Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[O:13]1[CH2:16][C:15](=O)[CH2:14]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][N:9]([CH:15]3[CH2:16][O:13][CH2:14]3)[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Temperature: 50 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
A mixture of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 124d (238 mg, 1.40 mmol), oxetan-3-one (252 mg, 3.5 mmol), NaBH3CN (260 mg, 4.2 mmol), and zinc chloride (567 mg, 4.2 mmol) in methanol (10 mL) was stirred at 50° C. for 6 hours. The mixture was added to water and extracted with dichloromethane three times. The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 155a (200 mg, 64%). MS: [M+H]+ 225.3
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=2)[CH2:24][CH2:23]1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:31][CH2:30][C:28]2[N:29]=[C:25]([CH:22]3[CH2:24][CH2:23]3)[S:26][CH:27]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1csc(C2CC2)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(NCc1csc(C2CC2)n1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9, 54 mg, 0.35 mmol) as starting materials; off white solid (66 mg, 45.4%). MS (ESI): 440 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1F.[SH:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:16][CH2:17][CH2:18][OH:19]
Reactant: OCCS
Reactant: N#Cc1ccc(C2OCCCO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2OCCCO2)c(SCCO)c1

Procedure:
The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (2.07 g, 10 mmol; 1.1 eq.) and 2-mercaptoethanol (0.71 g, 9.1 mmol; 1 eq.) were initially charged in DMF (50 ml). Potassium carbonate (3.14 g, 22.7 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at boiling point for 1 h. TLC control then showed complete conversion. The mixture was concentrated and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:2). The title compound was obtained as a solid (2.33 g, 88% of theory).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:12]=[C:13]5[C:17](=[CH:18][CH:19]=4)[NH:16][CH:15]=[CH:14]5)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc3[nH]ccc3c2)nc1Nc1ccc2[nH]ccc2c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted to yield N2,N4-bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.26 min.; purity: 99%; MS (m/e): 359 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15]2)=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH2:15]1[C:16]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:17][CH2:18][CH:14]1[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(OCC2CCC3(CCCCCC3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccc(OCC2CCC3(CCCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
To a solution of 3-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionic acid methyl ester (75 mg) obtained in Step 8 in a mixed solvent of ethanol (1 mL)-tetrahydrofuran (1 mL) was added 1N aqueous sodium hydroxide solution (0.22 mL), followed by stirring the reaction mixture at room temperature for 5 hours. Then, after concentrating the reaction mixture, to the residue was added dropwise 2N aqueous hydrochloric acid solution. The precipitate was filtered, washed with water and dried in vacuo to give 3-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionic acid (70.6 mg) as the desired compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:11]([O:18][C:19](=[O:36])[NH:20][C@@H:21]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19](=[O:36])[NH:20][C@@H:21]([CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:22][S:23](=[O:25])(=[O:24])[NH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(N[C@@H](COCc1ccccc1)CS(=O)(=O)Cl)OCc1ccccc1
Product: CC(C)N1CCC(NS(=O)(=O)C[C@H](COCc2ccccc2)NC(=O)OCc2ccccc2)CC1

