Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.N([O-])=O.[Na+].[BrH:35]>O.[Cu]Br>[C:1]([C:20]1[CH:26]=[CH:25][C:23]([Br:35])=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Brc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
25 parts by weight of 4-tritylaniline, 400 parts by weight of acetone, and 162 parts by weight of hydrobromic acid were put into a reaction vessel and stirred. While cooling the vessel in an ice bath, a solution of 7 parts by weight of sodium nitrite dissolved in 100 parts by weight of water was slowly added dropwise thereto. After the dropwise addition was complete, stirring was carried out for 30 minutes in an ice bath. Slowly added dropwise to this solution in an ice bath was a solution of 17.4 parts by weight of copper (I) bromide that had been dissolved in 31.5 parts by weight of hydrobromic acid. After the dropwise addition was complete, stirring was carried out at room temperature for 2 hours. After the reaction, a precipitate deposited in the reaction solution was collected by filtration, thus giving 25.8 parts by weight of 4-tritylbromobenzene (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([NH2:11])=[O:10].O.[C:22]12([CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][C:23]2=[O:24]>CC(C)=O>[C:22]12([CH2:32][S:33]([OH:36])(=[O:34])=[O:35])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][C:23]2=[O:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Yield: 37.8 %

Procedure:
A solution of 5 g (16.31 mmol) of (±)-(2-chloro-phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide (prepared as given in Examples 10-15) and 4.15 g (16.2 mmol) (1S) (+)-camphor-10-sulphonic acid monohydrate in 100 mL acetone was stirred at room temperature for 20 h. Subsequently it was kept for 1 week in a freezer. Few crystals appeared concentration of volume by evaporating solvent under reduced pressure and repeated recrystallization in freezer for few days gave 3.3 g (75% yield) of (S)-2-(2-chloro-phenyl)-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)acetamide (+)-camphor sulfonic acid salt. The salt was further purified by recrystallization in acetone, until constant specific optical rotation was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@@H:9]1[C:18](OC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (3.96 g: 12.2 mmole) in a mixture of tetrahydrofuran (12 ml) and ethanol (18 ml), sodium borohydride (1.85 g: 48.8 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 45 minutes at room temperature to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (2.97 g). Yield: 83%. Colorless crystals. mp. 95° to 96° C. NMR δ(CDCl3) ppm: 1.49(s, 9H), 1.7 to 2.1(m, 1H), 2.3 to 2.5(m, 1H), 3.06(s, 3H), 3.4 to 3.7(m, 2H), 3.7 to 4.0(m, 2H), 4.0 to 4.3(m, 1H), 5.2(m, 1H). IR ν (KBr) cm-1 : 3400, 3420, 1648.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].CCOC(C)=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:11]([CH3:10])(=[O:13])=[O:12])[S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (PharmaBlock) (2.000 g, 10.69 mmol) in pyridine (15.0 mL) was added 4-dimethylaminopyridine (Aldrich) (0.131 g, 1.069 mmol) and methanesulfonyl chloride (2.5 mL, 32.1 mmol). The resulting mixture was heated to 100° C. under N2 for 2 h. Reaction was cooled to rt. The reaction mixture was poured into the beaker which filled with EtOAc (50 ml) and hand stirred for 10 minutes. The organic layer was decanted into a round-bottom flask. The original mixture (black paste) was dissolved into DCM (3 ml) followed by adding EtOAc (20 ml) and hand stirred for 10 min and decanted to the same round-bottom flask that was mentioned earlier. The combined organic layers were concentrated in-vacuo. The crude product was purified by column chromatography (120 g, 10% to 20% acetone in hexanes) to afford the desired product as light brown solid (1.1 g). MS (ESI pos. ion) m/z: 342.8. 1H NMR (300 MHz, CDCl3) δ ppm 2.64 (s, 3H) 3.47 (s, 6H) 7.73 (d, J=2.05 Hz, 1H) 8.67 (d, J=2.05 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25](O)=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.CC[N:31]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:31])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)CC1=O
Reaction time: 8 h

