. Brine (60 ml) and diethyl ether (100 ml) were added and the mixture was stirred for 45 min while warming to RT. The organic layer was separated and washed with 1N HCl, dried over sodium sulfate, filtered and concentrated. A colorless liquid was isolated that solidified upon slight cooling.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:14]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:14][C:3]1[C:4]2=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cnc2cc[nH]c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a 0° C. solution of methyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate (1.00 g, 5.68 mmol) in N,N-dimethylformamide (15 mL) was added N-chlorosuccinimide (895 mg, 5.96 mmol). The reaction was allowed to gradually warm to room temperature and stir overnight. The reaction was diluted with water (125 mL) and stirred for 20 minutes. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (1.11 g, 93%) as an orange powder. +ESI (M+H) 211.0; 1H NMR (400 MHz, DMSO-d6, δ): 11.99 (br. s., 1H), 8.92 (d, J=2.0 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.08 (d, J=3.1 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCc1ccccc1
Yield: 100.6 %

Procedure:
5-Phenyl-pentanol (40 g, 244 mmoles) in methylene chloride (80 ml) at 0° C. was added with triethylamine (39 ml, 28.34 g, 280 mmoles) and a solution of methyl-sulfonyl chloride (20.7 ml, 30.69 g, 268 mmoles) in methylene chloride (40 ml). The temperature was left to rise to the room value, then the mixture was poured into water and the organic phase was isolated, washed with water, anhydrified and concentrated to give 59.49 g of the title product (yield: 99%).
Reaction SMILES: CC([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2CC1)=[O:3].[OH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]2[C@H:31]3[C@H:41]([CH2:42][CH2:43][C@:26]12[CH3:27])[C@:39]1([CH3:40])[C@H:34]([CH2:35][C:36](=[O:44])[CH2:37][CH2:38]1)[CH2:33][CH2:32]3>>[OH:3][C@@H:42]1[CH2:43][C@@:26]2([CH3:27])[C@@H:28]([CH2:29][CH2:30][C@@H:25]2[OH:24])[C@H:31]2[C@H:41]1[C@:39]1([CH3:40])[C:34]([CH2:33][CH2:32]2)=[CH:35][C:36](=[O:44])[CH2:37][CH2:38]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Product: C[C@]12C[C@@H](O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
Using this method, 11α acid succinates of pregnenolone and 17β-hydroxy-5α-androstan-3-one were prepared.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[C:1]1([S:7][CH2:12][CH:11]([OH:10])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: c1cncc(CCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)CSc1ccccc1
Yield: 76.7 %

Procedure:
Prepared according to the method described in Example 1a) from thiophenol (0.142 g), sodium hydride (0.062 g) and 3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide at room temperature to give the title compound as an oil (0.200 g).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].O>C(#N)C>[CH:11]1([N:10]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CCCCCl)NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCCN1C1CCCCC1
Yield: 59.1 %

Procedure:
Add NaH (550 g, 14 mmol) into a solution of 5-chloro-N-cyclohexylpentanamide (3 g, 14 mmol) in acetonitrile (100 mL). Stir the reaction at room temperature for 12 hours. Add NaH (1 g, 28 mmol) and continue to stir for 2 days. Pour the reaction into ice and water. Wash the reaction with brine, dry with sodium sulfate, filter and concentrate. Purify the residue by column chromatography to afford the title compound (1.5 g, 60%) as a white solid. 1H NMR (CDCl3): 4.44-4.54 (m, 1H), 3.14 (m, 2H), 2.36-2.42 (m, 2H), 1.70-1.84 (m, 6H), 1.60-1.70 (m, 4H), 1.32-1.48 (m, 4H), 1.00-1.12 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[N+:12]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[NH2:12]
Reactant: COCc1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: COCc1ccc(N)c(OC)c1
Yield: 90.8 %

Procedure:
In a 250 mL Parr apparatus, 2.1 g (10.6 mmol) of 2-methoxy-4-methoxymethyl-1-nitro-benzene, in 40 mL of ethanol was hydrogenated at 2 atm over 300 mg of 10% Pd on carbon for 2.5 h. The catalyst was removed by filtration through a glass fiber filter and the filtrate was concentrated to give 1.61 g (91%) of product as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.80 (s, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.8 Hz), 4.35 (s, 2H), 3.86 (s, 3H), 3.78 (br d, 2H), 3.35 (s, 3H). MS ESI-pos, M+1=168.1.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[C:7]([CH3:22])[C:6](=[O:23])[CH2:5][CH2:4]2.OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2>>[CH3:22][C:7]1[C:6](=[O:23])[CH2:5][CH2:4][C@@:3]2([CH:2]=[O:1])[C:8]=1[CH:9]=[CH:10][C@@H:11]1[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]1[CH2:13][CH2:14][C:15]2=[O:21]
Reactant: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)CCC1=O
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Product: CC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C=O)CCC1=O

