Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:14][S:15]([C:18]1[C:19]2[CH:20]=[CH:21][NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13].CC(SCC[NH2+]C(CN)=O)=O.C([O-])(C(F)(F)F)=O.C1C(=O)N([Cl:53])C(=O)C1>CN(C=O)C.CC#N>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:14][S:15]([C:18]1[C:19]2[C:20]([Cl:53])=[CH:21][NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C(CCn1cccc1C#N)NS(=O)(=O)c1cccc2[nH]ccc12
Agent: CC(=O)SCC[NH2+]C(=O)CN
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)C(CCn1cccc1C#N)NS(=O)(=O)c1cccc2[nH]cc(Cl)c12
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A solution of 0.20 g (0.52 mmol) of 4-(2-cyano-pyrrol-1-yl)-2-(1H-indole-4-sulfonylamino)-butyric acid methyl ester (from the synthesis of I-102) and 0.070 g (0.52 mmol) of NCS in 1 mL of DMF is stirred overnight, and then diluted with MeCN and purified by preparative HPLC to provide 0.15 g (0.36 mmol; 69%) of 2-(3-chloro-1H-indole-4-sulfonylamino)-4-(2-cyano-pyrrol-1-yl)-butyric acid methyl ester. This material is stirred in 1.4 mL of THF with 1.4 mL of 1M NaOH for 3 h, and then 2N HCl is added until the pH is 3. The mixture is extracted with EtOAc, and the extract washed with brine, dried over Na2SO4, filtered, and concentrated to provide 0.12 g (85%) of I-103 as a tan powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:24]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimiazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.6 g, 0.0554 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the residue was triturated in 100 ml of water, the solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature, and water was added to the cloud point. The resulting solid was collected by filtration, rinsed with water, and dried under high vacuum at 42° C. overnight to give 2.22 g (34%) of title compound, mp. 135°-136° C.
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(#N)C>O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]2[C@H:11]([OH:12])[C@H:2]([CH2:3][C:15]3[NH:14][CH:18]=[CH:17][N:16]=3)[S:4][C:5]=2[CH:6]=1
Reactant: c1c[nH]cn1
Reactant: OC1c2ccc(Cl)cc2SCC1Br
Solvent: O
Solvent: CC#N
Product: O[C@H]1c2ccc(Cl)cc2S[C@H]1Cc1ncc[nH]1

Procedure:
Add 3-bromo-7-chlorothiochroman-4-ol (5.27 gms., 18.8 mmols) and imidazole (12.8 gms., 188 mmols) to acetonitrile (100 ml.), and heat at reflux temperature for 4 hours. Pour the reaction mixture into water (500 ml.), and extract with chloroform (500 ml.). Wash the organic layer with water (500 ml.), dry the organic layer over anhydrous magnesium sulfate, filter and evaporate in vacuo. Triturate the resultant residue with anhydrous ether, filter and recrystallize from acetonitrile to give cis-6-chloro-2,3-dihydro-3-hydroxy-2-(1'-imidazolylmethyl)benzo(b)thiophene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([OH:14])[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH2:41][C:42](Cl)=[O:43]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([O:14][C:42](=[O:43])[CH2:41][C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[CH3:33])[CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(O)CCN(OC)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)C1(OC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
To a solution of 4-hydroxy-1-methoxy-piperidine-4-carboxylic acid ethyl ester (1.0 g, 4.92 mmol) in 10 ml pyridine under argon was added 4-dimethylaminopyridine DMAP (30 mg, 0.25 mmol). The solution was cooled down to 0° C., then (2,5-dimethyl-phenyl)-acetyl chloride (0.99 g, 5.4 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and left stirring for 5 days. Then the reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel (ethyl acetate/cyclohexane first 1:15, then 1:9) to give pure 4-[2-(2,5-dimethyl-phenyl)-acetoxy]-1-methoxy-piperidine-4-carboxylic acid ethyl ester (compound P3.2) as light yellow oil. Yield: 530 mg.
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+].[OH:25][CH:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:27]([O:29]C)=O>>[OH:1][CH:2]([CH2:21][OH:22])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:27](=[O:29])[CH:26]([OH:25])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)OC
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCCCCCCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-hexadecylamine (1.0 g, 0.0032 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl 2-hydroxyhexadecanoate (0.907 g, 0.0032 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.79 g). The waxy solid was recrystalized from hot hexane (yield=0.94 g).
Reaction SMILES: N[C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:14]([C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)(=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12]
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)c1nc(Cl)c2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a 100 ml round bottom flask was charged 4.0 g (23.8 mmol) of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine dissolved in 50 ml of anhydrous pyridine. To this solution was added 10.2 ml (83 mmol) of trimethylacetyl chloride, and after several minutes a precipitate began forming. The reaction was stirred at RT under a nitrogen atmosphere for 30 min. The volatiles were removed in vacuo, and the residue was dissolved in 1 L of CHCl3, washed twice with 0.1 N HCl, dried over Na2SO4, and removed in vacuo. The crude residue was flash chromatographed on silica gel eluting with a gradient of 100% CHCl3 to 2% MeOH/CHCl3. After collecting the correct fractions, the solvents were removed in vacuo to give 4.4 g (73%) of 2-pivaloyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=4)[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: COc1cccc(NC(=N)N)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Product: COc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(3-methoxyphenyl)guanidine were converted to I-15 (25%): HRMS Calcd. for C11H15ClN4O2: 367.0961, Found 367.0961.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][N:8]=1>O1CCOCC1>[N+:16]([C:10]1[C:9]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][CH:7]=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=1)([O-:18])=[O:17]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(N2CCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 89.6 %

