Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[N:5]=[CH:4][N:3]=1.[C:10](OCC)(=[O:14])[C:11]([CH3:13])=O>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[N:8]=[C:11]([CH3:13])[C:10](=[O:14])[NH:9][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc(N)c1N
Reactant: CCOC(=O)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c(N)ncnc2[nH]c1=O

Procedure:
More specifically, with reference to FIG. 2, 4,5,6-triaminopyrimidine (1), (see, J. Baddiley et al., J. Chem. Soc. 386 (1943)) and ethyl pyruvate are heated in glacial acetic acid for 2 hours. After cooling the precipitate is collected and washed with water and purified by recrystallization using a suitable solvent system, such as DMF/H2O, to yield 4-amino-6-methyl-7(8H)-pteridone (3) (see, D. Söll et al., Chem. Ber. 96:2977 (1963)). Compounds wherein R1 is an methyl group can be generated similarly by starting with 4,5,triamino-2-methylpyrimidine (2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH3:17]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:17])=[O:11]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccccc2[nH]1
Yield: 99.2 %

Procedure:
To 300 ml of a methanol solution of 30.0 g (186.2 mmol) of 2-indolecarboxylic acid was dropwise added 44.3 g (372.3 mmol) of thionyl chloride at 0° C. The reaction mixture was refluxed for 2 hours and the solvent was then distilled off under reduced pressure. Ice water was poured onto the resulting residue. The mixture was made basic by the addition of concentrated ammonium hydroxide. The mixture was extracted three times with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 32.34 g (99.2%) of methyl 2-indolecarboxylate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].C([O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)(=O)C>O>[CH:8]([C:29]1[N:25]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=2[OH:14])[C:19]([O:21][CH3:22])=[O:20])[CH:26]=[CH:27][CH:28]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(OC(C)=O)c(-n2cccc2)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(O)c(-n2cccc2C=O)c1
Reaction time: 20 h

Procedure:
To a solution of phosphorus oxychloride (8.3 ml) and N,N-dimethylformamide (70 ml) was added methyl 4-acetoxy-3-(pyrrol-1-yl)benzoate (11.7 g) at ambient temperature and the mixture was stirred for 20 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tetrahydrofuran. To the solution was added 28% methanolic sodium methoxide (9.7 ml) under ice-cooling and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added acetic acid (6 ml) and evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and adjusted to pH 7 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from toluene, collected by filtration and the precipitate was washed with ether to give methyl 3-(2-formylpyrrol-1-yl)-4-hydroxybenzoate (7.89 g).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])C>CS(C)=O.[Cl-].[Na+].O>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][C:8]2([OH:19])[C:6]([OH:7])=[O:5])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1(O)CCCc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)C1(O)CCCc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
NaOH (10M, 1 mL) was added to a solution of 7-chloro-1-hydroxytetraline-1-carboxylic acid, ethyl ester (0.8 g; 3.1 mmol; from step (iii) above) in DMSO (20 mL), and the mixture was heated to 100° C. for 3 hours. The resultant mixture was diluted with crushed ice (40 g) and brine (40 mL), and the mixture was extracted with EtOAc. The aqueous layer was acidified to pH 2 with 2M HCl and extracted with EtOAc (2×40 mL). The combined organic layer was dried (Na2SO4) and concentrated. Yield 0.22 mg (30%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[CH:9]2)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:11]3[N:10]=[CH:9][N:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:12]=3)=[O:15])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: Cc1cccc(-n2cnc(C(=O)O)c2)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: Cc1cccc(-n2cnc(C(=O)N[C@@H](C)Cn3ccc(-c4cc(F)c(C#N)c(Cl)c4)n3)c2)n1
Yield: 55.3 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid (0.190 g, 0.933 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.2 g, 0.718 mmol). The product was purified by recrystallization from acetonitrile. Yield 55.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 2.53 (s, 3H), 4.31-4.52 (m, 3H), 7.01 (d, 1H), 7.29 (d, 1H), 7.72 (d, 1H), 7.87-7.96 (m, 3H), 8.02-8.04 (m, 1H), 8.35 (d, 1H), 8.40 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH:33]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:33][C:32]3[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8-acetyl -3methylflavone (2.5 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 121-23° C., 1H-NMR (CDCl3)δ: 2.20 (s, 3H); 3.87 (m, 9H); 4.73 (d, 2H, J=5,1 Hz; 5.25-5.45 (m, 2H); 5.91-6.02 (m, 1H); 6.75 (s, 2H); 6.96 (d,1H, J=16 Hz); 7.10 (d, 1H, J=8.9 Hz); 7.30 (d, 1H, J=16 Hz); 7.42-7.46 (m, 3H); 7.55-7.59 (m, 2H); 8.34 (d, 1H, J=8.9 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[F:11])#[N:2].C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH3:36][S:37]([O:40][C:41]1[CH:50]=[C:49]2[C:44]([CH:45]=[CH:46][CH:47]=[C:48]2[N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C:59]3[N:60]=[CH:61][N:62](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:63]=3)[CH2:53][C:52]2=[O:83])=[CH:43][CH:42]=1)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:40][C:41]1[CH:50]=[C:49]2[C:44]([CH:45]=[CH:46][CH:47]=[C:48]2[N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C:59]3[N:60]([CH2:7][C:6]4[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[C:4]([F:11])[CH:5]=4)[CH:61]=[N:62][CH:63]=3)[CH2:53][C:52]2=[O:83])=[CH:43][CH:42]=1)(=[O:39])=[O:38]
Reactant: N#Cc1ccc(CO)cc1F
Reactant: CS(=O)(=O)Oc1ccc2cccc(N3CCN(CCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)CC3=O)c2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2cccc(N3CCN(CCc4cncn4Cc4ccc(C#N)c(F)c4)CC3=O)c2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step J (15 mg, 0.75 mmol) in 3 mL of dichloromethane at −78° C. was diisopropylethylamine (0.40 mL, 2.28 mmol), followed by triflic anhydride (0.128 mL, 0.76 mmol). After 20 minutes, a solution of the product from Step G (500 mg, 0.762 mmol) in 2 mL of dichloromethane was added, and the reaction was stirred at −78° C. for 30 minutes, and at room temperature for 1.5 hours. After concentrating the reaction in vacuo, 5 mL of methanol was added and the solution was heated at reflux for 30 minutes. The solution was concentrated in vacuo, acidified with 5% HCl solution, triturated with hexane, and partitioned between EtOAc and 20% NaOH solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.S(Cl)(Cl)=O.[CH3:18]O>>[Br:1][CH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH3:18])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CO
Reactant: O=C(O)CC1(CCBr)CCCCC1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1(CCBr)CCCCC1
Reaction time: 18 h