Procedure:
Substituting 19-hydroxy-4-methyl-4-androstene-3,17-dione for the 19-hydroxy-4-androstene-3,17-dione above results in the preparation of 4-methyl-4,6-androstadiene-3,17,19-trione.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+].B([O-])[O-].[Cl-].[Li+]>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 91 %

Procedure:
A mixture of 4-bromo-2-methoxy-1-nitrobenzene (I24) (2.364 g, 10.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.00 g, 9.70 mmol), potassium carbonate (4.02 g, 29.1 mmol) and DMF (60 mL) was degassed with three vacuum/nitrogen cycles then PdCl2(dppf)-DCM solvate (450 mg, 6 mol %) added under nitrogen in a Schlenk tube. A second tube was prepared in the same manner (ie. a total of 6.00 g starting boronate), and both tubes were heated to 85° C. under nitrogen. After 17 hours both tubes were cooled under nitrogen and added to 5% w/v aqueous lithium chloride (600 mL). The resulting mixture was extracted with ether (300 mL) and ethyl acetate (3×300 mL). The combined organic extracts were washed with water (600 mL) and brine (600 mL), dried (sodium sulphate) then evaporated to dryness. The residue was chromatographed (120 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I25) (5.863 g, 91% yield) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.5 Hz, 1H), 7.04-6.97 (m, 2H), 6.17 (s, 1H), 4.12 (d, J=2.5 Hz, 2H), 3.98 (s, 3H), 3.65 (t, J=5.6 Hz, 2H), 2.52 (s, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.27 min; m/z 279.0 [M-tBu+2H]+, 235.1 [M-Boc+2H]+.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C:20]4=[CH:19][CH:18]=[C:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]>CCCCCC>[CH3:27][C:21]1[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C:20]=1/[CH:19]=[CH:18]\[C:17]1[C@@H:12]2[CH2:11][CH2:10][C@H:9]([C@@H:2]([CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH3:1])[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH:16]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCCCCC
Product: CC1=C(/C=C\C2=CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)CC1

Procedure:
From the hexane data, it was concluded that the material eluted at 12.2 min is tachysterol. The size and kind of microreactor is important to the ratio of products formed. Where the microreactor is several times the size of the 7-DHC, the undesirable side reactions are more favored. For example the silica with 60 Å pores (Ex. 10 and 11) give a ratio of previtamin D3 :tachysterol similar to that of the reaction in hexane (Ex. 9). In micelles (Ex. 16), however, which form a similarly sized microreactor, but with an environment similar to that of a hydrocarbon solvent, tachysterol is very heavily favored.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][C:6]=1[CH:7]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:28][N:29]([C:17]([C:16]1[CH:20]=[CH:21][C:13]([NH:12][CH:7]([C:6]2[CH:5]=[C:4]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:3][C:2]=2[CH3:1])[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)=[O:19])[CH2:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)CCNC
Reactant: CCCCC(Nc1ccc(C(=O)O)cc1)c1cc(-c2ccccc2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCC(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 4-{[1-(2-methyl-5-phenylfuran-3-yl)pentyl]amino}benzoic acid (182 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (211 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([F:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([F:11])=[CH:9][N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: Fc1c[nH]c2nc(Cl)nc(Cl)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(F)c2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
2,4-Dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (see Seela, et al., Helvetica Chimica Acta, 91(6):1083-1105 (2008)) (654 mg, 3.2 mmol) was dissolved in DMF (6.5 mL). After cooling to 0° C., NaH (254 mg, 6.35 mmol, 60% in mineral oil) was added. After complete addition, the mixture was warmed to rt and allowed to stir for 30 min. A solution of (2-(chloromethoxy)ethyl)trimethylsilane (529 mg, 3.2 mmol) in DMF (2 mL) was added dropwise to the mixture and stirring was continued for 3 hrs. The reaction was quenched by pouring the mixture over ice water (75 mL). The resulting aqueous layer was then extracted with Et2O (three×50 mL). The combined organics were washed with water (two times), brine (two times) and dried over MgSO4. After concentrating, the brown solid was purified via flash chromatography eluting with a gradient of 1%-10% EtOAc in heptanes to afford the title compound (0.45 g, 42% yield) as a white, low melting solid. 1H NMR (400 MHz, chloroform-d) δ ppm-0.03 (s, 9H), 0.87-0.97 (m, 2H), 3.48-3.58 (m, 2H), 5.57 (s, 2H), 7.14 (d, J=2.78 Hz, 1H). APCI (MH+). m/z (APCI+) for C12H16Cl2FN3OSi 336.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7].N1C=CC=CC=1.[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18].O>C(OCC)C>[Br:15][CH:16]([CH3:20])[C:17]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7])=[O:18]
Reactant: COC(=O)NCCO
Reactant: CC(Br)C(=O)Br
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)NCCOC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.0 g of methyl 2-hydroxyethylcarbamate and 6.7 g of pyridine are dissolved in 70 ml of diethyl ether and cooled to 0°-5° C. 18.0 g of 2-bromopropionyl bromide, dissolved in 20 ml of diethyl ether are now added dropwise within 30 minutes and the mixture is stirred at ice temperature for a further 30 minutes and at room temperature for 1 hour. For the working-up, the mixture is poured into water and extracted with diethyl ether. The ether phase is washed twice with sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. There is obtained methyl 2-(2-bromopropionyloxy)ethylcarbamate as a yellow oil which is used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:20][NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:21]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CNC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCCCC1)S(=O)(=O)c1ccc(CBr)cc1
Yield: 24.7 %

