Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16]C)=[C:14]([O:18]C)[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([OH:16])=[C:14]([OH:18])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)[N:3]=1
Reactant: COc1cc(F)c(F)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(O)c(O)cc(F)c3F)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-5,6-dimethoxy-phenyl)-methanone (100 mg, 0.212 mmol, Example 261) in methylene chloride (50 mL) cooled to −78° C. was added boron tribromide (2.19 mL, 2.190 mmol, 1 M solution in methylene chloride, Aldrich). The reaction mixture was warmed slowly to 0° C. over a period of 1 hour. After being stirred at 0° C. for 1 hour, the reaction was quenched with a solution of aqueous sodium bicarbonate. The aqueous layer was extracted with methylene chloride. The combined layers were washed with water and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by reversed phase HPLC (C18, eluting with water and acetonitrile) yielded [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-5,6-dihydroxy-phenyl)-methanone as yellow solids (50 mg, 52%). HR-MS (ES, m/z) calculated for C17H20N5O5SF2 [(M+H)+] 444.1151, observed 444.1148.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of benzyl 3-hydroxycyclobutanecarboxylate (Intermediate 32; 0.90 g; 4.4 mmol), Et3N (1.20 mL; 8.6 mmol) in DCM (50 mL) was added MsCl (0.40 mL; 5.2 mmol) under nitrogen. The reaction mixture was stirred for 1 hour, quenched with water (20 mL), and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.24 g (100%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23](F)([F:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(#N)C.[I-].[Na+]>C(OCC)(=O)C>[F:22][CH:23]([F:32])[O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[C:3]3[CH2:11][CH2:10][N:9]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)[CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:30][CH:31]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 150 °C

Procedure:
In a 5 mL microwave vial was combined 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.113 g, 0.000356 mol), 4-(trifluoromethoxy)aniline (0.0964 mL, 0.000711 mol), acetonitrile (2 mL, 0.04 mol), and sodium iodide (0.00533 g, 0.0000356 mol). The mixture was heated at at 150° C. for 10 minutes and reduced in vacuo. The remaining solid was taken up in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate (2×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate and reduced in vacuo to yield an off white solid. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-50%) gradient to yield the desired product as an off white solid (0.052 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(N)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(C)c(C=O)c(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 4-amino-2,6-dimethylbenzaldehyde (600 mg) and bromoacetic acid methyl ester (0.4 mL) in DMF (20 mL) was added K2CO3 (1.4 g) and the suspension was heated at 80° C. After 1 h, additional bromoacetic acid methyl ester (0.4 mL) was added and this process was continued until the starting material was consumed (check by LC/MS). The reaction mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated and the residue was purified by flash chromatography using hexanes/ethyl acetate (2:1) to give (4-formyl-3,5-dimethylphenylamino)-acetic acid methyl ester as a yellow solid. MS (ESI)m/z 222 (M+H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].O.[N+:6]([C:9]1[CH:18]=[C:17]2[C:12]([NH:13][C:14](=[O:20])[C:15](=[O:19])[NH:16]2)=[CH:11][C:10]=1[S:21](Cl)(=[O:23])=[O:22])([O-:8])=[O:7]>>[OH:2][CH2:1][CH2:3][NH:4][S:21]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N+:6]([O-:8])=[O:7])[NH:16][C:15](=[O:19])[C:14](=[O:20])[NH:13]2)(=[O:22])=[O:23]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: NCCO
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)NCCO)cc2[nH]c1=O
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of 6.11 g (0.1 mole) of ethanolamine in 40 ml of water 6.11 g (0.02 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added under stirring, the reaction mixture is stirred at room temperature for 6 hours and then allowed to stand for 16 hours. The separated crystals are filtered off, washed with acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from this solution with 2-propanol. Thus 3.70 g (56%) of 1,2,3,4-tetrahydro-N-(2-hydroxyethyl)-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 281-289° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][NH:24][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:25]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(c(N3CCOCC3)c1)CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(cccc2N2CCOCC2)C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].CC([O-])(C)C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:32]5[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: O=C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: O=C1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CCN1
Temperature: 115 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (100 mg, 0.24 mmol), piperazin-2-one (48 mg, 0.48 mmol), tBuONa (47 mg, 0.48 mmol), Pd2(dba)3 (22 mg, 0.2 mmol) and Xphos (23 mg, 0.048 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 115° C. for 5 min under the irradition of microwave. The mixture was filtered by celite. The filtrate was concentrated to dryness and purified by pre-TLC (EtOAc) and pre-HPLC to afford 15 mg of 352. (yield: 13%) 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H, ArH), 7.49-6.96 (m, 5H), 6.41 (d, J=8.8 Hz, 1H), 5.95 (s, 1H), 4.19 (t, J=4.8 Hz, 2H), 3.99 (s, 2H), 3.76 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.2 Hz, 2H), 3.06 (t, J=4.8 Hz, 2H). LC-MS (ESI): m/z=481 [M+H]+
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[S:28][C:27]([Br:29])=[N:26][CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CN(C=O)C>[Br:29][C:27]1[S:28][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][N:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3cnc(Br)s3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1cccc2c(C(CCC#N)c3cnc(Br)s3)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
14 mg (0.21 mmol) of potassium cyanide were added to 50 mg (0.11 mmol) of the compound from Example 69A in 1 ml of DMF. The mixture was stirred at 80° C. for 5 h, water was added to the reaction solution, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, the solid was filtered off, and the solvents were removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 38 mg (89% of theory) of the target compound were obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Br:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([CH2:25][Br:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CBr)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Diisopropylethylamine (0.99 ml, 5.6 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.37 g, 1.85 mmol) in DCM (20 ml) at room temperature. To this mixture was added 4-bromomethyl-benzenesulfonyl chloride (0.5 g, 1.85 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to give the title compound (0.56 g, 70% yield) as an off-white solid. Tr=2.12 min, m/z (ES+) (M+Na)+ 457.
