Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.C[O:43][C:44]([C:46]1[CH:51]=[CH:50][C:49](Br)=[CH:48][N:47]=1)=[O:45]>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:49]3[CH:50]=[CH:51][C:46]([C:44]([OH:43])=[O:45])=[N:47][CH:48]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (1.3 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one (0.60 g) and 5-bromo-pyridine-2-carboxylic acid methyl ester (0.41 g) in N,N-dimethylformamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane complex (61 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted with water and brine. The aqueous extracts were combined, acidified (pH ca. 5-6) using citric acid, and extracted with CH2Cl2/MeOH (ca. 10:1). The combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2→50:50) to afford the title compound as a resin-like solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:28])[NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[N:19]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)(C)(C)C.FC(F)(F)C(O)=O.[Cl:37]CCl>>[ClH:37].[NH2:7][C@@H:8]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:16]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:25])[CH3:26])[N:19]=1)=[O:28]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCO2)NC(=O)OC(C)(C)C)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCO2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(S)-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-2-(tetrahydro-pyran-2-yl)-ethyl]-carbamic acid t-butyl ester (570 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 30 min. Solvents were evaporated and the residue was dried in vacuo. The waxy solid was dissolved in a methanolic hydrogen chloride solution. Solvents were evaporated and the residue was dried in vacuo. The white solid was triturated with diethyl ether and filtered to afford (S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (529 mg). LR-ES-MS m/z calculated for C15H26N4O3 310 [M]+, observed [M+H]+ 311.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][CH:29]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O3 (m/e) 420, obsd 421 (M+H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[N:16]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1
Yield: 66 %

Procedure:
A solution of 24 g (0.1199 mol) of the compound of (b), 15 ml (12.78 g/0.1796 mol) of pyrrolidone, 240 mg of p-toluenesulfonic acid, and 100 ml of benzene is stirred at reflux with the azeotropic removal of water for 6 hours. After cooling, the resulting precipitate is collected and triturated with ethyl ether to afford 20 g (66%) of title compound: m.p. 126°-129° C.; IR (KBr) 2200, 1635, and 1600 cm-1 ; 'H NMR (CDCl3) δ 7.48 (d, 2H), 6.7 (d, 2H), 4.3-4.1 (m, 1H), 3.95-3.45 (m, 4H), 3.2-2.85 (m, 4H), 2.65-2.25 (m, 2H), and 1.95-1.75 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[NH:36]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][S:46][CH2:47][CH2:48][NH2:49])[N:44]=1)[C:37]([NH2:39])=[NH:38]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:24]([NH:49][CH2:48][CH2:47][S:46][CH2:45][C:43]2[N:44]=[C:40]([NH:36][C:37]([NH2:39])=[NH:38])[S:41][CH:42]=2)=[O:25])[CH3:17])=[CH:6][CH:7]=1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.75 g (2 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.54 g (2.3 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=589 ([M+H]+, 2), 230 (100); IR (KBr): 1650 cm-1 (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: from 90° C. with decomposition.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][C@@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:6]1[OH:23])[CH:2]=[CH2:3].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)(Cl)Cl>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C@@H:19]([O:20][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:18]([CH2:21][O:22][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:17][C@@H:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C@@H:6]1[O:23][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCO[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](Oc2ccc(OC)cc2)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](Oc2ccc(OC)cc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of compound 8 (1.21 g, 3.71 mmol) in anhydrous DMF (15 mL), under nitrogen and cooled at 0° C., was added NaH (116 mg, 4.83 mmol). The reaction mixture was stirred 15 minutes at 0° C. and treated with benzyl bromide (0.66 mL, 5.57 mmol). After 12 hours at room temperature, the reaction mixture was cooled at 0° C., quenched by slow addition of water and extracted with chloroform. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, filtered and the solvents were evaporated. Purification by chromatography on silica gel (ethyl acetate-petroleum ether, v/v 1:3) afforded 91% as white crystals in 91% yield (2.01 g). mp=59-61° C.; [αD]24=−23° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3): δ3.48 (dd, 1H, J2,3 9.6 Hz, J3,4 2.8 Hz, H-3), 3.63 (bs, 3H, H-5, H-6a and H-6b), 3.75 (s, 3H, OMe), 3.90 (d, 1H, J4,5<1.5 Hz, H-4), 4.01 (dd, 1H, J1,2 7.8 Hz, H-2), 4.22 (m, 2H, OCH2), 4.40, 4.45, 4.64, 4.84, 4.96 and 4.97 (6 d, 1H each, JA,B 11.7 Hz, CH2Ph), 4.83 (d, 1H, H-1), 5.19 and 5.33 (2 dd, 1H each, CH═CH2), 5.95 (m, 1H, CH═CH2), 6.78 and 7.02 (2 d, 2H each, C6H4), 7.22-7.40 (m, 15H, 3C6H5). Anal. Calcd for C37H40O7 (596.7): C 74.48, H 6.76; found: C 74.32, H 6.75.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[C:4](C)[CH:3]=1.BrC1C=CC(S(Cl)(=O)=O)=C([O:32][C:33]([F:36])([F:35])[F:34])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[C:4]([O:32][C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)NCCN1CCOCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(Br)cc1OC(F)(F)F

