Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(O)C>N1C=CC=CC=1>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1I
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2I)cc1
Temperature: 80 °C
Yield: 72.1 %

Procedure:
To a stirred solution of 2-iodoaniline (24.82 g, 113.3 mmol) in anhydrous pyridine (36 mL) was added 4-methoxybenzenesulfonyl chloride (23.42 g, 113.3 mmol). The dark solution was heated at 80° C. for one hour. The reaction mixture was evaporated in vacuo and the residue was poured onto an ice/water mixture. The aqueous phase was decanted and the oily residue was triturated several times with 150 mL portions of water. The resulting solid was collected by filtration and washed with water and hexane. The crude material was dried under a stream of air for three hours. Recrystallization from ethanol afforded tan crystals of the title compound (39.0 g, 81.71 mmol, 72% ). An analytically pure sample was prepared by recrystallization from acetone.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][CH:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[C:16]([O:15][C:13]([CH:11]([CH3:12])[CH2:10][C:7]1[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(CC(C)C(=O)OC(C)(C)C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Cc1ccc(C(=O)O)o1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
5-(2-tert-Butoxycarbonylpropyl)furan-2-carboxylic acid methyl ester (1.0 g, 3.76 mmol) obtained in step 1 was dissolved in tetrahydrofuran (4.5 mL) and methanol (3 mL), 1N aqueous sodium hydroxide solution (4.5 mL) was added, and the mixture was stirred overnight. The mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the drying agent was filtered off, and the solvent was evaporated to give the title compound (0.98 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCOc3ccncc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In a 25 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (370 mg, 2.72 mmol) and 4-methoxy-benzenesulfonyl chloride (618 mg, 2.99 mmol) were dissolved in dichloromethane (10 ml). Triethylamine (0.45 ml, 3.23 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain pale-green solid (700 mg, 84.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:35][CH:36]([F:38])[F:37])=[C:19]([C:21]2[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:23][C:22]=2[NH2:34])[CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:35][CH:36]([F:37])[F:38])=[C:19]([C:21]2[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[N:24]=[CH:23][C:22]=2[NH:34][C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][C:4]=23)=[O:12])[CH:20]=1
Reactant: C[Si](C)(C)CCOCn1ncc(N)c1-c1cc(Cl)ccc1OC(F)F
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3ccc(Cl)nc23)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (500 mg, 2.3 mmol) (prepared according to the procedure in Journal of Medicinal Chemistry, 55(22), 10090-10107; 2012) and 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine (868 mg, 2.3 mmol) were suspended in triethylamine (0.35 mL, 2.5 mmol) and DCM (10 mL) and the mixture was left to stir at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and the resultant organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and brine, dried (Na2SO4) and evaporated to afford an oil. The resultant oil was purified by flash chromatography on silica eluting with 0-2% MeOH in DCM. Collecting appropriate fractions, followed by evaporation gave 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide as a brown oil (1.19 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.07 (s, 1H), 8.72 (s, 1H), 8.67 (d, 1H, J=7.3 Hz), 8.38 (s, 1H), 7.60 (d, 1H, J=2.3 Hz), 7.51 (dd, 1H, J=2.6, 8.8 Hz), 7.38 (d, 1H, J=8.9 Hz), 6.95 (d, 1H, J=7.2 Hz), 6.43 (t, 1H, J=72.8 Hz), 5.41 (d, 1H, J=10.9 Hz), 5.31 (d, 1H, J=11.0 Hz), 3.76-3.49 (m, 2H), 1.27 (s, 1H), 0.94-0.84 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C[Si](C)(C)[C:24]#[C:25][CH3:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([C:24]#[C:25][CH3:26])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: CC#C[Si](C)(C)C
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Temperature: 50 °C
Reaction time: 22 h
Yield: 118.5 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.0 g, 2.5 mmol), bis(triphenylphosphine)palladium dichloride (290 mg, 0.25 mmol), 1-(trimethylsilyl)-1-propyne (0.44 mL, 3 mmol) and tetrabutyl ammonium fluoride (3 mL, 3 mmol) were added to 20 mL dry THF under nitrogen. The reaction mixture was stirred under nitrogen at 50° C. for 22 hours, then 150 mg of bis(triphenylphosphine)-Palladium dichloride, 0.22 mL of 1-(trimethylsilyl)-1-propyne and 1.5 mL tetrabutyl ammonium fluoride, and 0.1 mL ethanol were added to the reaction mixture. The reaction mixture was stirred under nitrogen for 18 hours at 50° C. The reaction mixture was cooled and poured into saturated aqueous NaHCO4 and extracted into EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 125 g of flash silica (2%-4% MeOH/CH2Cl2) to give 925 mg of 5-(2-isopropyl-4-methoxy-5-prop-1-ynyl-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=313.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CC([O-])(C)C.[K+].[SiH:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21]>O1CCCC1>[CH2:20]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=1)[CH3:21]
Reactant: CC[SiH](CC)CC
Reactant: COc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2cc1OC
Yield: 58 %

Procedure:
