Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SiH:1]([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25]([F:28])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([CH3:3])[CH3:2].[Br:29]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][Si:1]([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25]([F:26])([F:27])[F:28])([F:23])[F:24])([F:20])[F:21])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([CH3:2])[CH3:3]
Reactant: C[SiH](C)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(Br)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A mixture composed of 7.65 [lacuna] of HSi(CH3)2C8F17 (15.8 mmol) and 62 mmol of bromine in 25 ml of CCl4 is stirred at 60° C. for 18 hours. After removing the volatile compounds under reduced pressure, a liquid is obtained and is subjected to flash distillation. 8.35 g of BrSi(CH3)2C8F17 are obtained (yield 95%, which exists in the form of a pale pink liquid) [sic].
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][C:15]([CH3:21])([CH3:20])[CH2:16][C:17](O)=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[Li].Cl>O1CCCC1.CO>[C:7]([O:11][C:12](=[O:13])[NH:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][OH:18])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(CCO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
At 0° C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0° C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0° C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0° C. for 2 h, and then warmed to room temperature. over a period of 4 h. It was cooled to 0° C. Methanol (5 mL) was added carefully. 1 N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2×100 mL, 3×50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1=[N:9][O:10][C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([CH:19]=3)[C:17]#[N:18])=[C:7]1[CH2:6][CH2:5]2.[Br-].[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][Zn+])[CH3:29]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.C1COCC1>[C:17]([C:16]1[CH:19]=[C:12]([C:11]2[O:10][N:9]=[C:8]3[C:24]4[C:4]([CH2:5][CH2:6][C:7]=23)=[CH:3][C:2]([CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[CH:26][CH:25]=4)[CH:13]=[CH:14][C:15]=1[O:20][CH:21]([CH3:23])[CH3:22])#[N:18]
Reactant: CCOC(=O)CC[Zn+]
Reactant: CC(C)Oc1ccc(-c2onc3c2CCc2cc(Br)ccc2-3)cc1C#N
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-(7-bromo-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)-2-isopropoxybenzonitrile (Preparation 15B, 0.1 g, 0.244 mmol) in a 2-dram vial was added THF (1 mL). The vial was purged with nitrogen gas for 3 min and (3-ethoxy-3-oxopropyl)zinc(II) bromide (0.5 M in THF) (0.977 mL, 0.489 mmol) was added followed by dichlorobis(tri-o-tolylphosphine)palladium(II) (1.921 mg, 2.443 μmol) at room temperature. The vial was again purged with nitrogen gas for 30 seconds and the pale yellow heterogeneous reaction mixture was stirred at room temperature for 18 h. To the reaction mixture was added potassium fluoride (60 mg) dissolved in 0.2 mL of water at room temperature. The contents were stirred at room temperature for 5 min. and then filtered. The solid was washed with ethyl acetate (2×5 mL). The filtrate was concentrated under reduced pressure to yield a pale yellow solid. LC/MS M+1=401.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:18])[CH:17]=1)[N:14]=[CH:13][C:12]([C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:20])=[C:11]2[OH:30])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:18])[CH:17]=1)[N:14]=[CH:13][C:12]([C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:20])=[C:11]2[OH:30]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 1 h

Procedure:
