Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.O>[CH2:20]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 4,6-dichloro-5-nitropyrimidine (7 g, 36 mmol) and TEA (10 mL, 72 mmol) in DCM (60 mL) at 0° C. under N2 was added Bn2NH in 10 mL dropwise over 2 hrs. Stirring was continued for 30 min before the reaction mixture was diluted with water (100 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4 and concentrated in vacuo. N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (12.8 g, 100%) was obtained as a brown slurry. LC-MS (ESI): m/z (M+1) 355.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:21])C>>[OH:21][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(SCCN2CCOCC2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: Cc1c(SCCN2CCOCC2)ccnc1CO
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
2,3-Dimethyl-4-(2-morpholinoethylthio)pyridine-N-oxide (3.0 g) was dissolved in acetic anhydride (30 ml) and the mixture was stirred at 90° C. for 1.5 hours. The solvent was distilled away and water was added to the residue. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent was distilled away. The residual 2-acetoxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine (3.2 g) was dissolved in methanol (30 ml) and thereto was added sodium hydroxide (0.88 g) in water (10 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1.5 hours and at room temperature for 2 hours. After the completion of the reaction, the methanol was distilled away and the residue was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 2.1 g of 2-hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C.C(N(CC)CC)C.[Br:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>O1CCCC1.[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([Br:38])=[CH:40][CH:41]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)CNc1ncccc1N
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)cc1
Yield: 80 %

Procedure:
To a stirred and chilled (10°-20° C.) solution of N-(3-amino-2-pyridinyl)glycine ethyl ester (14.7 g, 0.075 mole) [freshly prepared by the hydrogenation of a solution of N-(3-nitro-2-pyridinyl) glycine ethyl ester in tetrahydrofuran over 5% palladium on carbon at room temperature], triethylamine 8.1 g, 0.080 mole), and tetrahydrofuran (150 ml) was added (rapid drop) 4-bromobenzoyl chloride (6.9 g, 0.077 mole), followed by 100 ml of methylene chloride. The reaction mixture was stirred at room temperature for 2 hr and was filtered. The filtrate was concentrated in vacuo and the residue combined with the filter cake. The combined mixture was twice suspended in water and filtered. The filter cake was recrystallized from ethanol, giving 22.7 g of crystals (80%). Recrystallization of a 1.6-g samples from ethanol gave 1.5 g of white flocculent solid, mp 153°-154° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:29][CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CC(C)N
Product: CC(C)Nc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-Isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and isopropylamine. Mass spectrum (ES) MH+=379.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[C:6]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:5]=1)([CH3:3])=[CH2:2]>C(O)C.[Pd]>[CH:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:11])=[O:12])[CH:7]=[C:6]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 91.5 %

Procedure:
0.05 g (0.0001456 Mol) 4-(2-Isopropenyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine were dissolved in ethanol (5 ml) and hydrogenated under an atmosphere of H2 -gas with a catalytic amount of Pd/C (10%) at ambiente temperature for 3 h. After filtration and evaporation of the solvent the residue was chromatographed on SiO2 with ethyl acetate hexane 1:2. After drying in a high vacuum it was obtained 0.046 g (92%) 4-(2-isopropyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as a white solid; mp.: 148-150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH:21]O>ClCCl.C[Re](=O)(=O)=O>[C:14]([O:13][C:11]([C:10]1[CH:9]=[C:8]([C:7]2[CH:6]=[CH:5][N+:4]([O-:21])=[CH:3][C:2]=2[CH3:1])[CH:20]=[CH:19][CH:18]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1cnccc1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: Cc1c[n+]([O-])ccc1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 5 h

Procedure:
tert-Butyl 3-(3-methylpyridin-4-yl)benzoate (0.500 g, 1.86 mmol) was dissolved in a mixture of dichloromethane (0.800 mL) and 30% hydrogen peroxide (0.421 mL). Methyltrioxorhenium (VII) (2.3 mg, 0.92 mmol) was added and the reaction mixture was stirred vigorously for 5 hours. The layers were then separated and the organic layer was treated with sodium sulfite, and then dried over sodium sulfate. The crude product filtered, evaporated to dryness, and used without further purification. ESI-MS m/z calc. 285.1. found 286.1 (M+1)+. Retention time 1.22 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].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.C(#N)C>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[C:2]1[N:3]=[C:4]([C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:5]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2ncc(Cl)nc2-c2cc(C)cc(C)c2)c1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)cc(-c2ncc(-c3c(C)cccc3C)nc2-c2cc(C)cc(C)c2)c1
Yield: 89 %

