Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12](O)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[NH2:25][CH:26]([CH3:40])[C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:28].C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])[C:5]2[N:6]([C:8]([C:12]([NH:25][CH:26]([CH3:40])[C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:28])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Reactant: CC(N)[C@H](C)NC(=O)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NC(C)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
164 mg of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 16A, 0.47 mmol, 1 equivalent) were dissolved in 1.4 ml of DMF, 145 mg of benzyl [(2S)-3-aminobutan-2-yl]carbamate (Example 141A, 0.65 mmol, 1.4 equivalents), 230 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.6 mmol, 1.3 equivalents) and 180.7 mg of N,N-diisopropylethylamine (0.23 ml, 1.4 mmol, 3 equivalents) were added and the mixture was stirred at RT overnight. A drop of water was then added and the precipitated solid was filtered off and dried under reduced pressure. This gave 160 mg (53% of theory; purity 86%) of the title compound as colourless crystals.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].C(C(C(C([O-])=O)O)O)([O-])=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 38.7 %

Procedure:
To a solution of the (R)-amlodipine-hemi-L-tartrate-DMSO-solvate (68.25 g) obtained in Step (2) in methylene chloride (345 mL, 5 mL/g) was added a solution of 50% sodium hydroxide (73 mL) in water (72 mL). The solution was stirred at ambient temperature for 40 minutes. The layers were separated and the organic layer extracted with water (1×150 mL) and gravity filtered through a magnesium sulphate (25 g) bed. The magnesium sulphate was washed with methylene chloride (40 mL) and the methylene chloride removed on a rotary evaporator using a water aspirator. Heptane was added to the evaporation flask as the volume allowed. Eventually, all of the methylene chloride was removed and 600 mL of heptane was added to the flask. The resulting solid was collected by suction filtration, washed with heptane and dried in vacuo at 50° C. overnight to give (R)-amlodipine free base (19.4 g, 53.4% yield) as an off-white solid.
Reaction SMILES: [CH2:1]1[N:16]2[C:17]3[C:8]([S:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=42)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:18])[CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:2]2[C:3](=[O:18])[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:17]=3[N:16]([CH:1]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:9]4)[CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1CCN2c3ccccc3Sc3cccc1c32
Product: O=c1c(Cc2cccnc2)cn2c3c(cccc13)Sc1ccccc1-2
Yield: 83 %

Procedure:
According to Example 1<step 4>, 1,2-dihydro-3H-pyrido[3,2,1-kl]phenothiazin-3-one (20 mg) prepared by the procedure described in literature( J. Heterocycl. Chem., 29, 675 (1992)) was reacted with pyridine-3-aldehyde (12 μl) to obtain the title compound (17 mg; 83%). The chemical structure thereof is shown below.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:19][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14](C#N)=[CH:13][CH:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[F:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:47]([C:54](OCC)=O)=NC(OCC)=O>C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:1][CH2:2][C@@H:3]2[CH2:19][N:6]3[CH2:7][CH2:8][N:9]([C:11]4[CH:12]=[C:13]([C:54]#[N:47])[CH:14]=[CH:15][CH:16]=4)[CH2:10][C@@H:5]3[CH2:4]2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)cc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(N2CCN3C[C@@H](COc4ccc(F)cc4)C[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A solution of 0.25 g (0.97 mmol) of (7S,8aS)-7-hydroxymethyl-2-(4-cyanophenyl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 16), 0.164 g (1.46 mmol) of 4-fluorophenol, 0.31 g (1.15 mmol) of triphenylphosphine in 10 mL of THF was treated with 0.18 mL (1.15 mmol) of diethyl azodicarboxylate and the solution stirred at ambient temperature for 16 h. The solvent was removed by rotary evaporation, and the residue partitioned between chloroform and 1M sodium hydroxide. The layers were separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 1:1 ethyl acetate:hexane gave 0.225 g (66%) of the title compound. mp (.HCl) 81°-85° C. HRMS calcd for C21H23FN3O (MH+): 352.1825, found: 352.1817.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[CH:7][C:6](Br)=[CH:5][C:4]=1[F:11].[C:12]([Cu])#[N:13]>CN(C=O)C.O>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([F:9])[C:3]=1[O:2][CH3:1])[C:12]#[N:13]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)cc(C#N)cc1F
Temperature: 120 °C
Reaction time: 48 h
Yield: 30.9 %

