Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:37])(=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:38])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:38][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:36])(=[O:37])[NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCc3ccc(OC)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(CNS(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(Cl)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Lithium hydroxide monohydrate (0.029 g, 0.68 mmol) was added to a solution {6-chloro-4-[4-(4-methoxy-benzylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.090 g, 0.18 mmol) in a 3:1 mixture of THF—H2O mixture (12 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave {6-chloro-4-[4-(4-methoxy-benzylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.086 g, 98%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43-12.61 (m, 1 H), 8.22 (t, J=6.30 Hz, 1 H), 7.98 (d, J=8.80 Hz, 1 H), 7.89-7.95 (m, 3 H), 7.49 (dd, J=8.80, 2.20 Hz, 1 H), 7.42 (d, J=7.83 Hz, 2 H), 7.15 (d, J=8.80 Hz, 2 H), 7.04 (d, J=1.96 Hz, 1 H), 6.81-6.86 (m, 2 H), 4.09 (d, J=5.87 Hz, 2 H), 3.86 (s, 2 H), 3.68 (s, 3 H), 2.06 (s, 3 H). MS calcd. for C27H23ClNO5S [(M−H)−] 508, obsd. 508.3.
Reaction SMILES: C1(O)C=CC=CC=1.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH2:19])[CH:12]=[CH:11][CH:10]=1.[CH:20]1[CH:25]=[C:24]2[C:26](O[C:29]([C:31]3=[CH:32][CH:33]=[CH:34][C:22](=[C:23]23)[CH:21]=1)=O)=[O:27]>CO>[CH:16]1[C:17]2=[C:18]3[C:13]([CH:12]=[CH:11][CH:10]=[C:9]3[N:8]=[C:29]3[C:31]4[CH:32]=[CH:33][CH:34]=[C:22]5[CH:21]=[CH:20][CH:25]=[C:24]([C:23]=45)[C:26](=[O:27])[N:19]32)=[CH:14][CH:15]=1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: Nc1cccc2cccc(N)c12
Solvent: Oc1ccccc1
Solvent: CO
Product: O=c1c2cccc3cccc(c32)c2nc3cccc4cccc(c43)n12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
250 g of phenol are melted at about 60° C. 47.4 g of 1,8-diaminonaphthalene and 59.4 g of 1,8-naphthalic acid anhydride are introduced, while passing over nitrogen, and the mixture is heated to 150° C. in the course of 1 hour and kept at this temperature for 2 hours. The reaction mixture is cooled to 80° C., 120 ml of methanol are added at a temperature of 80° to 65° C. in the course of 30 minutes, and the mixture is cooled to room temperature and filtered with suction. After the residue has been washed with 240 ml of methanol and dried at 150° C., 88.8 g of the stated dyestuff are obtained in a very good quality.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:9][C:10](S(C)(=O)=O)=[N:11][C:12]=1[Cl:13])=[O:6])[CH:2]=[CH2:3].[C-:34]#[N:35].[Na+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:4][C:5]([C:7]1[C:8]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:9][C:10]([C:34]#[N:35])=[N:11][C:12]=1[Cl:13])=[O:6])[CH:2]=[CH2:3]
Reactant: [C-]#N
Reactant: C=CCOC(=O)c1c(Cl)nc(S(C)(=O)=O)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)c1c(Cl)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic procedure as described in Ref. Example 2, a solution of 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]6-chloro-2-methanesulfonylpyrimidine-5-carboxylic acid allyl ester (1.8 mmol) in CH2Cl2 (5 mL) is treated with a solution of NaCN (2.2 mmol) and tetra-n-butylammonium bromide (0.10 mmol) in water (2 mL) for 0.5 h. After usual work-up, the crude material is purified by silica gel chromatography to give 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-6-chloro-2-cyanopyrimidine-5-carboxylic acid allyl ester as colorless oil; 1H-NMR (CDCl3), δ: 1.12-1.73 (9H, m), 1.48 (9H, s), 2.68 (2H, brt), 4.05-4.09 (2H, m), 4.55 (2H, t), 4.87 (2H, dt), 5.33-5.37 (1H, m), 5.41-5.47 (1H, m), 5.98 (1H, ddt).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:13][CH2:12]2.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1>C(OCC)(=O)C.O>[C:36]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:13][CH2:12]3)=[CH:34][CH:33]=1)(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Oc1ccc2c(c1)CCC(CCN1CCCCC1)C2
Reactant: O=C(Nc1ccc(CBr)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1)c1ccccc1
Reaction time: 1 h
Yield: 22.1 %

Procedure:
Sodium hydride (60% oily, 85 mg) was added to DMF solution of 6-hydroxy-2-(2-piperidinoethyl)tetralin (500 mg) at room temperature, which was stirred for 1 hour. N-[4-(bromomethyl)phenyl]benzamide (670 mg) was added to the reaction mixture at room temperature, which was stirred for 1 hour. Water was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: THF), and recrystallized (ethyl acetate) to give the titled compound (200 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:24]([O:41][CH3:42])[CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:24]([O:41][CH3:42])[CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 98.2 %