Procedure:
To a solution of 1-(2-bromoethyl)cyclohexylacetic acid (4.98 g) in methanol (50 mL) was added thionyl chloride (1.76 mL) dropwise under ice cooling. After completion of the dropwise addition, the reaction solution was stirred for 18 hours, while its temperature was allowed to rise to room temperature. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. The solution was washed in turn with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure to give the title compound (5.41 g). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:20][CH:19]=1
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(CNCc1ccc(-n2ccnc2)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2,2-dimethoxyethylamine (526 mg) and 4-(1H-imidazol-1-yl)benzaldehyde (861 mg) in methanol (25 ml) was added acetic acid (600 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, sodium triacetoxyborohydride (1.59 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and to the residue was added 1 N sodium hydroxide solution. The mixture was extracted with dichloromethane, dried and concentrated to give colorless oil of the title compound (1.21 g).
Reaction SMILES: C(OC([NH:8][C:9]1([C:42](O)=[O:43])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[N:23](C4CCCCO4)[N:22]=3)[N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:45][NH2:46]>>[NH2:8][C:9]1([C:42]([NH:46][CH3:45])=[O:43])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[NH:23][N:22]=3)[N:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Reactant: CN
Product: CNC(=O)C1(N)CCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Yield: 24 %

Procedure:
Following the procedures of Example 229, and starting with 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid and methylamine, were reacted and purified via reverse phase HPLC using a gradient of MeCN in water with 0.1% HCOOH to afford 19 mg (24%) of 236 over two steps. ESI MS m/z 429.2 (M+1). 1H NMR (400 MHz, DMSO): 13.95 (s, 1H), 9.22 (d, J=8.4 Hz, 2H), 8.92 (s, 1H), 8.61 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 4.27 (d, J=13.0 Hz, 2H), 3.53 (t, J=12.5 Hz, 2H), 2.67 (s, 3H), 2.29 (m, 2H), 1.87-1.73 (m, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH2:7][O:8][CH3:9])[CH2:5][OH:6].C(S[C:15]1[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:19]=2[N:20]=1)CC.O>O1CCCC1>[F:3][C:4]([F:10])([CH2:7][O:8][CH3:9])[CH2:5][O:6][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:36])([F:38])[F:37])=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:19]=2[N:20]=1
Reactant: COCC(F)(F)CO
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(F)(F)COc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 29 mg) in tetrahydrofuran (5 ml) was added 2,2-difluoro-3-methoxypropan-1-ol (151 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (8 mg).
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[OH:22])=[O:12])([CH3:9])[CH3:8])(C)(C)C.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C:7]([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[O:22][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][N:27]=1)=[O:12])([CH3:8])[C:6]([OH:5])=[O:23]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1O
Reactant: FC(F)(F)c1ccc(CBr)nc1
Product: CC(C)(NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cn1)C(=O)O

