Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C@H:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:14][C@H:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)Cl
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)C(CSC(C)=O)CC(C)C

Procedure:
2-Acetylthiomethyl-4-methylpentanoyl chloride and (L)-phenylalanine, ethyl ester are reacted in methylene chloride in the presence of diisopropylethylamine at a temperature below 0° according to the procedure of Example 26 to yield (±)-N-[2-(acetylthiomethyl)-4-methyl-1-oxopentyl]-L-phenylalanine, ethyl ester as an off-white foam.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH:25](O)(C)[CH3:26]>>[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:25][CH3:26].[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)O
Product: CCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 50 °C

Procedure:
In 1200 kg of isopropyl alcohol was dissolved 100 kg of behenic acid (Edenor C22-85R) by heating at 50° C. The solution was filtered through a 10 μm filter and cooled to 30° C. for recrystallization at a cooling rate of 3° C./hr. The crystals thus formed were collected by centrifugal filtration, washed under running isopropyl alcohol, and dried. The resulting crystals were found to have a silver behenate content of 96%, a lignoceric acid content of 2%, and an arachidic acid content of 2% as a result of GC-FID measurement on an esterified sample.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[O:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[O:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCSc3ccccc3)cccc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2c(OCCCCS(=O)c3ccccc3)cccc21

Procedure:
Prepared analogously to Example 2 from 8-(4-phenylmercapto-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li]CCCC.B(F)(F)F.CCOCC.[CH2:24]([N:31]1[CH2:38][CH2:37][C:34]2([O:36][CH2:35]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:31]1[CH2:38][CH2:37][C:34]([CH2:35][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[F:9])([OH:36])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(F)c(Br)c1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(F)c(CC2(O)CCN(Cc3ccccc3)CC2)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-1-fluoro-4-methylbenzene (0.76 g, 4 mmol) in THF (15 ml) at −70° C. under Ar a solution of n-BuLi (1.6 M in hexane, 2.5 ml, 4 mmol) was added dropwise. The reaction mixture was stirrred at −70° C. for 1 h, then BF3.Et2O (0.5 ml, 4 mmol) was added. After stirring for 20 min at −70° C., a solution of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (0.41 g, 2 mmol) in dry THF (5 ml) was added dropwise. The stirring was continued for 2 h at −70° C., then the reaction mixture was quenched with sat. aq. NH4Cl (20 ml). The layers were separated, the aqueous layer extracted with THF. The combined organic layers were dried over Na2SO4. The solvent was removed in vacuo. Diethyl ether (50 ml) was added to the residue, folowed by a 2 M HCl in Et2O (5 ml). The precipitate was collected, washed with Et2O, and dissolved in minimal volume of methanol (ca. 5 ml). Water (50 ml) was added, and pH adjusted to 10 by addition of 2 M aq. NaOH. The mixture was extracted with ethyl acetate (2×25 ml), and the combined organic extracts were dried with Na2SO4. Evaporation of solvent afforded brownish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:14][C:15]1N=[C:19]([O:21][CH:22]([F:24])[F:23])[CH:18]=[C:17]([CH3:25])[N:16]=1.O1CCOC[CH2:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[CH:27]=[C:19]([O:21][CH:22]([F:24])[F:23])[CH:18]=[C:17]([CH3:25])[N:16]=1)=[O:13])(=[O:10])=[O:9]
Reactant: Cc1cc(OC(F)F)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: C1COCCO1
Product: Cc1cc(OC(F)F)cc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Yield: 49.9 %

