Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[C@@H:17]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[O:16][C@@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].CC(C)=[O:35]>[N+]([O-])([O-])=O.[Ag+]>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[C@@H:17]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[O:16][C@@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:35])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(CBr)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc(CO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of 1.89 g of the compound 2 in 80 ml of acetone is mixed with an equal volume of a 0.1N aqueous solution of silver nitrate. The mixture is stirred at 25° C. for 2 h, the acetone is then evaporated off under reduced pressure, the remaining aqueous phase is extracted with CH2Cl2 and the extract is washed with water and then dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The dry residue obtained (1.52 g) is then purified by flash chromatography on a column of silica (solvent: hexane/ethyl acetate: 60/40 v/v). The product 4 (0.94 g) is obtained with a yield of 56%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[C:25]1([CH:31]([CH2:36][C:37](Cl)=[O:38])[CH2:32][C:33](Cl)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([N:1]2[C:37](=[O:38])[CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][C:33]2=[O:34])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)CC(CC(=O)Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N2C(=O)CC(c3ccccc3)CC2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a stirred solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.50 g, 2.0 mmol) in chloroform (15 mL) with triethylamine (1.8 mL, 10.0 mmol) was added 3-phenylpentanedioyl dichloride (0.45 g, 1.84 mmol). The mixture was stirred at ambient temperature for 2 h, washed with 20% hydrochloric acid solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from ethyl acetate/hexane to afford a solid, which was washed with cold methanol and dried in air to afford the title compound (0.46 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.50-7.20 (m, 10H), 6.07 (br s, 1H), 4.60 (d, J=5.6 Hz, 2H), 3.60-3.50 (m, 1H), 3.13 (dd, J=17.1, 4.2 Hz, 2H), 2.95 (dd, J=17.1, 12.0 Hz, 2H), 2.68 (s, 3H); MS (ES+) m/z 420.1 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([O:23][CH3:24])[CH:9]=1)(=[O:7])[CH3:6]>O>[C:5]([C:8]1[C:22]([N+:1]([O-:4])=[O:2])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([O:23][CH3:24])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: CCOC(=O)CCCOc1ccc(C(C)=O)cc1OC
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
70% Nitric acid (60 mL) was cooled in an ice bath. Ethyl 4-(4-ethanoyl-2-methoxylphenoxy)butanoate (21 g, 0.075 mol) was added in portions over 20 minutes. The solution was stirred for 1.5 h while monitoring the temperature, which did not rise above 22° C. The solution was cautiously poured into water (800 mL), which was then cooled to 4° C. for several hours. The product was collected via filtration and recrystallized from ethanol (250 mL) to yield ethyl 4-(4-ethanoyl-2-methoxy-5-nitrophenoxy)butanoate (11.04 g, 45.3%) as a yellow flocculent powder. 1H NMR (δ, ppm): 1.31 (t, CO2CH2CH3), 2.21 (p, ArOCH2CH2CH2), 2.52 (s, ArCOCH3), 2.56 (t, ArOCH2CH2CH2), 3.98 (s, ArOCH3), 4.19 (m, ArOCH2 and CO2CH2), 6.76 (d, aromatic H ortho to ArOCH2), 7.65 (s, aromatic H ortho to ArOCH3).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1.Cl.[CH3:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][N:4]1[CH:5]=[CH:6][C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:3]1=[O:2]
Reactant: CN(C)CCCl
Reactant: CCOC(=O)CCc1ccnc(O)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCc1ccn(CCN(C)C)c(=O)c1
Yield: 64.1 %

Procedure:
To a cooled solution of sodium (7.50 g) in ethanol (150 ml) was added a solution of ethyl β-(2-hydroxy-4-pyridyl)propionate (29.07 g) in ethanol (175 ml). After the solution was stirred for 40 minutes a solution of dimethylaminoethyl chloride hydrochloride (21.78 g) in ethanol (175 ml) was added and the reaction mixture was stirred under reflux for 6 hours and then was allowed to cool overnight. The reaction mixture was filtered and evaporated under reduced pressure to remove most of the solvent. Water (150 ml) was added and the solution was extracted with ethyl acetate (3×200 ml). The combined ethyl acetate extracts were dried over MgSO4 and evaporated under reduced pressure to yield an oil which was subjected to medium pressure column chromatography (using Kieselgel 60 silica gel 70-230 mesh-pre column and 230-400 mesh-main column) with gradient elution (dichloromethane→10% methanolic dichloromethane). The fractions containing the desired product were combined and evaporated under reduced pressure to yield ethyl β-[N-(2 -dimethylaminoethyl)-2-oxo-4-pyridyl]propionate (25.43 g) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH3:20][O:21][CH2:22][CH2:23][NH:24][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: COCCN
Product: CCc1cc(-c2cncc(C(=O)NCCOC)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-methoxy-ethyl)-amine to afford the title compound. MS: m/e=316 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:34]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([NH2:34])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(N)=O)n1Cc1ccccc1Cl

