Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O)(=O)C.[NH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH:2]([NH:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: Nc1ncccn1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Nc1ncccn1
Reaction time: 8 h

Procedure:
Ethanol (200 mL), acetone (21 mL, 1.5 eq.), and glacial acetic acid (3.0 mL, 0.28 eq.) were added to the aminopyrimidine solution in the hydrogenation flask. After evacuating and purging, the flask was pressurized with H2 (60 psi). The reductive amination was allowed to proceed overnight. TLC on silica using EtOAc as the eluant gave an Rf=0.41 (streaky) for the isopropylamino-pyrimidine and an Rf=0.11 for the starting aminopyrimidine carbamate. Both TLC and LC/MS confirmed complete reaction with virtually no bis-isopropylaminopyrimidine produced. If necessary, HPLC can be used as an alternative means to monitor progress of the reaction. The crude reaction solution was diluted with EtOAc (1 L) and filtered through a pad of basic alumina (400 mL). The alumina was rinsed with EtOAc (200 mL) and EtOH (200 mL) and the combined organic solutions were concentrated in vacuo. The flask was vented under N2. The viscous oil was redissolved in anhydrous toluene (700 mL) and concentrated. After venting the flask under nitrogen, the product was dried again by azeotropic removal of another 400 mL of toluene. A viscous reddish-brown oil was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:28][OH:29].Cl>CO>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[N:28][OH:29]
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 2-chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde (i.e. the product of Step 2, 1.20 g) in methanol (5 mL) was added hydroxylamine hydrochloride (296 mg) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at 70° C. for 3 h and concentrated in vacuum. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were dried (Na2SO4) and evaporated to obtain the title compound (1.2 g, 97%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:10]2[C@@H:6]([CH2:7][N:8]([C:11](=[O:22])[CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]([CH3:15])[CH3:14])[CH2:9]2)[CH2:5][CH2:4]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:23]([NH:2][C@@H:3]1[C@@H:10]2[C@@H:6]([CH2:7][N:8]([C:11](=[O:22])[CH:12]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:13]([CH3:15])[CH3:14])[CH2:9]2)[CH2:5][CH2:4]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)C(C(=O)N1C[C@H]2CC[C@H](N)[C@H]2C1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(C(=O)N1C[C@H]2CC[C@H](NCc3ccccc3)[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-((3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methyl-2-phenylbutan-1-one hydrochloric acid salt (49 mg, 0.152 mmol) and benzaldehyde (0.023 mL, 0.228 mmol) were combined in dichloromethane (1.5 mL). Acetic acid (1.5 mL) was added. The reaction was stirred at room temperature for 30 minutes, then PS-cyanoborohydride (64.9 mg, 0.152 mmol) was added. After 72 hours, 1 cms of the reaction showed no more starting material. The reaction mixture was filtered, and the solvent was removed under a stream of nitrogen. The crude material was purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.69-7.60 (m, 2H), 7.54-7.44 (m, 2H), 7.44-7.34 (m, 5H), 7.29 (tdd, J=4.8, 7.8, 13.0, 2H), 3.90-3.36 (m, 4H), 3.29 (dd, J=3.8, 10.6, 0.5H), 2.99 (dd, J=5.7, 11.4, 0.5H), 2.93 (dd, J=6.0, 11.3, 0.5H), 2.75-2.63 (m, 1H), 2.59-2.48 (m, 1H), 2.46-2.31 (m, 1H), 2.25 (dt, J=4.1, 8.7, 0.5H), 1.97 (dt, J=9.3, 11.6, 1H), 1.93-1.85 (m, 0.5H), 1.84-1.74 (m, 1H), 1.65-1.55 (m, 0.5H), 1.51-1.35 (m, 1H), 1.33-1.21 (m, 1H), 1.18-1.10 (m, 3H), 1.01 (td, J=7.7, 13.1, 0.5H), 0.87 (dt, J=6.6, 12.9, 0.5H), 0.75 (t, J=7.2, 3H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:30]([C:32]1[C:37]([CH3:38])=[CH:36][C:35]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=1)#[N:31]>C(O)(C)(C)C.ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:42][S:39]([C:35]3[CH:36]=[C:37]([CH3:38])[C:32]([C:30]#[N:31])=[CH:33][C:34]=3[CH3:43])(=[O:40])=[O:41])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: Cc1cc(S(N)(=O)=O)c(C)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c(C)cc1C#N
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-c]pyridine-2-carboxylic acid (2.5 g, 9.5 mmol, prepared as described in Example 1 Step C) in t-butanol (70 mL) and dichloromethane (70 mL) was added 4-(dimethylamino)pyridine (3.47 g, 28.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.54 g, 23.7 mmol). The reaction mixture was stirred for 15 min after which time 4-cyano-2,5-dimethylbenzenesulfonamide (1.85 g, 8.85 mmol) was added, and stirring was continued at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×100 mL), the organic phase was collected and dried over magnesium sulfate and then concentrated under reduced pressure to afford a solid. The solid was isolated by filtration, rinsed with diethyl ether, and recrystallized from hexane/ethyl acetate to afford 1.5 g of the title compound, a compound of the present invention, as a solid, m.p. 228-229° C. 1H NMR (CDCl3) δ 9.97 (br s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 2.71 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]1[O:12]C(C)(C)O[C:8](=[O:9])[CH:7]=1>>[SH:1][CH2:2][CH2:3][O:4][C:8](=[O:9])[CH2:7][C:6]([CH3:5])=[O:12]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: OCCS
Product: CC(=O)CC(=O)OCCS
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
In a 300 ml. round bottom flask fitted with a thermometer, mechanical stirrer, Dean Stark trap and reflux condenser was placed 25.0g.(0.32 mole) of 2-mercaptoethanol. This was stirred and heated to 130° C.; 45.4g. (0.32 mole) of 2,2,6-trimethyl-1,3-dioxen-4-one (TKD) was added dropwise at a uniform rate over the period of one hour. Heating was continued for 1/2 hour; acetone distillate was collected in the Dean Stark trap. After distillate collection was completed, the mixture was distilled under vacuum and the portion boiling at 110°-115° C.(at 5 mm. Hg.) was collected to give a colorless liquid of mercaptoethylacetoacetate. The yield was about 90% based on starting material. The product was identified by NMR spectroscopy.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24][CH3:25])[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].I[CH2:28][CH3:29].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[C:12]([O:24][CH3:25])=[N:11][C:10]3[C:14]2=[N:15][C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[N:8][C:9]=3[NH2:26])[CH2:19]1)[CH3:29]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1

