Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
To a solution of 4-(4-Chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (80 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:17]1(C)C=CC=C[CH:18]=1>C(O)C>[CH2:17]([O:10][C:9]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([Cl:8])[N:4]=1)=[O:11])[CH3:18]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1nc(Cl)ccc1Br
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1nc(Cl)ccc1Br

Procedure:
To a solution of 3-bromo-6-chloropicolinic acid (21, 8.0 g, 33.83 mmols) in a mixture of toluene (80 mL) and ethanol (40 mL) was added sulfuric acid (0.66 mL, 6.76 mmols). The reaction mixture was refluxed for 16 h, then allowed to cool, and partitioned between CHCl3 (200 mL) and saturated aq. NaHCO3 (250 mL). The aqueous layer was extracted with CHCl3 (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 10% EtOAc in hexane) to yield title compound 22 (9.0 g, quantitative) as transparent oil. 1H NMR 400 MHz (DMSO-d6) δ: 8.31 (d, J=8.6 Hz, 1H), 7.68 (d, 1H, J=8.2 Hz), 4.39 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([Sn:20]([CH3:23])([CH3:22])[CH3:21])[CH:4]=1.[BH4-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([Sn:20]([CH3:21])([CH3:23])[CH3:22])[CH:4]=1
Reactant: COc1cc([Sn](C)(C)C)c(C=O)cc1OCOCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([Sn](C)(C)C)c(CO)cc1OCOCC[Si](C)(C)C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
4-Methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-benzaldehyde (2.36 g, 5.3 mmol) was stirred in MeOH (30 mL) at 0° C. Sodium borohydride (400 mg, 10.6 mmol) was added, and the reaction stirred for 1 h. The solution was diluted with H2O (60 mL), and extracted with EtOAc (2×50 mL). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo to give 2.16 g (91%) of [4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.18 (t, 1H, J=6.9 Hz), 7.03 (t, 1H, J=9.3 Hz), 5.27 (s, 2H), 4.584.63 (m, 2H), 3.89 (s, 3H), 3.80 (t, 2H, J=8.4 Hz), 1.53 (t, 1H, J=6.0 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.31 (t, 9H, J=27.3 Hz), 0.01 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([CH3:33])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:31]#[N:32])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[CH:14]=2)=[O:9])C.[OH-].[Na+]>CO>[C:31]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:34])([CH3:33])[C:4]([OH:35])=[O:3])=[O:9])[N:11]=1)#[N:32]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(NC(=O)Nc3ccccc3)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(NC(=O)Nc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
3-{[1-Cyano-4-hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (35 mg, 0.0736 mmol) was methanol (5 mL) and aqueous sodium hydroxide (5 mL, 2M) was added via syringe. The reaction was permitted to stir overnight at room temperature. Upon completion, the reaction was concentrated, diluted with water and acidified to pH 3 with 1M hydrochloric acid. The resulting precipitate was isolated by filtration and dried to provide the title compound as a white solid in 73% yield. MS ESI(−) m/e: 446.0440 (M−1), MS ESI(+) m/e: 448.1482 (M+1).
Reaction SMILES: CSC.[CH3:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([CH:10]=[N:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[C:24]1([CH:30]=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.C(OC)(C)(C)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:10]2[C@H:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:22][CH:23]=1
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: COc1ccc(C=NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: CSC
Product: COc1ccc([C@H]2[C@H](c3ccccc3)N2S(=O)(=O)c2ccc(C)cc2)cc1
Yield: 51 %

