Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)=[O:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Cl>C1COCC1.O.[OH-].[Li+]>[F:36][C:34]([F:35])([F:37])[O:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 210 mg (0.4 mmol) [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-acetic acid methyl ester in THF/H2O (10 mL; 4:1), 5 mL (4M) aqueous Lithium Hydroxide solution was added and the mixture stirred at 60° C. for 5 hours. Acidified with concentrated hydrochloric acid which precipitated the desired compound. Filtered and dried under vacuum to afford [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-acetic acid, which was subsequently dissolved in methanol (5 mL) one equivalent of potassium hydroxide and 2 mL of H2O were added and the resulting mixture was stirred at 40° C. for 2 hours. Evaporated to dryness to afford [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}phenyl)-cyclohexyl]-acetic acid as the potassium salt: 1H NMR (400 MHz, MeOD) δ ppm 1.03-1.14 (m, 2H) 1.45 (td, J=12.57, 9.98 Hz, 2H) 1.75-1.87 (m, 5H) 2.03 (d, J=7.07 Hz, 2H) 2.37-2.47 (m, 1H) 7.12 (d, J=8.34 Hz, 2H) 7.21 (d, J=8.34 Hz, 2H) 7.43-7.51 (m, 2H) 7.64-7.73 (m, 3H) 7.96 (dd, J=8.72, 2.65 Hz, 1H) 8.58 (d, J=2.27 Hz, 1H); (M+H)+514.2.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:33][C:34](=O)[O:35]C(C)=C.CN1CCCC1>O1CCOCC1.C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:33][C:34]([NH:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[O:35]
Reactant: Nc1cc(C(F)(F)F)c[nH]c1=O
Reactant: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)c[nH]c4=O)c(F)c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 57.6 %

Procedure:
3-Amino-5-(trifluoromethyl)pyridin-2(1H)-one (44 mg, 0.247 mmol), prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate from Example 21 (85 mg, 0.231 mmol) and N-methylpyrrolidine (7.5 mg, 0.088 mmol) were combined in 1,4-dioxane (0.8 mL). The resultant mixture was heated to 80° C. After 13 h, the mixture was cooled to RT and diluted with ethyl acetate (3 mL). The resultant precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to provide 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea as an off-white solid (65 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1 H), 9.56 (s, 1 H), 9.35 (s, 1 H), 8.36 (d, J=5.3 Hz, 1 H), 8.25 (br s, 2 H), 8.17 (t, J=9.4 Hz, 1 H), 7.96 (s, 1 H), 7.59 (s, 1 H), 7.25-7.22 (m, 2 H), 7.00 (d, J=8.5 Hz, 1 H), 6.68 (m, 1 H), 3.84 (s 3 H); MS (ESI) m/z: 489.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Br)cc1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1sc2c(c1C(=O)c1ccc(Br)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-bromobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue puri fied by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 89-90 ° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([NH2:11])[C:4]=1[C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.CO.[BH4-].[Na+].[H][H]>[Pd].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([NH2:11])[C:4]=1[C:12](=[O:22])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: COc1cc(N)c(C(=O)C=Cc2ccc(O)cc2)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N)c(C(=O)CCc2ccc(O)cc2)c(OC)c1

Procedure:
0.5 g of 1-(2,4-dimethoxy-6-aminophenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one, 20 mL methanol, and 1 g of palladium on carbon were mixed; and to the mixture was added 50 μL of sodium borohydride and placed under vacuum. The reaction was continued for 30 minutes or until hydrogen evolution ceased. The reaction mixture was diluted with 100 mL of water. Pale yellow to tan crystals of 1-(2,4-dimethoxy-6-aminophenyl)-3-(4-hydroxyphenyl)-propan-1-one formed. The crystals were obtained from the mixture via centrifugation at 1000×g for 10 minutes. The crystals were resuspended in water, and centrifugation was repeated.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[H][H]>[Pd].CO>[NH2:8][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:12])[F:13])[CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)cnc1O
Yield: 99.3 %

