Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[C:10]([NH:13][CH2:14][CH2:15][NH2:16])(=[O:12])[CH3:11]>C(Cl)Cl.C(N(CC)CC)C>[NH:13]([CH2:14][CH2:15][NH:16][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:8])[C:10]([CH3:11])=[O:12]
Reactant: O=C(Cl)c1ccc(Br)o1
Reactant: CC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNC(=O)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 22.6 g of 5-bromo-2-furancarboxylic acid chloride in 100 ml of methylene chloride was added dropwise within 20 minutes at 0°-8° to a solution, pre-cooled to 0°, of 11.0 g of monoacetyl-ethylenediamine in 250 ml of methylene chloride and 18 ml of triethylamine. The reaction mixture was stirred at room temperature overnight, suction filtered and washed with methylene chloride. There was obtained N-(2-acetamino ethyl)-5-bromo-2-furancarboxamide as pale beige crystals, m.p. 175°-176°.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:44])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@@H:10]1[Cl:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 80.7 %

Procedure:
3.0 g (5.5 mmol) of 2,3,4,6-tetra-O-benzyl-D-glucopyranose were dissolved in 30 ml of anhydrous methylene chloride and the solution was stirred with 1.45 ml (2.11 g; 16.5 mmol) of oxalyl dichloride and 0.3 ml of dimethylformamide at room temperature. After one hour, the solution was concentrated under a high vacuum, the residue was taken up in 10 ml of methylene chloride and the mixture was filtered over about 10 g of silica gel. Renewed concentration gave 2.48 g (80%) of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride as a colorless syrup. The crude product was taken up in 20 ml of anhydrous acetonitrile and the mixture was heated under reflux with 3.0 g (38 mmol) of potassium hydrogen fluoride (24 hours at 100° C., dried over P2O5) for 8 hours. It was possible to purify the crude product by column chromatography on silica gel (methylene chloride/ether, 20:1). Yield: 1.1 g (47%) of 2,3,4,6 -tetra-O-benzyl-α-D-glucopyranosyl fluoride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:17][C:18]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)Cc1ccc(C#N)cc1

Procedure:
4.8 g (3 mmol) of (4-cyano-phenyl)-acetic acid are suspended in 25 ml of methylene chloride and refluxed for 15 minutes after the addition of 5 ml thionyl chloride. The solvent is distilled off, the residue dissolved in 100 ml chlorobenzene and after the addition of 4.9 g (2.5 mmol) of methyl 2-amino-5-nitro-benzoate refluxed for 2 hours. Three-quarters of the volume of chlorobenzene is distilled off and the residue is combined with ether/petroleum ether. The crystalline product is suction filtered and dried.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH:12]([CH3:14])[CH3:13].[CH3:15][CH2:16][O:17]CC.O>C(O)(=O)C.Br>[CH2:11]([C:4]1[C:5]([OH:9])=[C:6]([C:16](=[O:17])[CH3:15])[CH:7]=[CH:8][C:3]=1[OH:2])[CH:12]([CH3:14])[CH3:13]
Reactant: COc1cccc(OC)c1CC(C)C
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(O)c(CC(C)C)c1O

Procedure:
1,3-Dimethoxy-2-(iso-butyl)benzene (11.3 g) was dissolved in acetic acid (250 ml) and 48% hydrobromic acid (150 ml). The resultant solution was heated to reflux for 2 days, cooled, and ether and water added. The ether layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated to dryness. The concentrate was chromatographed by HPLC (column eluted with a gradient of 1 to 10% ethyl acetate in hexane) to yield 3.87 g of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]1.[Cl:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:21])=[O:20])[CH2:17][CH2:18]3)=[O:12])[N:8]2[C:43]2[CH:42]=[CH:41][N:40]=[C:39]([Cl:38])[CH:44]=2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)[nH]c3cc2Br)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1
Temperature: 35 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
A suspension of 0.15 g (0.25 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 1), 119 mg (0.76 mmol) 2-chloropyridine-4-boronic acid, 91 mg (0.50 mmol) copper(II) acetate and 80 μL (78 mg, 1.0 mmol) pyridine in 4 ml chloroform was stirred 18 h at 35° C. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant to afford 84 mg (47%) of the title compound as a light-yellow solid.
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[CH2:5][CH2:6][C:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[OH-].[K+].C([OH:33])C>O>[CH:23]([N:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:17][C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:26]([CH3:28])[CH3:27])([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:8]([NH2:9])=[O:33])([CH3:25])[CH3:24]
Reactant: Cc1ccc(C(C#N)(CCN(C(C)C)C(C)C)CCN(C(C)C)C(C)C)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(CCN(C(C)C)C(C)C)(CCN(C(C)C)C(C)C)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 10 parts of the preceding acetonitrile, 20 parts of potassium hydroxide, 2 parts by volume of water and 50 parts by volume of ethanol is refluxed for 22 hours. The mixture is then cooled to room temperature, poured into water and extracted with ether. The ether extract is dried over calcium sulfate and stripped of solvent to afford an oil which solidifies upon standing. The crude solid is crystallized from pentane to afford α,α-bis[2-(diisopropylamino)ethyl]-α-(p-tolyl)acetamide, melting at about 97°-100° C. This compound is represented by the following structural formula ##STR16##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][N:18]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=343.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-5-chloromethyl-pyridine.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([C:33]([O:35][CH3:36])=[O:34])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 30 mg, 0.076 mmol) in tetrahydrofuran (0.5 mL) is added to a suspension of sodium hydride (60% in mineral oil, 4 mg, 0.1 mmol) in dry tetrahydrofuran. After 20 min methyl chloroformate (6 μL, 0.078 mmol) is added, and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is a) extracted with dichloromethane. The combined organic layers are concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 2 mg; ESI mass spectrum [M+H]+=456; Retention time HPLC: 1.10 min (V011_S01).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH2:17])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([CH3:27])[C:25]=1[F:26].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH:17][C:22]1[CH:23]=[C:24]([CH3:27])[C:25]([F:26])=[C:20]([CH3:19])[CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: COC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: Cc1cc(B(O)O)cc(C)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 87 h
Yield: 79.8 %