Procedure:
To a mixture of ethyl (2E)-3-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoate (1.20 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was heated under reflux for 3 hrs. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the precipitated crystals were collected by filtration to give (2E)-3-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoic acid as colorless crystals (1.12 g, yield 98%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [OH:1]O.[F:3][C:4]1([F:12])[CH2:7][CH:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH2:5]1.O=O>CO.O.[Pd]>[OH2:1].[F:3][C:4]1([F:12])[CH2:7][CH:6]([CH2:8][N+:9]([O-:1])([CH3:11])[CH3:10])[CH2:5]1
Reactant: CN(C)CC1CC(F)(F)C1
Reactant: OO
Agent: [Pd]
Agent: O=O
Solvent: CO
Solvent: O
Product: C[N+](C)([O-])CC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
30% Aqueous H2O2 (18 mL) was added dropwise to a stirred solution of 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine (12 g, 80 mmol) prepared in Part B in methanol (100 mL) at 5 to 22° C. over 2 h. After stirring at RT for 20 h, additional 30% H2O2 (18 mL) was added. After 3 h, Pd black slurry (150 mg) in water (3 mL) was added to the stirred reaction mixture in small portions such that the temperature could be maintained between 5 to 25° C. with a cooling bath. The reaction mixture was stirred at RT for 1 h until the O2 evolution ceased. After filtration, the filtrate was concentrated in vacuo to give 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine oxide hydrate as a thick colorless oil (15 g, semisolid). 1H NMR (400 MHz, CD3OD) δ ppm 3.47 (2 H, d, J=5.29 Hz), 3.16 (6 H, s), 2.75-2.92 (3 H, m), 2.42-2.58 (2 H, m).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].BrC[CH2:23][C:24]([N:26]([CH:37]([CH3:39])[CH3:38])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)=[O:25].O>CN(C=O)C>[CH:37]([N:26]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=1)[C:24](=[O:25])[CH2:23][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:39])[CH3:38]
Reactant: CC(C)N(C(=O)CCBr)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a stirred solution of 1.16 g (6.32 mmol) of N-Phenyl phenylenediamine in 15 mL of DMF is added 1.05 g (7.58 mmol, 1.2 equiv) of K2CO3 and 2.05 g (6.32 mmol) of Bromomethyl-N-isopropyl-N-(4-trifluoromethyl-phenyl) acetamide. The resulting mixture is stirred 1 h at RT then is heated to 50° C. for 16 h. The reaction mixture is then cooled to RT, poured into 100 mL H2O and extracted with Et2O (2×100 mL). The organic layers were washed in series with 1N HCl (2×80 mL), NaHCO3 (1×80 mL), and H2O (1×80 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 2.05 g of N-Isopropyl-2-(2-phenylamino-phenylamino)-N-(4-trifluoromethyl-phenyl)-acetamide as a light tan solid: 1H NMR (CDCl3, 400 MHz) δ7.72 (d, 2H, J=8.2), 7.26 (d, 2H, J=8.2), 7.15 (m, 3H), 6.95 (dd, 1H, J=7.7, 7.7), 6.80 (dd, 1H, J=7.1, 7.1), 6.74 (d, 2H, J=7.9), 6.68 (dd, 1H, J=7.4, 7.4), 6.29 (d, 1H, J=7.9), 5.20 (s, 1H), 5.00 (m, 1H), 3.40 (s, 2H), 1.06 (d, 6H, J=6.6); low resolution MS (FAB)m/e 427 (MH+); high resolution MS (C24H24F3N3O) Calc. 427.1871 Found 427.1871.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:31][C:32]([S:35][CH2:36][C:37](O)=[O:38])([F:34])[F:33]>C(N(CC)CC)C>[F:31][C:32]([S:35][CH2:36][C:37]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:17][N:18]=[N:19][N:20]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:38])([F:34])[F:33]
Reactant: O=C(O)CSC(F)(F)F
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 3.85 g. (0.01 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide was treated with 2 ml. of triethylamine and the mixture was stirred for 15 minutes at 25°. The activated ester of trifluoromethylmercaptoacetic acid (2.57 g., 0.016 mol.) was added to the mixture and it was stirred an additional hour. The reaction mixture was evaporated to dryness and water and ethyl acetate were added to the residue. The layers were separated, ethyl acetate was added to the aqueous phase and it was acidified to pH 2.5 by addition of 6 N hydrochloric acid. The mixture was filtered, the layers were separated and the aqueous phase was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=2[N:11]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[F:22][C:23]([F:31])([F:32])[C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([NH:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][C:12]=2[CH:18]=1)=[O:20]
Reactant: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 0.75 h