Procedure:
To a stirred solution of dimethylsulphide (7 μl, 0.1 mmol), rhodium (II) acetate (2 mg, 0.005 mmol) and N-(4-methoxybenzylidene)toluene-p-sulphonamide (144 mg, 0.5 mmol) in dichloromethane (2 ml) was added phenyldiazomethane (prepared as in Example 36; 8.96 ml of a 0.067M solution in t-butylmethylether) over a period of 12 hours. Upon completion of the addition the solvent was removed in vacuo and the residue was chromatographed using silica gel eluting with 15:85 ethyl acetate:petrol to give the title compound (96 mg, 51%). δH (CDCl3) 7.62(2H), 6.75-7.45(11H,m), 4.35(1H,d,J=6 Hz), 4.18(1H,d,J=6 Hz), 3.62(3H,s), 2.35(3H,s)ppm.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].Cl[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[N:60]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44]([C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)=[O:45])[C@@H:37]1[CH2:36][NH:35][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[N:60]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cccc(C(F)(F)F)n2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-6-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:9]=1>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:18][CH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:9]=[C:8]2[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc(CO)ccc21
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)n1nc(C#C[Si](C)(C)C)c2cc(CO)ccc21
Yield: 137.2 %

Procedure:
A mixture of trimethylsilylacetylene (1.60 mL; 11.3 mmol; 2.1 eq.), tert-butyl 3-bromo-5-(hydroxymethyl)-1H-indazole-1-carboxylate (1.80 g; 5.50 mmol; 1.0 eq.), Pd(OAc)2 (54 mg; 0.24 mmol; 0.04 eq.), triphenylphosphine (115 mg; 0.44 mmol; 0.08 eq.) and Copper iodide (62 mg; 0.33 mmol; 0.06 eq.) in TEA (50 mL) was degassed then heated at reflux for 3 h. After cooling, it was poured into HCl (0.1 N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown oil (2.6 g). 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=8.7 Hz, 1H), 7.71 (s, 1H), 7.60 (dd, J=1.6, 8.7 Hz, 1H), 5.41 (t, J=5.7 Hz, 1H), 4.66 (d, J=5.7 Hz, 2H), 1.65 (s, 9H), 0.32 (s, 9H). MS (ESI+): 345.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH2:23][C:24]#[N:25])=O>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]2[CH:12]=[C:23]([C:24]#[N:25])[O:22][C:15]=2[CH:16]=1
Reactant: COc1ccc(C=O)c(OCC#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C#N)oc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 49.4 %

Procedure:
Potassium carbonate (15.1 g) and molecular sieves 4A (3 g) were added to a DMF solution (100 ml) of (2-formyl-5-methoxyphenyl)oxyacetonitrile (10.4 g), which was stirred at 100° C. for 10 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the entitled compound (4.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:14])=[C:7]([CH2:12][OH:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(OC)(O[CH3:19])(=O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[C:7]([CH2:12][OH:13])=[CH:8][N:9]2[CH3:19])=[CH:4][CH:3]=1
Reactant: OCc1cnc2cc(Cl)ccc2c1O
Reactant: COS(=O)(=O)OC
Product: Cn1cc(CO)c(=O)c2ccc(Cl)cc21

Procedure:
In a similar manner to that described in Example 3 7-chloro-4-hydroxy-3-hydroxymethylquinoline was treated with dimethyl sulphate to give the novel 7-chloro-1-methyl-3-hydroxymethyl-4-quinolone, m.p. 204°-206° (from industrial methylated spirit). Reaction of this product with thionyl chloride gave 7-chloro-3-chloromethyl-1-methyl-4-quinolone hydrochloride, m.p. 205°-207°, which was reacted with sodium methanethiolate to give the novel 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 163°-164° (from industrial methylated spirit).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14])(=[O:17])[CH3:16]
Reactant: COc1cc2c(=O)[nH]cnc2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of 7-hydroxy-6-methoxyquinazolin-4-(3H)-one (8.0 g, 41.6 mmol), pyridine (7.5 ml) and acetic anhydride (63 ml) was heated at 100° C. for 4.5 hours and left to cool to ambient temperature 18 hours. The reaction mixture was poured into ice/water (400 ml) and the resultant precipitate collected by filtration and dried in vacuo. Analysis revealed that hydrolysis of the acetate group on the 4 position of the quinazoline was incomplete. The mixture was therefore treated with water (150 ml) and pyridine (0.5 ml) at 90° C. for 15 minutes. The reaction was cooled and the solid was collected by filtration, washed with water and dried in vacuo to yield 7-(acetoxy)-6-methoxyquinazolin-4-(3H)-one (7.4 g, 76% yield):
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:18]=[C:19]1[C:24](=[O:25])[CH:23]2[CH2:26][CH2:27][N:20]1[CH2:21][CH2:22]2>C(O)C.C(O)(=O)C>[O:25]=[C:24]1[CH:23]2[CH2:26][CH2:27][N:20]([CH2:21][CH2:22]2)[CH:19]1[CH2:18][C:7]([CH3:6])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(CC1C(=O)C2CCN1CC2)C(=O)OCC
Reaction time: 16 h

