Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:27](I)[CH:28]([CH3:30])[CH3:29]>CN(C=O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To a solution of 1-boc-4-(2-methanesulfonylamino-phenyl)-piperazine (1.07 g, 3.0 mmol) in 50 mL of DMF was added NaH (240 mg of a 60% dispersion in oil, 6 mmol). After stirring for about 15 minutes at r.t., isobutyl iodide (420 □L, 3.65 mmol) was added and the solution warmed to 60° C. After stirring at 60° C. overnight, the reaction was quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The solution was washed twice with water and brine, and then dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (40M Biotage column, 10-30% linear gradient EtOAc/Hex, over 45 min at 35 mL/min) afforded about 1.07 g (2.6 mmol, 87%) of the title compound as a white foam. LRMS: 412.3 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]([CH:18]=C)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.CC(C)=[O:26].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:18]([C:11]1[C:10]([CH3:20])=[C:9]([CH3:21])[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:26]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate (13.6 g) in a mixed solvent of acetone (135 mL)-acetonitrile (135 mL)-water (135 mL) were added osmium oxide (fixed catalyst I) (5.57 g) and sodium periodate (46.9 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (13.5 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH2:18][OH:19])=[O:12])[CH2:7][CH2:6]1.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.O>CS(C)=O>[F:30][C:29]([F:32])([F:31])[C:27]1[CH:26]=[N:25][CH:24]=[C:23]([O:19][CH2:18][C@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:4]([F:3])([F:20])[F:21])[CH2:10][CH2:9]2)=[O:12])[CH:28]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1COc1cncc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (60% oil dispersant, 11 mg, 0.27 mmol) was placed on the reaction tube, and a solution of [(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol (68 mg, 0.24 mmol, EXAMPLE 31 Step 1) in DMSO (2.0 mL) was added at ambient temperature. After being stirred for 15 min at room temperature, 3-bromo-5-(trifluoromethyl)pyridine (50 mg, 0.22 mmol) was added to the mixture at ambient temperature. The mixture was heated stepwise with continuous stirring, at room temperature for 19 h, at 50° C. for 3 h, at 80° C. for 15 h, and at 100° C. for 15 h. After cooling to room temperature, water was added to the mixture. The mixture was extracted with ethyl acetate twice and washed with brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel preparative thin layer chromatography (TLC) (ethyl acetate/hexane 3:2) to afford 40 mg (43%) of the title compound as a colorless viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:6][CH2:5]2.[CH3:19][O:20][C:21](=[O:27])[CH2:22][CH2:23][S:24]([O-:26])=[O:25].[Na+]>[Cu]I>[Si:12]([O:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([S:24]([CH2:23][CH2:22][C:21]([O:20][CH3:19])=[O:27])(=[O:26])=[O:25])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cc(Br)ccc21
Reactant: COC(=O)CCS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Product: COC(=O)CCS(=O)(=O)c1ccc2c(c1)CCC2O[Si](C)(C)C(C)(C)C
Temperature: 110 °C