Procedure:
2.2 g (0.03 mol) of pyrrolidine were added over 10 minutes to a solution containing 3 g (0.015 mol) of 2-chloro-3,5-dinitropyridine in 30 ml of dioxane, at 40° C. The reaction medium was maintained at 60° C. until the reagents disappeared. The reaction medium was then poured into a water/ice mixture with vigorous stirring and the precipitate was filtered off by suction, washed with water and then dried to constant weight to give 3.2 g of 3,5-dinitro-2-pyrrolidin-1-ylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[C:18]([O:30][CH2:31][CH2:32][C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[H][H]>CC(=O)OCC.[Pd]>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:30][CH2:31][CH2:32][C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OCc3ccccc3)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Yield: 45.2 %

Procedure:
The compound of step 3 of example 253 (800 mg, 1.49 mmol) was dissolved in EA (15 ml) and hydrogenated in the presence of palladium (10%) on charcoal (200 mg) at a hydrogen pressure of 5 bar and room temperature for 6 h. The mixture was filtered over silica gel and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield 300 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.Cl>O>[NH2:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: O
Product: N#Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
300 mg (1.83 mmol) of 2-amino-4,6-dichloropyrimidine and 216 mg (1.83 mmol) of 4-aminobenzonitrile are suspended in 6 ml of water. 180 μl of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. The precipitate is filtered off with suction.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:21](=[O:22])[C:20]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:19]=2[F:18])/[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(N)s1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1c[nH]/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
A mixture of 5-tert-butylthiazol-2-amine (1.93 g, 12.3 mmol) and triethylamine (3.44 mL, 2.46 mmol) in dichloromethane (50 mL) was treated with 2-fluoro-5-(trifluoromethyl)benzoyl chloride (Alfa, 1.87 mL, 12.3 mmol) and stirred at room temperature for 6 hours. The reaction mixture was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to give the title compound (3 g, 71% yield). MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:26][CH2:27][F:28])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 86.6 %

Procedure:
290 mg (corresponding to 1.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 10 mL of N,N-dimethylformamide, and 413 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. 138 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane was added to the resulting solution, and then the solution was stirred at room temperature for 20.5 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 302 mg (corresponding to 0.866 mmol) of 6-bromo-2-[4′-(3″-fluoropropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 7, Step 3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[C:19]([O:23][C:24](OC([O-])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>[OH-].[Na+]>[C:19]([O:23][C:24](=[O:25])[NH:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)C1
Yield: 96.8 %

Procedure:
1-benzylpyrrolidin-3-ylamine (10 g, 57 mmol) was dissolved in 3M aqueous sodium hydroxide solution (21 ml) and t-butanol (114 ml) in a 500 ml vessel, and t-butyl-dicarbonate ((t-Boc)2O; 13.07 g, 59.9 mmol) was added thereto while stirring. The resulting mixture was reacted for 12 hrs. After the completion of the reaction, the reaction product was extracted with ethyl acetate twice. The organic layer was separated, washed with 0.1N hydrochloric acid solution and brine in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 15.25 g of the title compound as a white solid (yield 97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14].N1C=CC=CC=1C(O)CCC>>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([CH:12]([OH:15])[CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CCC=O
Agent: CCCC(O)c1ccccn1
Product: CCC(O)c1cccc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-bromo-6-(trifluoromethyl)pyridine (purchased from Oakwood Products Inc., West Columbia, S.C.) and propionaldehyde following the procedure as described above for the synthesis of 1-(pyridin-2-yl)butan-1-ol (Example 231, Step A). Mass Spectrum (ESI) m/z=206.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18](=N)[N:17]([CH3:20])[C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH:9]=1.Cl.[OH2:22]>>[NH2:16][C:13]1[N:14]=[CH:15][C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:18](=[O:22])[N:17]([CH3:20])[C:11]=2[N:12]=1
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2n(C)c1=N
Reactant: O
Agent: Cl
Product: Cc1ccccc1-c1cc2cnc(N)nc2n(C)c1=O
Temperature: 25 °C