Procedure:
A mixture of 4-bromo-2,6-difluorophenyl methyl ether (11.5 g, 0.0516 mol; see step (ii) above) and CuCN (6.92 g, 0.0774 mol) in dry DMF (15 mL) was stirred at 120° C. for two days under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel, using 2% ethyl acetate in petroleum ether as eluent, yielded 2.7 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:22]=[CH:21][C:20]2[NH:19][C:18](=[O:23])[C:17]3[NH:24][CH:25]=[CH:26][C:16]=3[C:15]=2[CH:14]=1.[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28].O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:22]=[CH:21][C:20]2[NH:19][C:18](=[O:23])[C:17]3[NH:24][CH:25]=[CH:26][C:16]=3[C:15]=2[CH:14]=1)(=[O:4])=[O:3].[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28]
Reactant: Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CS(=O)(=O)Cl
Agent: CCC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1-c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
24 μL (0.3 mmol) of methanesulfonyl chloride is added to a solution of 70 mg (0.2 mmol) of 8-(2-aminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 0.3 mL of anhydrous pyridine. The solution is stirred at room temperature for 4 hours then water is added. The compound is extracted with ethyl acetate. The organic phases are washed with an aqueous solution of copper sulfate, dried over magnesium sulfate, filtered and evaporated to give 22 mg (25%) of 8-(2-methanesulfonylaminophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH2:17][CH3:18])[C@@H:11]2[OH:19])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:21][C@@H:22]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[O:24][CH2:23]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:19])[C@@H:12]([O:16][CH2:17][CH3:18])[C:13]([NH:21][C@@H:22]2[C:28](=[O:29])[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[O:24][CH2:23]2)=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1COc2ccccc2NC1=O
Reactant: CCO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Temperature: 25 °C

Procedure:
110 mg of 52 (407 μmol), 87 mg of 4 (407 μmol) and 169 mg of sodium 2-ethylhexanoate (1.02 mmol) in 2 mL of THF are successively introduced into a Wheaton tube, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. The reaction medium is concentrated to dryness. The residues are chromatographed on a silica cartridge (8 g, eluent AcOEt). 75 mg of expected product Ex20 are recovered.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)=[CH:2]1.[OH-].[Na+]>C(O)(=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:2]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(CCc3coc4ccccc34)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c(CCc3c[nH]cn3)coc2c1
Temperature: 25 °C

Procedure:
4-(1-Benzofuran-3-yl-ethyl)-1-trityl-1H-imidazole (Intermediate I4) (0.52 g) in acetic acid (10 mL) and water (5 mL) was heated to reflux for 1 h. The mixture was cooled to rt and the pH was adjusted with 2M NaOH until basic. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and filtered through paper. The solvent was removed under a vacuum. The residue was purified by chromatography on silical gel with 2.5% NH3-MeOH: CH2Cl2 to give 4-(1-benzofuran-3-yl-ethyl)-1H-imidazole Intermediate I5) 0.29 g.
Reaction SMILES: [N:1]1([CH2:12][CH2:13][C:14](N)=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[OH-:17].[K+].Cl.C1C[O:23]CC1>>[OH:17][C:12]1[C:13]([CH3:14])=[C:4]([C:2]([OH:23])=[O:3])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: NC(=O)CCN1C(=O)C(=O)c2ccccc21
Agent: Cl
Agent: [K+]
Product: Cc1c(O)nc2ccccc2c1C(=O)O

Procedure:
A mixture of 5-chloroisatin acetamide (IV, 5.00 g), potassium hydroxide (1N, 56 ml) and THF (18 ml) is heated at reflux for 1 hr, allowing the THF to boil off, and is allowed to cool to 20°-25°. The basic mixture is cooled to 0° and acidified to pH 5.5 (pH paper) with hydrochloric acid (4N). The resulting solids are filtered, washed with water and methylene chloride, dried, and triturated overnight in methylene chloride (200 ml, to remove a small amount of 5-chloroisatin byproduct). These solids are filtered, washed with methylene chloride, and dried to give 6-chloro-2-hydroxyquinoline-4-carboxylic acid (V), mp >300°; IR (mineral oil) 1711, 1645, 1430, 1221,1179, 887 and 881 cm-1 ; NMR (d6 -DMSO) 12.25,8.30, 7.62, 7.38 and 7.00 δ; MS (El, m/e) 223, 178 and 151.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23](Cl)=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:25].[Na+].[Cl-].[Na+]>C(OC)(C)(C)C.O.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23](=[O:25])[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3nc2Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3[nH]c2=O)CC1