Procedure:
[(5-bromo-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (1.62 g, 4.95 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (3.45 g, 19.8 mmol) and CuI (3.77 g, 19.8 mmol) were charged in a sealable microwave flask. The flask was closed and degassed twice, after which dry DMSO (10 mL) was added and the reaction mixture was degassed before being heated at 110° C. in an oil bath overnight. The reaction mixture was cooled and diluted with ethyl acetate (40 mL), filtered on a silica gel pad, and eluted with ethyl acetate. The organic solvents were concentrated under reduced pressure. The crude concentrate was purified on silica gel eluting with hexanes and ethyl acetate, then with DCM and methanol to afford the title compound.
Reaction SMILES: [NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:18]>N1C=CC=CC=1>[NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4](=[S:18])[NH2:5]
Reactant: CCOC(N)=C(C#N)C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(N)=C(C#N)C(N)=S
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A mixture of 51.2 g of 3-amino-3-ethoxy-2-cyano-2-propenenitrile (above) and 37.8 g of triethylamine in 200 ml of pyridine was continuously stirred and heated to 70° while 60 g of gaseous hydrogen sulfide was bubbled in during 1.5 hours. Heating was continued at 65°-70° for 0.5 hour. Thin-layer chromatographic analysis indicated that no reaction had occurred. The mixture was heated overnight at 55° but still no reaction had occurred. An additional 150 ml of pyridine was added and the mixture was heated to 75°-80° while 17 g of hydrogen sulfide was bubbled in during 0.5 hour. Thin-layer chromatographic analysis indicated that a reaction had occurred, but was incomplete. An additional 18 g of hydrogen sulfide was added during 1 hour at 75°-80°; thin-layer chromatography indicated that the reaction was completed. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give a first crop of 28 g of 3-amino-2-cyano-3-ethoxypropenethioamide; m.p. 170°-171°. A second crop of 15 g of this product (m.p. 169°-171°) was obtained by diluting the mother liquor with ice-water. A small sample of crop I was recrystallized again from ethanol (charcoal) to give an analytical sample; m.p. 180°-181°. A total of 43.0 g of 3-amino-2-cyano-3-ethoxypropenethioamide was obtained. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[CH2:32][OH:33])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])[CH:13]=1.[CH2:34]([Mg]Br)[CH3:35]>>[CH2:27]([C:11]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:34][CH3:35])([OH:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:29]=[CH:30][C:31]([CH2:32][OH:33])=[C:3]([CH2:2][OH:1])[CH:4]=2)=[CH:9][CH:10]=1)[CH3:28]
Reactant: CCC(=O)c1ccc(-c2cc(OCc3ccc(CO)c(CO)c3)ccc2CC)c(C(C)C)c1
Reactant: CC[Mg]Br
Product: CCc1ccc(OCc2ccc(CO)c(CO)c2)cc1-c1ccc(C(O)(CC)CC)cc1C(C)C

Procedure:
In a manner similar to that of Example 1(q), by reacting 810 mg (1.8 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-isopropylbiphenyl-4-yl}-1-propanone with 4.8 ml (15 mmol) of ethylmagnesium bromide (3M/ether), and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (35/65), 600 mg (70%) of {4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-isopropylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol are obtained in the form of white crystals with a melting point of 109° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][C:10](Cl)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:13]12CCC(CO)(CC1)CC2.S([O-])(=O)(=O)C.[C-]#N.[Na+]>CN(C)C=O>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][C:10]#[N:13])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=C(Cl)CC12CCN(CC1)CC2
Reactant: OCC12CCN(CC1)CC2
Agent: CS(=O)(=O)[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC12CCN(CC1)CC2

Procedure:
2-(Quinuclidin-4-yl)acetyl chloride may be made by converting (quinuclidin-4-yl)methanol (vide supra) to the mesylate (methanesulfonylchloride/triethylamine in chloroform) which is then treated with sodium cyanide in dimethylformamide to form (quinuclidin-4-yl)acetonitrile. Heating this in ethanol saturated with hydrogen chloride gas produces the corresponding ethyl ester which is hydrolyzed to the acid by treatment with 6N hydrochloric acid. Finally, the acid is converted to the acid chloride as described above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]([C:12]([OH:14])=O)=[CH:11]2.[Si:24]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][C:10]([C:12](=[O:14])[N:35]([CH2:34][CH2:33][CH2:32][O:31][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:36][CH2:37][CH3:38])=[CH:11]2
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(Br)ccc2C=C(C(=O)O)C1
Reactant: CCCNCCCO[Si](C)(C)C(C)(C)C
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid and 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS APCI (+) m/z 594, 596 (M+1, Br pattern) detected.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[N:17]=[CH:16][C:10]2[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=2[CH:8]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:14]1[C:9]2[CH:8]=[C:7]([Cl:6])[N:17]=[CH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1cc2c(Cl)ncnc2cn1
Reaction time: 1 h

Procedure:
DMF (0.1 ml) was added to 6chloro-3H-pyrido[3,4-d]pyrimidin-4-one (1.82 g, 10 mmol) followed by dropwise addition of thionyl chloride (10 ml). The flask was fitted with a condenser and a drylng tube and the contents heated to reflux for ˜20 minutes whereupon the solids dissolved. The heating was continued for a further 1 h and then cooled. Toluene was added to wash the sides of the flask and the solvents were evaporated in vacuo. Azeotroping with toluene was repeated twice and the crude so obtained was taken through to the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:27](=[O:28])[NH:26][CH2:24][CH3:25])[N:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCN=C=O
Reactant: CSc1ccc2c(c1)C(c1ccc(NC(C)=O)cc1)=NNC2C
Solvent: ClC(Cl)Cl
Product: CCNC(=O)N1N=C(c2ccc(NC(C)=O)cc2)c2cc(SC)ccc2C1C
Yield: 50 %