Procedure:
A solution of 4.9 g (0.0225 mole) of 2-chlorophenylsulfonyl isocyanate and 3.5 g (0.02 mole) of 2-amino-4-difluoromethoxy-6-methylpyrimidine in 70 ml of dioxan is stirred for 2 hours at 60°-70° C. The reaction mixture is filtered and the filtrate is concentrated. The residue is triturated with ether to give 3.8 g (49.9% of theory) of N-(2-chlorophenylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyridin-2-yl)urea with a melting point of 169°-170° C.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.C[Si]([N:39]=[C:40]=[O:41])(C)C>C(Cl)Cl>[S:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:27]=[C:19]1[O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([CH2:8][N:2]3[CH2:7][CH2:6][N:5]([C:40]([NH2:39])=[O:41])[CH2:4][CH2:3]3)=[CH:10][O:11][C:12]=2[CH:17]=1
Reactant: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
To a suspension of 2-(3-piperazin-1-ylmethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (122 mg, 0.30 mmol) in DCM (3 mL) was added Et3N (0.21 mL, 1.51 mmol) and the reaction mixture was stirred (rt, 15 min). The resulting solution was treated with trimethylsilyl isocyanate (0.14 mL, 0.91 mmol) and stirred (rt, 4 h). The reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase HPLC to afford the title compound as a white solid (55 mg, 44%). MS (ESI): mass calcd. for C20H19N5O3S, 409.47; m/z found, 410.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.02 (dd, J=7.9, 1.6, 1H), 7.77 (d, J=8.5, 1H), 7.59 (d, J=1.9, 2H), 7.29 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 4.43 (s, 2H), 3.66 (d, J=0.7, 2H), 3.47-3.36 (m, 4H), 2.55-2.46 (m, 4H).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[Na+].C(OP([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(OCC)=O)C.O1CC1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>COCCOC>[C:19]([O:18][C:16]([CH:15]1[CH2:2][CH:1]1[C:27]1[CH:26]=[CH:31][CH:30]=[CH:29][N:28]=1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: c1cncc(C2CO2)c1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)C1CC1c1ccccn1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
To a stirred suspension of sodium tert-butoxide (7.63 g, 79.4 mmol) in 1,2-dimethoxyethane (70 mL) at ambient temperature was added tert-butyl diethylphosphonoacetate (20.0 g, 79.4 mmol) over 30 minutes, then allowed to stir a further 40 minutes then 3-(oxiran-2-yl)pyridine (4.8 g, 39.7 mmol) was added drop wise. The suspension was stirred at for 30 minutes then heated to 65° C. overnight. The reaction was poured onto ice and extracted with diethyl ether. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), and evaporated to provide an orange oil which was purified by flash chromatography (elution solvent: 20% (v/v) hexane/dichloromethane) to obtain 3.0 g of purified material.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[C:24]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]3[C@@H:15]4[CH2:16][C@@H:12]([CH:13]=[CH:14]4)[C@@H:11]3[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1C=O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)ccnc2[nH]1
Yield: 17.7 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-benzaldehyde (67.3 mg, 0.212 mmol) were reacted to produce 19 mg (20%) of the title compound. mp: 185-195° C., 1H NMR (300 MHz, DMSO-d6): 11.84 (s, 1H), 7.99 (d, J=9 Hz, 1H), 7.87 (d, J=5 Hz, 1H), 7.65 (s, 1H), 7.16 (s, 1H), 6.72 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz, 1H), 6.58 (s, 1H), 6.37 (d, J=5 Hz, 1H), 6.32 (s, 2H), 3.95 (s, 3H), 3.90 (d, J=12 Hz, 2H), 2.87-2.74 (m, 4H), 2.59 (d, J=8 Hz, 1H), 2.33 (m, 4H), 2.23 (d, J=8 Hz, 1H), 2.14 (s, 3H), 1.86 (d, J=12 Hz, 2H), 1.50 (q, J=12 Hz, 2H), 1.42 (d, J=8 Hz, 1H). MS: 557 (M+H), HPLC: 1.58 min (G method).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][S:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)(=[O:15])=[O:14])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CNCCO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN(CCOS(=O)(=O)c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-methylamino ethanol and 4-fluorophenyl sulfonyl chloride using the method described in Description 1.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]1[CH:18]=[C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:21][C:22]=1O.C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[F:16][C:17]1[CH:18]=[C:19](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:21][C:22]=1[O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11]
Reactant: COC(=O)/C=C/c1ccc(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)/C=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
1.40 mL (8.3 mmol, 1.1 eq) of triflic anhydride are added to a solution of 1.47 g (7.5 mmol, 1 eq) of methyl (E)-3-(3-fluoro-4-hydroxyphenyl)acrylate and 1.57 mL (9.0 mmol, 1.2 eq) of diisopropylethylamine in 10 mL of dichloromethane. The reaction mixture is stirred at room temperature overnight. The reaction medium is hydrolyzed in water, acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and 2.51 g of methyl (E)-3-(3-fluoro-4-trifluoromethanesulfonyloxyphenyl)acrylate are obtained in the form of a brown oil. Yield=100%
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:21]=[N:20][CH:19]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]3[CH:21]=[N:20][CH:19]=[N:18][CH:23]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrimidin-5-yl-benzaldehyde, of Preparation 26, using the method described in Example 3, Step A, except that the reaction time for imine formation was 1.5 hand no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.93 (s, 2H), 7.65 (m, 1H), 7.48 (m, 3H), 7.24 (m, 1H), 6.94 (m, 2H), 6.77 (d, 1H), 4.51 (s, 2H), 3.85 (s, 2H), 3.79 (s, 2H), 1.46 (s, 9H); MS 406 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](OC2C=CC([N+]([O-])=O)=CC=2)=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CCN(CC)CC>C1COCC1>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[O:21])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)Nc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 45 %

