Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:40]=2)[CH:35]=[CH:34]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:39]2[CH:40]=[C:41]3[C:36]([CH:35]=[CH:34][N:33]3[CH3:32])=[CH:37][CH:38]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: Cn1ccc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccn(C)c2c1
Yield: 73.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.129 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.076 g (61%) of the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([S:8][C:9](=N)N)=[N:6][N:5]=[N:4]1.[OH-].[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([CH2:22][CH2:23]CCl)=[O:21]>C(O)C>[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH2:23][CH2:22][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[O:21])=[N:6][N:5]=[N:4]1
Reactant: Cn1nnnc1SC(=N)N
Reactant: O=C(CCCCl)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Yield: 19.5 %

Procedure:
S-(1-Methyl-1,2,3,4-tetrazole-5-yl)isothiourea hydrochloride (1.9 g) is dissolved in ethanol (50 ml). To the solution are added 10% aqueous sodium hydroxide (5 ml) and 3-chloropropyl 2-pyridyl ketone (1.8 g) and the mixture is refluxed for 2 hours. Ethanol is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200, eluant: chloroform) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole (0.5 g) as colorless needles, m.p. 73°-75° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH:9][CH2:10][CH3:11])[N:5]=[C:4]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[N:13]2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH:9][CH2:10][CH3:11])[N:5]=[C:4]([N:12]2[CH:16]=[C:15]([C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=[N:13]2)[N:3]=1
Reactant: C1COCCN1
Reactant: CCNc1nc(-n2cc(C(=O)O)cn2)nc(N)c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNc1nc(-n2cc(C(=O)N3CCOCC3)cn2)nc(N)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
A mixture of 50 mg (0.15 mmol) of 1-[4-amino-5-bromo-6-(ethylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (example 48), 15 μl (0.17 mmol) of morpholine, 32 μl (0.23 mmol) of triethylamine and 64 mg (0.17 mmol) of HATU in 1 ml of acetonitrile was stirred at room temperature for 10 min. The formed precipitate was filtered, washed with cold water and dried. 39 mg (64.4%) of a white solid were obtained.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[O:9]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>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>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1nccnc1Cl
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Nc1nccnc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 96.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.268 g) was added to a suspension of 3-chloropyrazin-2-amine (1.00 g), 4-phenoxyphenylboronic acid (2.15 g) and sodium carbonate (1.64 g) in DME (37.5 mL) and water (7.5 mL) and the mixture was stirred at 80° C. under N2 for 4 hr. The reaction mixture was added with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.97 g) as a white solid.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:23](=[CH2:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CS(C)=O>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[C:16]=1[C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:29]1
Reactant: C=C(C(=O)OCC)c1c(OC)cccc1OC
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(c2c(OC)cccc2OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To trimethylsulfoxonium iodide (32 g, 1.2 equiv) in DMSO (250 ml) was added ground KOt-Bu (17.62 g, 1.3 equiv) and this mixture was stirred at r.t. for 30 min. A solution of the styrene 17 (28.53 g, 121 mmol) in DMSO (55 ml) was then added and this mixture was stirred at r.t. for 3 h. The reaction was poured into water (1.0 L) mixed with sat. NHCl (350 ml). The product was extracted into hexane (2×300 ml) and this solution was washed with water and brine, dried over Na2SO4 and filtered through silica (400 ml). The product was then eluted with EtOAc/hexane 15 and 20% to yield 18 (21.1 g, 70%) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:13][CH:14]=[CH:15][CH2:16]Cl.O.CCOCC>C(O)C>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH:15]1[CH:14]=[CH2:13])=[O:8])[CH3:11]
Reactant: ClCC=CCCl
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC

Procedure:
To a solution of 18.4 g (2 equivalents) in 300 ml of anhydrous ethanol is added rapidly 164 g (1 equivalent) of diethyl malonate. 1,4-Dichloro-2-butene (98% mixture of cis and trans, Aldrich) (50 g, 1 equivalent) is slowly added to the warm, stirred suspension of the diethyl sodio malonate during 15 minutes after which the mixture is refluxed for 3 hours. Upon cooling, the mixture is poured into 1.2 liters of water and an oil isolated by ether extraction. The ether extract is dried over magnesium sulfate and distilled to give 1,1-bis-ethoxycarbonyl-2-vinylcyclopropane, B.P. 108°-116° C./14 mm.
Reaction SMILES: CC(C)([O-:4])C.[K+].[CH:7]([OH:14])(O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([O:4][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][OH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCC(O)O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Pure potassium t-butoxide (50 mmoles, 5.61 g) is added portionwise to a stirred solution of 100 mmoles of hexanediol (11.82 gr) dissolved in 30 ml of THF at room temperature under argon. When addition is complete, 50 mmoles of benzylbromide (5.9 ml) are introduced and the reaction mixture is stirred at room temperature overnight. The white solid is then removed by filtration, the filtrate is evaporated and the residue is dissolved in ethylacetate, washed with saturated ammonium chloride, H2O and brine. Usual workup and purification by flash chromatography gives finally 7.51 g of product (72%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:25]([F:28])([F:27])[F:26])[N:15]=2)=[CH:10][CH:9]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>CC(=O)CC>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:23]=[C:22]([O:24][CH2:30][C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:25]([F:28])([F:26])[F:27])[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: Cc1ccc(C2=Nc3cccc(C(F)(F)F)c3C(=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(C(F)(F)F)cccc3n2)cc1
Temperature: 20 °C
Yield: 76.3 %