Procedure:
To a solution of dihydrophthalazine 8 in chloroform was added ethyl isocyanate (3 eq) at room temperature. The resulting solution was stirred at such temperature for a few days until there is no starting material left from TLC. The solvent was removed under reduced pressure. Purification of the crude product by using a silica gel gave the desired products 9 (Yield: 50%). 1HNMR (CDCl3): 7.70-7.55 (m, 5H), 7.35 (dd, J=4.3 Hz, 1H), 7.19 (m, 2H), 6.53 (br, 1H), 5.73 (q, J=13.2 Hz, 1H), 3.42 (m, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.22 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:23](Cl)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:23](=[O:25])[CH3:24])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Yield: 47.4 %

Procedure:
3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.77 g of acetyl chloride and 20 ml of pyridine are treated in the same manner as described in Preparation 7. The crude product is recrystallized from a mixture of ether and n-hexane. 1.6 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless needles.
Reaction SMILES: [CH3:1][O-].[Na+].[I-].C[S+](C)(C)=O.[CH3:10][C:11]([C:14]([CH2:16][N:17]1[N:21]=[CH:20][N:19]=[CH:18]1)=[O:15])([CH3:13])[CH3:12]>CS(C)=O.O1CCCC1>[C:11]([C:14]1([CH2:16][N:17]2[CH:18]=[N:19][CH:20]=[N:21]2)[CH2:1][O:15]1)([CH3:10])([CH3:12])[CH3:13]
Reactant: C[O-]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C1(Cn2cncn2)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
6 g (0.11 mol) of sodium methylate were introduced in portions into a suspension of 24 g (0.11 mol) of trimethylsulphoxonium iodide in 24 g of dimethylsulphoxide. 10 ml of tetrahydrofuran were also added, and the reaction mixture was then stirred for 5 hours at room temperature. Thereafter, a solution of 16.8 g (0.1 mol) of 1,2,4-triazol-1-yl-pinacolin in 100 ml of tetrahydrofuran was added dropwise, and the mixture was heated at 70° C. for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform, and the solution was washed with water, dried over sodium sulphate, filtered and concentrated. 13.8 g of a 69.4% pure 2-tert.-butyl-2-(1,2,4-triazol-1-yl-methyl)-oxirane of refractive index nD20 =1.4872 were obtained.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19])([CH3:3])[CH3:2].[O:20]=[S:21]1(=[O:37])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35]Br>>[O:37]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35][N:16]1[CH2:17][CH2:18][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2=[O:19])[CH2:14][CH2:15]1
Reactant: CC(C)n1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Product: CC(C)n1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
From 4-(3-isopropyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol and diethyl ether), melting point 229-234° C. Analysis calculated for C26H31ClN4O4S.HCl.0.4 H2O: C, 54.33; H, 5.75; N; 9.75; found: C, 54.35; H, 5.60; N, 9.70. The NMR was consistent with the structure.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=[O:5])C.[OH-].[K+].O>CO>[F:15][C:11]1[CH:10]=[C:9]([C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 0.062 mol) in MeOH (310 mL) was added a solution of KOH (35.0 g, 0.625 mol) in MeOH (150 mL) at 0° C. After addition of the base the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with methylene chloride (2×50 mL). The aqueous layer was acidified with 10% HCl. The resulting mixture was extracted with methylene chloride (2×150 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness to give rac-trans-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid as colorless crystals (9.5 g, 85%). Separation of the isomers by chiral SFC (Method D) gave the title compound (1S,2S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid IM47 as colorless crystals (3.27 g, 17% overall yield from 3-fluorostyrene) sufficiently pure for the next step. Specific optical rotation +263.4° [α]D20 (C=1% MeOH)
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:7]1)=[N+:2]=[N-:3].[CH:30]12CC(C=C1)C=[CH:31]2>O1CCOCC1>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C@@H:8]3[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:1]4[CH:31]=[CH:30][N:3]=[N:2]4)[CH2:7]3)[CH2:14][CH2:15]2)=[O:20])[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCn3ccnn3)C2)CC1
Temperature: 180 °C