Procedure:
To a mixture of 6-(2-methylphenyl)-7-imino-8-methyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamine (0.30 g) from Example 8 and concentrated HCl (0.6 mL) was added water (11 mL). The reaction mixture was refluxed for 20 hours, then allowed to cool to room temperature. The white precipitate from the reaction mixture was filtered and washed with water. The product was dried in vacuo to give 0.21 g of 2-amino-6-(2-methylphenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one; mp 239°-241° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][S:37]([NH:40][CH3:41])(=[O:39])=[O:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][S:37]([NH:40][CH3:41])(=[O:38])=[O:39])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: CNS(=O)(=O)C[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CNS(=O)(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (25.8 mg, 0.290 mmol) and triethyloxonium tetrafluoroborate (51.9 mg, 0.273 mmol) in tetrahydrofuran (0.40 mL) was stirred at room temperature for 1 h. After evaporated to dry under reduced pressure, the clear oil was mixed with ethanol (0.20 mL, 3.4 mmol) and added to a solution of 1-{trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}-N-methylmethanesulfonamide (32 mg, 0.090 mmol) in ethanol (0.60 mL) in a microwave vial. The mixture was then heated at 80° C. for 1 h. The mixture was concentrated under reduced pressure. The resultant residue was purified using prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (9.8 mg, 26%). LCMS calculated for C18H25N4O3S2 (M+H)+: m/z=409.1. Found: 409.1.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([OH:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]1CCN2C(=NCCC2)CC1.P(OC)(OC)(OC)=O>O1CCOCC1>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]([CH3:27])[C:18](=[O:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(O)c3)nc2N1C1CCCC1
Solvent: C1COCCO1
Solvent: COP(=O)(OC)OC
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccn(C)c(=O)c3)nc2N1C1CCCC1
Yield: 45.4 %

Procedure:
To a solution of (R)-8-cyclopentyl-7-ethyl-2-(2-hydroxypyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 14, 200 mg, 0.6 mmol) in 5 mL of 1,4-dioxane, DBU (26 mg, 3 mmol) and PO(OMe)3 (42 mg, 3 mmol) were added, and the mixture was heated to reflux for 18 h, then concentrated under reduced pressure, and extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure and the residue was chromatographed (PE:EA=1:1) to give the title compound as a yellow solid (100 mg, 50% yield). 1H NMR (CDCl3) δ: 7.95 (s, 1H), 7.53 (s, 1H) 7.35 (d, 1H), 7.11 (m, 1H), 4.54 (m, 1H), 4.29 (m, 1H), 3.6 (s, 3H), 3.38 (s, 3H), 2.2-1.6 (m, 10H) and 0.87 ppm (t, 3H); LCMS: 368.2 m/z (M+H)+; ret. Time: 1.53 min (Analytical Method E).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:40][CH2:39][CH2:38][O:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: COCCN
Product: COCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 91.7 %

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and 2-methoxyethylamine (225 mg, 2.97 mmol) as starting materials to afford the title compound as a colourless oil (372 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(=O)(CCCCCl)Cc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCS(=O)(=O)Cc2ccccc2)CC1
Yield: 65.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2 g) and 4-(benzylsulfonyl)butyl chloride (1.46 g) were reacted and treated in the same manner as in Example 199 to give 0.96 g of 4-amino-N-((1-(4-(benzylsulfonyl)butyl)piperidin-4-yl)-methyl)-5-chloro-2-methoxybenzamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][O:26][CH3:27])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:27][O:26][CH2:25][CH2:24][NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: COCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-(2-methoxyethylamino)phenyl)-5-phenylbenzoxazole (131 mg, 0.36 mmol) and 1,2,4-benzenetricarboxylic anhydride (70 mg, 0.36 mmol) the title compound was obtained (138 mg, 72%). 1H NMR (DMSO) δ 8.61(t, 1H), 8.42(dd, 1H), 8.31(s, 1H), 8.13(d, 1H), 8.08(m, 2H), 7.83(d, 1H), 7.53(m, 3H), 7.50(m, 3H), 7.41(t, 1H), 7.08(d, 1H), 3.69(m, 2H), 3.59(m, 2H), 3.35(s, 3H). MS 534 m/z (M+H)+.