To a flask containing tert-butyl-3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinylcarbamate from Preparation No. 25 (0.06 g) and dichloromethane (2 mL) is added trifluoroacetic acid (2 mL). The reaction mixture is stirred 1 hour then concentrated under reduced pressure. The residue is triturated with toluene (3×) and dried in vacuo. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% MeOH:CH2Cl2 to 6% MeOH:CH2Cl2. The product-containing fractions are evaporated to give 0.04 g of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH:11]=[CH2:10]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of 2,3-dichlorophenol (35.5 g., 0.22 mole), allyl bromide (29.4 g., 0.24 mole) and potassium carbonate (33 g., 0.24 mole) in dimethylformamide (200 ml.) is vigorously stirred and heated at 55°-60° C. for one hour, poured into ice water, extracted with ether, washed with water and dried over magnesium sulfate. Evaporation of the ether leaves 2,3-dichlorophenyl allyl ether which is subjected to a Claisen rearrangement by heating at 250° C. for ten minutes. Distillation gives 36 g. of 2,3-dichloro-6-allylphenol which boils at 132°-4°/13 mm.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C(=O)C>[C:15]1([S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3.96 g 25 mmol) in N,N-dimethylacetamide (36 mL) was rapidly added thionyl chloride (3.10 g, 26 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -15° C. to -5° C. for 1 hour. 4-(Phenylsulfonyl)benzenamine (3.97 g, 17 mmol) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into water, the resulting solid was filtered off, washed with 3N HCl, then water and dried at 65° C. for 2 hours. The solid was dissolved in 300 mL of refluxing methylene chloride and stirred and heated as hexane was added to replace the methylene chloride as it boiled off. When 250 mL of hexane had been added (precipitate formed at about 180 mL addition) the mixture was concentrated to 250 mL and refrigerated. The yield of light tan solid was 5.92 g (93%), mp 164°-166° C. 1H-NMR (250 MHz, d6 -DMSO): 1.59 (s, 3H, CH3), 7.57-7.72 (m, 4H, OH, aromatic), 7.92-8.04 (m, 6H, aromatic), 10.43(s, 1H, NH). Analysis for C14H14F3NO4S: Calculated: C, 51.47; H, 3.78; N, 3.75 Found: C, 51.22; H, 3.83; N, 3.72
Reaction SMILES: [CH2:1]([N:8]([CH:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:13](N)=[O:14])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>CC(C)=O>[CH2:1]([N:8]1[CH:9]=[CH:10][O:11][C:13](=[O:14])[CH:12]1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C(c1ccc(F)cc1)N(CCO)Cc1ccccc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)=O
Product: O=C1OC=CN(Cc2ccccc2)C1c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
20 g of 2-(N-benzyl-N-(2-hydroxyethyl) amino)-2-(4-fluorophenyl) acetamide of Formula X, 200 ml of acetone and 10 g of L-(+)-tartaric acid were charged in a clean and dry 4 neck round bottom flask. The resultant reaction suspension was heated to reflux followed by stirring for about 3 hours. The reaction solution was cooled to about 30° C. followed by filtration of the solid and the solid was washed with 40 ml of acetone. Filtrate was distilled completely at about 50° C. under vacuum, to the residue 200 ml of dichloromethane, 30 ml of water and 3 g of sodium carbonate were charged followed by stirring for about 15 minutes. Organic and aqueous layers were separated and the organic layer was washed with 30 ml of water. Organic and water layer were separated and 70% of the solvent on the total volume was distilled at about 45° C. under vacuum followed by addition of 10 ml of dilute hydrochloric acid. The resultant acidified organic layer was distilled completely at about 45° C. under vacuum. 100 ml of acetone was charged to the residue and was stirred for about 30 minutes. Separated solid was filtered and the solid was washed with 40 ml of acetone. The resultant wet solid was charged in a clean and dry 4 neck round bottom flask followed by charging of 200 ml of dichloromethane, 30 ml of water and 3 g of sodium carbonate. Resultant reaction suspension was stirred for about 15 minutes, followed by separation of organic and aqueous layers. Organic layer was washed with 30 ml of water. Organic and water layers were separated and the organic layer was distilled completely at about 40° C. under vacuum to yield 16 g of the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].NC(N)=O.[OH-].[Na+].[BrH:25]>O>[Br:25][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: Br