Procedure:
Anhydrous potassium carbonate (2.2 g) is added to a stirred suspension of 2-(4-methylphenyl)-5-trifluoromethyl-4-quinolone (2.4 g) and 4-(2-chloroacetyl)morpholine (1.3 g) in 2-butanone (50 cc). The mixture is heated to reflux for 3 hours and cooled to room temperature (approximately 20° C.). The insoluble matter is removed by filtration and rinsed with 2-butanone. The organic phases are combined and the solvent is removed under reduced pressure. After recrystallation of the residue from acetonitrile, 4-{[2(4-methylphenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morpholine (2.6 g), m.p. 172° C. is isolated.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].[F:11][C@@H:12]1[C:32]2[C@:27]([CH3:34])([CH:28]=[CH:29][C:30](=[O:33])[CH:31]=2)[C@@H:26]2[C@H:14]([C@H:15]3[C@:23]([CH3:36])([CH2:24][C@@H:25]2[OH:35])[C@@:18]([OH:37])([C:19](=[O:22])[CH2:20][OH:21])[C@H:17]([OH:38])[CH2:16]3)[CH2:13]1>>[F:11][C@@H:12]1[C:32]2[C@:27]([CH3:34])([CH:28]=[CH:29][C:30](=[O:33])[CH:31]=2)[C@@H:26]2[C@H:14]([C@H:15]3[C@:23]([CH3:36])([CH2:24][C@@H:25]2[OH:35])[C@@:18]([OH:37])([C:19](=[O:22])[CH2:20][OH:21])[C@H:17]([O:38][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[CH2:16]3)[CH2:13]1
Reactant: CCOC(C=[N+]=[N-])OCC
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)OCC

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.18 mole of precursor as described in Example 2A) in methanolether at 0°C is treated with 6α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate until nitrogen evolution ceases. The solution is evaporated to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8](=[O:14])OC(C)(C)C.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1C([Cl:30])=O>C(Cl)Cl>[ClH:30].[NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[C:27]1[C:26]([O:25][CH3:24])=[CH:34][CH:33]=[CH:32][C:31]=1[O:35][CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1N
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@H]1N
Product: Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl N-[(1R,2S)-2-aminocyclopentyl]carbamate (CAS number 721395-15-9; 0.50 g, 2.50 mmol) in dry DCM (8.3 ml) was added DIPEA (1.3 ml, 7.49 mmol) and 2,6-dimethoxybenzoyl chloride (CAS number 1989-53-3; 0.75 g, 3.74 mmol). The reaction was stirred at room temperature under an atmosphere of nitrogen for 17 hours and then partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. This was purified by column chromatography (silica, 50-100% ethyl acetate/petrol). To the resulting solid was then added 1,4-dioxane (2 ml) and HCl in 1,4-dioxane (4M, 2 ml) and the reaction was stirred at room temperature for 2 hours and then concentrated in vacuo, and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: CCOC(=O)c1cc(-c2ccc(N)c(C)c2)no1
Reactant: O=C=Nc1c(F)cccc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
Ethyl 3-(4-amino-3-methylphenyl)isoxazole-5-carboxylate (1.0 equiv.), 2,6-difluoro phenyl isocyanate (1.2 equiv.) and tetrahydrofuran was taken in a round bottom flask and was stirred at room temperature for 48 hours. The solid precipitate was filtered and washed with minimum quantity of THF and dried in vacuo to afford the title compound as a white solid (91%); 1H NMR (300 MHz, DMSO-d6) δ: 1.29-1.34 (t, J=7.0 Hz, 3H), 2.31 (s, 3H), 4.33-4.40 (q, 2H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 1H), 7.71-7.74 (dd, J=8.7 Hz, 1.8 Hz, 1H), 7.81 (s, 2H), 8.04-8.07 (d, J=8.7 Hz, 1H), 8.31 (s, 1H), 8.65 (s, 1H); IR (KBr) 3292, 3132, 2984, 1723, 1644, 1621, 1588, 1560 1471, 1449, 1288, 1235, 1125, 1006, 849, 768 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH:15][C:36]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[O:37])[CH:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH2:5]2
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: Nc1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1)Nc1ccncc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
60 mg of 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b), 20 mg of 4-aminopyridine, and 34 mg of CDI were dissolved in 1.2 mL of THF, followed by stirring at 60° C. for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 10 mg (yield 12%) of a title compound as a yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1.[I-].[Li+].N1C=CC=C[CH:33]=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:10]=1.[CH3:33][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:10]=1
Reactant: c1ccncc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1O
Agent: [I-]
Agent: [Li+]
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1O
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1OC
Yield: 5 %
Yield: 21 %