Procedure:
2-{[(4-nitrophenoxy)carbonyl]amino}phenyl 4-(trifluoromethyl)-benzenesulfonate (0.25 mmol, 120 mg) is dissolved in THF, and 2-(aminomethyl)pyridine (0.25 mmol, 26 μl) and Et3N (0.3 mmol, 42 μl) are added to the solution. The reaction mixture is heated at 60° C. for overnight. After purification by preparative HPLC, 2-({[(pyridin-2-ylmethyl)amino]carbonyl}amino)phenyl 4-(trifluoromethyl)benzenesulfonate is obtained in 45% yield. 1H NMR (400 MHz, MeOD-d6) 8.54 (d, 1H), 8.01(d, 2H), 7.82(m, 4H), 7.42(d, 1H), 7.34(t, 1H), 7.26(m, 4H), 7.05(t, 1H), 4.41(s, 2H). ESI+ for C20H16F3N3O4S m/z=452, (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[O:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:18][S:19]([C:22]1[N:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([O:7][CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:14]=2)=[CH:26][N:27]=1)(=[O:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CCOCC1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Temperature: 110 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
To a solution of 4-(5-fluoro-2-nitrophenoxy)tetrahydro-2H-pyran (19.5 g) and 6-(methylsulfonyl)pyridin-3-ol (14 g) in N,N-dimethylformamide (250 mL) was added potassium carbonate (22.3 g), and the mixture was stirred at 110° C. for 4 hr. 1N HCl was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 50:50, volume ratio) to give the title compound (26.4 g, yield 83%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[N:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:25][CH:26]=3)[N:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nccc(NCC3CC3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2nccc(NCC3CC3)n2)cc1
Reaction time: 3 h
Yield: 96.2 %

Procedure:
Dissolve 4-[4-(cyclopropylmethyl-amino)-pyrimidin-2-yl]-N-(tert-butoxycarbonyl)-benzylamine (100 mg, 0.28 mmol) in DCM (3 mL) containing trifluoroacetic acid (2 mL). Stir under nitrogen for 3 h. Concentrate in vacuo and purify the crude mixture by SCX chromatography (5 g) to obtain the title compound (68.5 mg, 90%) suitable for use without additional purification. MS (ES+) m/z: 255 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[C:14]([CH3:26])=[N:13]1.[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=2)[C:14]([CH3:26])=[N:13]1
Reactant: COc1nc(Br)ccc1N
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1nc(-c2cn(C)nc2C)ccc1N
Temperature: 150 °C
Yield: 74.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.085 g, 0.074 mmol) was added to a solution of 6-bromo-2-methoxypyridin-3-amine (0.15 g, 0.739 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.180 g, 0.813 mmol) and cesium fluoride (0.337 g, 2.216 mmol) in DME/MeOH 2/1 (4.6 mL). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes. The reaction was concentrated in vacuo. The residue was purified via Biotage silica gel column chromatography eluting with DCM/EtOH (99/1 to 90/10, 12 g column) and then eluted through an SCX-2 column to afford the title product as a yellow solid (120 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]([C:21]1[C:14]2[C:13]([NH:1][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=3)=[N:18][CH:17]=[N:16][C:15]=2[NH:19][CH:20]=1)=[O:23]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)c1c[nH]c2ncnc(Cl)c12
Product: CC(=O)Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4C)c23)c1