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)c(Br)c1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
3-Amino-4-trifluoromethylbenzoic acid (8.20 g, 40.0 mmol), prepared according to Astrid Giencke and Helmut Lackner, Liebigs Ann. Chem., 569-579:6 (1990), in 48% HBr (20 mL) and H2O (67 mL) at 0° C. was treated with NaNO2 (2.99 g) in small portions over 15 minutes. After stirring for 30 minutes, the mixture was treated with urea (0.250 g) and then the mixture was added dropwise to a solution of CuBr (10.0 g) in 48% HBr (40 mL) and H2O (100 mL). The reaction mixture was heated at 75° C., stirred for 2 hours, cooled to room temperature, and stirred overnight. The mixture was treated with with 20% NaOH until the pH>10. The resulting blue copper salts were removed by filtration through Celite. The mixture was acidified to pH 1 with HCl, extracted with CH2Cl2(3×200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Br:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([OH:17])=[C:12]([N+:18]([O-])=O)[CH:11]=1>O.C(O)C>[NH2:18][C:12]1[CH:11]=[C:10]([Br:9])[C:15]([F:16])=[CH:14][C:13]=1[OH:17]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)c(F)cc1O

Procedure:
A suspension of Na2S2O4 (51.6 g, 296 mmol) in water (122 mL) was added slowly to a refluxed mixture of 4-bromo-5-fluoro-2-nitrophenol (14 g, 59.3 mmol) in ethanol (1000 mL). The resulting mixture was refluxed for 1 h. After cooling down the salts were filtered off and the filtrate was partially concentrated. Brine was added, extracted with diethyl ether, the extract dried and concentrated to give the crude title compound which was used without further purification (9.2 g, 75%). 1H-NMR (400 MHz, DMSO) 4.65 (br, 2H), 6.60 (d, J=11.3, 1H), 6.76 (d, J=7.8, 1H), 9.80 (br, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]([O:20][C:21](=[O:33])[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:33])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:29])=[CH:31][CH:32]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-(2-t-butoxy-2-oxoethoxy)benzoic acid (113 mg; 0.45 mmol; 1.2 eq.) as a white foam (21.6 mg, 13%). HPLC, Rt: 3.98 min. (purity 98.3%). LC/MS, M+(ESI): 435.1, M−(ESI): 433.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[O:16]1[C@:18]2([CH2:23][CH2:22][CH2:21][C@H:20]([CH2:24][N:25]3[C:29]4[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=4[N:27]=[CH:26]3)[CH2:19]2)[CH2:17]1>C(O)(C)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]2[N:27]=[CH:26][N:25]([CH2:24][C@H:20]3[CH2:21][CH2:22][CH2:23][C@:18]([CH2:17][NH:1][CH2:2][C:3]4([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]4)([OH:16])[CH2:19]3)[C:29]=2[CH:30]=1)#[N:35]
Reactant: N#Cc1ccc2ncn(C[C@H]3CCC[C@@]4(CO4)C3)c2c1
Reactant: CC1(CN)CCN(C(=O)OC(C)(C)C)C1
Solvent: CC(C)O
Product: CC1(CNC[C@]2(O)CCC[C@H](Cn3cnc4ccc(C#N)cc43)C2)CCN(C(=O)OC(C)(C)C)C1
Yield: 62.4 %

Procedure:
A solution of 1,1-dimethylethyl 3-(aminomethyl)-3-methyl-1-pyrrolidinecarboxylate (0.677 g, 3.16 mmol) and 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (0.844 g, 3.16 mmol) in isopropanol (5 mL) was heated at 102° C. overnight. The reaction mixture was concentrated and purified via silica gel chromatography (ISCO, 40 g silica gel column. Solvent A: DCM; B: MeOH; 0-10% B: 15 min; 10% B: 10 min) to give 1,1-dimethylethyl 3-{[({(1S,3S)-3-[(6-cyano-1H-benzimidazol-1-yl)methyl]-1-hydroxycyclohexaneyl}methyl)amino]methyl}-3-methyl-1-pyrrolidinecarboxylate (950 mg, 62.4% yield).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH2:25]([C@H]1N(C(=O)C2C=CC=C(OC)C=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Product: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 76 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 4) to yield (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (76%). MS (ESI) m/z 343 ([M+H]+); HRMS: calcd for C19H19FN2O3, 342.13804; found (ESI+), 343.14480.