Procedure:
Ethanolic sodium ethoxide, previously prepared from 2.9 g of metallic sodium and 100 ml of ethanol, was added to diethyl methyl-malonate, 50 g, and the mixture was refluxed for 30 min. then cooled to 5°. A solution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml, was then added dropwise and with stirring. After 16 hrs. at room temperature, the resulting solution was neutralized with acetic acid then subjected to evaporation at reduced pressure. Water, 100 ml was added and the mixture was extracted with chloroform. Evaporation of this solvent gave diethyl (3-oxo quinuclidin-2-yl)methyl-methylmalonate, 72 g (81%), m.p., 58.4° (from petroleum ether).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:19][C:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:17][C:9]=3[N:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O>C(Cl)Cl>[Br:27][C:11]1[N:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9]2[CH:17]=[C:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[S:19][C:8]=2[C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cn1cc(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Solvent: ClCCl
Product: COC(=O)Cn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 0 °C
Yield: 87 %

Procedure:
tert-Butyl 6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., from Step 2) was dissolved in anhydrous CH2Cl2, cooled to 0° C. and treated portionwise over 40 mins with N-bromosuccinimide (1 eq.). The reaction mixture was quenched by the addition of 1 M sodium thiosulfate solution and extracted with EtOAc. The combined organic layers were washed with 1 M sodium thiosulfate solution and with brine and dried over sodium sulfate. Evaporation afforded the pure title compound (87%) as light-yellow foam. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.86 (s, 1H), 5.12 (s, 2H), 3.69 (s, 3H), 2.67-2.56 (m, 1H), 1.81-1.70 (m, 5H), 1.52 (s, 9H), 1.52-1.27 (m, 5H). MS (ES+) m/z: 456, 458 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[NH:8][C:7](=S)[CH2:6][O:5][CH2:4]1.[NH3:18]>CO>[F:1][CH:2]([F:17])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:4][O:5][CH2:6][C:7]([NH2:18])=[N:8]1
Reactant: N
Reactant: Fc1ccccc1C1(C(F)F)COCC(=S)N1
Solvent: CO
Product: NC1=NC(c2ccccc2F)(C(F)F)COC1
Reaction time: 8 h

Procedure:
5-Difluoromethyl-5-(2-fluoro-phenyl)-morpholine-3-thione (160 g, 570 mmol) was dissolved in 2.4 L of a NH3 solution 7 mol/L in methanol for 6.5 h and afterwards left standing overnight. The reaction mixture was evaporated and taken up in 2 L 1N aqueous HCl and 2 L TBME. The aqueous phase was washed with TBME and made basic by the addition of 300 ml 30% aqueous NaOH and some ice. The mixture was extracted with DCM three times and the combined organic layers were dried with Na2SO4 and concentrated in vacuo. The title compound was obtained by crystallization from DCM/heptanes (128.45 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:25]3[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na].C(=O)(O)[O-].[Na+]>ClC(Cl)C.O>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:25]3[CH2:26][CH2:27][C@@H:28]([N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[CH2:29][CH2:30]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC(=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A suspension of the 4-{4-amino-5-[4-(benzyloxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-1-cyclohexanone (1.22 g, 2.96 mmol) in dichloroethane (40 ml) was treated with N-methylpiperazine (0.889 g, 8.88 mmol) and glacial acetic acid (0.534 g, 8.88 mmol) at 0° C. for 1 hour. Subsequently, sodium triacetoxyborohydride (0.816 g, 3.85 mmol) was added and the reaction mixture was stirred overnight. Additional N-methylpiperazine (0.445 g, 4.44 mmol), sodium triaceoxyborohydride (0.407 g, 1.92 mmol), and glacial acetic acid (0.267 g, 4.44 mmol) were added and the reaction mixture was stirred for an additional 1.5 hour. To the reaction solution, a solution of sodium bicarbonate (1.49 g, 17.76 mmol) in 25 mL water was added and stirred for 1 hour. The aqueous layer was extracted with ethyl acetate (4×125 mL), The organic layers were combined, washed with water and brine (each 4×125 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.6 g of crude material. The compound was purified by flash chromatography on silica gel using 10% methanol in dichloromethane, 20% methanol in dichloromethane, and then 30% methanol in dichloromethane. The column yielded 0.83 g (56%) of Cis-5-[4-(benzyloxy)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, and 0.305 g (21%) of transs-5-[4-(benzyloxy)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:19]([O:23][C:24](=[O:36])[NH:25][C:26]1([C:34]#[CH:35])[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl.O>[C:19]([O:23][C:24](=[O:36])[NH:25][C:26]1([C:34]#[C:35][C:2]2[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([C:7]#[N:8])[CH:9]=2)[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CCCCCCCCOc1ccc(Br)cc1C#N
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C#N