Procedure:
2-Methyl-2-{[4-(5-trifluoromethyl-pyridin-2-ylmethoxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid was prepared in analogy to example 13 via a sequence of an alkylation reaction of 2-[(4-Hydroxy-benzo[b]thiophene-5-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester using 2-bromomethyl-5-trifluoromethyl-pyridine and an acidic hydrolysis of the amino acid ester to the free amino acid
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:31])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH3:30])[N:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:19]=[CH:18][N:17]=[C:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:31])[CH:21]=1)[CH3:30]
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (IV), (0.500 g, 1.17 mmol) in dry dichloromethane (1.5 ml), TFA (1.5 ml) was added at 0° C. and the reaction mixture was stirred for 2-3 hours. After completion of the reaction (monitored by TLC) the solvent mixture was removed under reduced pressure and dichloromethane was added to the residue. Solid sodium carbonate was added and the mixture was stirred for 3-4 hours. Then it was filtered and washed with dichloromethane. The combined filtrate was concentrated under reduced pressure to obtain a solid which was washed with 10% ethyl acetate/hexane to remove nonpolar impurities, giving piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) as pure white solid (0.19 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:10])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)Nc2ccc(F)cc2)sc1C(=O)NCc1ccccc1
Yield: 83 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use 4-fluorophenyl isocyanate in place of phenyl isocyanate to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 83% yield; m.p.>300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.03 (s, 1H), 8.47 (t, J=6.0 Hz, 1H), 7.49-7.05 (m, 10H), 4.35 (d, J=5.7 Hz, 2H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.2, 140.2, 128.7, 127.7, 127.2, 121.1, 121.0, 120.5, 116.1, 115.9, 115.8, 43.0, 39.1; MS (ES+) m/z 385.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[C:17]([CH3:24])[CH:16]=1>>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([CH3:19])=[C:17]([CH2:24][C:11]2[S:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:13][CH:12]=2)[CH:16]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: COc1ccc(-c2cccs2)cc1
Product: COc1ccc(-c2ccc(Cc3cc(Br)ccc3C)s2)cc1

Procedure:
The above 2-(4-methoxyphenyl)thiophene and 4-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-(4-methoxyphenyl)-2-thienylmethyl)-2-methylbenzene as a pale yellow solid. APCI-Mass m/Z 373/375 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=O)[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.CC(C)([O-])C.[Na+].C(Br)C.Cl>O1CCCC1>[Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCNc1cn(-c2cccnc2)nc1Cl
Temperature: 35 °C
Reaction time: 144 h
Yield: 110.1 %

Procedure:
To a 3-neck, 100-mL round bottom flask was charged N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (5 g, 21.13 mmol) and tetrahydrofuran (50 mL). Sodium tert-butoxide (4.06 g, 42.3 mmol) was added (causing a temperature rise from 22° C. to 27.6° C.), followed by ethyl bromide (6.26 mL, 85 mmol). The reaction was stirred at 35° C. for 144 h at which point only 3.2% (AUC) starting material remained. The reaction mixture was concentrated to give a brown residue, which was dissolved in 1 N hydrochloric acid (106 mL, 106 mmol) and heated at 80° C. for 24 hours, at which point HPLC analysis indicated that the starting material had been consumed. The reaction was cooled to 20° C. and basified with sodium hydroxide (50 wt % in water) to pH>9. The resulting suspension was stirred at 20° C. for 1 hour and filtered. The filter cake was rinsed with water (25 mL) to afford a brown solid (5.18 g). The resulting crude product was dissolved in ethyl acetate and passed through a silica gel plug (50 g) using ethyl acetate (500 mL) as eluent. The filtrate was concentrated to dryness to afford a white solid (3.8 g, 80%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24](O)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:28]1([NH:27][CH:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:26])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: O=C1c2ccccc2C(Nc2ccccc2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 9 h
Yield: 93.8 %

Procedure:
Para-toluenesulphonic acid (50 mg) is added to an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (5 g) and aniline (1.7 g) in xylene (100 cc) at a temperature close to 20° C. in a Dean Stark apparatus. Agitation is continued for 9 hours at a temperature close to 135° C. After cooling to a temperature close to 20° C., the solution is washed with aqueous sodium bicarbonate solution (2×50 cc) then with distilled water (2×30 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 80° C. The residue obtained is dissolved in methylene chloride (10 cc) and poured onto silica (100 g) contained in a column of 2 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume) (1300 cc) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The precipitate formed is recrystallized from boiling acetonitrile (30 cc). 5.7 g of 3-phenylamino-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are obtained, melting at 119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:23]([C:30]1[N:31]=[C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:33][C:34]=1[CH2:35]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([C:30]1[N:31]=[C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:33][C:34]=1[CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1oc(-c2ccccc2)nc1Cc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(Cc2oc(-c3ccccc3)nc2Cc2ccccc2)CC1
Yield: 74 %

Procedure:
A suspension containing 2-methoxyphenylpiperazine (1.0 mmole), potassium carbonate (2.0 mmole), potassium iodide (0.5 mmole) and 4-benzyl-5-chloromethyl-2-phenyloxazole (1.0 mmole) from example 6, was stirred in acetone (15 ml) at ambient temperature for 16 hr. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (2×50 ml). The combined organics were washed with water (40 ml), brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as an off-white crystalline powder (0.74 mmole, 74% yield). This was transformed into its mono-fumarate salt, an off-white crystalline powder, using the procedure outlined in example 10 above. mp 175-175° C.