Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:36]2[CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:37]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CS(=O)(=O)Nc1cc(B(O)O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(C)(=O)=O)cc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)boronic acid (529 mg, 24% purity, 0.45 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 284 μl of a 2M aqueous solution of cesium carbonate in dioxane (3 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (0 to 80%, hexane-ethyl acetate) using SP1® Purification System to give 52 mg (38% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O.Cl.[CH:23]1([NH:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C1C=CN=CC=1)C>[CH:23]1([N:29]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NNC1CCCCC1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(C3CCCCC3)c3c(C(F)(F)F)cccc23)cc1

Procedure:
Prepared according to Method C step A (2-fluoro-3-trifluoromethyl-phenyl)-(4-methoxyphenyl)-methanone (0.149 g, 0.5 mmol), cyclohexylhydrazine hydrochloride (0.90 g, 0.6 mmol) and DMAP (0.061 g, 0.5 mmol) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])(C)(C)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:24]([CH:25]=[O:26])=[CH:23][N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:19]2=[N:20][CH:21]=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:24]([CH:25]([OH:26])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][OH:9])=[CH:23][N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])[C:19]2=[N:20][CH:21]=1
Reactant: OCc1ccccc1Br
Reactant: CC(C)(C)C(=O)OCn1cc(C=O)c2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1cc(C(O)c2ccccc2CO)c2cc(Br)cnc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a −78° C. solution of (2-bromo-phenyl)-methanol (2.27 g, 12.14 mmol) in tetrahydrofuran (100 ml) was added tert-butyllithium (1.7 M in hexanes, 15.7 ml, 26.69 mmol). The reaction mixture was stirred for 10 minutes at −78° C. A solution of 2,2-dimethyl-propionic acid 5-bromo-3-formyl-pyrrolo[2,3-b]pyridin-1-ylmethyl ester (2.06 g, 6.07 mmol) in tetrahydrofuran (30 ml) was added to the stirring reaction mixture. After the reaction mixture was allowed stirred for an additional 20 minutes at −78° C., the reaction was quenched with saturated, aqueous sodium bicarbonate solution. The quenched solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the mixture was concentrated in vacuo. The crude material was purified by flash chromatography (0-100% ethyl acetate in hexanes) to give 1.60 g (59%) of 2,2-dimethyl-propionic acid 5-bromo-3-[hydroxy-(2-hydroxymethyl-phenyl)-methyl]-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 446.0, 448.0 (M+H+).
Reaction SMILES: [H-].[Na+].O=C1C(NC(=O)[C@@H]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])C)C)CSC2C=CC=CC=2N1.C(Br)C1C=CC=CC=1.CN(C=[O:41])C>Cl>[O:41]=[CH:21][CH:18]([O:17][C:16](=[O:22])[NH:15][CH3:23])[CH3:20]
Reactant: C[C@@H](C(=O)NC1CSc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Product: CNC(=O)OC(C)C=O
Reaction time: 0.58 h
Yield: 77 %

Procedure:
NaH (60% in mineral oil, 16 mg, 0.40 mmol, Eq: 1.50) was added to a solution of tert-butyl (S)-1-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (100 mg, 0.26 mmol, Eq: 1.00) in DMF at RT. After 5 min. benzyl bromide (35 μL, 0.29 mmol, Eq: 1.10) was added, the mixture was stirred for 35 min., diluted with 1 N HCl and extracted with EtOAc. The organic extracts were washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford tert-butyl (S)-1-(5-benzyl-4-oxo-2,3,4,5-tetrahydro-benzo[1)][1,4]thiazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (96 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1.C(Cl)Cl.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:29])[N:27]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(Br)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate (1.04 g, 5.00 mmol) and 2-bromothiazole-4-carboxylic acid (1.46 g, 5.00 mmol) in Methylene chloride (10 mL, 200 mmol) was added N,N-Diisopropylethylamine (3.48 mL, 20.0 mmol) and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (2.28 g, 6.00 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was purified on silica eluting with 0 to 5% MeOH in DCM with 1% NH4OH (2.41 g, 99.9%). ESIMS m/z=484.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:20](N)[CH2:21][CH3:22]>CC1C=CC=CC=1C>[CH2:20]([NH:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:21][CH3:22]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCCN
Solvent: Cc1ccccc1C
Product: CCCNc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 94.3 %