Procedure:
To a suspension of (R)-2-Amino-6-tert-butoxycarbonylamino-hexanoic acid methyl ester (3.000 g, 10.108 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (3.398 g, 20.216 mmol), Cu(OAc)2 (2.019 g, 11.119 mmol), and molecular sieves 4 Å (7.591 g) in 45 mL of dichloromethane, was added triethylamine (2.8 mL, 20.216 mmol). After stirring at room temperature under O2 (1 atm) for 87 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (3.084 g, 80% yield). LC-MS: tR=9.8 min; m/z 383 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:17]([O:24][NH:25][C:13](=[O:15])[C@H:9]([C@@H:10]([CH3:12])[OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NOCc1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Reaction time: 26 h
Yield: 55.6 %

Procedure:
A solution of 8.76 g of t-butoxycarbonyl threonine and the free amine from 6.4 g of O-benzylhydroxylamine HCl (ethyl acetate-sodium bicarbonate liberation) in 100 ml of tetrahydrofuran was treated with 6.12 g of N-hydroxybenzotriazole and 8.24 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. The mixture was stirred under nitrogen for 26 hours, filtered, and evaporated in vacuo. The residue was chromatographed on a 300 g silica gel column (elution with chloroform and chloroform/ethyl acetate (3:1) yielding 7.2 g of compound. Crystallization from ether-hexane gave 4.18 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH3:25][NH:26][CH2:27][C@H:28]([OH:37])[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([OH:36])[CH:30]=1.CS(C)=O>CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([N:26]([CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([OH:36])[CH:30]=3)[OH:37])[CH3:25])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CNC[C@H](O)c1ccc(O)c(O)c1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CN(CC(O)c1ccc(O)c(O)c1)C(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.3 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.167 g (0.9111 mmol) of (R)-(-)-epinephrine were placed into a 10 ml round bottom flask with 2 ml dimethylsulfoxide (dried over barium oxide) and a magnetic stirring bar. The solution was stirred at room temperature (25°) and was initially heterogeneous. After about 45 minutes, as the epinephrine began to react with AIT-0081, the solution was a nearly homogeneous yellow orange color. The solution was stirred an additional two hours, drawn into a pasteur pipet, and added with stirring to a flask containing 50 ml acetone and a magnetic stirring bar. A copious white precipitate formed and the solution was stirred for ten minutes. The solution was filtered by vacuum and the white solid washed with acetone. The Buchner funnel was immediately placed under high vacuum to remove small traces of dimethylsulfoxide. 120 mg of a white solid, 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-N-methylpropanamide (AIT-0100), was obtained. Yield: 48%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3C(OC(C)(C)C)=O)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccnc(Nc2cccc(Cl)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(Nc2nccc(NC[C@@H]3CCCN3)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
To a solution of tert-butyl (2S)-2-[({2-[(3-chlorophenyl)amino]-pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate, 15, (150 mg, 0.37 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (3 mL). The reaction is stirred at room temperature for 24 hours then partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 36 mg (32% yield) of the desired material: 1H NMR (CDCl3, 300 MHz) δ 1.43-1.56 (m, 1H), 1.70-1.91 (m, 2H), 1.93-2.06 (m, 1H), 2.97 (t, J=6.9 Hz, 2H), 3.16-3.29 (m, 1H), 3.41-3.52 (m, 1H), 3.54-3.66 (m, 1H), 5.71 (t, J=5.1 Hz, 1H), 5.91 (d, J=6.0 Hz, 1H), 6.96 (ddd, J=7.8, 5.7, 0.9 Hz, 1H), 7.20 (t, J=8.1 Hz, 1H), 7.26-7.32 (m, 1H), 7.57 (bs, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.99 (s, 1H); HRMS calcd for C15H18ClN5, 304.1329 m/z (M+H)+; observed 304.1319 m/z.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](C(O)=O)[C@H:22](O)[C:23](O)=[O:24].[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:11]3[CH:21]=[CH:22][C:23](=[O:24])[O:20][C:12]=3[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2ccc(=O)oc2c1OC
Temperature: 0 °C