The reaction was conducted according to the General Procedure by heating 2-methoxynaphthalene (79 mg, 0.5 mmol, 1 equiv.), KOt-Bu (19.6 mg, 0.18 mmol, 0.35 equiv.) and Et3SiH (319 microliters, 2.0 mmol, 4 equiv.) in 1 mL of tetrahydrofuran for 48 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with hexanes (isochratic) to obtain 79 mg (58%) of the title compound as colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.84 (s, 1H), 7.78-7.73 (d, 1H), 7.73-7.68 (d, 1H), 7.38 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.27 (ddd, J=8.1, 6.8, 1.2 Hz, 1H), 7.15 (s, 1H), 3.90 (s, 3H), 1.01-0.90 (m, 9H), 0.68-0.53 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 163.03, 137.88, 136.83, 130.10, 128.58, 128.09, 127.29, 127.21, 124.03, 104.57, 55.25, 8.02, 7.48.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)(=O)C.C[O-].[Na+].O>CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:18]2[CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[N:15]3[N:14]=[CH:13][C:12]([C:10]4[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=4)=[C:16]3[N:17]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)OCc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Reaction time: 17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4-[5-(4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-ylmethyl acetate (0.16 g, 0.33 mmol) in MeOH (1 ml) was added at room temperature NaOMe (5.4M in MeOH, 0.2 ml). The reaction mixture was stirred for 17 h, poured into water (40 ml) and extracted with dichloromethane (3 times 40 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield the title compound (112 mg, 78%) as an orange solid. MS (ISP) 439.3 [(M+H)+]; mp 2102° C.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH2:39]OS(C)(=O)=O)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]23[CH2:39][CH:29]2[C:28](=[O:30])[N:27]([C:31]2[C:32]([CH3:38])=[CH:33][CH:34]=[CH:35][C:36]=2[CH3:37])[CH2:26]3)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COC(=O)C1(COS(C)(=O)=O)CC(=O)N(c2c(C)cccc2C)C1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC2(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 560 μL, 1.39 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (216.5 μL, 0.545 mmol) in THF (3 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 1-(2,6-dimethyl-phenyl)-3-methanesulfonyloxymethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step b, 165 mg, 0.465 mmol) in THF (2 mL) was added and stirred for 2 h at 75° C. The reaction mixture was then purified by preparative HPLC (15→85% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford 3-(2,6-dimethyl-phenyl)-4-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (22 mg, 10% yield). LC-MS: R, (retention time): 2.98 min, MS: (ES) m/z 457.2 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.32 (s, 2H), 7.78 (s, 1H), 7.02-7.18 (m, 3H), 4.18 (d, 1H, J=9.7 Hz), 3.68 (d, 1H, J=9.7 Hz), 2.68-2.75 (m, 1H), 2.18 (s, 3H), 2.08-2.12 (m, 1H), 2.05 (s, 3H), 1.45 (t, 1H, J=3.9 Hz).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[NH:20]1[CH:24]=[N:23][C:22]([C:25]([OH:29])([C:27]#[CH:28])[CH3:26])=[N:21]1>>[F:19][C:3]1[C:2]([C:28]#[C:27][C:25]([OH:29])([C:22]2[N:23]=[CH:24][NH:20][N:21]=2)[CH3:26])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1nc[nH]n1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1nc[nH]n1
Yield: 20 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1H-1,2,4-triazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (40 mg, 20%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]3[CH2:1][CH3:2])=[C:8]([CH3:16])[C:9]=2[F:15])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(N3CCC(N)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 0.36 g (1.25 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.26 g (1.39 mmol) of 3-(t-butoxycarbonyl) aminopyrrolidine, 0.38 g (3.76 mmol) of triethylamine, and 20 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The solids were collected by filtration and washed with acetonitrile and ether. The crude product was dissolved in 5 mL of 6N hydrochloric acid and 5 mL of glacial acetic acid and stirred for 5 hours at room temperature. The solution was concentrated to a solid which was suspended in water, made basic (pH 12), filtered through a fiberglass pad, and neutralized (pH 6.8). The solids were collected by filtration, washed with water, and dried in vacuo to give 0.32 g of white solid, mp 218°-220° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([N+:14]([O-])=O)[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2].[H][H]>[Ni].CC(C)=O.C1COCC1>[CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([NH2:14])[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Agent: [Ni]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN1CCC2C(=C(N)C=CC2Br)C1
Reaction time: 1 h

Procedure:
Raney nickel was refluxed in acetone for 2 hours prior to use to deactivate the metal. The product from Example 26 (0.1 g, 0.35 mmol) was dissolved in THF (10 mL), the Raney nickel added, and the reaction vessel charged with hydrogen gas. After stirring for 1 hour, the Raney nickel was removed by filtration and the solvent removed by filtration to give N-ethyl-5-bromo-8-aminotetrahydroisoquinoline (used without further purification).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[OH:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16]([O:18][P:19]([CH2:24]OS(C1C=CC(Cl)=CC=1)(=O)=O)(=[O:23])[O:20][CH2:21][CH3:22])[CH3:17].O>CS(C)=O>[C:5]([O:13][C:11]([NH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][P:19](=[O:23])([O:18][CH2:16][CH3:17])[O:20][CH2:21][CH3:22])=[CH:7][CH:6]=1)=[O:12])([CH3:8])([CH3:6])[CH3:4]