Reaction SMILES: CCN(CC)CC.[CH:8]([O:11][C:12]1[CH:17]=[C:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:15]([CH3:24])=[CH:14][C:13]=1[NH:25][C:26]1[N:27]=[C:28]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([CH:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])[C:29]2[C:34]([CH3:35])=[CH:33][NH:32][C:30]=2[N:31]=1)([CH3:10])[CH3:9].Br[CH2:50][C:51]([NH2:53])=[O:52]>CN(C=O)C>[CH:8]([O:11][C:12]1[C:13]([NH:25][C:26]2[N:27]=[C:28]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43]([CH:46]([CH3:48])[CH3:47])(=[O:44])=[O:45])[C:29]3[C:34]([CH3:35])=[CH:33][NH:32][C:30]=3[N:31]=2)=[CH:14][C:15]([CH3:24])=[C:16]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:20][CH2:19]2)[CH:17]=1)([CH3:10])[CH3:9]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)c[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)c[nH]c3n2)c(OC(C)C)cc1C1CCN(CC(N)=O)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
82 uL of Et3N (0.69 mmol) was added into a solution of 40 mg N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (11) (0.069 mmol) and 28.5 mg 2-bromoacetamide (0.207 mmol) in 1 mL of DMF. The reaction mixture was heated to 100° C. and stirred for 10 minutes under microwave irradiation. After cooling to room temperature, the solvent was removed under vacuum and the residue was redissolved in 1 mL of DMSO and purified by mass-triggered HPLC to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C(=O)([O-])O.[Na+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(OCC)(=O)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][N:5]([C:6]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:12])[CH3:13])(=[O:29])=[O:28]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (12.0 g) and triethylamine (11.5 ml) in ethyl acetate (300 ml), methanesulfonyl chloride (5.4 ml) was added under cooling with ice. After 2 hours' stirring, saturated aqueous sodium hydrogencarbonate solution was added to the reaction liquid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and condensed under reduced pressure to provide 3-[(tert-butoxycarbonyl)-(methyl)amino]propyl methanesulfonate (14.8 g) as an oily substance.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][CH2:16][NH2:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Br:1][C:2]1[C:7]([CH2:8][NH:17][CH2:16][CH2:15][CH:11]2[O:12][CH2:13][CH2:14][O:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCC1OCCO1
Reactant: O=Cc1cccnc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Brc1ncccc1CNCCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromopyridine-3-carbaldehyde (3.53 g, 19.0 mmol, 1.0 eq) (Melnyk et al., Synthetic Commun. 23(19):2727-2730, 1993) in 1,2-dichloroethane (50 mL) was added 2-(1,3-dioxolan-2-yl)ethylamine (TCI-GR, 2.67 g, 22.8 mmol, 1.2 eq), sodium triacetoxyborohydride (Aldrich, 1.61 g, 76 mmol, 4.0 eq) and glacial acetic acid (1.14 g, 19 mmol, 1.0 eq). The reaction mixture was stirred under nitrogen at room temperature for 2 h. The reaction was quenched with 1.0 N aqueous NaOH to about pH 8 and the solution was extracted with EtOAc (200 mL×3). The organic extracts were washed with saturated NaCl, dried with MgSO4, filtered and concentrated. Flash column chromatography (silica gel, 0-10% EtOAc-Hexane) afforded the title compound as a colorless oil. MS m/z 377 (Br=79, M+H), 379 (Br=81, M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]1[CH2:9][CH:8]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:14][CH:13]=1)=O)[CH2:4][CH3:5])[CH3:2].[OH-].[K+].NN>C(O)COCCO>[CH2:4]([N:3]([CH2:1][CH3:2])[CH2:6][CH:7]1[CH2:9][CH:8]1[CH2:10][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:14][CH:13]=1)[CH3:5]
Reactant: CCN(CC)CC1CC1C(=O)c1ccc(-n2ccnc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CCN(CC)CC1CC1Cc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Example 28, react [2-[(diethylamino)methyl]cyclopropyl][4-(1H-imidazol-1-yl)phenyl]-methanone with potassium hydroxide and hydrazine in diethylene glycol to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)O)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:43])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[Cl:43])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(C(O)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(C(Cl)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.2 %

Procedure:
A solution of 290 milligrams (0.504 mmole) of ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]hydroxymethyl}piperidine-4-carboxylate, 110 μL (1.513 mmole) of thionyl chloride, and 408 μL (5.04 mmole) of pyridine in 5 mL of methylene chloride was stirred at ambient temperature for 1 hour. The reaction mixture was then poured into 25 mL of an aqueous solution saturated with sodium bicarbonate, and the mixture was extracted with three 50 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:10 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 240 milligrams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]/[CH:11]=[CH:12]/[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][CH2:17][N:18]([CH2:26][CH3:27])C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].[ClH:49]>C(OCC)C>[ClH:49].[ClH:49].[ClH:49].[ClH:49].[CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10]/[CH:11]=[CH:12]/[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:26][CH3:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCCCNCCCNC/C=C/CNCCCNCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 0.3 g (0.438 mmol) of (E)-1-butyl-14-ethyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 6 ml of 3N methanolic hydrochloric acid is stirred for 15 h at room temperature, and then 10 ml of diethyl ether are added. Working up analogously to Example 1 yields the title compound, m.p. >260° C. 1H-NMR (D2O): δ0.91 (t,3H); 1.27(t, 3H); 1.32-1.45(m,2H); 2.05-2.16(m,4H); 3.03-3.19(m,12H); 3.77(d,4H); 6.04-6.07(m,2H).