Procedure:
Compound 7-1 (0.636 g), (2,2-dimethyl-5-ethynyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (0.571 g), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.045 g), bis(acetonitrile)palladium(II) dichloride (0.008 g) and cesium carbonate (0.668 g) were stirred in acetonitrile (10 ml) at 70-80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give [2,2-dimethyl-5-(3-cyano-4-octyloxyphenylethynyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester as a brown oil. The oil was dissolved in ethyl acetate (6 ml), 10% palladium carbon (about 50% water containing, 0.080 g) was added, and the mixture was stirred at room temperature for 3.5 hr under a hydrogen atmosphere. The solution was filtrated, and the filtrate was concentrated to give the object product (0.610 g) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:27]([CH3:30])([O-:29])=[O:28]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:30]/[N+:27]([O-:29])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCCCF)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCCCF)c(OCc2ccccc2)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
3-(Benzyloxy)-4-(3-fluoropropoxy)benzaldehyde described in Production Example 33-2 (6.14 g, 21.3 mmol) was dissolved in acetic acid (17.0 mL), then ammonium acetate (1.97 g, 25.6 mmol) and nitromethane (2.8 mL, 51.7 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours. The mixture was cooled to mom temperature, then the precipitate was collected by filteration and washed with a small quantity of ethanol to quantitatively obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].O1CCCC1.N1C=CC=CC=1>O.C(OCC)(=O)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(Br)ccc(O)c1C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc(OC(=O)C(C)(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1B (6.45 g, 28 mmol), pivaloylchloride (3.62 g, 30 mmol), tetrahydrofuran (60 ml) and pyridine (2.45 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with water and ethyl acetate. The organic phase is washed with water twice. The organic phase is concentrated in vacuo and the residue is re-crystallized from petrol ethers/diisopropylether (9:1 v/v) yielding the pure product as a white crystals, 6.3 g, (71.6%), mp. 144-145° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]4)[CH:16]=[C:11]3[C:10]([CH3:34])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:34][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([NH:17][C:18]3[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=3)[CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Nc4cccc(CN5CCN(CCO)CC5)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ncc(Nc3cccc(CN4CCN(CCO)CC4)c3)cc12
Temperature: 60 °C

Procedure:
To a stirred solution of 2-(4-(3-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)benzyl)piperazin-1-yl)ethanol (163) (50 mg, 0.103 mmol) in CHCl3 (10 mL) was added trifluoroacetic acid (6 mL) and the reaction mass heated at 60° C. overnight. After completion of the reaction the solvents were completely distilled off and diluted with water and the pH was adjusted to 9 and extracted with chloroform twice. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed and the crude material was passed through 100-200 mesh silica gel, eluting with 10% MeOH/CH2Cl2 obtained pure 2-(4-(3-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)benzyl)piperazin-1-yl)ethanol 164 as a pale yellow colored solid (6 mg). MS m/z 353.54 (M+H)+.