Procedure:
A solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (45 mg, 0.124 mmol), iodoethane (0.012 ml, 0.149 mmol) and triethylamine (0.035 mL, 0.248 mmol) in DMF (3 ml) was heated at 50° C. for 18 hours.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])(C)(C)C.CN([CH:20]=[O:21])C.O.O.C(O)(=O)C(O)=O>CCOCC.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[O:4][CH:5]=[CH:6][C:2]=1[CH:20]=[O:21]
Reactant: Brc1ccoc1C1OCCO1
Reactant: CN(C)C=O
Agent: O=C(O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccoc1C1OCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
2-(3-Bromo-2-furyl)-1,3-dioxolane (438 mg, 2.0 mmol) is dissolved in Et2O (5 mL) in an oven-dried flask, under nitrogen, cooled to −78° C., treated dropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 h. DMF (178 μL, 2.3 mmol) in Et2O (2 mL) is added dropwise, the mixture stirred for 4 h at −78° C., then treated with oxalic acid dihydrate (504 mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed and the mixture allowed to warm to rt over 1 h. The mixture is diluted with water (20 mL) and EtOAc (20 mL), the layers are separated and the aqueous layer extracted with EtOAc (1×20 mL). The organics are dried over Na2SO4 and concentrated to a yellow oil. The crude material is chromatographed over 12 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 228 mg (68%) of 2-(1,3-dioxolan-2-yl)-3-furaldehyde as a pale yellow oil. MS (EI) m/z: 168 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from 2-Methoxy-5-pyridine boronic acid and (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 366.4
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12].O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:11]([NH2:12])=[N:16][NH:17][C:13]=1[NH2:14]
Reactant: N#CC(C#N)Cc1cccc(Cl)c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Yield: 46.8 %