Procedure:
A mixture of 3.13 g of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, 40 ml of methanol and 0.85 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for two hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 2.66 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine.
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:21]>>[ClH:21].[N+:18]([C:14]1[CH:13]=[C:12]([CH:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)NC(=S)NC(CO)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: NC1=NC(c2cccc([N+](=O)[O-])c2)CS1
Temperature: 100 °C

Procedure:
The process is performed as in Example 2, starting with 4.77 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea and 44 cm3 of aqueous 6N hydrochloric acid, and this mixture is maintained at a temperature in the region of 100° C. for 2 h 30 min. After an identical work-up, 3.1 g of 4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of a cream-colored solid melting at 232° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=O)[C:5]([O:12][CH3:13])=[N:4][C:3]=1[NH:14][CH2:15][CH3:16].[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24].Cl>C1(C)C=CC=CC=1>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][NH:17][C:8]([C:6]1[C:5]([O:12][CH3:13])=[N:4][C:3]([NH:14][CH2:15][CH3:16])=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: CCNc1nc(OC)c(C(=O)OC)nc1Cl
Reactant: CN1CCCC1CN
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNc1nc(OC)c(C(=O)NCC2CCCN2C)nc1Cl

Procedure:
To 30 ml. of toluene were added 3.0 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 3.0 g. of 2-aminomethyl-1-methylpyrrolidine and the mixture was refluxed for 4 days. The reaction mixture was acidified with hydrochloric acid at room temperature and then extracted twice each time with 30 ml. of water. From the toluene layer, 0.9 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate used as the starting material was recovered. The extracts were combined, basified with aqueous ammonia and extracted three times each time with 30 ml. of chloroform. The extracts were combined and evaporated to dryness. By adding 50 ml. of ether to the residue formed, 1.0 g. of crystals of N-(1-methylpyrrolidin-2-ylmethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide were obtained. The colorless acicular crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane melted at 126°-127° C.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10](C(O)=O)=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1>Cl>[CH3:14][C:4]1[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1
Reactant: Cc1cc(S)n2ncc(C(=O)O)c2n1
Agent: Cl
Product: Cc1cc(S)n2nccc2n1

Procedure:
110 g of 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid were heated to reflux temperature for 2.5 hours in 500 ml of 20 percent hydrochloric acid. The reaction mixture was cooled, the product was filtered off under suction and then recrystallized from water/ethanol at a pH of 6. There was obtained 5-methylpyrazolo [1.5-a]pyrimidine-7-thiol as yellow crystals of a melting point above 250°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[CH2:7]2.[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:15][C:13]([F:16])([CH3:14])[CH2:12][N:6]1[CH2:5][CH2:4][C:3]2[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([CH3:17])=[C:19]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: CC(F)(F)CN1CCc2c(Br)cccc2C1
Reactant: Cc1ccc(-c2cc(N)ccc2C)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(Nc3cccc4c3CCN(CC(C)(F)F)C4)ccc2C)nc1
Temperature: 96 °C
Reaction time: 18 h

Procedure:
To a reaction tube under argon containing 5-bromo-2-(2,2-difluoropropyl)-1,2,3,4-tetrahydroisoquinoline (29 mg, 0.1 mmol), 4-methyl-3-(5-methylpyridin-2-yl)aniline (20 mg, 0.1 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), xantphos (17 mg, 0.02 mmol), potassium phosphate (60 mg, 0.3 mmol) is added anhydrous dioxane (0.5 ml). The mixture is stirred at 96° C. under argon for 18 hours, cooled to room temperature and filtered through a celite pad. The filtrate is concentrated and preparative HPLC is used to isolate 2-(2,2-Difluoropropyl)-N-(4-methyl-3-(5-methylpyridin-2-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-5-amine as a white solid. LC-MS m/z: 408.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.48 (s, 1H), 7.52 (dd, 2H, J=1.6, 8 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.14 (d, 1H, J=8.0 Hz), 7.07-7.00 (m, 2H), 6.95 (dd, 1H, J=2.4, 8.0 Hz), 6.62 (d, 1H, J=6.8 Hz), 5.30 (s, 1H), 3.77 (s, 2H), 2.92 (t, 2H, J=6.0 Hz), 2.83 (t, 2H, J=13.6 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.36 (s, 3H), 2.27 (s, 3H), 1.66 (t, 3H, J=18.8 Hz).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)nc1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(Cl)nc1C
Yield: 27 %

