Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])=[N:11][N:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)C(C)C)(C)C.Br.Br.[N:35]1([C@H:41]2[CH2:50][CH2:49][C:44]3[N:45]=[C:46]([NH2:48])[S:47][C:43]=3[CH2:42]2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:48][C:46]3[S:47][C:43]4[CH2:42][C@@H:41]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[CH2:50][CH2:49][C:44]=4[N:45]=3)=[O:19])=[N:11][N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2nnc(Cc3cccc(C(=O)O)c3)s2)cc1
Reactant: Nc1nc2c(s1)C[C@@H](N1CCOCC1)CC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Solvent: O
Product: N#Cc1ccc(-c2nnc(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N4CCOCC4)CC5)c3)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
Dissolve 3-[5-(4-cyano-phenyl)-[1,3,4]-thiadiazol-2-ylmethyl]-benzoic acid (0.13 g, 0.28 mmol) in 3 mL of dimethylacetamide. Add N,N-diisopropylethyl amine (0.17 mL, 0.95 mmol), of 7-aza-hydroxybenzotriazole (0.05 g, 0.37 mmol) and EDC (0.07, (0.36 mmol). Stir the mixture at room temperature for 1 h and add (S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-ylamine dihydrobromide (0.14 g, 0.35 mmol) in one portion. Heat the mixture at 60° C. for 15 h. Cool to room temperature and dilute with H2O. Add a saturated aqueous solution of sodium bicarbonate until the pH of the solution is alkaline causing a solid to precipitate from solution. Collect the solid by filtration, wash with H2O and dry on the filter pad. Purify the material by preparative reverse phase HPLC (CH3CN:H2O with 0.1% trifluoroacetic acid) to give 0.025 g, 14% yield of 3-[5-(4-cyano-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-N—((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-benzamide as a solid. MS, ES+ 543.62 (M+H), rt 1.50 min.
Reaction SMILES: Cl.Cl.N1CCO[CH:5]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:4]1.[C:36]([O:40][C:41](=[O:50])[NH:42][C@H:43]1CC[C@@H](N)[CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37].C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)C>[C:36]([O:40][C:41](=[O:50])[NH:42][CH:43]1[CH2:4][CH2:5][CH:9]([NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCCCc1nnc(C(=O)NCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (Example 90, 0.234 mmol, 130 mg), (±)-(cis)-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.1 mL), ethyl-diisopropyl-amine (0.3 mL) in THF (2 mL) may be stirred for 3 h. The reaction mixture may be diluted with diethyl ether, washed with water and 2 M aq. sodium hydroxide solution and dried over magnesium sulfate. Purification by column chromatography on silica gel using 10-40% ethyl acetate in hexanes provides (4-{[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:22])[C:14]3[N:15]([N:17]=[C:18]([CH2:20]O)[CH:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:29])CC)C>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:22])[C:14]3[N:15]([N:17]=[C:18]([CH2:20][F:29])[CH:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)c1ccc(-c2cn3nc(CO)cc3c(=O)[nH]2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cn3nc(CF)cc3c(=O)[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A suspension of 149 mg (0.50 mmol) 6-(4-tert-butyl-phenyl)-2-hydroxymethyl-5H-pyrazolo[1,5-a]pyrazin-4-one in 1.25 ml dichloromethane is cooled to −78° C. Then 264 μl (2.00 mmol) diethylaminosulfurtrifluoride are added. The reaction mixture is allowed to reach room temperature over 30 minutes. The reaction mixture is evaporated and the residue is treated with water and saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 6-(4-tert-butyl-phenyl)-2-fluoromethyl-5H-pyrazolo[1,5-a]pyrazin-4-one as white powder; HPLC/MS 2.80 min (B), [M+H] 300; 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.03 (s, 1H), 7.73-7.64 (m, 2H), 7.55-7.46 (m, 2H), 7.15 (d, J=2.0 Hz, 1H), 5.52 (d, J=48.1 Hz, 2H), 1.32 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:8]2[CH2:11][C:12]([O:14]CC)=O)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:25])[N:7]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:8]2[CH2:11][C:12]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:14]
Reactant: CCOC(=O)CC1c2cc(Cl)ccc2C(=O)N1c1ccc(OC)cc1
Reactant: CN1CCNCC1
Solvent: O
Product: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)N2CCN(C)CC2)cc1
Yield: 86.9 %

Procedure:
Ethyl 6-chloro-3-oxo-2-(4-methoxyphenyl)isoindoline-1-acetate (1.0 g) and N-methylpiperazine (1.3 g) was heated at 110° C. for 4 hours in an nitrogen stream. After cooling, water (40 ml) was added to the reaction mixture and crystals separated were collected by filtration, washed with water and then dried. Recrystallization from ether gave 5-chloro-2-(4-methoxyphenyl)-3-(4-methylpiperazin-1-yl)carbonylmethylisoindolin-1-one (1.0 g). The product was identified with the compound No. 13 in Table 5 and melted at 169°-171° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH2:6])=[O:5])[NH2:3].[C:7](Cl)(=[O:11])[CH:8]([CH3:10])[CH3:9]>C(N(CC)CC)C.ClCCl>[C:7]([NH:3][N:2]([CH3:1])[C:4]([NH2:6])=[O:5])(=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)Cl
Reactant: CN(N)C(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NN(C)C(N)=O

Procedure:
1-Methylhydrazinecarboxamide was acylated with isobutyryl chloride in triethylamine and dichloromethane to give 2-isobutyryl-1-methylhydrazinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[Cl:9][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
