Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:16]2[CH2:15][CH2:14][NH:13][CH:12]([CH3:11])[CH2:17]2)=[S:10])=[CH:4][CH:3]=1
Reactant: CC1CNCCN1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC1CN(C(=S)Nc2ccc(Cl)cc2)CCN1
Temperature: 25 °C

Procedure:
A solution of 4-chlorophenyl isothiocyanate (8.0 g, 47.17 mmol) in dichloromethane (250 mL) was added dropwise over 30 minutes to an ice cooled solution of 2-methylpiperazine (9.45 g, 94.33 mmol) in dichloromethane (250 mL). Once the addition was complete, the reaction was stirred at room temperature for an hour. The reaction was then washed with water (3×), dried over MgSO4 and concentrated under reduced pressure, to give the title compound as a white solid, 11.8 g.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:33]=[CH:32][C:16]3[N:17]([CH3:31])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.[BH-](OC(C)=O)(OC(C)=O)[O:35][C:36]([CH3:38])=O.[Na+]>C(Cl)Cl>[OH:35][CH2:36][CH2:38][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[CH:33]=[CH:32][C:16]3[N:17]([CH3:31])[C:18]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCNCC3)ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(CCO)CC3)ccc21
Yield: 27.4 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-ylmethyl]-amide (35 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (piperidin-4-ylmethyl)-amide dihydrochloride (135 mg), [1,4]dioxane-2,5-dio (65 mg), and Na(OAc)3BH (95 mg) in DCM (2 mL). LC/MS: m/z 498.5.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[Br:17].C([O:22]O)(C)(C)C>O>[OH:22][C:15]1[C:10]([F:9])=[C:11]([Br:17])[CH:12]=[CH:13][C:14]=1[F:16]
Reactant: CC(C)(C)OO
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: O
Product: Oc1c(F)ccc(Br)c1F
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A quantity of 40.2 ml of 2.0 M lithium diisopropylamine (LDA) is dissolved in 80 ml of TIF at −78° C. and 15.4 g of 2,4-difluorobromobenzene is added keeping the temperature below −65° C. The reaction is stirred at −65° C. for 2 hours and 6.6 ml of 6 M anhydrous t-butyl hydroperoxide is added. After warming at room temperature, 100 ml of water is added and the mixture acidified. The solvent is removed by evaporation and the aqueous layer extracted with ether. The extracts are dried and then concentrated to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: C[C@@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(R)-methyl-piperazine (0.2 g, 0.95 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.11 mL, 0.94 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.63 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]([NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)=[O:25]>>[CH2:44]([O:43][CH:39]([O:40][CH2:41][CH3:42])[C@@H:38]([N:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH2:47][C:48](=[O:49])[NH:50][C:51]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[CH3:46])[CH3:45]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 67 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.CO.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.[BH3-]C#N.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CCOCC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C