Reaction SMILES: [NH2:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(O)C.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=O)[C:25]([OH:27])=[O:26])[N:23]=1)=[O:17].[OH-].[Na+]>O1CCCC1.CCCCCC.O>[C:9]([O:8][C:6](/[CH:5]=[CH:4]/[CH2:3][O:2][N:1]=[C:24]([C:22]1[N:23]=[C:19]([NH:18][CH:16]=[O:17])[S:20][CH:21]=1)[C:25]([OH:27])=[O:26])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)/C=C/CON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)/C=C/CON=C(C(=O)O)c1csc(NC=O)n1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To tert-butyl 4-aminooxycrotonate (10.0 g) were added ethanol (150 ml) and water (150 ml), followed by gradually adding (2-formamidothiazol-4-yl) glyoxylic acid (11.0 g) with stirring. During the addition, the mixture was adjusted to pH 5 to 5.5 with 10% aqueous sodium hydroxide, and the stirring was continued at ambient temperature for 2 hours. After removal of the ethanol, to the remaining aqueous solution was added ethyl acetate, followed by adjusting to pH 7.5 with 10% aqueous sodium hydroxide. The aqueous layer was separated and washed with ethyl acetate. Thereto was further added ethyl acetate, followed by adjusting to pH 2.0 with 10% hydrochloric acid. The separated organic layer was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with n-hexane and tetrahydrofuran, and collected by filtration. To this substance were added ethanol (50 ml) and water (30 ml), followed by adjusting to pH 7.5 with 10% aqueous sodium hydroxide. The precipitated substance was collected by filtration, washed with a mixed solvent of water and ethanol (1:1 by volume), followed by addition of water and ethyl acetate, and adjusting to pH 2.0 with 10% hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with n-hexane and tetrahydrofuran to obtain 2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl) acetic acid (syn isomer) (12.01 g).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1cccc(Br)c1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:19]1(C(Cl)=O)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[NH:1]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C@H:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)[C@@H](N)COCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](COCc1ccccc1)NN1CCOCC1

Procedure:
Morpholino-Ser(OBn) was prepared from N-Fmoc-Ser(OBn). Esterification of N-Fmoc-Ser(OBn) with isobutylene in the presence of a catalytic amount of H2SO4 afforded N-Fmoc-Ser(OBn)-OtBu. The Fmoc group was removed with piperidine in CH2Cl2 to produce Ser(OBn)-OtBu. Reaction of Ser(OBn)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OBn)-OtBu. Morpholino-Ser(OBn)-OtBu was hydrolyzed with TFA in CH2Cl2 to yield morpholine-Ser(OBn).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]1[NH:13][C:12]2[C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=2[N:6]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:31]([O:21][C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:10]1[C:11](=[O:14])[C:12]2[NH:13][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[N:6][C:7]=2[N:8]([CH3:23])[C:9]1=[O:22])(=[O:33])[CH3:32]
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a stirring mixture of (R)-8-(2-chloroethylamino)-1-(5-hydroxyhexyl)-3-methylxanthine (2.2 g, 6.4 mmol), triethylamine (1.94 g, 19.2 mmol) and 4-dimethylaminopyridine (0.39 g, 3.2 mmol) in chloroform (50 ml) at 0-5° C. was added acetic anhydride (1.30 g, 12.8 mmol). The mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethylacetate-methanol (7:1) to provide (R)-1-(5-acetoxyhexyl)-8-(2-chloroethylamino)-3-methylxanthine (2.2 g, 89% yield) as a white powder.