Procedure:
Then, 1.21 g of 5-chloro-2,3-bis(3,5-dimethylphenyl)pyrazine obtained in Step 3, 1.10 g of 2,6-dimethylphenylboronic acid, 0.78 g of sodium carbonate, 15 mg of Pd(PPh3)2Cl2, 14 mL of water, and 14 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 3 hours. Here, into the flask were further put 0.55 g of 2,6-dimethylphenylboronic acid, 0.39 g of sodium carbonate, and 7 mg of Pd(PPh3)2Cl2, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) again for 3 hours to be heated. The mixture was suction-filtered and the obtained solid was washed with ethanol. The obtained solid was dissolved in dichloromethane and filtered through a filter aid in which Celite, alumina, and Celite were stacked in that order, so that Hdmdppr-dmp (abbreviation), which was the pyrazine derivative to be produced, was obtained as a white powder in a yield of 89%. A synthesis scheme of Step 4 is shown in (h-4).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7]>P([O-])([O-])([O-])=O>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@@H:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Product: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 30 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
Microbial cells (IFO-1575; Zygoascus hellenicus) were cultured in an MY medium (pH 6.0; 50 ml) at 30° C. for 48 hours. Methyl 2-(2,3,4-trifluoroanilino)propionate (1.0 g) was suspended in a 0.1 M phosphate buffer solution (pH 6.5; 90 ml). Then the above-described liquid culture (10 ml) was added thereto and gently stirred. The mixture was stirred for additional 16 hours while maintaining at 30° C. Then it was treated as in Example 43 to thereby give methyl (2R)-2-(2,3,4-trifluoroanilino) propionate (0.39 g, optical purity 91% ee) and the title compound (0.45 g, optical purity 84% ee).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>CN1CCCC1=O.C(O)(=O)C.C(OCC)(=O)C>[CH3:25][C:24]1[CH:23]=[CH:22][N:21]=[C:20]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]4[NH:31][N:30]=[N:29][N:2]=4)=[CH:10][CH:11]=3)[C:17]([CH2:26][CH2:27][CH3:28])=[N:18][C:19]=12
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
5.3 g of 3-[(2'-cyanobiphenyl-4-yl)methyl]-7-methyl-2-n-propyl-3H-imidazo[4,5-b]pyridine, 5.85 g of sodium azide and 6.19 g of triethylamine hydrochloride were heated in 120 ml of N-methylpyrrolidone as a reaction solvent at an internal temperature of 138° C. for 8 hr under stirring. After cooling, a dilute aqueous sodium hydroxide solution and ethyl acetate were added thereto to cause phase separation, thus obtaining a watery phase. The watery phase was weakly acidified with acetic acid and extracted thrice with ethyl acetate, and the extract was washed four times with water. Methanol was added to the washed extract to dissolve the precipitated crystal in the organic phase, and the organic phase was dried over anhydrous magnesium sulfate. The dried organic phase was concentrated, and the residue was subjected to silica gel chromatography (chloroform:ethanol:acetic acid=97:3:0.2). A fraction of the intended title compound was concentrated and recrystallized from ethanol. The yield was 4.6 g. The melting point was 200° to 202° C.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=CC=[C:35]([O:39]C)C=2N=1>>[CH3:35][O:39][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: COc1cccc2sc(Cl)nc12
Product: COc1cccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc12

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-4-methoxy-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.09-2.30 (m, 4H), 3.05-3.19 (m, 2H), 3.42 (d, J=13.2 Hz, 2H), 4.01 (s, 3H), 4.46-4.56 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.07 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 8.25 (br. s., 1H), 8.36 (s, 1H), 8.49 (d, J=2.2 Hz, 1H). MS (ES+): m/z=407.14 [MH+]. HPLC: tR=1.93 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([C:10]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH:11]2[CH2:13]Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C>C(O)C>[CH3:1][N:2]([CH2:13][CH:11]1[CH2:12][C:10]1([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:3]
Reactant: CNC
Reactant: ClCC1CC1(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)CC1CC1(c1ccccc1)c1ccccc1
Reaction time: 32 h

Procedure:
To a solution of 40% aqueous dimethylamine (10 ml) in ethanol (10 ml) was added a solution of 2,2-diphenylcyclopropylmethyl chloride (0.50 g) in ethanol (10 ml) and triethylamine (1.0 g) at room temperature, and stirring was carried out at 35°-40° C for 32 hours. The reaction mixture was evaporated and poured into a 10% aqueous sodium hydroxide solution. The etheral extract was dried and chromatographed to afford N,N-dimethyl-2,2-diphenylcyclopropylmethylamine as an oily substance. M.P. 231°-233° C (hydrochloride).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[O:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][NH:26][CH:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: NC1CCOCC1
Product: Clc1nc(N2CCOCC2)c2nc(CNC3CCOCC3)ccc2n1