Procedure:
The solution of 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanoic acid (28 mg, 0.063 mmol), EDCI (38 mg, 0.189 mmol), HOBt (26 mg, 0.189 mmol), and DIEA (82 mg, 0.63 mmol) in CH2Cl2 was filled with NH3 at 0° C. The mixture was stirred overnight, and washed with water. The organic phase was separated and concentrated to give the crude product, which was purified by preparative HPLC to afford 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanamide (6 mg, 21%□. LC-MS Method 2, tR=1.869 min, m/z=447. 1H NMR (CDCl3): δ 1.46 (d, 3H), 1.77 (m, 1H), 1.92 (m, 1H), 1.96 (m, 1H), 2.08 (m, 1H), 2.14 (m, 3H), 2.24 (m, 1H), 2.51 (d, 1H), 3.02 (m, 1H), 3.12 (m, 1H), 5.32 (m, 1H), 5.71 (m, 1H), 5.94 (q, 1H), 6.76 (m, 2H), 6.99 (m, 2H), 7.16 (m, 2H), 7.24 (m, 2H).
Reaction SMILES: CC([O:4][C@:5]12[C@@H:33]3[CH:34]4[N:35]([CH3:37])[CH2:36][C@@:30]5([CH2:40][O:41][CH3:42])[C@@H:31]([C@H:32]3[O:38][CH3:39])[C@@:26]4([C@@H:27]([O:44][CH3:45])[CH2:28][C@H:29]5[OH:43])[C@@H:7]3[CH2:8][C@:9]([OH:25])([C@@H:20]([O:23][CH3:24])[C@@H:21]1[OH:22])[C@H:10]([O:11]C(C1C=CC=CC=1)=O)[C@H:6]23)=O.[H-].[K+]>CO>[CH3:37][N:35]1[C@H:34]2[C@:26]34[C@@H:7]5[CH2:8][C@:9]6([OH:25])[C@@H:20]([O:23][CH3:24])[C@H:21]([OH:22])[C@@:5]([OH:4])([C@H:6]5[C@H:10]6[OH:11])[C@H:33]2[C@H:32]([O:38][CH3:39])[C@@H:31]3[C@@:30]([CH2:40][O:41][CH3:42])([C@H:29]([OH:43])[CH2:28][C@@H:27]4[O:44][CH3:45])[CH2:36]1
Reactant: COC[C@]12CN(C)C3[C@@H]4[C@H](OC)[C@H]1[C@@]3([C@@H](OC)C[C@H]2O)[C@@H]1C[C@@]2(O)[C@H](OC(=O)c3ccccc3)[C@@H]1[C@]4(OC(C)=O)[C@@H](O)[C@@H]2OC
Agent: [H-]
Agent: [K+]
Solvent: CO
Product: COC[C@]12CN(C)[C@@H]3[C@@H]4[C@H](OC)[C@H]1[C@@]3([C@@H](OC)C[C@H]2O)[C@@H]1C[C@@]2(O)[C@H](O)[C@@H]1[C@]4(O)[C@@H](O)[C@@H]2OC
Yield: 55.8 %

Procedure:
Mesaconitine 70 mg was dissolved in 5 ml of methanol. To this solution, 1 ml of 5% potassium hydride was added, and the mixture was heated under reflux for 3 hours. After methanol in the reaction mixture was distilled off, 5 ml of water was added to the residue and the mixture was extracted three times with 10 ml of methylene chloride. The extract was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was subjected to thin-layer chromatography for separation and purification (eluting solvent: 10% methanol/ammonia-saturated chloroform) to give mesaconine (30 mg). 14-O-p-Chlorobenzoylmesaconine 20 mg was obtained in the same manner as in Example 90, except for the use of 30 mg of mesaconine and 30 mg of p-chlorobenzoyl chloride as each substitute for 30 mg of aconine and 30 mg of m-chlorobenzoyl chloride in Example 90.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:32]([C:27]1[NH:28][C:29]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:22][CH3:21])=[CH:31][CH:30]=2)=[O:33]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Product: COc1ccc2[nH]c(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cc2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 5-methoxy-1H-indole-2-carboxylic acid. MS: 447.5 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:6].[Br-].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Zn+]>C(OCC)(=O)C>[Cl:21][C:20]1[CH:19]=[CH:18][C:4]([C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1
Reactant: [Zn+]c1ccccn1
Reactant: COc1cc(NC(=O)c2ccc(Cl)c(Br)c2)cc(OC)c1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2ccc(Cl)c(-c3ccccn3)c2)cc(OC)c1
Temperature: 155 °C