Procedure:
A mixture of 2-(2,6-dichloro-phenylamino)-1H-benzimidazole-5-carboxylic acid (600 mg, 1.86 mmol) and 1-chloro-N,N-2-trimethyl-1-propenylamin (420 μL, 3.2 mmol) in 8 mL dichloromethane was stirred for 45 min. 2-Trifluoromethyl-aniline (2.3 mL, 18.6 mmol) in pyridine was added. After stirring overnight, the mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated i.vac.
Reaction SMILES: Br[C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Li])CCC.[B:38](OC(C)C)([O:43]C(C)C)[O:39]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:3]2[C:2]([B:38]([OH:43])[OH:39])=[CH:6][N:5]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]=2)=[CH:27][CH:28]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
47.5 g 4-bromo-3-(4-fluorophenyl)-1-trityl-1H-pyrazole was dissolved in 400 mL anhydrous tetrahydrofuran, and then 40.7 mL solution of 1.6 M n-butyl lithium in hexane was added dropwise thereto at −70° C. The mixture was stirred for 30 minutes, 17.2 mL triisopropyl borate was added dropwise thereto, and the mixture was stirred at −70° C. for 1 hour and at −40° C. for 1 hour. The temperature was increased to 0° C., 50 mL aqueous saturated ammonium chloride solution was added thereto and stirred for 30 minutes, and water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was removed under reduced pressure, and upon addition of toluene to the resulting oil, colorless crystals were formed. The crystals were collected by filtration, to give 31 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#N)=[N:6][CH:7]=1.B(F)(F)F.CC[O:16][CH2:17]C.C([O-])(O)=[O:20].[Na+]>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:16][CH3:17])=[O:20])=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cnc(N)cn1
Reactant: CCOCC
Agent: FB(F)F
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(N)cn1
Yield: 49 %

Procedure:
Reflux a solution of 2.24 g (18.65 mmol) of 5-aminopyrazine-2-carbonitrile and 9.45 mL (74.40 mmol) of boron trifluoride etherate in 50 mL of methanol for 2 h. Concentrate the reaction mixture under reduced pressure and take up the residue obtained in 200 mL of EtOAc and 10 mL of a saturated aqueous solution of NaHCO3. Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc 1:1 mixture. After concentration under reduced pressure, we obtain 1.4 g of methyl 5-aminopyrazine-2-carboxylate in the form of oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=1)[CH2:32][O:33][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[Cl:10].[Na+].[I-].[C:13]([S-:15])#[N:14].[K+]>CN(C=O)C.O>[Cl:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:2][N:14]=[C:13]=[S:15]
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)c(CN=C=S)c1
Temperature: 90 °C

Procedure:
To a solution of 2-(bromomethyl)-1-chloro-4-fluorobenzene (25, 22.3 g, 100 mmol) in dry DMF (150 mL) were added NaI (16.0 g, 107 mmol) and KSCN (19.5 g, 200 mmol) The mixture was heated under N2 at 90° C. for 18 h. After cooling to RT, the mixture was diluted with water (200 mL), and extracted with EtOAc (200 mL×2). The combined extracts were washed with brine, dried over MgSO4, and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with petroleum ether to provide 1-chloro-4-fluoro-2-(isothiocyanatomethyl)benzene (26).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:21][OH:22])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH:39]=O)[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[NH4+:45]>C(O)(=O)C>[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]2[N:21]([OH:22])[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:45]=2)[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(C(=NO)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c(-c3ccnc(F)c3)n2O)CC1
Temperature: 75 °C

Procedure:
To a mixture of 1-(2-fluoropyridin-4-yl)-2-(3-trifluoromethylphenyl)ethane-1,2-dione-1-oxime (11.4 g, 0.037 mole) and N-benzyloxycarbonylpiperidin-4-carboxaldehyde [Amici et al Eur. J. Med. Chem. 26, 625-631 (1991)] (9.93 g, 0.040 mol), in acetic acid (250 mL) was added ammonium acetate (56.29 g, 0.730 mole). The mixture was heated to 75° C. for 1H, cooled and concentrated to remove most of the acetic acid. The residue was poured into concentrated NH4OH (100 mL), ice (200 g) and methylene chloride (800 mL) and the pH adjusted to 8 with NH4OH. The methylene chloride layer was removed and the aqueous layer washed with methylene chloride (2×300 mL). The combined organic phases were washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give an oil used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][N:75]1[CH2:80][CH2:79][CH:78]([NH2:81])[CH2:77][CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:81][CH:78]4[CH2:79][CH2:80][N:75]([CH3:74])[CH2:76][CH2:77]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 1-methylpiperidin-4-amine (10 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 1-methylpiperidin-4-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(1-methylpiperidin-4-yl)acetamide. (49 mg, 0.097 mmol, 69%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([OH:18])[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]([O:31][C@@H:32]1[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:34][C@@H:33]1Br)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(#N)C>O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([O:18][C@@H:33]4[O:34][C@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:32]4[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1n[nH]c2nccc(CCc3ccccc3)c12
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
A mixture of 4-(2-phenylethyl)-1H-pyrazolo[3,4-b]-pyridin-3-ol (0.59 g), potassium carbonate (0.68 g), 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (1.71 g) and acetonitrile (10 mL) was stirred at 50° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) to give the title compound (0.22 g).