Procedure:
4-(3-Chloro-quinoxalin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 28.7 mmol; from Step 1) was added to a mixture of sodium hydroxide (40 g), water (40 g) and DMSO (40 g) at 100° C. After being stirred for 1 h at this temperature, water (200 g) and methyl tert-butyl ether (1000 g) and sodium chloride (50 g) were added. The crystals formed from the organic layer were collected by filtration and dried. This furnished 4.0 g (42%) of the title compound as white crystals. 1H NMR analysis supports the stated structure.
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:27]=1>>[C:1]1([C@H:7]([CH3:11])[C:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[N:18][C:17]=3[CH:27]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Product: C[C@H](C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1)c1ccccc1

Procedure:
Similarly prepared as per compound 8, using starting materials (S)-2-phenylpropanoic acid and compound 4 (R, =2-pyridine) to obtained title compound Q48 as white solid (77%). 1H NMR (CDCl3, 400 MHz) δ 1.52 (d, J=7.2 Hz, 3H), 3.67 (q, J=7.2 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.21-7.35 (m, 5H), 7.69 (s, 1H), 7.83 (s, 1H), 7.91 (d, J=5.6 Hz, 2H), 8.68 (d, J=5.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.9, 31.1, 42.7, 48.0, 110.8, 112.2, 119.7, 120.5, 121.1, 127.7, 127.8, 128.1, 129.3, 134.3, 135.6, 141.1, 142.1, 147.7, 148.4, 149.1, 150.8, 161.4, 172.9; ESI-HRMS for C21H18N3O2(M+H)+ calcd. 344.1399. found 344.1397 purity (% ee >99, tR=8.07 min).
Reaction SMILES: Br[CH:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[C:18]([NH2:33])=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:27]=4)[CH:22]=3)=[N:15][N:14]=[N:13]2)=[C:8]([F:34])[C:7]=1[F:35].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O.O1CCN(CCCCOC2C=CC(N3C(C4C(N)=NC=C(C5C=NN(CCC(C)C)C=5)C=4)=NN=N3)=C(F)C=2F)CC1>C1COCC1>[N:37]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[C:16]([C:17]4[C:18]([NH2:33])=[N:19][CH:20]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:27]=5)[CH:22]=4)=[N:15][N:14]=[N:13]3)=[C:8]([F:34])[C:7]=2[F:35])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCC(C)Br)c(F)c3F)c2)cn1
Reactant: C1CCNCC1
Agent: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCCCN4CCOCC4)c(F)c3F)c2)cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCCN4CCCCC4)c(F)c3F)c2)cn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
As shown in step 5-iii of Scheme 5,3-(1-(4-(3-bromobutoxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)pyridin-2-amine (Compound 1021, 111 mg, 0.203 mmol) was dissolved in 5 mL of THF and cooled to 0° C. The mixture was treated with piperidine (0.06 mL, 0.61 mmol), warmed to 70° C., and stirred for 16 hours. The reaction was cooled to room temperature, treated with cold water, and extracted with CHCl3 (50 mL). The organics were washed with water, washed with brine, dried over sodium sulfate, filtered, and the volatiles removed under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH/CHCl3) to provide 3-(1-(4-(3-(piperidin-1-yl)propoxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)pyridin-2-amine (Compound 150, 70 mg, 78% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11]>C(Cl)(Cl)Cl.N1C=CC=CC=1.CCOCC>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH:6][S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CN
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC#CCOc1ccc(S(=O)(=O)NCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43 %