Procedure:
3-bromo-4-chloro-N-(3,5-dimethoxyphenyl)benzamide was dissolved in 0.5 M 2-pyridylzincbromide (2.5 mL) and treated with Pd(PPh)3)4 (20 mg, 0.02 mmol). The reaction mixture was heated to 155° C. in a sealed tube for 20 min. in a microwave reactor. The resultant solution was diluted with Ethyl acetate and washed with 0.1 N sodium hydroxide and then brine. The organic layer was dried (MgSO4) and concentrated, and the crude residue was partially purified by silica gel chromatography. Pure 4-chloro-N-(3,5-dimethoxyphenyl)-3-(pyridin-2-yl)benzamide was obtained by a second purification on reverse phase HPLC. MS (Q1) 369.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[NH:13][N:12]=2)=[N:4][C:5]([C:8]([NH2:9])=[O:20])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
The mixture of 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbonitrile (1.0 g, 3.85 mmol, 1.0 eq) and K2CO3 (2.0 g, 14.49 mmol, 3.8 eq) in DMSO (20 mL) was stirred at room temperature, and 30% hydrogen peroxide (3 mL) was added dropwise. The reaction mixture was stirred at rt for 1 h, water was added and the suspension was filtered to afford 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carboxamide (950 mg, 89%). LC-MS (m/z)=279.0 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([C:33](O)=[O:34])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:11][N:12]=3)[CH2:2][CH2:3]2)=[O:34])[CH:22]=1)(=[O:19])=[O:20]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)nc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)cn3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2-Piperazin-1-yl-5-trifluoromethyl-pyrimidine (Example AE) and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 431.1 MH+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]([NH:12][S@@](C(C)(C)C)=O)[CH2:10][CH3:11])=[CH:4][C:3]=1[CH3:19].Cl>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]([NH2:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[CH3:19]
Reactant: CC[C@@H](N[S@](=O)C(C)(C)C)c1cc(C)c(Cl)c(C)c1
Agent: Cl
Solvent: CO
Product: CC[C@@H](N)c1cc(C)c(Cl)c(C)c1
Reaction time: 8 h

Procedure:
A solution of intermediate INT 37 (3.4 g, 11.26 mmol) in MeOH (75 mL) was treated with HCl (4 M in dioxane, 5.63 mL, 22.53 mmol) and stirred overnight. After evaporation of the solvents, a white solid was obtained which was washed with Et2O. The solid was then dissolved in water, slightly acidified with 2 M HCl and washed with EtOAc. The aqueous layer was separated and the pH adjusted to about 11 using 2 M NaOH followed by extraction with Et2O (3×). The Et2O layers were combined, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([C:11](=O)[C:12]#[C:13]C)=[C:4]2[CH:3]=1.Cl.[CH:24]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:32]=[C:30]([NH:29][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:31]=3)=[C:4]2[CH:3]=1
Reactant: N=C(N)NC1CCCC1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one (0.61 g, 2.0 mmol) in N,N-dimethylformamide was added cyclopentyl guanidine hydrochloride (0.67 g, 4.1 mmol) followed by anhydrous potassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heated at 80° C. for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give, after recrystallization from acetonitrile, 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.6 g, 74%) as a white solid. 1H-NMR (CDCl3): δ8.54 (broad s, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28 (d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4-2.2 (m, 8H); 19F-NMR (CDCl3): δ−112.5; MS m/z 408 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: COc1ccc2nc(Cl)sc2c1
Product: COc1ccc(C(=O)N2CC3CN(c4nc5ccc(OC)cc5s4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-6-methoxy-benzothiazole. MS (ESI) mass calcd. for C23H25N3O4S, 439.54; m/z found, 440.2 [M+H]+.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]([C:7]1[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=[C:9]([NH:18][C:19]([NH2:21])=[S:20])[N:8]=1)([CH3:6])[CH3:5]>C(O)C>[CH3:6][C:4]([C:7]1[C:12]([OH:13])=[C:11]([C:14]([CH3:15])([CH3:17])[CH3:16])[N:10]=[C:9]([NH:18][C:19](=[NH:21])[S:20][CH3:1])[N:8]=1)([CH3:3])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)c1nc(NC(N)=S)nc(C(C)(C)C)c1O
Solvent: CCO
Product: CSC(=N)Nc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Yield: 71.3 %

Procedure:
Methyl iodide (1.05 g, 7.4 mmol) is added to an ethanol (50 mL) solution of N-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]thiourea (2.0 g, 7.1 mmol) and the mixture is heated at reflux under argon for 2.5 hours. The ethanol is evaporated under reduced pressure and the residue is taken up in 50 mL EtOAc. The EtOAc solution is washed with saturated NaHCO3 (3×50 mL) and 50 mL of brine. Drying over MgSO4 and evaporation of solvent gives an off-white solid. Recrystallization from ether/hexane gives 1.5 g (71%) of N-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-S methyl isothiourea; mp 163°-165° C.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[N:12]=[C:11]([N:24]2[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[N:25]2)[CH:10]=1.[I:38]I>C(Cl)(Cl)Cl>[I:38][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[N:12]=[C:11]([N:24]2[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[N:25]2)[CH:10]=1
Reactant: CCOC(=O)c1cnn(-c2cc(N)cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2cc(I)cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Temperature: 60 °C

