Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.Cl.Cl.[CH3:26][NH:27][CH2:28][CH2:29][N:30]([CH2:46][C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1)[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][CH2:39][CH2:38]2.[O:53]1[C:57]2[C:58]([C:62](O)=[O:63])=[CH:59][CH:60]=[CH:61][C:56]=2[CH2:55][CH2:54]1.C(OC(=O)C)C.Cl>C(OCC)(=O)C.O.CN(C=O)C>[ClH:1].[ClH:1].[CH3:26][N:27]([CH2:28][CH2:29][N:30]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][CH2:39][CH2:38]2)[CH2:46][C:47]1[CH:48]=[CH:49][N:50]=[CH:51][CH:52]=1)[C:62]([C:58]1[C:57]2[O:53][CH2:54][CH2:55][C:56]=2[CH:61]=[CH:60][CH:59]=1)=[O:63]
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: CNCCN(CCCOc1ccc2c(c1)CCNC2=O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCN(CCCOc1ccc2c(c1)CCNC2=O)Cc1ccncc1)C(=O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(144 mg), and 1-hydroxy benzotriazole (HOBt)(115 mg) were added to a DMF solution (5 ml) of 6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-3,4-di hydro-2H-isoquinolin-1-one trihydrochloride (234 mg), and 2,3-dihydrobenzofuran-7-carboxylic acid (123 mg). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.19 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (164.6 mg) as a white powder.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH3:31][O:32][CH2:33][O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=O.[C:44]([BH3-])#[N:45].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:45]([CH2:44][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:42][C:38]3[N:37]([CH2:36][CH2:35][O:34][CH2:33][O:32][CH3:31])[CH:41]=[CH:40][N:39]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: COCOCCn1ccnc1C=O
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3CCOCOC)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 139.1 %

Procedure:
The compound (120 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml). The solution was added with the compound (73.0 mg) obtained in Example 92-2 and sodium cyanoborohydride (18.0 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 2 days. After completion of the reaction, the reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (121 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].Cl>CC(C)=O.O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1c(OCc2ccc(OCC(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 1 g (5.15 mmoles) of 2,4-dihydroxy-3-propylacetophenone and 2.0 g (5.15 mmoles) of ethyl 4-bromomethylphenoxyacetate in 50 ml of dry acetone was stirred and refluxed with 800 mg of K2CO3 for 48 hours. The reaction mixture was diluted with H2O, rendered acidic with 6N HCl and extracted into CH2Cl2. Evaporation of the CH2Cl2 gave an oil that was chromatographed on silica gel by gradient elution with 50% CH2Cl2 /hexane to 75% CH2Cl2 /hexane to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O>[Si:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccco1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccco1
Temperature: 25 °C
Reaction time: 22 h
Yield: 65 %

Procedure:
To a 1 liter flask containing dimethyl formamide (150 mL) was added furfuryl alcohol (17.7 mL, 0.20 mol), t-butyldimethylsilyl chloride (33.7 g, 0.22 mole), and imidazole (15.3 g, 0.22 mol). After 22 hours stirring at RT, the reaction was filtered and the volatiles removed in vacuo. The resulting material was partitioned between diethyl ether (500 mL) and a saturated aqueous solution of citric acid (100 mL). Additionally, the ether layer was washed 2×100 mL sat. citric acid. The combined aqueous layers were back extracted 1×50 mL ether. The combined organic layers were washed 1×100 mL water followed by 1×100 mL brine. The ether layer was dried over anhydrous sodium sulfate, filtered, and evaporated to yield 28.1 g (65% yield). 1H NMR: (DMSO-d6) δ 0.01 (s, 6H), 0.82 (s, 9H), 4.55 (s, 2H), 6.29 (d, 1H), 6.36 (dd, 1H), 7.58 (d, 1H)
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C(C)(C)C)c1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2cccc(C(C)(C)C)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3-tert-butyl-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure of Example 24. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.37 (dd, 1H, J=5.09 Hz, 1.17 Hz), 7.19-7.16 (m, 3H), 7.08-7.06 (m, 2H), 6.89 (t, 1H, J=2.35 Hz), 6.82 (d, 2H, J=8.60 Hz), 6.71 (dd, 1H, J=8.60 Hz, 2.74 Hz), 4.19 (t, 2H, J=6.26 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15 (d, 1H, J=14.08 Hz), 2.96 (t, 2H, J=6.26 Hz), 2.35 (s, 3H), 1.43 (s, 3H), 1.26 (s, 9H). HRMS (ES+) m/z exact mass calcd for C30H34NO5S 520.2157, found 520.2182.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O.CO>[CH2:1]([O:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][OH:9])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(OCc1ccccc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Benzyl bromide (7.8 mL, 66 mmol) was added to a suspension of 4-hydroxymethylbenzoic acid (10 g, 66 mmol) and cesium carbonate (11 g, 33 mmol) in a mixed solvent (DMF (100 mL)-methanol (30 mL)-water (30 mL)), and then the mixture was stirred at room temperature for 2 hours. Water (500 mL) was added thereto, the whole was extracted with ethyl acetate (500 mL), and then the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) twice and water (300 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with hexane, and dried at 35° C. under reduced pressure to give 13 g of the title reference compound as a white solid. (Yield 81%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid (204.5 mg, 0.70 mmol), 2-aminothiazole (71 mg, 0.70 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (314 mg, 0.70 mmol) in N,N-dimethylformamide (3.55 mL) was treated with N,N-diisopropylethylamine (260 μL, 1.49 mmol). The mixture was stirred under nitrogen at 25° C. for 18 h. At this time, the reaction was diluted with water (50 mL). This solution was extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-N-thiazol-2-yl-propionamide (232.2 mg, 88.4%) as a white solid: mp 69-71° C.; EI-HRMS m/e calcd for C16H16Cl2N2O2S (M+) 370.0309. found 370.0309.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[CH2:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11].[CH:16]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:15][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CCS(N)(=O)=O
Reactant: Br[Mg]C1CCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CCCC1
Temperature: -40 °C
Yield: 27.6 %