Procedure:
To a solution of 1.00 g (7.163 mmol) of glycine ethyl ester in 10 mL of chloroform and 2.0 mL of pyridine was added 1.75 g (7.163 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride and the reaction was stirred at room temperature for 15 h. The reaction mixture was then diluted with ether and the organics were washed with 5% HCl solution and water, dried over MgSO4, filtered and concentrated in vacuo. The resulting brown solid was washed with ether to provide 0.96 g (43%) of the sulfonamide as a white solid. Electrospray Mass Spec 311.8 (M+H)+
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:16]2[S:21][C:20]([CH:22]=O)=[CH:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:16]2[S:21][C:20]([CH2:22][N:9]3[CH2:10][CH2:11][CH:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)=[CH:19][C:17]=2[N:18]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Product: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-Methanesulfonyl-piperidine hydrochloride salt was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 following General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])C.C(N(CC)CC)C.[NH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1>C1(C)C=CC=CC=1>[CH3:32][C:30]1[CH:29]=[C:28]([CH3:33])[N:27]=[C:26]([NH:25][C:4](=[O:17])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[O:6])[CH:31]=1
Reactant: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)nc(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(NC(=O)C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
A solution of N-(4-nitro-phenyl)-oxalamic acid ethyl ester (4.9 g, 20.5 mmol), triethylamine (4.2 g, 41 mmol) and 2-amino-4,6-dimethylpyridine (2.5 g, 20.5 mmol) in dry toluene (30 mL) was heated at reflux overnight. The mixture was cooled to 0° C., and a precipitate was filtered and washed with water. Drying under vacuum afforded N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-oxalamide (4.8 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1.[CH3:7][C:8]1[CH:14]=[C:13]([N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=1[NH2:10]>C1(C)C=CC=CC=1>[ClH:1].[CH3:7][C:8]1[CH:14]=[C:13]([N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=1[NH:10][C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: ClC1=NCCC1
Reactant: CC(=O)N(C)c1ccc(N)c(C)c1
Solvent: Cc1ccccc1
Product: CC(=O)N(C)c1ccc(NC2=NCCC2)c(C)c1
Product: Cl

Procedure:
A mixture of 2-chloro-1-pyrroline, prepared as in Example 1 using toluene instead of acetonitrile, and 0.8 g of the product aniline of Example 38 in anhydrous toluene was heated at reflux for five hours. Upon cooling the toluene was removed by decanting and the residue was partitioned between water and dichloromethane. The aqueous layer was made alkaline with 50% sodium hydroxide and extracted with dichloromethane. The organic phase was dried over potassium carbonate, filtered, concentrated to an oil. The crude product was purified by low-pressure chromatography on silica gel, using as eluent 74:25:1 dichloromethane/ethanol/concentrated aqueous ammonia. The oily product was dissolved in ethanol and acidified with HCl in isopropyl alcohol. Addition of diethyl ether produced the title compound as the hydrochloride salt, m.p. 367°-370°. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
The product from Example 193a (1.06 g, 5.2 mmol), N-(4-hydroxyphenyl)acetamide (0.70 g, 4.5 mmol) and K2CO3 (0.79 g, 5.7 mmol) in DMF (14 ml) was heated at 110° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound as a pale brown crystal, which was purified by washing with i-Pr2O to give the desired product as pale brown crystal (1.28 g, 92%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)=O.Cl>O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: C1CNCCN1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Clc1cnc(N2CCNCC2)cn1
Yield: 36.7 %

Procedure:
A mixture of 2,5-dichloropyrazine (14.9 g, 0.1 mol), piperazine (50.5 g, 0.59 mol), acetone (22.5 ml), water (20 ml) and concentrated aqueous HCl (1.8 ml) was heated at reflux for 3 hr. The reaction mixture was cooled, diluted with water, filtered and the acetone was removed by distillation. The aqueous solution was then extracted thrice with chloroform. The combined extracts were washed twice with water, dried (Na2SO4) and evaporated to dryness to afford 7.3 g of solid, m.p. 98°-102°. J. K. Boissier et al., J. Med. Chem., 6, 541 (1963) report a m.p. of 101° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:9][N:3]1[C:4]([CH:7]=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1].[CH3:9][N:6]1[CH:5]=[C:4]([CH:7]=[O:8])[N:3]=[C:2]1[CH3:1]
Reactant: Cc1ncc(C=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc(C=O)cn1C
Product: Cc1ncc(C=O)n1C
Yield: 22 %
Yield: 2 %

Procedure:
According to Step 1 of Reference Example 8-47, by use of 2-methyl-1H-imidazole-5-carbaldehyde (500 mg, 4.54 mmol) dissolved in N,N-dimethylformamide (7.5 mL), potassium carbonate (1.25 g, 9.08 mmol) and methyl iodide (0.311 mL, 4.99 mmol), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=20/1) was performed to give 1,2-dimethyl-1H-imidazole-5-carbaldehyde (125 mg, yield: 22%) and 1,2-dimethyl-1H-imidazole-4-carbaldehyde (12.7 mg, yield: 2%).