Procedure:
(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, prepared in Example 1, was treated with thionyl chloride and then ammonium hydroxide, as described in Example 54, to give the title compound; mp 184°-185° C.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=1>CN(C=O)C>[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)=[CH:7][C:8]=2[O:13][CH3:14])[N:17]=1
Reactant: COc1cc(CCO)ccc1O
Reactant: Fc1cccc(F)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(CCOc2cccc(F)n2)ccc1Oc1cccc(F)n1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To a suspension of KOH (2 mmol; 112 mg) in anhydrous DMF (1 mL) under argon, was added 4-(2-hydroxyethyl)-2-methoxyphenol (1 mmol; 168 mg) followed by 2,6-Difluoropyridine (1 mmol; 0.1 ml). The reaction mixture was stirred at 110° C. for 20 h.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[C:7](=[CH:12][N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]>>[C:16]([O:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[C:7](=[CH:12][N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1cc(NCCO)c2nn(C)cc2n1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)OCCNc1cc(C)nc2cn(C)nc12
Yield: 74 %

Procedure:
The title compound was prepared from 7-(2-hydroxyethylamino)-2,5-dimethylpyrazolo[4,3-b]pyridine (D2) (400 mg) and valeryl chloride by the general method of Example 4. The solid obtained was recrystallized from ether/methanol to give the title compound (300 mg, 74%), m.p. 78°-80° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH3:14])(C(OCC)=O)[C:6]=1[CH2:7][CH3:8].[CH:15](=O)[CH2:16][CH3:17]>>[CH3:1][C:2]1[NH:3][C:4]([CH2:15][CH2:16][CH3:17])=[C:5]([CH3:14])[C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)C1(C)C=NC(C)=C1CC
Reactant: CCC=O
Product: CCCc1[nH]c(C)c(CC)c1C

Procedure:
2,4-Dimethyl-3-ethyl-4-carbethoxy-pyrrole was reductively alkylated with propionaldehyde to yield 2,4-dimethyl-3-ethyl-5-n-propylpyrrole. ##STR102##
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=4[N:18]([CH3:27])[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[N:5][CH:4]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4c(C)ccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.15 g) and N-acetylpiperazine (90 mg) in N,N-dimethylformamide (10 ml) was added potassium carbonate (120 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (95 mg, yield 52%) as colorless crystals. melting point 171-172° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH:22]=1
Reactant: ClCc1cccnc1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccnc2)c1
Yield: 23.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (88 mg, yield: 23.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:22])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methylphenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow oil (0.405 g), which was subsequently deprotected.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH3:14].[C:15]([NH:18][C:19]1[CH:20]=[C:21]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])(=[O:17])[CH3:16]>O1CCCC1>[C:15]([NH:18][C:19]1[CH:20]=[C:21]([S:27]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=3)[C:8]([CH3:14])=[CH:9]2)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])(=[O:17])[CH3:16]
Reactant: COc1ccc2[nH]cc(C)c2c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (2.15 grams, 49.3 mmol) was taken into a 250 mL three-necked round bottom flask containing tetrahydrofuran (50 mL) under nitrogen atmosphere. Added a solution of 5-methoxy-3-methyl indole solution (5.3 grams, 32.9 mmol) in tetrahydrofuran (25 mL) to the above mixture at 25° C., over a period of 15 minutes. The above reaction mass was stirred further for a period of 1 hour and mass was cooled to 0° C. and a solution of 3-acetamido-4-methoxy benzenesulfonyl chloride (13.01 grams, 49.3 mmol) in tetrahydrofuran (65 mL) was added through a dropping funnel over a period of 20 minutes. This mass was allowed to cool to room temperature and stirred over night (˜24 hours). The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction it was quenched into ice water (100 mL) under stirring and extracted the product with ethylacetate (2×250 mL). Organic phase was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain thick syrupy mass, which was used as such for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([CH3:28])[CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][C@H:17]([CH3:28])[CH2:16]1
Reactant: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate (1.40 g, 3.56 mmol, 1.00 equiv), dichloromethane (15 mL). Trifluoroacetic acid (3.80 g, 33.3 mmol, 9.40 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.90 g (86% yield) of 4-(3-fluoro-4-[[(3R)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine as yellow oil. LCMS (ESI, m/z): 294 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:20]([C:15]1[C:14]([CH2:13][O:12][C:9]2[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=2)=[C:18]([CH3:19])[O:17][N:16]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OCC)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (960 mg, 3.0 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (252 mg, 6.0 mmol) in water (10 mL) and the resulting mixture stirred at room temperature for 30 min. The mixture was acidified to pH 1 with HCl (1 N) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (850 mg, 87%) which was obtained as a red gum. MS: m/e=290.1 [M−H]−.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[N:33]([CH3:44])[C:34](=[O:43])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([N:33]([CH3:44])[C:34](=[O:43])[CH2:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:27]([O:26][CH3:25])[CH:28]=3)[C:10]=12
Reactant: COc1cc(B(O)O)ccc1N(C)C(=O)CCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N(C)C(=O)CCc1ccccc1
Temperature: 85 °C