Procedure:
A mixture of 50.6 g of 1-nitro-anthraquinone (99% pure) and 240 ml of o-xylene is reacted with 118 g of n-propylamine (molar ratio 10:1) at a temperature of 170° C. and under a pressure of 30 bars and for a reaction time of 80 minutes. Working up analogously to Example 1 gives 50 g (94% of theory) of 1-n-propylamino-anthraquinone, in which no further 1-nitro-anthraquinone can be detected.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]#[N:13]>CN(C=O)C>[CH2:2]([O:1][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:11]=1[C:12]#[N:13])[CH3:3]
Reactant: CC[O-]
Reactant: N#Cc1ccncc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cnccc1C#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium ethoxide (53 mg, 0.74 mmol) was added to a 0° C. solution of 3-chloro-4-cyanopyridine (100 mg, 0.72 mmol) in DMF (1 mL). The mixture was stirred at 0° C. for 30 min and at rt for 2 h, then the mixture was concentrated in vacuo. To the residue Et2O was added, and the salts were filtered off. The filtrate was concentrated in vacuo to yield the title compound as a white solid. LC-MS A: tR=0.67 min; [M(35Cl)+H]+=149.06.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (490 mg, 1.4 mmol) in Acetone (5 mL), Cesium Carbonate (706 mg, 2.17 mmol)was added; after 15 min, Methyl iodide (95.0 uL, 1.53 mmol) was added and the mixture stirred at room temperature. After 4 h, a second aliquot of Methyl iodide (15 uL, 0.24 mmol) was added to drive the reaction to completion. After 30 min, the mixture was partitioned between 20 mL DCM/20 mL water, extracted 2×20 mL DCM. The combined organics were dried over sodium sulfate, filtered and con. in vacuo to afford N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide as an oil in quantitative yield. 1H-NMR (CDCl3): 8.02 (s, 1H), 5.94 (d, 1H, J=7.6 Hz), 4.11 (m, 1H), 3.74 (m, 1H), 2.84 (s, 3H), 2.80 (s, 3H), 2.35 (m, 1H), 1.84 (m, 3H), 1.71 (m, 1H), 1.42 (m, 2H), 1.27 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[CH:4][CH:3]=1.[CH3:17][S:18]([CH2:21][C:22]1[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:24]=[CH:25][N:26]=1)(=[O:20])=[O:19].[H-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:36][CH:35]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3)n2)cc1
Yield: 55.5 %

Procedure:
Using 2-[(E)-2-(4-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (274 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (300 mg) and 65% sodium hydride (39.5 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (275 mg) as a colorless crystal powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[C:4]([O:16]C)[CH:3]=1.B(Br)(Br)Br>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[C:4]([OH:16])[CH:3]=1
Reactant: COc1cc(Cl)ccc1Sc1cccc(F)c1
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Product: Oc1cc(Cl)ccc1Sc1cccc(F)c1
Reaction time: 8 h

Procedure:
A solution of 4-chloro-1-(3-fluoro-phenylsulfanyl)-2-methoxybenzene (3.12 g, 11.6 mmol) in dry toluene (60 mL) was cooled to 0° C. Neat BBr3 (1.50 mL, 15.9 mmol) was added dropwise and the mixture was allowed to reach room temperature overnight. The mixture was quenched by the addition of H2O/ice (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethylether (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and adsorbed onto silica gel. After flash chromatography using silica gel, eluting with heptanes/EtOAc, 95:5, the title compound was obtained as a light yellow oil (2.26 g, 77%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH2:12][CH2:13][C@@H:14]([NH:59]C(OC(C)(C)C)=O)[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:59][C@H:14]([CH2:13][CH2:12][CH2:11][N:8]=[N+:9]=[N-:10])[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.5 %

Procedure:
Trifluoroacetic acid (0.09 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk71) (24.5 mg, 0.028 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 25 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-azidopentanoate (Orn(N3)-pdCpA) (Compound tk72) (18.8 mg, 87%).
Reaction SMILES: Cl[CH:2]([C:11]1[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH4+:17].[OH-]>C1COCC1.ClCCl>[NH2:17][CH:2]([C:11]1[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: Cn1cncc1C(Cl)c1ccc(C#N)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cncc1C(N)c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 77 %