Procedure:
4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.3 g) was reacted with tetrahydro-2H-pyran-4-amine via General Procedure B to afford quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)tetrahydro-2H-pyran-4-amine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:37][CH3:38])[C:35]=1[F:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([O:37][CH3:38])[C:35]([F:36])=[C:30]([F:29])[CH:31]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(B(O)O)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(F)c1F
Temperature: 100 °C
Yield: 57.6 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.3 mmol) was treated with (3,4-difluoro-5-methoxyphenyl)boronic acid (93 mg, 0.49 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (29 mg, 0.03 mmol) and aqueous solution of sodium carbonate (2M, 492 μl, 0.98 mmol) in dioxane. The reaction mixture was submitted at vacuum-argon cycles and heated at 100° C. overnight. The solvent was cooled at room temperature and diluted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1® Purification System to obtain 87 mg (53% yield) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1C=CC(C(OC)=O)=CC=1.C1(CCCO)CC1>>[CH:3]1([CH2:1][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:2][CH2:21]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: OCCCC1CC1
Product: O=C(O)CNC(=O)c1ccc(OCCCC2CC2)cc1
Yield: 51 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (6.09 g, 40.0 mmol) and 3-cyclopropyl-1-propanol (compound described in Helv. Chim. Acta, (2003), 86, 865-893, 4.41 g, 44.0 mmol) to give 5.74 g of the title compound (white powder, yield: 51%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve (R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (1.291 g, 2.86 mmol) in 25 ml of dry dichloromethane at 0° C. Add triethylamine (0.73 ml, 5.77 mmol) followed by methanesulfonyl chloride (0.25 ml, 3.17 mmol). Stir at room temperature for 3 hours. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with 1N HCl, NaHCO3 and brine. Dry over magnesium sulfate, filter, and concentrate. Purify by column chromatography to receive 1.315 g of the title compound: Mass spectrum (apci) m/z=526 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN1CCN(CCO[C:44]2[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=2)CC1>>[CH2:2]1[C:45]2[C:44](=[CH:50][CH:49]=[C:47]([NH:48][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:46]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-{[2-(4-methyl-1-piperazinyl)ethyl]oxy}aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.11 (s, 3H), 2.20-2.35 (m, 4H), 2.62 (t, 2H, J=5.8 Hz), 3.00-3.60 (m, 4H overlapping with H2O), 3.98 (t, 2H, J=5.8 Hz), 6.47 (d, 1H, J=5.1 Hz), 6.80 (d, 2H, J=9.0 Hz), 7.08 (t, 1H, J=6.9 Hz), 7.22 (t, 2H, J=8.0 Hz), 7.31 (d, 1H, J=7.5 Hz), 7.41-7.60 (m, 5H), 7.80 (d, 1H, J=8.1 Hz), 7.97 (s, 1H), 8.16-8.21 (m, 1H), 8.39 (bd, 1H, J=7.4 Hz), 8.81 (d, 1H, J=6.8 Hz), 9.31 (s, 1H), 10.91 (s, 1H); ESIMS (M+H)+=661.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[C:26]([O:29][C:30]12[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][C:32]([C:40]([OH:42])=O)([CH2:33]3)[CH2:31]1)[CH2:37]2)(=[O:28])[CH3:27]>CN(C=O)C>[C:26]([O:29][C:30]12[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][C:32]([C:40](=[O:42])[N:2]([CH3:3])[CH3:1])([CH2:33]3)[CH2:31]1)[CH2:37]2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: CNC
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CC(=O)OC12CC3CC(C1)CC(C(=O)N(C)C)(C3)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-acetyloxy-3-carboxyadamantane obtained by the above method was dissolved in 10 ml of DMF. To the mixture, 15 mmole of N,N′-carbodiimidazol in the form of powder was added in one portion. After stirring for 1 hour at the room temperature, 15 mmole of dimethylamine and 15 mmole of diazabicycloundecene were added. The mixture was heated to 100° C. and stirred for 8 hours. As a result, the conversion of 1-acetyloxy-3-carboxyadamantane was 80%, and 1-acetyloxy-3-(N,N-dimethylcarbamoyl)adamantane (yield 70%) was formed.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:32]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)[CH2:33][CH3:34]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH2:32][CH2:33][CH3:34])[CH:24]=1
Reactant: CCCOc1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCOc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 74.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-propoxyphenylboronic acid (33 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (42 mg, 74%). MS m/e 407.23 (M+H+)