Procedure:
The title compound was prepared in the same manner as described for 4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide, replacing 4-bromo-2-methyl-benzene sulfonyl chloride with 4-bromo-2-trifluoromethoxybenzene sulfonyl chloride. 1H-NMR (DMSO-d6) δ 7.88 to 7.77 (m, 4H), 3.43 (t, J=4.2 Hz, 4H), 2.99 to 2.97 (broad s, 2H), 2.29 to 2.20 (m, 6H); MS LC-MS [M+H]+=433 & 435, RT=2.03 min.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)=[C:7]([C:24]([O:26][CH3:27])=[O:25])[CH:6]=1)(=[O:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][C:34]=3[O:36][CH3:37])=[CH:19][CH:18]=2)=[C:7]([C:24]([O:26][CH3:27])=[O:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(-c2ccc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere, the product of Step 3 (25 g), 2,4-dimethoxyphenylboronic acid (11.1 g) and sodium carbonate (14.2 g) were stirred in 1,2-dimethoxyethane (125 mL) and deionized water (40 mL). A nitrogen purge line was inserted directly into the reaction mixture for 10 minutes and then removed. Tetrakis(triphenylphosphine)palladium(0) (1.4 g) was added to the reaction mixture. It was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was poured into a beaker containing deionized water (1 L) and ice. Concentrated hydrochloric acid was added while stirring vigorously until the pH reached 3. The mixture was transferred to a separatory funnel and extracted with chloroform 3 times (400 mL each time). The organic layers were recovered, combined and then placed directly onto a silica gel column (600 g) eluting with a mixture of 30% ethyl acetate/70% hexanes. Fractions containing product were combined and concentrated by rotary evaporation. The resulting residue was slurried in a minimal amount of a solution of 10% ethyl acetate/90% hexanes. A solid precipitate was collected by vacuum filtration. 25.4 grams of methyl 4-acetoxy-1-(2′,4′-dimethoxy-[1,1′-biphenyl]-4-yl)-7-methoxy-2-naphthoate was isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:13][C:14](=O)[CH:15]=[C:16]([NH2:20])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:20][C:16]1[NH:6][N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[C:14](=[O:13])[CH:15]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccccc1CNN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccccc1Cn1[nH]c(N)cc1=O
Reaction time: 8 h