Procedure:
A mixture of 5-bromonicotinaldehyde (930 mg, 5 mmol), ethanesulfonamide (546 mg, 5.00 mmol) and titanium(IV) isopropoxide (2930 μl, 10.00 mmol) in toluene (20 mL) was heated to reflux for 4 h. After concentration, the residue was dissolved in THF (25 mL) and cooled to −40° C. A solution of cyclopentylmagnesium bromide (2M in THF, 6.25 mL, 12.5 mmol) was added dropwise and the resulting mixture was slowly warmed up to 0° C. over 4 h. The reaction was quenched with a saturated NH4Cl solution. The mixture was filtered, separated, and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated, and the residue was purified by flash column (ethyl acetate/heptane, v/v, 10%-30%) to give a yellow oil (480 mg). ESI-MS m/z: 348.9 [M+1]+; 1H NMR (400 MHz, CDCl3): δ 1.13-1.80 (m, 7H), 1.26 (t, J=7.4 Hz, 3H), 1.97-2.05 (m, 1H), 2.20-2.29 (m, 1H), 2.67-2.92 (m, 2H), 4.27 (t, J=8.8 Hz, 1H), 5.59 (brs, 1H), 7.87 (s, 1H), 8.56 (s, 1H), 8.68 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:15]([O-])(=[O:17])C.[NH4+].C(O)=O>O>[CH:15]([NH:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17]
Reactant: CC(=O)[O-]
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: CCCc1cc(C(=O)OCC)c(NC=O)s1
Temperature: 137.5 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
A mixture of compound 2c [Formula 2 wherein R1=COOEt, R2=H and R3=Pr] (5.0 g, 0.023 mol), ammonium acetate (1.80 g, 0.023 mol) and formic acid (17.70 mL, 0.469 mol) was stirred at 135-140° C. for 7 h, cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3×150 mL), dried over Na2SO4, concentrated and purified by column chromatography to give pure compound of Formula (3c); 5.27 g; Yield: 95%; 1H NMR (200 MHz, CDCl3): δ 0.96 (t, J=7 Hz, 3H), 1.38 (t, J=7 Hz, 3H), 1.59-1.76 (m, 2H), 2.69 (t, J=8 Hz, 2H), 4.33 (q, J=7 Hz, 2H), 6.88 (s, 1H), 8.49 (s, 1H) 10.93 (bs, 1H).
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6](C[CH2:8][CH2:9][CH:10]2[C:13]#[N:14])=[CH:5][C:4]=1[CH3:15].[CH2:16]([NH2:19])[CH2:17]N.C1(C)C=CC(S(O)(=O)=[O:27])=CC=1>>[NH:19]1[CH2:16][CH2:17][N:14]=[C:13]1[CH:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:15])=[CH:3][CH:12]=2)[O:27][CH2:8][CH2:9]1
Reactant: NCCN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2c(cc1C)CCCC2C#N
Product: Cc1ccc2c(c1)OCCC2C1=NCCN1

Procedure:
This compound was prepared in a manner analogous to that of Step G of Example 1, by the reaction of 0.6 gram (0.003 mole) of 7-methylchromane-4-carbonitrile (iv) and 2 grams (0.008 mole) of the ethylenediamine salt of p-toluenesulfonic acid (prepared in Step F of Example 1). The reaction product was purified by column chromatography on Grade II basic alumina (3% water) using mixtures of methylene chloride and methanol as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 0.25 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:16]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(C)cc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(C(=O)CCC(=O)O)c(C)c1
Yield: 54 %