Reaction SMILES: [C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:32])[CH3:31])[CH:25]=2)(=[O:23])=[O:22])=[CH:12][C:11]=1[C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:72]Br.CC(C)=O>O1CCOCC1.CCCCCC>[C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:32])[CH2:31][Br:72])[CH:25]=2)(=[O:23])=[O:22])=[CH:12][C:11]=1[C:33]([N:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[O:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2cccc(C(C)=O)c2)c2ccccc2c1OC(=O)c1ccccc1
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2cccc(C(=O)CBr)c2)c2ccccc2c1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of 15.7 g (15.7 mmol) of 1-benzoyloxy-4-(3-acetylbenzenesulfonamido)-N,N-dioctadecyl-2-naphthamide in 150 ml of dioxane was treated with 2.51 g (15.7 mmoles) of bromine at 40° to 45° C. The reaction was held for one hour at this temperature, during which time the bromine color discharged. Analysis by TLC (25 percent acetone in hexane) indicated a complete reaction and only one main product was observed. The solution was drowned to ice water and the resulting mixture was extracted with chloroform. The chloroform extracts were combined and washed well with water, dried (MgSO4), and stripped to give 15 g (89 percent) of an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1ccccc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
4′-Chloro-biphenyl-2-carbaldehyde (6.50 g, 30.0 mmol) was dissolved in CH2Cl2 (75 mL) and methanol (75 mL). The solution was cooled to 0° C. in an ice bath, and then sodium borohydride (1.36 g, 36.0 mmol) was added slowly portionwise. The reaction was allowed to warm gradually to room temperature and stir for 16 hours. The reaction was quenched by addition of 2M NaOH, and the organics were extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried over MgSO4 and concentrated to afford (4′-chloro-biphenyl-2-yl)-methanol (6.42 g, 98% yield), which was carried on to the next step without further purification. MS (ES1) m/e (M−H)−: 217.4
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[N:18][CH:19]=1)=[O:13]>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[N:3]([NH:11][C:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=2)=[O:13])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC1Cc2ccccc2N1NC(=O)c1cnc(-c2cccc(F)c2)nc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc2ccccc2n1NC(=O)c1cnc(-c2cccc(F)c2)nc1
Yield: 67.8 %

Procedure:
A suspended solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (2-methyl-2,3-dihydro-indol-1-yl)-amide (0.98 mmol) and MnO2 (4.88 mmol) in DCM (15 mL) is stirred at rt for 2 h. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-40% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (2-methyl-indol-1-yl)-amide (230 mg, 97%) as a solid. MS: 347 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.08-2.40 (m, 3H), 6.27 (s, H), 6.95-7.35 (m, 4H), 7.36-7.65 (m, 2H), 8.20-8.44 (m, 2H), 8.49-9.20 (d, 2H). IC50=6 nM.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@H:20]2[C@:24]([CH3:26])([OH:25])[C@H:23]([OH:27])[C@@H:22]([CH2:28][OH:29])[O:21]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.[C:31]1(C)[CH:36]=CC(S(O)(=O)=O)=C[CH:32]=1.COC(OC)(C)C.CO>CC(C)=O.C(Cl)(Cl)Cl>[C@@H:1]1([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@H:20]2[C@:24]3([CH3:26])[O:25][C:31]([CH3:36])([CH3:32])[O:27][C@@H:23]3[C@@H:22]([CH2:28][OH:29])[O:21]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1(C)O[C@@H]2[C@@H](CO)O[C@@H](n3cnc4c(N[C@H]5CCc6ccccc65)ncnc43)[C@]2(C)O1
Yield: 66.8 %

Procedure:
A solution of (2R,3R,4R,5R)-2-(6-((S)-2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol (0.21 g, 0.53 mmol), p-toluenesulfonic acid monohydrate (0.10 g, 0.53 mmol), 2,2-dimethoxypropane (1.0 mL, 8.1 mmol) in acetone (5 mL) was stirred for 8 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate (15 mL), the aqueous was extracted with ethyl acetate and the organic phases combined, dried (MgSO4) and concentrated in vacuo. Flash chromatography (2% methanol in chloroform) gave the title compound 0.155 g, 67% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1)[CH3:11].C(N(CC)CC)C>CS(C)=O.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]=[O:23])=[CH:19][CH:20]=1)[CH3:11]
Reactant: CN(CCOc1ccc(CCO)cc1)c1nc2ccccc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(CCOc1ccc(CC=O)cc1)c1nc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of pyridine-sulphur trioxide complex (1.53 g) in dimethylsulphoxide (5 mL) was added to a stirred, ice cooled mixture of 2-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]ethanol (1.00 g), triethylamine (2.25 mL) and dichloromethane (30 mL) under a nitrogen atmosphere. The mixture was stirred at 0° C. for 10 minutes, then at room temperature for 5 hours before being diluted with dichloromethane (100 mL) and washed with water (2×100 mL), hydrochloric acid (0.5M; 100 mL), water (2×100 mL) and brine (100 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 5% ethyl acetate in dichloromethane as solvent to afford the title compound, a gum.