Procedure:
[(S)-1-Benzyloxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-carbamic acid benzyl ester was prepared by an analogous procedure as described for example 26 vi) starting from 142 mg (1.0 equiv.) 1-isopropyl-piperidin-4-ylamine and 398 mg (1.0 mmol) ((S)-1-benzyloxymethyl-2-chlorosulfonyl-ethyl)-carbamic acid benzyl ester. The product was obtained in crude form as a light yellow foam. Yield: 217 mg MS (ES+): m/e=504.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]NC(=O)CCC(N)=O>CC(O)=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([Br:28])=[CH:12][N:11]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=c1ccn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Solvent: CC(=O)O
Product: O=c1c(Br)cn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one (2.41 g, 6.8 mmol) in AcOH (68 mL) was added N-bromosuccinamide (2.67 g, 15 mmol) and the reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by flash chromatography (80 g SiO2, 0-100% ethyl acetate/hexanes) to provide 3-(benzyloxy)-1-(biphenyl-3-yl)-5-bromopyridin-4(1H)-one. LC/MS (M+H)+ 432/434.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC([O-])(C)C.[Na+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:18]1([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (0.65 mL, 5.0 mmol), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (255 mg, 0.375 mmol), sodium 2-methylpropan-2-olate (1.44 g, 15 mmol), bromobenzene (0.684 mL, 6.5 mmol), tris(dibenzylideneacetone) dipalladium(0) (114 mg, 0.125 mmol) and toluene (15 mL) was stirred at 110° C. for 5 h under Ar atmosphere. Water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give the title compound (1.09 g, 99%) as an orange oil:
Reaction SMILES: S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+].[I:12]I.[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[CH3:15].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[I:12][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:16]=1[CH2:14][CH3:15]
Reactant: CCc1ccc(C(F)(F)F)cc1
Reactant: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sulfuric acid (96%, 1.9 mL) was added drop wise to a solution of sodium periodate (3.73 g, 17.4 mmol) and iodine (2.95 g, 11.6 mmol) in a mixture acetic acid (8.45 mL) acetic anhydride (4.23 mL) at 0° C., followed by the drop wise addition of 1-ethyl-4-(trifluoromethyl)benzene (2.0 g, 11.6 mmol). The reaction mixture was let warming up to room temperature while stirring for a period of 24 h. A solution of sodium metabisulfite (10%) was added to quench the remaining iodine and successively, sodium hydroxide (35%) was added to reach pH=7. The aqueous layer was extracted with DCM (3×50 mL) and the combined organic layers were dried over sodium sulfate. Once the solvent was removed, the crude was used without further purification in the next step.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[CH2:3].C(OCCCl)=O.C(#N)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>O.C(N(CC)CC)C>[NH2:26][S:23]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: O=COCCCl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Yield: 65 %

Procedure:
31.0 g of methacrylic acid, 39.1 g of chloroethyl formate, and 200 ml of acetonitrile were put in an ice water bath, and this mixture was agitated while cooling. 36.4 g of triethylamine was dropped into the mixture by a dropping funnel over about 1 hour. After the dropping was finished, the ice water bath was taken away, the mixture was agitated for 30 minutes at room temperature. 51.7 g of p-amino benzene sulfonamide was added to the reaction mixture, and the mixture was agitated for 1 hour while being heated at 70° C. After finishing the reaction, an obtained mixture was introduced into 1,000 ml of water while agitating the water, and the obtained mixture was agitated for 30 minutes. The mixture was filtrated for taking out a precipitate. After adding 500 ml of water to the precipitate to make a slurry, the slurry was filtrated, and an obtained solid was dried so as to obtain N-(p-aminosulfonyl phenyl) methacrylamide (yield 46.9 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Br:8][C:9]1[C:14](Br)=[N:13][CH:12]=[CH:11][N:10]=1>C1COCC1>[Br:8][C:9]1[CH:14]=[N:13][C:12]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:11][N:10]=1
Reactant: Brc1nccnc1Br
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnc(-n2ccnc2)cn1
Temperature: 0 °C