Procedure:
To a suspension of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (2.50 g, 6.0 mmol) in a mixed solvent of MeOH (42 mL) and DCM (10 mL) was added dihydro-2H-pyran-4(3H)-one (3.33 mL, 36.0 mmol) and TEA (8.36 mL, 60.0 mmol). The reaction mixture was heated at 60° C. for 1 h before NaCNBH3 (1.66 g, 26.4 mmol) was added. The mixture was heated at 60° C. for another 2 h, cooled down to room temperature, diluted with DCM (60 mL), dry loaded onto silica gel (12.5 g), and purified by silica gel chromatography (DCM with 1% NH3 to 10% MeOH in DCM with 1% NH3 gradient) to provide 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; 1H NMR (DMSO-d6, 400 MHz) δ 12.08 (br, 1H), 9.58 (br, 1H), 8.65 (d, J=28.4 Hz, 1H), 8.02 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.03 (d, J=12.4 Hz, 1H), 6.08 (br, 1H), 3.89 (dd, J=10.8, 3.6 Hz, 2H), 3.28 (t, J=10.4 Hz, 2H), 2.99 (d, J=10.8 Hz, 2H), 2.64-2.43 (m, 2H), 2.24-2.15 (m, 8H), 1.71-1.40 (m, 8H); ESMS m/z 500.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].CI.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:32][N:5]([C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 36 from (Z)-3-[1-(3-methylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone, methyliodide and potassium carbonate in acetone.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:15][N:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:15][N:16]4[CH:21]=[CH:20][C:19]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine (60 mg, 0.15 mmol) in anhydrous pyridine (5 mL) was added methylsulfonyl chloride (36 mg, 0.3 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, then saturated aquous bicarbonate was added. The phases were separated, the organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration, followed by flash chromatography (1:1 ethyl acetate-hexane) gave N-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide (35 mg, 50%) as a solid. 1H-NMR (CDCl3): δ 8.42 (d, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.60 (q, 2H), 7.13 (t, 2H), 6.90 (dd, 1H), 6.30 (d, 1H), 5.34 (d, 1H), 4.30 (m, 1H), 3.12 (s, 3H), 1.5–2.2 (m, 8H); 19F-NMR (CDCl3): δ −112.64; MS m/z 467 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH3:30][C@H:31]([NH:40][CH3:41])[C@@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:40]([CH:31]([CH3:30])[CH:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:41])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(O)c1ccccc1)N(C)C(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a dry round-bottomed flask equipped with a magnetic stirrer and an argon inlet was dissolved N (benzyloxycarbonyl)-glycine (5.00 g, 23.9 mmol, 1.0 equiv) in dichloromethane (25 mL). Triethylamine (3.66 mL, 26.3 mmol, 1.1 equiv) was added and the resulting mixture was cooled to 0° C. To the reaction was added dropwise trimethylacetylchloride (2.94 mL, 23.9 mmol, 1.0 equiv). A white precipitate formed and dichloromethane (25 mL) was added to allow efficient stirring. The reaction was stirred for 30 min at 0° C. and then a solution of (+)-pseudoephedrine (4.15 g, 25.1 mmol, 1.05 eq) and triethylamine (3.66 mL, 26.3 mmol, 1.1 eq) in dichloromethane (40 mL) was added via cannula. The reaction was stirred for 30 min at 0° C. Most of the solvent was removed under reduced pressure and water and saturated sodium bicarbonate were added. The product was extracted with two portions of ethyl acetate and the organic extracts were washed with saturated ammonium chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel with ethyl acetate/hexanes as the eluent (30%-80% gradient) gave [S-(R*,R*)-N2-(benzyloxycarbonyl)-N1-(2-hydroxy-1-methyl-2-phenylethyl)-N1-methyl glycinamide (6.67g, 78%) as a white foam (1:1 mixture of rotamers): 1H NMR (CDCl3, 300 MHz) δ7.25-7.40 (m, 10H), 6.04 (m, 1H), 5.09 (28, 4H), 4.67 (m, 0.5H), 4.51 (d, 0.5H, J=4.5 Hz), 4.49 (d, 0.5H, J=4.7 Hz), 4.23 (dd, 0.5H, J1 =16.7 Hz, J2=3.8 Hz), 4.15 (s(br), 1H), 4.04 (dd, 0.5H, J1=16.5 Hz, J2=5.1 Hz), 3.92 (d, 1H, J=4.3 Hz), 3.77 (m, 0.5H), 2.88 (s, 1.5H), 2.77 (s, 1.5H), 0.94 (d, 1.5H, J =6.4 Hz), 0.92 (d, 1.5H, J=6.3 Hz); 13C NMR (CDCl3, 75.5 MHz) δ169.3, 169.0, 156.2, 141.4, 141.1, 136.30, 136.26, 128.4, 128.2, 128.02, 127.95, 127.7, 126.6, 126.5, 75.2, 74.6, 66.5, 57.4, 56.1, 42.9, 42.6, 29.3, 26.8, 14.9, 13.9; FTIR (neat film) cm-1 3405, 3323, 3031, 2980, 1719, 1638.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1F>CS(C)=O.C(OCC)C>[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask containing potassium hydride (0.90 g, pre-washed three times with hexanes) under an atmosphere of argon and the solution is stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) is added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium chloride, three times with water, then with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:25]I.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Reactant: II
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Reaction time: 3 h

Procedure:
To a dry solution of N-(6-chloropyridin-2-yl)-2,2-dimethyl propionamide (Preparation 107, 8.0 g, 37.6 mmol) in THF (120 mL), cooled to −78° C., was added dropwise, a solution of tert-butyllithium in pentane (1.7M, 48.7 mL, 82.8 mmol) over 40 min. The reaction was stirred at —78° C. for 3 h before adding a solution of iodine (11.46 g, 45.1 mmol) in THF (40 mL) dropwise. The mixture was brought up to rt and stirred for 16 h. 2M HCl (3 mL) was added to the reaction, and after 20 min the solvent was removed in vacuo. Crude material was partitioned between ethyl acetate (200 mL) and water (150 mL). Organics were separated and washed with 10% sodium thiosulfate solution (4×100 mL) then NaHCO3 solution (2×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to give the title compound. m/z (ES+)=338.93 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C@@H:17]([OH:19])[CH3:18])[CH2:13]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[N:11]=[C:10]([N:12]4[CH2:16][CH2:15][CH:14]([C@@H:17]([OH:19])[CH3:18])[CH2:13]4)[C:9]4[C:4](=[N:5][CH:6]=[CH:7][N:8]=4)[CH:3]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1
Reactant: C[C@H](O)C1CCN(c2nc(Cl)cc3nccnc23)C1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Product: C[C@H](O)C1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
The title compound was prepared according to the procedure of Compound 1 (B) using (S)-1-(1-(7-chloropyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)ethanol and 4-morpholinophenylboronic acid. MS (m/z): 406 (M+H)+.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:18][C:19]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Si:22]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:19]([CH3:21])([CH3:20])[CH3:18])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 87.7 %