Procedure:
N-(3-((5-(2-Methylbenzo yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide was synthesized using N-(3-aminophenyl)acetamide and ((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone according to the general procedure A. An off-white solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.36 (s, 1H), 10.01 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.49-7.45 (m, 2H), 7.39-7.28 (m, 4H), 2.34 (s, 3H), 2.02 (s, 3H); LCMS [M+H] 386.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1>CO.C(Cl)Cl>[CH:12]12[CH2:13][CH2:14][CH:15]([CH:10]=[CH:11]1)[O:8][N:7]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9]
Reactant: CC(C)(C)OC(=O)NO
Reactant: C1=CCCC=C1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1OC2C=CC1CC2
Temperature: 37 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Solid N-hydroxycarbamic acid tert-butyl ester (100.19 g, 752.3 mmol) was added to a slurry of NaIO4 (168.68 g, 788.6 mmol), 1,3-cyclohexadiene (86.0 mL, 902 mmol) and 50% MeOH/CH2Cl2 (3 L) cooled in an ice bath. The ice bath was removed after the addition. After 2 h, a warm (37° C.) water bath was installed for 5 min to raise the temperature from 17° C. to 24° C., at which point the bath was removed. The mixture thickened from a turbid solution to a white slurry, and the temperature climbed over 50 minutes to a peak of 40° C. before dropping slowly. Analysis by TLC (50% EtOAc/hexanes) at the temperature peak indicated the reaction was all but complete, and when it had cooled to room temperature the mixture was filtered and rinsed with EtOAc (3×175 mL). The filtrate was concentrated in vacuo to a cloudy oil which was partitioned between EtOAc (700 mL) and satd NaHSO3 (400 mL). Organic layer was extracted with satd NaHSO3 (200 mL), and the combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were washed with H2O (100 mL) and satd NaCl (100 mL), and were then dried (Na2SO4) and concentrated to provide 146.80 g (92%) of amber oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:29])[CH:23]2[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24]2)[O:12]1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>C(Cl)Cl>[CH3:37][S:38]([O:28][CH2:27][CH:25]1[CH2:24][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:29])[CH2:26]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(COS(C)(=O)=O)C1
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)methanol taken directly from the previous step in DCM (25 ml) was added Et3N (467 mg, 4.62 mmol) and MsCl (264 mg, 2.31 mmol) as a solution in DCM (5 ml). The mixture was stirred for 2 h. Water (20 ml) and DCM (30 ml×2) was added. The organic layer was dried over Na2SO4 and concentrated, purified with Prep-TLC (DCM:MeOH=10:1) to give the title compound (390 mg, Yield 35% for two steps). 1H NMR (500 MHz, MeOD): δH 8.27 (s, 1H), 8.21 (s, 1H), 6.203-6.200 (m, 1H), 5.529 (dd, J=2.0, 7.0 Hz, 1H), 5.010 (dd, J=3.0, 6.0 Hz, 1H), 4.354 (dd, J=3.5, 8.0 Hz, 1H), 4.197-4.182 (m, 2H), 3.585 (brs, 1H), 3.073-2.948 (m, 5H), 2.595-2.513 (m, 2H), 2.394 ((brs, 114), 2.207 (brs, 1H), 2.107 (s, 3H), 2.030-1.989 (m, 1H), 1.840-1.811 (m, 2H), 1.586 (s, 3H), 1.390 (brs, 1H), 1.329-1.280 (m, 6H), 0.905-0.878 (m, 1H) ppm; ESI-MS (m/z): 483.3 [M+1]+.