Procedure:
A solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.293 g, 0.664 mmol) in ethylene glycol dimethyl ether (10 mL) was treated with 3-methoxy-4-[methyl(3-phenylpropanoyl)amino]phenylboronic acid (0.290 g, 0.730 mmol), tetrakis(triphenylphosphine)palladium (0.046 g, 0.040 mmol), and a solution of sodium carbonate (0.169 g, 1.59 mmol) in water (5 mL). The reaction mixture was stirred over night at 85° C. under a nitrogen atmosphere. The solvent was removed under reduced pressure, and ethyl acetate was added to the aqueous layer. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 4% methanol in dichloromethane, 8% methanol in dichloromethane, and then 12% methanol in dichloromethane as eluent. A second column using a Supelco flash chromatography silica gel column using 30% methanol in dichloromethane afforded 0.037 g (10%) of cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide. 1H NMR (CDCl3, 400 MHz) δ 8.374 (s, 1H), 7.315-7.312 (m, 1H), 7.285-7.213 (m, 3H), 7.174-7.087 (m, 4H), 5.795 (br. s., 2H), 4.965-4.922 (m, 1H), 3.892 (s, 3H), 3.213 (s, 3H), 2.948-2.918 (m, 2H), 2.667 (m, 6H), 2.455-2.349 (m, 10H), 2.25-2.15 (m, 2H), 1.867-1.845 (m, 2H), 1.718-1.710 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.947 min (98%).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]([CH2:11][N+:12]([O-:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[C:5]([O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)CCC>CN(C=O)C.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>[CH2:17]([O:16][C:5]1[C:6]2[B:7]([OH:15])[O:8][CH:9]([CH2:11][N+:12]([O-:14])=[O:13])[C:10]=2[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][CH:4]=1)[CH3:18]
Reactant: CCOc1ccc(Br)c2c1B(O)OC2C[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccccc2)c2c1B(O)OC2C[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A mixture of 4-bromo-7-ethoxy-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (315 mg, 1 mmol), tributyl-phenyl-stannane (750 mg, 2 mmol) and Pd(Ph3P)4 (Cat.) in DMF (15 mL) was degassed for 15 min with N2 and then stirred at 100° C. for 30 min in microwave reactor (Biotage). After the reaction was quenched with ice-water, the resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and then concentrated to dryness. The residue was purified by column chromatography on silica gel to give the compound as white solid (60 mg, yield 20%). 1HNMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.46-7.49 (m, 5H), 7.34-7.48 (m, 2H), 6.17-6.20 (m, 1H), 4.88-4.92 (m, 1H), 4.21-4.25 (m, 1H), 4.05-4.16 (m, 2H), 1.34-1.37 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([O:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]2)=[N:4][C:5]([N:9]2C(C)=CC=C2C)=[N:6][C:7]=1[CH3:8].Cl.NO.C(O)C>O>[NH2:9][C:5]1[N:4]=[C:3]([NH:16][C@@H:17]2[CH2:18][CH2:19][C@H:20]([O:23][CH2:24][CH2:25][OH:26])[CH2:21][CH2:22]2)[C:2]([Br:1])=[C:7]([CH3:8])[N:6]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(N[C@H]2CC[C@@H](OCCO)CC2)c1Br
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(N[C@H]2CC[C@@H](OCCO)CC2)c1Br
Yield: 69.4 %

Procedure:
A solution of 2-(cis-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol (1.23 g, 2.91 mmol) and hydroxylamine hydrochloride (1.01 g, 14.5 mmol) in 10:1 ethanol:water (22.0 mL) was heated to reflux overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0-4%) to afford the title compound (697 mg, 70%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12](Br)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC[O-].[Na+].[Na]>C(O)C>[CH2:12]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)C(=O)OCC

Procedure:
45 g of diethyl malonate and 30 g of phenethyl bromide were mixed and added dropwise, cooling in ice, to a solution of sodium ethylate prepared from 6.5 g of sodium and 130 ml of absolute ethanol. The mixture was then boiled under reflux for 6 hours and allowed to cool down overnight. The major part of the ethanol was removed in vacuo, the residue was taken up in water, extracted with ether, this was dried over Na2SO4, evaporated and distilled.