Procedure:
27.5 g of o-methylbenzylhydrazine, dissolved in 100 ml of ethanol, were added dropwise at room temperature to a solution of 32 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 300 ml of ethanol. After standing overnight, the reaction solution was concentrated in vacuo and the compound identified above, which separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 138°, 15 g (37%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH:9]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>C(#N)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:15][CH2:14][CH2:13][N:12]([CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)N(CCO)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCCC#N
Product: CC(C)N(CCOc1cc(Cl)ncn1)C(C)C
Temperature: 180 °C
Yield: 20.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (0.5 g, 3.4 mmol), 2-(diisopropylamino)ethanol (0.44 g, 3.0 mmol), and cesium carbonate (2.18 g, 6.7 mmol) in butyronitrile (4 mL) was heated in a microwave oven at 180° C. for 20 min. Filtration followed by purification using preparative HPLC (XTerra®PrepMS C8 column 10 μm, 30×150 mm; 0.1 M NH4OAc buffer/acetonitrile, (80:20-20:80), as the eluent) gave 0.156 g (20% yield) of the title compound: MS (ESP) m/z 258 (M++1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])[N:19]=1
Reactant: COC(=O)Cc1ccccc1OCc1coc(CCc2nc(-c3ccccc3)oc2C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2ccccc2CC(=O)O)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a mixture of methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetate (0.44 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.34 g, 81%) of 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 109-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5][C:6]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[N:7][CH:8]=1.[N:23]#[C:24]Br>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:24]([NH2:23])=[N:16][C:11]=3[CH:10]=2)=[N:7][CH:8]=1
Reactant: N#CBr
Reactant: COc1cnc(-c2ccc(N)c(N)c2)nc1N1CCOCC1
Solvent: CC#N
Solvent: O
Product: COc1cnc(-c2ccc3[nH]c(N)nc3c2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-benzene-1,2-diamine (0.58 g, 1.0 eq.) and ACN/H2O (5 ml/1 ml). In ice bath, cyanogen bromide (0.3 g, 1.5 eq) was added to mixture solution dropwisely. The solution was stirred overnight at room temperature, quenched with a NaHCO3(sat.) solution, and then filtered to give a light brown solid (0.32 g, 51.78%), which was dried in vacuo to give a product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].C([Mg]Br)(C)C.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[C:3]([F:11])[C:4]=1[O:9][CH3:10]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1c(Cl)ccc(Br)c1F
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (2.6 g, 10.86 mmol) in tetrahydrofuran (30 mL) cooled to −10° C. was added isopropylmagnesium bromide (4.49 mL, 13.03 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled to −10° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.215 mL, 10.86 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirring continued for 16 h. The reaction was quenched with 5% aqueous sodium hydroxide and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.15 g, 7.50 mmol, 69% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 1 H), 7.13 (m, 1 H), 3.96 (s, 3 H), 1.36 (s, 12 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:14]3[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([C:10]([NH:9][CH2:8][C:4]4[CH:3]=[C:2]([C:49]5[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=5)[CH:7]=[CH:6][CH:5]=4)=[O:11])[CH:13]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(Br)c2)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)c1
Yield: 67.2 %

Procedure:
N-[(3-Bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (0.825 g, 1.302 mmol), (3-formylphenyl)boronic acid (0.195 g, 1.302 mmol), potassium carbonate (0.540 g, 3.91 mmol), and Pd(Ph3P)4 (0.075 g, 0.065 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated, and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4 filtered and evaporated to give the crude residue. The residue was taken up in DCM and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give (N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (584.1 mg, 0.875 mmol, 67.2% yield)) as a white solid. LC-MS m/z 659.6 (M+H)+, 1.01 min (ret time); mp 109-112° C.
Reaction SMILES: [CH2:1]([N:8]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC=CC=1.Cl>O>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][C:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)N(Cc1ccccc1)C(=O)CCl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccccc1
Yield: 75 %

Procedure:
34.1 g. (0.1 moles) of diethyl N-benzyl-N-(chloroacetyl)-amino-malonate prepared according to Example 19 and 18.2 ml. (13.2 g., 0.13 moles) of triethyl amine in 100 ml. of benzene are stirred at room temperature for 8 hours. The mixture is shaken with 100 ml. of water, 50 ml. of a 10% aqueous hydrochloric acid solution and again with 100 ml. of water. The organic phase is dried with magnesium sulfate, filtered and from the filtrate benzene is distilled off. The oily residue is distilled at 149° to 150° C., under a pressure of 0.1 mmHg. 23 g. (75%) of the named compound are obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:33](=[O:35])[CH3:34])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2 dram vial was charged with 0.09 g (0.2 mmol) of 4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-2-bromo-phenylamine and 0.87 mL CH2Cl2. This mixture was treated with 36 μL triethylamine (0.26 mmol) and 17 μL acetyl chloride and stirred at rt for 15 h. The reaction was quenched with aqueous 1M NaHCO3, the organic layer separated, dried, and concentrated in vacuo. This gave a quantitative yield of the desired product as a white solid. MS (APCI): 461 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.26 (s, 1H), 6.95–6.93 (m, 1H), 6.7 (d, J=8 Hz, 1H), 3.98 (br s, 2H), 3.57–3.55 (m, 4H), 2.72–2.58 (m, 8H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:15]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-chlorosuccinimide (1 eq, 7.45 g, 55.8 mmol) was added to a solution of ethyl 4-aminophenylacetate (10 g, 55.8 mmol) in chloroform (200 mls). The reaction mixture was stirred at room temperature, under argon, for 15 minutes. The reaction mixture was washed with water (250 mls) and the organic layer collected using a hydrophobic frit. This was evaporated to dryness to give a dark brown oil, 9.8 g.