Procedure:
A suspension of Example 41E (200 mg, 0.746 mmol) in THF (5 mL) at room temperature was treated dropwise with concentrated NH4OH (2.0 mL), stirred for 2 hours, diluted with dichloromethane, washed with water, dried (MgSO4), filtered, and concentrated to provide 123 mg (77%) of the desired product. MS (ESI) m/z 213 (M+H)+; 1H NMR (CDCl3) δ 7.65 (m, 2H), 7.48 (m, 2H), 7.39 (s, 1H), 6.84 (s, 1H), 5.26 (s, 1H), 3.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH:31][C:18]([C:17]2[CH:16]=[N:15][N:11]3[C:12]([CH3:14])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 441.3 [(M+H)+]; mp 250-251° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[NH2:17][C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].C(N(CC)CC)C>CN(C=O)C>[N+:13]([C:12]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:17]([C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:5]2=[O:7])([O-:15])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a stirred mixture of 18 (0.25 g, 0.912 mmol) and 4 (0.337 g, 0.912 mmol) in DMF (3.0 mL) was added triethylamine (0.320 mL, 2.28 mmol) and resulting mixture was stirred at 114° C. to 130° C. After 18 h, the mixture was cooled and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 19 (0.27 g, 60%) as a light brown fluffy solid. 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.45 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.80 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.44-7.19 (m, 5H), 5.17-4.84 (m, 4H), 3.05-2.96 (m, 2H), 2.69-2.52 (m, 3H), 2.20-1.94 (m, 3H), 1.35 (m, 4H). MS (ESI) m/z calcd for C25H27N4O7 [M+H]+ 495.5, found 495.9.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([N:10]1[C:14](=O)[CH2:13][O:12][C:11]1=[S:16])[CH3:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C(OCC)(=O)C>[CH2:8]([N:10]1[C:14](=[S:26])[CH2:13][O:12][C:11]1=[S:16])[CH3:9]
Reactant: CCN1C(=O)COC1=S
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN1C(=S)COC1=S
Yield: 94 %

Procedure:
A toluene (10 mL) solution of 3-ethyl-2-thioxooxazolidin-4-one 3 (145 mg, 1.0 mmol) and Lawesson's reagent (607 mg, 1.5 mmol) was refluxed overnight. The solution was cooled and diluted with ethyl acetate (100 mL), then washed with water (2×20 mL). The organic layer was dried with brine and MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=10:1), and the desired product 6 was obtained in 94% yield (152 mg, orange oil). 1H NMR (400 MHz, CDCl3): δ 5.12 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:15]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH3:14])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cccn2)c(OC)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A suspension of methyl 4-(bromomethyl)-3-methoxybenzoate (400 mg, 1.544 mmol) and 1H-pyrazole (105 mg, 1.544 mmol) and K2CO3 (533 mg, 3.86 mmol) in DMF (5 ml) was stirred for 3.5 h at rt. A saturated solution of NaHCO3 was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude Methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoate. MS [M+H]+=247.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17]O)[N:3]=1.C(N(S(F)(F)[F:25])CC)C>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:25])[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CO)n1
Solvent: ClCCl
Product: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CF)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a stirred suspension of 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine (185 mg; 1 mmol) in dry dichloromethane (25 ml), under nitrogen at -70° C., was added dropwise diethylaminosulphur trifluoride (263 μl; 2 mmol). The mixture was allowed to warm to 0° C. and kept at this temperature for 4 hours. After cooling to -70° C. the mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane (2×50 ml), washed with saturated brine and dried (MgSO4). Concentration gave a colourless gum (0.2 g). Chromatography on silica gel, eluting with 0.01:1:19 Et3N:MeOH:CH2Cl2 gave the desired product which was triturated with CCl4 and dried in vacuo. 111 mg, mp. 224°-6° C.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][O:51][CH3:52])=[N:40]2>>[F:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH:27][C:45]([C:43]2[CH:42]=[C:41]3[C:36]([CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][O:51][CH3:52])=[N:40]3)=[C:35]([F:34])[CH:44]=2)=[O:46])[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Reactant: COCCNc1ncc2c(F)cc(C(=O)O)cc2n1
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COCCNc1ncc2c(F)cc(C(=O)N[C@@H](c3ccc(OC)c(F)c3)c3cnn(C)c3)cc2n1

Procedure:
5-Fluoro-2-(2-methoxy-ethylamino)-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-methoxy-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide (I-58) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87a.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH2:45][OH:46]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH:45]=[O:46])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 29.9 g of t-butyloxycarbonyl-phenylalanine. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from chloroform to obtain a white solid substance which was then dissolved in 400 ml of THF. To this solution was added 7.4 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 29.2 g of WSCD.HCl and 120ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently 5.8 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 250 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 250 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 3.3 g (8.4%).