Reactant: O=C(O)NCCc1ccc(O)cc1
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(Cl)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOP(=O)(COc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC

Procedure:
A solution of 2-(4-hydroxyphenyl)ethylcarbamic acid, t-butyl ester1 (4.0 g, 16.9 mMol) in dry DMSO (37.5 ml) was cooled in an ice-bath and treated with sodium hydride (80% in mineral oil 0.557 g, 1.1 equiv) with stirring under argon according to the method described by Cornforth2. When effervescence ceased a solution of 4-chlorobenzenesulfonyloxymethylphosphonate diethyl ester (6.07 g, 1.05 equiv) in dry DMSO (110 ml) was added and the resulting pale yellow solution stirred at room temperature overnight. The mixture was then poured into water (550 ml) and extracted with diethyl ether/ethyl acetate (1:1, 3×150 ml) and finally ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting oil was purified by chromatography on silica gel with a gradient of 3:2 pentane:ethyl acetate rising to 100% ethyl acetate to give the title compound as a colourless viscous oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][CH:15]=1.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:21][N:20]([CH3:22])[C:18]1[N:19]=[C:14]([F:13])[C:15]([B:23]([OH:28])[OH:24])=[CH:16][CH:17]=1
Reactant: CN(C)c1cccc(F)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc(B(O)O)c(F)n1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.500 mL, 5.47 mmol), dimethylamine, (2.0 M solution in THF, 4.11 mL, 8.21 mmol). The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 536 mg of a crude yellow oil, which was purified by column chromatography (3/1 Hex/ethyl acetate) to give 500 mg of 6-fluoro-N,N-dimethylpyridin-2-amine as a light yellow oil. To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in 2 mL of THF at 0° C. was added butyllithium (1.6 M in hexane, 0.69 mL, 1.1 mmol). The reaction stirred for 30 minutes and was then cooled to 60° C. at which time 6-fluoro-N,N-dimethylpyridin-2-amine (0.124 g, 0.88 mmol) was added in 1 mL of THF. The reaction stirred at −60° C. for 45 min. Then triisopropyl borate (0.25 mL, 1.1 mmol) was added and the reaction was allowed to stir for 1 h at 23° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 136 mg of a brown oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 EtOAc/hexanes) to give 46 mg of a white solid. ES+=185.1 (M+H)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][S:19](O)(=[O:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][S:19]([Cl:27])(=[O:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=S(=O)(Cl)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
(1-(3-(Trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methanesulfonic acid was dissolved in benzene (3 ml), thionyl chloride (0.034 ml) was added and the mixture was refluxed for 4 h. After cooling, the reaction mixture was concentrated in vacuo and the crude product was employed in the next stage without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[N+:34]([O-])([OH:36])=[O:35]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([N+:34]([O-:36])=[O:35])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc([N+](=O)[O-])c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (1.59 g) was dissolved in THF (4 mL) under N2 then 70% HNO3 (4 mL) was added and the mixture was stirred at 50° C. overnight. The mixture was diluted with AcOEt (150 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was dissolved in anhydrous MeOH (100 mL) and dry HCl gas was bubbled through the mixture at 0° C. for a few minutes. The mixture was stirred at room temperature overnight, concentrated, taken up with AcOEt and washed with 1N HCl, satd. NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography (silica gel; eluent: hexanes and AcOEt) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-nitrophenyl)-L-phenylalanine methyl ester (1.1 g).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[N:8][C:7]2[NH:6][CH:5]=[N:4][C:3]1=2.C(O[CH:21]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@:23]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH:38]([F:40])[F:39])[O:22]1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>CC#N>[C:27]([O:26][C@@H:25]1[C@H:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@:23]([CH2:41][O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([CH:38]([F:39])[F:40])[O:22][C@H:21]1[N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:1])[NH:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[N:8][C:7]1=2)(=[O:29])[CH3:28]
Reactant: CC(C)C(=O)Nc1nc2[nH]cnc2c(=O)[nH]1
Reactant: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of compound N-(6-oxo-6,9-dihydro-1H-purin-2-yl)isobutyramide (0.57 g, 2.58 mmol) in anhydrous CH3CN (50 mL) was added BSA (1.26 mL, 5.17 mmol) portion-wise while maintaining the reaction temperature at 25° C. Then the reaction was stirred at 40° C. for 1 h until a clear solution persisted. Compound 5 (0.6 g, 1.29 mmol) in CH3CN (5 mL) was added into the mixture at 0° C. followed by TMSOTf (0.94 mL, 5.17 mmol). The mixture was stirred at 40° C. for 2 h and then poured into saturated NaHCO3 solution (10 mL) at 0° C., extracted with ethyl acetate, washed with water, brine solution, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude compound was purified by silica gel chromatography [petroleum ether:ethyl acetate (5:1 to 1:1)] to provide the product 21 as a white foam (0.5 g, 60%). LC-MS: (M+H)+=626