Procedure:
To sodium hydride (0.20 g) in THF (15 ml), imidazole (0.57 g) was added and cooled to 0° C. To the above mixture 2,3-dibromopyrazine (2 g) was added and entire reaction mixture was allowed to reflux for overnight. The reaction mixture was quenched with water 5 ml volatiles were removed under vacuum. The resulting crude mass was purified by column chromatography to afford 2-bromo-5-(1H-imidazol-1-yl)pyrazine as pure product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]([Br:12])=[C:10]([CH3:13])[S:9][C:8]=1[CH3:14].[O:15]1[CH:20]2[CH:16]1[CH2:17][O:18][CH2:19]2.B(F)(F)F.CCOCC.[Cl-].[NH4+]>C1COCC1>[Br:12][C:11]1[C:7]([C@@H:20]2[CH2:19][O:18][CH2:17][C@H:16]2[OH:15])=[C:8]([CH3:14])[S:9][C:10]=1[CH3:13]
Reactant: Cc1sc(C)c(Br)c1Br
Reactant: C1OCC2OC12
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1sc(C)c([C@@H]2COC[C@H]2O)c1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
n-Butyllithium (1.6 M in hexane; 0.239 mol) is added dropwise to a solution of 3,4-dibromo-2,5-dimethylthiophene (0.239 mol) in 325 ml of THF which has been cooled to −78° C. and the mixture is stirred for 30 minutes. 3,4-Epoxytetrahydrofuran (0.217 mol) and boron trifluoride etherate (0.217 mol) are added dropwise to this solution. The reaction solution is warmed to 0° C. and stirred for a further 3 hours. It is subsequently hydrolyzed with saturated ammonium chloride solution and the aqueous phase is extracted twice with tert-butyl methyl ether. After drying, the solvent is removed under reduced pressure and the crude product is purified by chromatography. The product is obtained as an oil in a yield of 64%.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([NH:11][C:12](=[O:14])[O-:13])[CH3:10].[CH3:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1>C(#N)C.C(Cl)Cl.O>[CH2:9]([NH:11][C:12](=[O:13])[O-:14])[CH3:10].[CH3:15][C:16]1[C:17]([Br:8])=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1
Reactant: Cc1ccc2c(c1)C1CNCC1C2C
Reactant: O=C1CCC(=O)N1Br
Agent: CCNC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1cc2c(cc1Br)C(C)C1CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NBS (34 mg, 0.2 mmol) was added to a solution of N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 21, Step A) (50 mg, 0.2 mmol) in acetonitrile (1 mL), and stirred overnight at room temperature. The reaction was diluted with CH2Cl2 (3 mL) and H2O (3 mL) and filtered through an Extrelut column. The column was washed with CH2Cl2 and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-50% EtOAc-hexanes gradient to afford the subtitle compound. MS calculated for C16H20BrNO2+H: 338, observed: 338.
Reaction SMILES: [CH3:1][CH:2]([CH2:28][CH2:29][CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:20]C(=O)OC(C)(C)C)[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]([CH2:28][CH2:29][CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:20])[CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7][CH:6]=1
Reactant: CCCC(C)COc1ccc([C@H](CN2CCN(C)CC2)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)COc1ccc(C(N)CN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of t-butyl (1R)-1-(4-(2-methylpentyloxy)phenyl)-2-(4-methylpiperazin-1-yl)ethylcarbamate (87 mg, 0.207 mmol) in dichloromethane (1 mL) at 0° C. was added trifluoroacetic acid (0.25 mL, 3.24 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the product was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA). The organic solvent was removed on the rotovapor and the aqueous mixture was frozen and placed on the lyophilizer to afford 1-(4-(2-methylpentyloxy)phenyl)-2-(4-methylpiperazin-1-yl)ethanamine.3TFA (85.9 mg, 63% yield, 2 steps) as a colorless amorphous semi-solid: 1H NMR (400 MHz, DMSO-d6) δ 9.84 (br. s., 1H), 8.21 (br. s., 3H), 7.38 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.6 Hz, 2H), 4.41 (dt, J=9.5, 4.7 Hz, 1H), 3.83 (dd, J=9.3, 5.8 Hz, 1H), 3.75 (dd, J=9.3, 6.5 Hz, 1H), 3.41 (d, J=11.8 Hz, 2H), 3.13 (d, J=12.6 Hz, 1H), 2.94-3.07 (m, 3H), 2.92 (d, J=13.3 Hz, 1H), 2.72-2.84 (m, 4H), 2.58 (dd, J=13.5, 4.7 Hz, 1H), 2.35 (t, J=11.1 Hz, 1H), 1.87 (dq, J=12.5, 6.3 Hz, 1H), 1.23-1.48 (m, 3H), 1.13-1.22 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.1 Hz, 3 H); LRMS (ESI) m/e 320.3 [(M+H)+, calcd for C19H34N3O 320.3].
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][C@H:5]([CH2:12][CH3:13])[CH2:6]OS(C)(=O)=O.[I-:19].[Na+]>CC(C)=O>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][C@@H:5]([CH2:6][I:19])[CH2:12][CH3:13]
Reactant: [I-]
Reactant: CC[C@H](COS(C)(=O)=O)Cc1ccc(F)cc1F
Agent: [Na+]
Solvent: CC(C)=O
Product: CC[C@H](CI)Cc1ccc(F)cc1F
Yield: 91.2 %