Procedure:
A solution of methyl 2-(4-(2-hydroxy-4-methylphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.040 g; 0.099 mmol) and lithium iodide (0.066 g; 0.494 mmol) in pyridine (0.5 mL) was irradiated at 170° C. in a microwave sealed tube for 3 h. The solvent was removed under reduced pressure, the residue was dissolved in water and the pH adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The suspension was extracted twice with ethyl acetate and the combined organic layers were concentrated under reduced pressure. The residue was again suspended in water, basified with a solution of sodium hydroxide 5N and washed with a mixture of heptane and ethyl acetate (1:1). The pH of the aqueous solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N, extracted twice with ethyl acetate and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.008 g (21%) of 2-(4-(2-hydroxy-4-methylphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoic acid and 0.002 g (5%) of 2-(4-(2-methoxy-4-methylphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4](C2C=CC=CC=2S(C)(=O)=O)[C:3]=1[CH3:24].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:3]=1[CH3:24]
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Product: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure G using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (380.0 mg, 1.50 mmol) and morpholine to give 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)morpholine. Mass Spectrum (ESI) m/e=299.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccccc3O2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccccc3O2)cc1
Reaction time: 6 h
Yield: 9.3 %

Procedure:
To a solution of (2R)-2H-chromen-2-ylmethyl 4-methylbenzenesulfonate (1.70 g, 55.00 mmol) in ethanol (100 mL) was added palladium on carbon (10 wt. %, 0.17 g) and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide (2R)-3,4-dihydro-2H-chromen-2-ylmethyl 4-methylbenzenesulfonate (1.62 g, 95%) as a colorless oil which crystallized upon standing. [α]D25=−52.69 (c 10.06 in methanol, >97% ee); Rf=0.60 (silica, ethyl acetate:hexanes 2:3); Anal. Calcd. for C17H18O4S: C, 64.13; H, 5.70. Found: C, 63.90; H, 5.71.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: c1ccc(-n2nnc3c2CCNC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1Cl)N1CCc2c(nnn2-c2ccccc2)C1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (17 mg, 0.085 mmol) and 2,3-dichlorobenzoic acid (18 mg, 0.093 mmol) in DCM (8 ml) was treated with Et3N (35 μL, 0.25 mmol) followed by HATU (38 mg, 0.1 mmol). The reaction was stirred overnight, then concentrated to minimum volume and purified on 16 g SiO2 with 0-3.5% NH3 in MeOH/CH2Cl2 to give 24 mg (75%) of 5-[(2,3-dichlorophenyl)carbonyl]-1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C18H14Cl2N4O, 372.0; m/z found, 373.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.63-7.42 (m, 5H), 7.38-7.17 (m, 2H), 5.23-4.88 (m, 1H), 4.54 (q, J=15.7 Hz, 1H), 4.23 (dt, J=13.2, 5.5 Hz, 1.0H), 4.10-4.00 (m, 1.0H), 3.65-3.48 (m, 1H), 3.03 (t, J=5.7 Hz, 1H), 3.00-2.74 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[CH2:30]([OH:33])[CH2:31][OH:32]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:32][CH2:31][CH2:30][OH:33])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)c1cccc(COCCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Yield: 52 %

Procedure:
Following a procedure similar to that described in Preparation 1(ii), but using N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in Preparation 28(iv)] and ethylene glycol as starting materials, in relative amounts similar to those used in that Preparation, the title compound melting at 153°-154° C. (after recrystallization from a mixture of diethyl ether and hexane), was obtained in a 52% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH:7]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:35][N:36]([CH3:41])[CH2:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:26]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH:7]=1)=[O:39]
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)CN(C)C)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 80 °C
Yield: 34.8 %

Procedure:
To a stirred mixture of N-(5-amino-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (200 mg, 0.45 mmol), N,N-dimethylglycine (70 mg, 0.68 mmol) and Hunig's base (365 μL, 2.1 mmol) in dimethylformamide (1 mL) was added HATU (310 mg, 0.82 mmol). The stirred mixture was heated to 80° C. for 1 h, the cooled to rt and purified by preparative reverse phase HPLC to give N-{5-[(N,N-dimethylglycyl)amino]-2-methylphenyl}-4-[(4-phenylquinazolin-2-yl)amino]benzamide (83 mg, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.71 (s, 1H), 8.18 (d, 2H), 7.99 (d, 2H), 7.85 (m, 6H), 7.65 (m, 3H), 7.45 (dq, 2H), 7.18 (d, 1H), 3.06 (s, 2H), 2.28 (s, 6H), 2.0 (s, 3H). MS (EI) for C32H30N6O2: 531.1 (MH+).