p-Chloroaniline (3.82 g) was dissolved in ethyl acetate (30 ml), and chloroacetyl chloride (2.39 ml) was added at room temperature to stir the mixture for 1 hour. After the reaction mixture was heated and stirred at 60° C. for 3.5 hours, crystals deposited were collected by filtration to obtain the title compound (4.78 g). The filtrate was concentrated to about 1/4, and crystals deposited were collected by filtration to obtain the title compound (1.01 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:10]1[O:11][CH2:12][CH2:13][N:14]=1)[CH3:9]>O>[O:7]([CH2:12][CH2:13][NH:14][C:10](=[O:11])[CH2:8][CH3:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC1=NCCO1
Reactant: Oc1ccccc1
Solvent: O
Product: CCC(=O)NCCOc1ccccc1
Yield: 92 %

Procedure:
Phenol (13.1 moles) was heated to 150° and stirred under N2 as 2-ethyl-2-oxazoline (12.2 moles) was added over 1 hr. The mixture was heated to 175±3°. After heating 16 hr the oil was cooled to about 140°, and then it was poured into water (12 L) with vigorous stirring. The mixture was stirred and cooled, and at about 25° the mixture was seeded with crystalline amide product. The material solidified and the supernatant was decanted. The residual solid was stirred with 17 L of hot (85°) water. The mixture was cooled to 25°, seeded with the amide product, and the mixture refrigerated. The resulting granular solid was collected on a filter, rinsed with several portions of water and left to air dry. This gave a 92% yield of material, m.p. 61.5°-64°.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:19]=3)[CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>CO.O1CCCC1.O>[S:25]1[CH:26]=[CH:27][C:23]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([CH:5]([OH:4])[CH3:6])[N:12]=2)[CH2:22][CH2:21]3)=[CH:24]1
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCc3cc(-c4ccsc4)ccc3C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1nccc(N2CCc3cc(-c4ccsc4)ccc3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of (R)-1-[4-(6-thiophen-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 248, Step C, 253 mg, 0.67 mmol) in a 3:1:1 mixture of methanol/tetrahydrofuran/water (5 mL) was added lithium hydroxide hydrate (84 mg, 2.0 mmol). This mixture was stirred at room temperature for 1 h, concentrated, re-suspended in water, and extracted with chloroform (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/chloroform) to give a yellow solid which was further purified by recrystallization from ether/methanol to give 163 mg (72%) of the title compound as a white solid. mp: 125.5-127.5° C.; 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, 1H), 7.47-7.35 (c, 5H), 7.22 (d, 1H), 6.42 (d, 1H), 4.78-4.72 (c, 2H), 4.46 (br s, 1H), 3.93-3.84 (c, 2H), 2.99 (t, 2H), 1.54 (d, 3H); MS (APCI) 338 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])=[CH2:5].C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH2:33])([CH3:27])([CH3:26])[CH3:25].ClCCl>C(#N)C>[CH3:1][O:2][C:3](=[O:17])[CH:4]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH2:5][NH:33][CH2:32][CH2:31][NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:34]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C=C(C(=O)OC)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)C(CNCCNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
To a solution of 12.60 g (51.38 mmol) of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acrylic acid methyl ester (described in Synthetic Communications, 33(8), 1375-1382; 2003) dissolved in 170 mL of acetonitrile was added at room temperature 42.60 g (308.28 mmol) of potassium carbonate and 9.05 g (56.52 mmol) of (2-amino-ethyl)-carbamic acid tert-butyl ester. The resulting mixture was stirred at room temperature for 12 h. 300 mL of dichloromethane was added and the mixture was filtered and the solid obtained was triturated with dichloromethane, filtered, and the resulting filtrates were evaporated to dryness. The residue was dissolved in diethyl ether, washed with a saturated aqueous solution of sodium hydrogen carbonate, saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of chloroform/methanol/aqueous ammonia solution (29%) in the proportions 98/2/0.2 led to afford 6.50 g (31%) of the desired compound.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[Br:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([C:18]4[NH:19][CH:20]=[C:21]([CH3:23])[N:22]=4)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([C:18]4[N:19]([CH:1]([CH3:3])[CH3:2])[CH:20]=[C:21]([CH3:23])[N:22]=4)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: CC(C)I
Reactant: Cc1c[nH]c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
Isopropyl iodide (165 uL, 1.65 mmol) was added to a mixture of 417 mg (1.21 mmol) of 9-bromo-2-(4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine and cesium carbonate (538 mg, 1.65 mmol) in 3 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours, mixed with water and extracted with ethyl acetate. The organic extract was washed with water, brine, dried over MgSO4, concentrated, and purified on 4 g silica column eluting with 4-5% methanol in DCM to give 210 mg of 9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. MS: 387.1.