Procedure:
A solution of ethyl 2-hydroxy-4-methylpyrimidine-5-carboxylate (5 g, 27.5 mmol) and POCl3 (84 g, 550 mmol) was heated at reflux under N2 for 1 h. The reaction was cooled and concentrated. The residue was partitioned between CHCl3 and H2O and the organic layer was dried (Na2SO4), filtered, and concentrated to yield the title compound in a yield of 27% (1.5 g); 1HNMR (CDCl3) δ 9.04 (s, 1H), 4.42 (q, 2H), 2.85 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH2:21]O)[CH:8]=[C:7]([Cl:23])[CH:6]=1.P(Br)(Br)[Br:26]>COCCOC>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([Cl:23])[CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH2:21][Br:26])[CH:10]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2CO)c1
Solvent: COCCOC
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [3-chloro-5-(2-hydroxymethyl-4-nitro-phenoxy)-phenyl]-acetic acid methyl ester (2.4 g, 6.8 mmol) in DME (20 mL) was added phosphorus tribromide (0.97 mL, 10.2 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up with EtOAc and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:23]2[C:24]([CH3:40])=[C:25]([NH:29]C(=O)OCC4C=CC=CC=4)[CH:26]=[CH:27][CH:28]=2)=[CH:6][N:5]=1)=[CH:15][C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=3)(=[O:3])[NH2:2]>CO.C1COCC1.[Pd]>[NH2:29][C:25]1[C:24]([CH3:40])=[C:23]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-6-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.125 g, 0.233 mmol) and 10% Pd/C (0.025 g, 0.023 mmol) in methanol (8.75 mL) and THF (2.92 mL) was stirred under a hydrogen balloon. After 1 hr, the reaction was flushed with nitrogen, filtered through a pad of CELITE®, rinsed with MeOH. The filtrate was concentrated in vacuo, dissolved in CH2Cl2 (100 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (0.0786 g, 0.196 mmol, 84% yield) as a light tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29].C1COCC1.[H-].[Na+]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([OH:26])[CH:28]([C:27]([O:31][CH3:32])=[O:30])[S:29][C:16]3[C:17]([C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=[CH:20][C:15]2=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1Sc2c(C(F)(F)F)cccc2C1(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 1.67 h
Yield: 56 %

Procedure:
To a room temperature solution of 4-(2-fluoro-3-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), methyl thioglycolate (2.40 mL, 26.8 mmol), and anhydrous THF (200 mL) under nitrogen was added NaH (1.15 g of a 60% oil dispersion, 28.7 mmol) in one portion. After the gas evolution ceased, the reaction was stirred at 55° C. After 100 min, the reaction was cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford a sticky white solid. Trituration with 20% ethyl acetate/heptane afforded 6.20 g (56%) of the desired product as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)=[O:9]
Reactant: CO
Reactant: O=C(O)[C@@H]1CCCCN1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCCN1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of (S)-piperidine-2-carboxylic acid (10 mmol, 1.29 g) in MeOH (20 mL) is dropwise added thionyl chloride (30 mmol, 2.17 mL) at room temperature. The mixture is stirred at 2 hours, and then concentrated under reduced pressure. To the residue is added water (5 mL) and basified with potassium carbonate. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure to give (S)-piperidine-2-carboxylic acid methyl ester as a pale brown oil (800 mg, 56%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].[CH2:27]([OH:30])[CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:30][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: OCCO
Reactant: CCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 168 h