Procedure:
A mixture of 1.38 g (0.005 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine and 1.01 g (0.0075 mole) of L-(-)-malic acid in polyphosphoric acid (30 g) was heated at 90°-100° for 4 hours. The resulting clear syrup was poured into ice-water (150 mL) and basified (pH 8) with conc'd ammonium hydroxide. The title compound was filtered off and washed with ethanol. Yield, 0.26 g (16%); m.p. 278°-280° dc; structure confirmed by 13C and 1H NMR and mass spectra. Anal. Calcd. for C16H18N4O3 : C, 58.53; H, 4.91; N, 17.07. Found: C, 58.27; H, 4.99; N, 16.97.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:25][CH3:26])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](B2OC(C)(C)C(C)(C)O2)[C:14]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][N:34]=[C:33](Br)[CH:32]=1.N#N>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][O:29][C:30]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:13]2[CH:12]=[N:11][CH:10]=[C:9]([CH2:8][N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])[CH2:25][CH3:26])[C:14]=2[CH3:15])[CH:32]=1)=[O:38]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CCN(Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: CCN(Cc1cncc(-c2cc(C(=O)OC)ccn2)c1C)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 69.2 %

Procedure:
Ethyl-[4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester (1.5 g, 5.1 mmol) and 2-bromo-isonicotinic acid methyl ester (1.3 g, 6.1 mmol) were suspended in 1,4-dioxane (25 mL). To the mixture was added K3PO4.3H2O (0.90 g, 4.52 mmol, 1 M in water). The reaction was degassed with N2 and PdCl2(PPh3)2 (72 mg, 0.1 mmol) was added. The reaction was heated to 60° C. for 3 hours. The mixture was then diluted with water and neutralised to pH 7. The mixture was concentrated in vacuo, to remove organic solvent, and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO4) and then evaporated to dryness. Purification by SiO2 chromatography gave the title compound (1.36 g). m/z 386 (M+H)+
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1.[ClH:28].N([O-])=O.[Na+].N>O.C(#N)C>[Cl:28][C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1
Reactant: Cl
Reactant: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12
Agent: N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(Cl)sc12
Temperature: 5 °C
Yield: 67 %

Procedure:
The product from step (e) (0.485 g) was suspended in conc.HCl (18 ml) which was then cooled to 15° C. A mixture of water (15 ml) and acetonitrile (25 ml) added to give a solution. Cooled to 5° C. and a solution of sodium nitrite (0.162 g) in water (1 ml) added drop-wise. Stirred at 5° C. for several hours then allowed to warm overnight. Solution cooled to −10° C. and neutralized with ammonia, then concentrated in vacuo. The yellow precipitate was collected by filtration and washed with water. Dried in vacuo to give 0.339 g of product. 67% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:35][CH2:34]2)=[CH:28][C:27]=1[CH3:49].Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F.C(Cl)Cl>[C:20]([C:19]1[CH:18]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:40])[CH2:37][CH2:38]4)=[CH:28][C:27]=3[CH3:49])[N:7]=2)[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1N
Reactant: N#Cc1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C#N)c3)nc3ccccn23)n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzonitrile (Intermediate Example 5) (0.462 g, 1.39 mmol) and phenylmethyl 4-[(4-amino-3-methylphenyl)oxy]-1-piperidinecarboxylate (0.567 g, 1.67 mmol) were dissolved in 16 mL of trifluoroethanol with stirring in a pressure vessel. HCl (4N in dioxane, 0.17 mL, 0.68 mmol) was added via syringe. The vessel was sealed and placed in an 80° C. oil bath. The reaction was stirred at 80° C. for 40 h and cooled to rt. The reaction was poured into half-saturated NaHCO3 solution and DCM. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.700 g (79%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (br. s., 1H), 8.90 (s, 1H), 8.20 (d, J=5.1 Hz, 1H), 8.04 (s, 1H), 7.96-7.86 (m, 2H), 7.72-7.61 (m, 2H), 7.46-7.21 (m, 7H), 6.93-6.79 (m, 3H), 6.41 (d, J=5.3 Hz, 1H), 5.06 (s, 2H), 4.59-4.50 (m, 1H), 3.77-3.65 (m, 2H), 3.36-3.21 (m, 2H), 2.18 (s, 3H), 1.97-1.86 (m, 2H), 1.61-1.49 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([CH3:13])[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:13])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOC(=O)c1ccc(N)cc1C
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O

Procedure:
Using ethyl 4-amino-2-methylbenzoate (5.3 g) and 3-chloropropane-1-sulfonyl chloride (4.8 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (6.49 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:12]([F:14])([F:13])[F:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in THF (250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25° C. for 8 h. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with water and was extracted with ethyl acetate (EtOAc; 3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (8.41 g, 60%).