Procedure:
A flask was charge with 9.54 g (34.3 mmol) of (2S)-methanesulfonic acid 2-(2,4-difluoro-benzyl)-butyl ester, 10.3 g (68.6 mmol) of sodium iodide, and 60 mL of acetone. The solution was heated at reflux for 30 hours. The acetone was removed under reduced pressure. The residue was partitioned between water and hexanes. The organic layer was collected and washed with sodium bisulfite solution and brine. The hexane was removed under reduced pressure, and the crude oil was purified by column chromatography (hexanes eluent). This procedure gave 9.7 g (91% yield) of the titled compound as a clear oil.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[C:15]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[OH-].[Na+]>[C:1]([NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[C:15]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c1CCCC2NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc2c1CCCC2NC(=O)c1ccccc1

Procedure:
50 mmol of methyl 5-benzoylamino-5,6,7,8-tetrahydro-naphth-1-yl-oxyacetate are stirred in 60 ml of 1N NaOH and 120 ml of MeOH at room temperature for 6 hours. The methanol is stripped off, the NaOH solution is extracted by shaking with ethyl acetate and the extract is then acidified with 10% strength HCl solution. The acid solution is extracted by shaking 3 times with ethyl acetate or tetrahydrofuran, the extract is dried over Na2SO4 and evaporated and the residue is dried under a high vacuum.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH3:19].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:20][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH3:19])(=[O:24])=[O:23]
Reactant: CCC#CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC#CCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (4.3 ml) was added to a solution of 9-dodecyn-1-ol (5.1 g, 28 mmol) in 50 ml CH2Cl2, and the mixture was then added dropwise at 0° C. to a solution of methanesulfonyl chloride (2,2 ml, 28 mmol) in 10 ml CH2Cl2. The mixture was stirred another 4 hours at room temperature, then cooled to 0°-5° C. The solution was washed with cold 5% aqueous sodium bicarbonate, cold 1N HCl, cold water, then saturated brine. The extract was dried over Na2SO4 and filtered and evaporated. The solvent was evaporated to leave crude 1-(9-dodecynyl) methanesulfonate.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:13][C:14]1([CH3:38])[CH2:23][CH2:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]([N:24]3[CH2:30][C:29]4[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:28]=4[O:27][CH2:26][CH2:25]3)[C:16]=2[CH2:15]1>>[CH3:13][C:14]1([CH3:38])[CH2:23][CH2:22][C:21]2[N:20]=[CH:19][N:18]=[C:17]([N:24]3[CH2:30][C:29]4[CH:31]=[C:32]([C:2]5[CH:11]=[N:10][C:9]6[NH:8][C:7](=[O:12])[CH2:6][O:5][C:4]=6[CH:3]=5)[CH:33]=[CH:34][C:28]=4[O:27][CH2:26][CH2:25]3)[C:16]=2[CH2:15]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: O=C1COc2cc(Br)cnc2N1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6c(c5)OCC(=O)N6)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 7-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, DMSO-d6): 8.38 (s, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 7.07 (d, 1H), 4.68 (s, 2H), 4.62 (s, 2H), 4.33 (m, 2H), 3.82 (m, 2H), 2.71 (t, 2H), 2.45 (s, 2H), 1.56 (t, 2H), 0.84 (s, 6H); MS (EI) for C26H27N5O3: 458 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:19])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-bromopyridine (8.65 g, 50 mmol) in THF (100 mL) was added lithium hexamethyldisilazide (105 mL, 105 mmol) under nitrogen at 0° C. After the addition, the mixture was stirred for 30 mins at 0° C. At this point, (BOC)2O (12 g, 55 mmol) was added to the reaction mixture and the mixture was stirred for another 30 mins at 0° C. TLC (petroleum ether/ethyl acetate=5:1) indicated the reaction was complete. The reaction mixture was washed with 1 N HCl (20 mL), and the residue was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by chromatography on silica to afford (I-29a) (8 g, 58.6%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)s1
Product: Cc1ccc(C=C[N+](=O)[O-])s1
Yield: 76 %

Procedure:
In close analogy to the procedure described above, 5-Methyl-thiophene-2-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[CH:3]=1.[C:31]([O:36][CH3:37])(=[O:35])[CH:32]([CH3:34])O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:10])=[O:11])[C@H:32]([C:31]([O:36][CH3:37])=[O:35])[CH3:34])=[C:4]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[CH:3]=1
Reactant: COC(=O)C(C)O
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Product: COC(=O)[C@H](C)N(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1

Procedure:
By reaction of 2 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide with methyl lactate according to process 35, 1.393 g of the expected product are obtained.