Procedure:
Tert-butyl nitrite (0.68 mL, 0.59 mmol) was added to a solution of the title compound from Example 19 Step E (1.2 g, 2.9 mmol) and iodine (0.87 g, 3.4 mmol) in chloroform (20 mL). The resulting mixture was heated at 60° C. for 30 min, cooled and quenched with aqueous sodium sulfite. Extraction with hexane-EtOAc, followed by silica gel flash chromatography using Hexane-EtOAc (20/1 to 7/1) provided the title compound: LCMS m/z 532.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=1.1 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J=1.1 Hz, 1H), 7.79 (d, J=2.1 Hz, 1H), 7.25 (dd, J=8.5 Hz, 2.1 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 2.39 (s, 3H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11](Cl)=[O:12])[CH:2]=[CH2:3].[NH3:14]>>[CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11]([NH2:14])=[O:12])[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Product: C=CCC12C=CC(CC1C(N)=O)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9.8 g of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are added dropwise over 10 minutes at 0° C. to 50 ml of 25% aqueous ammonia. The batch is stirred for 15 minutes at room temperature, and the water is decanted. The residue is dissolved in 50 ml of ether, washed with saturated soda solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated, affording 6.5 g (73% of theory) of a white solid. For purification the resultant solid is recrystallised from water; m.p.: 120°-122° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.N[C:35]1[C:40]([C:41]#N)=[C:39](N2CCC(C3N(CCNCC(C)C)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=[CH:37][N:36]=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:37][NH:36][CH2:35][CH:40]([CH3:41])[CH3:39])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNCC(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: Cc1cc(-c2cn(CCNCC(C)C)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=495, obsd.=495).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:32]([O:35][CH3:36])[O:33][CH3:34])=[N:9][C:10]2[N:11]([C:17](=[O:31])[NH:18][C:19]3[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:22]([C:29]#[N:30])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.[CH3:37][NH2:38]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:29]([C:22]1[C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][NH:38][CH3:37])=[C:8]([CH:32]([O:33][CH3:34])[O:35][CH3:36])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:31])=[N:20][CH:21]=1)#[N:30]
Reactant: COC(OC)c1nc2c(cc1COS(C)(=O)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of (8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 167, 2.59 g, 4.98 mmol) in THF (83 ml) was added methylamine 2 M in THF (37.4 ml, 74.70 mmol) at ambient temperature and the reaction mixture was stirred at room temperature for approximately 4 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated to yield the title compound as a light yellow solid. (UPLC-MS 3) tR 0.88 min, ESI-MS 455.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 14.00 (s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 5.51 (s, 1H), 4.88-4.79 (m, 1H), 4.06-4.01 (m, 2H), 3.86 (s, 2H), 3.50 (s, 6H), 2.88-2.80 (m, 2H), 2.49 (s, 3H), 2.03-1.96 (m, 2H), 1.43 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11]([C:15]([CH3:17])=O)[CH:12]([CH3:14])[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>[CH3:17][C:15](=[N:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: CC(=O)CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: CC(CC(C)C)=Nc1cc(O)c(Cl)cc1F
Temperature: 60 °C
Yield: 100 %

Procedure:
A 50-ml four-neck flask equipped with a Vigreux column (2 cmφ×25 cm) and a dehydrating column (filled with molecular sieve) attached thereon was charged with 5-amino-2-chloro-4-fluorophenol (1 g), methyl isobutyl ketone and heptane (weight ratio, 4:1; 40 g), and p-toluenesulfonic acid (4 mg). The mixture was dehydrated under reflux at 60° C. under reduced pressure (constant at 150 mmHg) for 6 hours. The concentration under reduced pressure gave 1.5 g of 5-(1,3-dimethylbutylidenamino)-2-chloro-4-fluorophenol (yield, 100%), m.p., 92°-97° C.; MS (m/z): 243 (M+) 228, 186; NMR (CDCl3, δ) as a 1:4 mixture of cis and trans forms: 0.80 and 1.00 (d, 6H, J=6 Hz), 1.80 and 2.20 (s, 3H), 2.0-2.2 and 2.35-2.38 (m, 3H), 6.3 and 6.4 (d, 1H, J=7.6 Hz), 6.6-7.0 (broad, 1H), 7.04 (d, 1H, J=9.6 Hz).