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([F:14])=[CH:6][CH:5]=1.C([Li])CCC.[B:20](OCC)([O:24]CC)[O:21]CC>CCCCCC.O1CCCC1>[F:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([B:20]([OH:24])[OH:21])=[CH:5][CH:6]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CCOB(OCC)OCC
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(F)c2ccccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 250 mL three-necked round-bottomed flask equipped with septum and N2 (nitrogen) inlet were added 4.62 g (20.53 mmol) 4-bromo-1-fluoronaphthalene and 100 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 15.4 mL (24.64 mmol) of a 1.6 M solution of butyl lithium in hexane was added dropwise over 5 min. The reaction was stirred at −70° C. for 10 min, then 4.2 mL (3.59 g, 24.64 mmol) triethyl borate was added, and the reaction stirred at −70° C. for 20 min and warmed to room temperature. After stirring overnight at room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution, acidified with 1 N hydrochloric acid, and extracted into ethyl acetate (twice). The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to give an off-white powder, 1.97 g (51%), as a mixture of monoaryl and diaryl boronic acids. 1H-NMR (δ, CDCl3): 7.2-7.4 (m, 1H), 7.5-7.7 (m, 3H), 8.0-8.5 (m, 1H), 8.5 and 9.2 (m, 1H); APCI (−) (%): 189 (parent−1, 60).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[S:19][CH:18]=[N:17][CH:16]=1)CCC.[F-].[Cs+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Cc1cc(Cl)cc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Product: Cc1cc(Cl)cc(-c2cncs2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-methylpyridine (29 mg, 0.18 mmol), 5-(tributylstannyl)thiazole (66 mg, 0.18 mmol), CuI (8 mg, 0.04 mmol), CsF (81 mg, 0.53 mmol), and Pd(PPh3)4 (10 mg, 8.9 μmol). The vial was capped with a septum screw-cap and then placed under N2 atmosphere. To the vial was added degassed DMF (1 mL). The vial was placed in a 80° C. heating block with stirring for 1 hour. The mixture was allowed to cool to room temperature and was then directly purified via C18 chromatography (water:MeOH w/0.1% TFA) to afford 5-(4-chloro-6-methylpyridin-2-yl)thiazole as a white solid. MS: MS m/z 211.1 (M++1). This material was directly carried forward into step 2.