Procedure:
4-{[(3R)-1-(2-Azidoethyl)piperidin-3-yl]methyl}-N-(3,4-dichlorophenyl)piperazine-1-carboxamide (100 mg, 0.23 μmmol) was dissolved in 1,4-dioxane (4 ml). Bicyclo(2.2.1)hepta-2,5-diene (0.5 ml) was added and the mixture heated in the microwave at 180° C. for 20 minutes. The reaction mixture was poured onto a bond elute column (SiO2, 20 g) and the product eluted with a gradient of dichloromethane through to 20% methanolic ammonia/dichloromethane to yield the title compound as a white solid (80.1 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[N:32]=[C:33]=[O:34]>N1C=CC=CC=1>[NH2:18][C:16]1[C:17]2[C:9]([S:8][C:4]3[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:26]4[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[O:34])[CH:7]=[CH:6][CH:5]=3)=[CH:10][N:11]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C=Nc1c(F)cccc1F
Reactant: Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Solvent: c1ccncc1
Product: Nc1ncnc2c1c(Sc1cccc(NC(=O)Nc3c(F)cccc3F)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a round-bottom flask with pyridine (3 mL) was added 5-(3-Amino-phenylsulfanyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (16.3 mg, 0.05 mmole) and 1,3-Difluoro-2-isocyanato-benzene (15.5 mg, 0.1 mmole). The reaction mixture was stirred at room temperature overnight and extracted with EtOAc (40 mL) and water (40 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification through flash column (methylene chloride/methanol: 96/4) gave the title compound as a light yellow solid (9.8 mg, 41%). MS: 481.1 (MH+); HPLC Rf: 7.559 min.; HPLC purity: 96%.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=3)[OH:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:23]=[CH:24][CH:25]=[N:26][C:5]1=2.[Si:27](N(C)C(=O)C(F)(F)F)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(#N)C>[Br:22][C:18]1[N:17]=[C:16]([CH:14]([O:15][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4[N:23]=[CH:24][CH:25]=[N:26][C:5]=4[N:4]([CH2:3][O:2][CH3:1])[C:9]=3[CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COCN1c2cc(C(O)c3cccc(Br)n3)ccc2Sc2nccnc21
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C(C)(C)C
Solvent: CC#N
Product: COCN1c2cc(C(O[Si](C)(C)C(C)(C)C)c3cccc(Br)n3)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 1.05 g of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(6-bromopyridin-2-yl)methanol in 15 ml of acetonitrile was added in a nitrogen atmosphere 3.2 ml of N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide and the resulting mixture was stirred at room temperature for 22 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.72 g of the title compound as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7]2.[CH3:16][N:17]([CH3:23])[C@H:18]([C:20](O)=[O:21])[CH3:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:16][N:17]([CH3:23])[C@@H:18]([CH3:19])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:7][CH2:8]1)=[O:21]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: C[C@@H](C(=O)O)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@H](C)N(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride (2 g, 8.67 mmol) in N,N-dimethylformamide (100 mL) was added N,N-dimethyl-L-alanine (1.524 g, 13.01 mmol), PyBOP (13.54 g, 26.0 mmol), and DIPEA (15.14 mL, 87 mmol). After stirring overnight at rt, the solvent removed, residue suspended in dichloromethane (150 mL), washed with water (100 mL), concentrated on the rotovap, and purified by column chromatography (DCM to 5% MeOH/DCM) to give (2S)-N,N-dimethyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanamine (2.2 g, 86%). ESIMS (M+H)+=294.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[C:17][C:18]3[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]=3[CH3:26])[CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[K+]>C(O)C.O>[CH3:26][C:19]1[CH2:20][CH2:21][CH2:22][C:23]([CH3:24])([CH3:25])[C:18]=1[C:17]#[C:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=[CH:14]2
Reactant: CCOC(=O)c1ccc2cc(C#CC3=C(C)CCCC3(C)C)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=C(C#Cc2ccc3cc(C(=O)O)ccc3c2)C(C)(C)CCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.130 g (0.38 mmol) of ethyl-6-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-ethynyl]2-naphthoate (Compound 2) in 0.7 ml of ethanol was added dropwise under nitrogen 0.9 ml of a 1.86M solution of KOH in ethanol and water. After being stirred at 50 degrees C. for 18 hours, solvent was removed in-vacuo and the residue treated with 1 ml of water and extracted with 1×3 ml portions of ether. The aqueous layer was then acidified with dilute HCl and extracted with 3×3 ml portions of ether. Combined ether extracts were dried (MgSO4) and concentrated in-vacuo to give the title product.