Procedure:
A stirring solution of thymidine (50.0 g, 207 mmol) and DMAP (10 mg, 8.2×10-2 mmol) in 400 mL of pyridine was treated with TBDPSCl (43.4 g, 248 mmol) at 25° C. for 16 h. The solvent was removed under reduced pressure and the residue was diluted with 1 L of AcOEt. The mixture was washed with 5% aqueous HCl (2×100 mL) and H2O (100 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The product was purified by silica gel chromatography (CH2Cl2 /MeOH 20:1) to give 87.3 g (88%) of 2 as a white solid. An analytical sample was crystallized from diethylether. mp 164-166° C. (170-171° C. per Matulic-Adamic, J. Chem. Soc., Chem. Comm. 1985, 21, 1535) Rf (CH2Cl2 /MeOH 10:1) 0.31. 1H-NMR (CDCl3): 1.08 (s, 9H, C-Me3), 1.61 (s, 3H, 5-Me), 2.18 (ddd, 1H, J=13.8, 8.5, 6.0 Hz, 2'Hβ), 2.19 (br s, 1H, D2O exchangeable, 3'-OH), 2.44 (ddd, 1H, J=13.8, 5.6, 2.1 Hz, 2'-Hα), 3.25 (br s, 1H, 5'-OH, D2O exchangeable), 3.85 (dd, 1H, J=11.5, 2.5 Hz, 5'-CHH), 3.98 (dd, 1H J=11.5, 2.3 Hz, 5'-CHH), 4.06 (dd, 1H, J=2.5, 2.3 Hz, 4'H), 4.55 (dd, 1H J=6.0, 5.6 Hz, 3'-H), 6.43 (dd, 1H, J=8.5, 5.6 Hz, 1'-H), 7.26-7.51 (m, 6H, aromatic-H), 7.64-7.68 (m, 5H, 6-H and aromatic-H), 9.57 (s, 1H, NH, D2O exchangeable).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:6]
Reactant: CC(C)(CO)C(=O)O
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)C(C)(C)CO)cc1
Yield: 97 %

Procedure:
Prepared as in Example 4c from 3-hydroxy-2,2-dimethylpropanoic acid and 4-methoxybenzylamine in 97% yield as a white solid. MS 238 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[N:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=412.4 (M+H+), was prepared in accordance with the general method of example 39 from N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 4-fluorobenzenesulfonylchloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.Cl.[NH2:14][OH:15]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[N:14][OH:15]
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NO)cc1F
Temperature: 62.5 °C
Yield: 77.3 %

Procedure:
A mixture of 3-fluoro-4-nitro-benzaldehyde (9.5; 56.21 mmol) and hydroxylamine hydrochloride (4.29 g; 61.83 mmol) in ethanol (50 mL) was heated at 60-65° C. for 2 hours. The solvent was distilled off. The residue was purified by flash chromatography over silica gel with 10-15% ethyl acetate in light petroleum to give 8 g of the title compound (77.4%); IR (KBr): 3091, 3056, 2501, 2431, 1597, 1513, 1488, 1400 cm−1; MS (m/z): 185 (M++1); 1H NMR (CDCl3) δ: 7.62-7.70 (m, 2H), 8.14-8.19 (m, 1H), 8.24 (s, 1H NH), 11.99 (s, 1H, NHOH).
Reaction SMILES: C(O[C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH2:24][NH:25][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)=[O:10])[CH2:26][CH3:27])[CH3:21]
Reactant: CCN(CC)CCN
Reactant: O=C(O)c1ccc(C(=O)OCc2ccccc2)cc1
Product: CCN(CC)CCNC(=O)c1ccc(C(=O)O)cc1

Procedure:
4-([2-(N,N-diethylamino)ethyl]aminocarbonyl)benzoic acid was prepared from 4-benzyloxycarbonylbenzoic acid by reaction with N,N-diethylethylene diamine to yield the mono amide derivative which was hydrogenolysed to give the acid (CI-MS: m/z 265 [M+b]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.[C:18]([OH:28])(=[O:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]=[CH:23][C:22]4[CH:25]=[CH:26][C:19]([C:18]([OH:28])=[O:27])=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1ccc(-c2cc3cc(C)ccc3o2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2oc(-c3ccc(C=Cc4ccc(C(=O)O)cc4)cc3)cc2c1

Procedure:
Proceeding in a manner similar to that used in Example 1, 5-methyl-2-(p-tolyl)benzofuran (2.22 g; 0.01 mole) was interacted with 2.25 g (0.01 mole) of the anil derivative of terephthalaldehydic acid in the presence of 6.72 g (0.06 mole) of potassium tert-butoxide in 150 ml of dimethylformamide. The product thus produced was sublimed to obtain 5-methyl-2-[4-(4-carboxystyryl)phenyl ]benzofuran, melting at 355°-358°C. The wavelength of maximum excitation of this compound was 374 nm and the wavelength of maximum emission was 437 nm.