Reaction SMILES: [ClH:1].CN1C(C)=CC(=O)C(O)=C1COC.Cl.[CH3:16][N:17]1[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([O:25]CC2C=CC=CC=2)=[C:18]1[CH:33]([O:35][CH3:36])[CH3:34]>[Pd]>[ClH:1].[CH3:16][N:17]1[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([OH:25])=[C:18]1[CH:33]([O:35][CH3:36])[CH3:34]
Reactant: COC(C)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd]
Agent: COCc1c(O)c(=O)cc(C)n1C
Agent: Cl
Product: COC(C)c1c(O)c(=O)cc(C)n1C
Yield: 90 %

Procedure:
In an analogous hydrogenation procedure in the preparation of 1,6-dimethyl-2-methoxymethyl-3-hydroxy-pyridin-4(1H)-one hydrochloride using 1,6-dimethyl-2-(1-methoxyethyl)-3-benzyloxy-pyridin-4(1H)-one hydrochloride (1.62 g, 5 mmol) and 5% Pd/C catalyst (0.35 g) yield the title compound 1.06 g (90%) after recrystallisation from methanol/diethyl ether, as a white crystalline solid. m.p. 205-207° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CC(O)C>[OH:14][CH2:13][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][O:18][CH:19]([CH3:20])[CH3:21]
Reactant: COC(=O)[C@H](COC(C)C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-Methyl 2-(((benzyloxy)carbonyl)amino)-3-isopropoxypropanoate (0.02 g, 0.068 mmol) was taken in 2-propanol (4 mL) and then NaBH4 (7.69 mg, 0.203 mmol) was added and the mixture stirred for overnight at 50° C. After cooling to 0° C., the mixture was quenched with 1N HCl and then extracted with diethyl ether (10 mL). The diethyl ether layer was collected and concentrated under reduced pressure to afford (R)-benzyl (1-hydroxy-3 isopropoxypropan-2-yl)carbamate) (14 mg, 0.058 mmol, 86% crude yield) as colorless oil. The product was carried on without further purification. 1H NMR (400 MHz, MeOD) δ 7.31-7.48 (m, 5H), 5.12 (s, 1H), 4.81 (bs, 1H), 3.41-3.91 (m, 6H), 1.12-1.26 (m, 6H).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C(C)C)=N2)C=CC=1C#N.NC1C=CC(C(N2CCCC2)=[O:84])=CC=1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:84])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccc(C(=O)N4CCCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Agent: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 59 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-{4-(pyrrolidine-1-carbonyl)phenylamino}benzonitrile was prepared using compound (6d) instead of compound (1e) and using (4-aminophenyl)(pyrrolidin-1-yl)methanone instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (34) (the second stage yield: 59%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-{4-(pyrrolidine-1-carbonyl)phenylamino}benzonitrile instead of compound (1f).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[N:10]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:16][C:11]1[CH:12]=[C:13]([Cl:15])[N:14]=[C:9]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: NC1CCCCC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)nc(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a solution of cyclohexanamine (1.1 mL, 9.57 mmol) in ethyl acetate (10 mL) was added 2,4,6-trichloropyrimidine (1.0 mL, 8.70 mmol) dropwise at 0° C. followed by dropwise addition of diisopropylethylamine (1.8 mL, 10.4 mmol). The reaction was warmed to ambient temperature and stirred for 3 h. Additional cyclohexanamine (0.3 mL) and diisopropylethylamine (0.5 mL) were added. After 4 h, the mixture was diluted with ethyl acetate and washed with 20% brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting oil was purified by flash chromatography on silica gel eluting with a gradient of 92:8 to 85:15 hexane/ethyl acetate to give 0.740 g (35%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:9]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc(Nc2ccccc2)cc1
Reaction time: 4 h

Procedure:
A mixture of 198 g. of methyl 4-chlorobutyrate, 269 g. of p-anilinophenol, and 636 g. of anhydrous potassium carbonate, all in 500 ml. of N,N-dimethylformamide was heated at 140° C. while stirring for 4 hours and about 300 ml. of the N,N-dimethylformamide was removed by distillation. The residue was poured into ice water and the resulting mixture was extracted with benzene. The dried benzene extract was chromatographed through a column of neutral alumina and the benzene solvent was stripped from the eluent leaving the product, methyl 4-(p-anilinophenoxy)butyrate, as a dark amber liquid. This ester was sufficiently pure to be used as an antioxidant. Crystallization of the crude ester from ethanol afforded a solid, mp. 40°-41° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[C:41]([CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)([O:43][CH3:44])=[O:42]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([N:47]4[CH2:48][CH2:49][CH:45]([C:41]([O:43][CH3:44])=[O:42])[CH2:46]4)=[O:21])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Reactant: COC(=O)C1CCNC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C1CCN(C(=O)c2ccc(CCC3CNc4nc(N)nc(O)c4C3)s2)C1
Yield: 38.5 %

Procedure:
To a sample of 150 mg (0.47 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.6 mL anhydrous dimethylformamide and 0.11 mL (0.99 mmol) of N-methylmorpholine. The reaction mixture was stirred and 90 mg (0.51 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine were added at once. The reaction mixture was stirred at room temperature for 0.5 hours and 162 mg (1.25 mmol) of 3-carbomethoxypyrrolidine were added in 1.0 mL of dimethylformamide. After stirring at room temperature for another 3.5 hours, the reaction was concentrated in vacuo and the residue was chromatographed on silica gel with 2-8% CH3OH/CHCl3 to give 78 mg (40%) of methyl 1-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl}pyrrolidine-3-carboxylate as a white solid. Mass Spectrum (FAB+): M+1=432; IR (KBr, cm-1): 643, 734, 768, 809, 1219, 1336, 1417, 1464, 1601, 1684, 1736, 2854, 2924, 3390; UV (C2H5 OH): λmax =222 (ε=21034), 279 (ε=19777).