Procedure:
The 4-(bromomethyl)benzene-1-sulfonyl chloride (1 g, 3.71 mmol), Et3N (0.776 mL, 5.56 mmol) and N-methylcyclohexylamine (0.42 g, 3.71 mmol) were reacted overnight in THF (6 mL) at ambient temperature. The mixture was diluted with DCM and washed with water. The organics were dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel using an heptane/EtOAc gradient (100/0 to 50/50) to give the title compound (0.317 g, 24.6%): 1H NMR (CDCl3) δ 7.88-7.77 (d, 2H, J=8.4 Hz), 7.52 (d, 2H, J=8.4 Hz), 4.62 (s, 2H), 3.87-3.60 (m, 1H), 2.75 (s, 3H), 1.79-1.69 (m, 2H), 1.66-1.57 (m, 1H), 1.52-1.50 (m, 1H), 1.30 (m, 4H), 1.14-0.84 (m, 2H)
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])C1C=CC=CC=1>[Pd].CO>[CH3:1][NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.20 g, 4.54 mmol), 10% Pd/C (0.90 g) and MeOH (60 ml) was stirred under a H2 atmosphere (0.8 MPa, RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with saturated NH3 in MeOH-DCM (0-10%) to afford tert-butyl 2-(methylamino)ethylcarbamate as a colorless oil (0.54 g, 68.3%). 1HNMR (CDCl3): δ3.25 (m, 2H, CH2), 2.7 (m, 2H, CH2), 2.49 (s, 3H, CH3), 1.49 (s, 9H, CH3).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([OH:6])([CH3:5])[CH3:4].[H-].[Na+].[N+]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)([O-])=O>CN(P(N(C)C)(N(C)C)=O)C.C(OCC)C>[F:1][C:2]([F:8])([F:7])[C:3]([CH3:5])([CH3:4])[O:6][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1
Reactant: CC(C)(O)C(F)(F)F
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C)(Oc1ccc(C#N)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
Add 2-trifluoromethyl-2-propanol (3.4 g, 27 mmol) slowly to a slurry of sodium hydride (0.6 g, 60% in mineral oil, washed with hexane) in HMPA (5 mL) under nitrogen. Stir the slurry for 15 min and add a solution of 4-nitrobenzonitrile (2.0 g, 13.5 mmol) in HMPA (10 mL). Stir the resulting purple slurry at ambient temperature for 16 h, dilute with diethyl ether (100 mL) and wash with 5% aqueous HCl (30 mL). Separate the layers and extract the aqueous layer with diethyl ether (2×50 mL). Combine the organic extracts and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate (780 mg, 25%). GC-MS m/z: 229 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[Cl-].[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([CH2:24][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:21][C:20]=2[CH:44]=1)#[N:15].C1CCN2C(=NCCC2)CC1>O1CCCC1.CO>[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([CH:24]=[CH:1][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)=[CH:21][C:20]=2[CH:44]=1)#[N:15]
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(C=Cc2cc3cc(C#N)ccc3o2)cc1

Procedure:
5.17 g of methyl 4-formylbenzoate and 13.97 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride were dissolved in a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol. A 5.02 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the thus prepared solution while stirring under ice cooling, followed by stirring at room temperature for 2 hours. By collecting the precipitated crystals through a filter, methyl 4-[2-(5-cyano-2-benzofuranyl)vinyl]benzoate was obtained as a mixture of E and Z forms. The thus obtained crystals were dissolved in a solvent mixture of 300 ml of tetrahydrofuran and 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure for 2 hours in the presence of 2.0 g of palladium oxide.1H2O.barium sulfate. After removing the catalyst by filtration and concentrating the resulting filtrate, the thus obtained residue was purified by subjecting it to silica gel column chromatography using benzene as an elution solvent to obtain 8.1 g of methyl 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoate in the form of prism crystals.