Procedure:
Ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (363 mg) was added to a solution of potassium tert.-butoxide (427 mg) in ethylene glycol (7 ml) and stirred at 100° C. for 7 days. The reaction mixture was then poured onto ice/water and extracted with ethyl acetate. The crude product was purified by chromatography over silicagel with DCM/MeOH=9/1 to give ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (310 mg) as a white powder. LC-MS: tR: 3.47, [M+H]+: 338.13.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:20]1([CH3:33])[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)=[CH:22][CH:21]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:29]2[N:30]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:33])=[CH:21][CH:22]=3)[S:27][CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: Cc1ccc(-c2nc(C=O)cs2)cc1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1csc(-c2ccc(C)cc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available 2-(p-tolyl)thiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 411.02 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10]>>[NH:9]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[NH2:10]
Reactant: NN
Reactant: Clc1cc(I)ccn1
Product: NNc1cc(I)ccn1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-4-iodopyridine (5000 mg, 20.88 mmol) (commercially available from Frontier Scientific, Inc., Logan Utah) and anhydrous hydrazine (32.8 mL, 1045 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) was heated at 70° C. for 30 minutes. LC-MS indicated complete conversion to desired product. The reaction mixture was concentrated under vacuum, and the solid was washed with water (3×15 mL) and air dried. The gray colored solid was used directly without further purification. m/z (ESI) 236.0 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=C[C:33]=2[N:32]=N1.CNCC1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:32]2[CH2:33][CH2:34][CH2:35][CH:36]2[CH3:37])=[O:23])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CNCc1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCC4C)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([C:20]3[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[C:22]([CH2:30][C:31]4[C:32]([NH2:38])=[N:33][C:34]([NH2:37])=[N:35][CH:36]=4)[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([C:20]3[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[C:22]([CH2:30][C:31]4[C:32]([NH2:38])=[N:33][C:34]([NH2:37])=[N:35][CH:36]=4)[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(-c2cccc(NS(=O)(=O)c3ccc([N+](=O)[O-])cc3)c2)c1OC
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2cccc(NS(=O)(=O)c3ccc(N)cc3)c2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
322 mg of 5-(3'-(4-nitrobenzene-sulphonylamino)-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine (Example 4f)) are dissolved in 15 ml of glacial acetic acid and treated portionwise with 650 mg of iron powder. The mixture is stirred at room temperature for 2 hrs. Subsequently, it is poured on to ice-water, made alkaline with dilute sodium hydroxide solution and filtered. The residue and the aqueous phase are washed with ethyl acetate; the combined organic phases are dried, evaporated and the residue is chromatographed on silica gel. Eluent: methylene chloride/methanol/conc. ammonia 90:10:1. 230 mg (76%) of 5-(3'-(4-aminobenzene-sulphonylamino)-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a yellowish solid. M.p. 223°-226°.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:27])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15](OCC)=[O:16].[Cl-].[NH4+]>C1COCC1>[CH3:13][C:14]([CH3:27])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCCCCC(C)(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCC(C)(C)C(=O)CP(=O)(OC)OC
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
To a solution of dimethyl methylphosphonate (6.1 ml, 56.0 mmol) in 100 ml anhydrous THF was added dropwise n-butyl lithium (1.61N, 34.7 ml, 55.9 mmol) at -78° C. under argon atmosphere. After stirring the mixture for 15 minutes, ethyl 2,2-dimethylnonanoate (5.00 g, 23.3 mmol) was added dropwise and the mixture was stirred at -78° C. for 20 minutes and then at room temperature for 2 hours. To the reaction mixture was added 20 ml of saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (50 ml×4). The ethyl acetate layers were washed with water (50 ml) and with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography on silica gel (ethyl acetate) gave pure dimethyl 3,3-dimethyl-2-oxodecylphosphonate (2.3312 g, 7.97 mmol, yield 34%). The structure of this product was confirmed by the following data.