Procedure:
Mesitylene 10i (99%, 4.8 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 72 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11i in 54% yield. 1H-NMR (DMSO-d6): 6.63 (s, 2H, Ar--H); 2.84 (t, 2H, CH2CH2COOH); 2.22 (s, 3H, p-CH3); 2.18 (t, 2H, CH2CH2COOH); 2.13 (s, 6H, o-CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].O.[NH2:15][NH2:16]>CCO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:15][NH2:16])=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-nitrobenzoate (940.7 mg; 5.19 mmol; 1 eq.) is dissolved in EtOH (24 ml). Hydrazine hydrate (4.04 ml; 83.09 mmol; 16 eq.) is added and the mixture is stirred 1 hour at rt. It is stirred at 60° C. for 6 hours and rt overnight. The precipitate formed is filtrated and dried under vacuo, affording 3-nitrobenzohydrazide as white-off solid (815.9 mg; 87%).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7]C.[C:15](=S)=[S:16]>ClCC(Cl)(Cl)Cl>[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:15]1=[S:16]
Reactant: S=C=S
Reactant: COCCNCC(N)c1ccccc1
Agent: ClCC(Cl)(Cl)Cl
Product: OCCN1CC(c2ccccc2)NC1=S
Temperature: 120 °C

Procedure:
The methoxyethylamine product of Example IV in the amount of 4.5 g is dissolved in 20 ml of tetrachloroethane, and is stirred with 2 ml carbon disulfide at room temperature for one hour. The resulting slurry is then slowly heated to 120° C. and maintained at that temperature for four hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH3:12].C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH2:12][Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C#N)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C#N)cc1CBr
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CCl4 (200 mL) was heated to reflux temperature for 3 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH2:21]([O:20][C:14](/[CH:15]=[CH:1]/[C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/c1cc(C)c(C(=O)OCC)[nH]1
Temperature: 100 °C
Reaction time: 38 h
Yield: 47.7 %

Procedure:
Ethyl 5-formyl-3-methyl-1H-pyrrole-2-carboxyate 470 mg, monoethyl malonate 378 mg, piperidine 0.05 mL and pyridine 6 mL were mixed and stirred at 100° C. for 38 hours. Ice water was added to the reaction liquid and the precipitate was recovered by filtration. The precipitate was washed with water and dried in flowing air under heating to provide 311 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3ccccc3n2)c1
Yield: 39.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (170 mg, yield: 39.8%).
Reaction SMILES: [N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]4[CH:14]=[N:13]3)[CH:9]=[CH:10][CH:11]=2)[NH:3][CH:2]=1.[H-].[Na+].[C:24](Cl)(=[O:26])[CH3:25]>CN(C=O)C>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([C:8]3[CH:7]=[C:6]([C:4]4[N:3]=[CH:2][N:1]([C:24](=[O:26])[CH3:25])[CH:5]=4)[CH:11]=[CH:10][CH:9]=3)[N:13]=[CH:14][C:15]=12
Reactant: Nc1ncnc2c1cnn2-c1cccc(-c2cnc[nH]2)c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1cnc(-c2cccc(-n3ncc4c(N)ncnc43)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.6 %

Procedure:
Title compound 6A, 1-[3-(3H-Imidazol-4-yl)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.0 eq, 0.11 mmol) was dissolved in DMF (2 ml) and to this was added sodium hydride as a 60% dispersion in oil (5 mg, 1.1 eq, 0.12 mmol), the mixture was then stirred under an inert atmosphere for 20 minutes. To this was added acetyl chloride (7.7 μl, 1.1 eq, 0.12 mmol) the reaction was the stirred for 18 hours and allowed to warm to room temperature. Solvent was then remove in vacuo. The resultant residue was purified using mass-directed preparative HPLC to yield the compound as an off white solid (2.1 mg, 0.0007 mmol, 6%). LCMS: [M+H]+=320, Rt=1.32 min, 87% purity.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH2:67][CH2:68][OH:69])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCO)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7)(90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with 2-aminoethanol (0.013 mL, 0.211 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-hydroxyethyl)nicotinamide (37 mg, 0.079 mmol, 37.3% yield) as a white solid. LC/MS (HpH, 2 min), Rt=0.70 min, MH+=501.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.Cl.[O:32]([NH2:34])[CH3:33].C(=O)(O)[O-].[K+]>O>[CH3:33][O:32][N:34]=[CH:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:27])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26]
Reactant: CON
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(CC=NOC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added methoxylamine hydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2 h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, was filtered and was concentrated to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal O-methyloxime as a mixture of isomers (70 mg, 90%) crude product. LC/MS (M+H)+: m/z=429.