Procedure:
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0° C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.57 mL, 52.4 mmol). The mixture is heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.77 (s, 2H) 7.09 (m, 1H) 7.19 (t, J=7.96 Hz, 1H) 7.38 (m, 1H); LC/MS: MS (ES+) m/e 257.0 [M+H]+.
Reaction SMILES: [F-].[Cs+].C(=O)([O-])[O-].[Cs+].[Cs+].C([Si]([S:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)(C(C)C)C(C)C)(C)C.[C:28]([CH2:30][NH:31][C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:40]Br)=[O:33])#[N:29]>CN(C)C=O.ClCCl>[C:28]([CH2:30][NH:31][C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:40][S:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=1)=[O:33])#[N:29]
Reactant: CC(C)[Si](Sc1ccc(CO)cc1)(C(C)C)C(C)C
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Cesium fluoride (0.829 g, 5.46 mmol) and cesium carbonate (0.456 g, 1.4 mmol) were added to a stirred solution of (4-triisopropylsilanylsulfanyl-phenyl)-methanol (0.808 g, 2.73 mmol) and trans-2-bromomethyl-cyclohexanecarboxylic acid cyanomethyl amide (0.906 g, 3.50 mmol) in dry dimethylformamide (910 mL). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was diluted with dichloromethane and washed with 1N HCl, then with saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation to yield trans-N-cyanomethyl-2-(4-hydroxymethyl-phenylsulfanylmethyl)-cyclohexanecarboxamide as a white solid that was carried forward without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:20])[C:18]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:20])[C:18]=1[N:8]1[CH2:7][CH2:6][CH:5]([C:3]([N:2]([CH3:11])[CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CN(C)C(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 80.9 %

Procedure:
General procedure C was followed using N,N-dimethylpiperidine-4-carboxamide 6 (43 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (66 mg, 80%), m.p. 120-122° C.; umax (CHCl3)/cm−1 3026, 2850, 1631, 1559, 1140, 1092, 934; m/z (ESI) C13H18Cl2N3O requires 302.0821, found [M+H]+ 302.0823.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: COc1cccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-methoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][CH:30]1[O:35][CH:34]([CH3:36])[CH2:33][NH:32][CH2:31]1>N1C=CC=CC=1>[CH3:36][C@H:34]1[CH2:33][N:32]([C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])(=[O:15])=[O:14])([CH3:21])[CH3:20])=[O:18])[CH2:31][C@@H:30]([CH3:29])[O:35]1
Reactant: CC1CNCC(C)O1
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: C[C@@H]1CN(C(=O)C(C)(C)S(=O)(=O)CC(Cc2ccccc2)C(=O)OCc2ccccc2)C[C@H](C)O1

Procedure:
In an analogous manner to that described in Example 2, paragraphs (c) and (d), by the reaction of (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride with 2,6-dimethylmorpholine in pyridine followed by chromatographic separation of the resulting diastereomers there was obtained benzyl (RS)-α-[[[1-[(cis-2,6-dimethylmorpholino)carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate, MS: 501 (M)+, as a colourless oil.
Reaction SMILES: [CH:1]1([C:4](=[O:16])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1.CC(C)C(O)=O.[CH3:23][N:24]([CH3:27])[CH:25]=O>O1CCOCC1>[CH:1]1([C:4](=[O:16])[C:5](=[CH:23][N:24]([CH3:27])[CH3:25])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CSc1ccc(C(=O)CC(=O)C2CC2)nc1
Reactant: CN(C)C=O
Solvent: C1COCCO1
Solvent: CC(C)C(=O)O
Product: CSc1ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl-1-[5-(methylsulphenyl)-pyrid-2-yl] propan-1,3-dione (2.9g), dimethylformamide dimethyl acetate and dioxane was stirred at room temperature overnight. It was evaporated to dryness and the residue was triturated with ether and filtered to give 3-cyclopropyl-2-(N,N-dimethylaminomethylene)-1-[5-(methylsulphenyl)-pyrid-2-yl ]propan-1,3-dione (3.24 g) as a brown solid which was used without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19](=O)[CH:20]=[CH:21]N(C)C)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:26]1([NH:29][C:30]2[N:32]=[C:19]([C:18]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][N:10]4[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=34)[CH:20]=[CH:21][N:31]=2)[CH2:28][CH2:27]1
Reactant: N=C(N)NC1CC1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C#N)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn2c1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-cyanopyrazolo[1,5-a]pyridine (1.3 g, 3.9 mmol) in dimethylformamide (20 mL), under N2, was added N-cyclopropylguanidine (0.78 g, 7.8 mmol) and potassium carbonate (1.1 g, 7.8 mmol). The mixture was stirred and heated at 100° C. for 17 h and then additional N-cyclopropyl-guanidine (0.39 g, 3.9 mmol) and potassium carbonate (0.55 g, 3.9 mmol) were added. The mixture was heated at 100° C. for an additional 4 h and then the reaction mixture was cooled and water added. The resulting solid was collected by filtration. This solid was dissolved in diethyl ether and purified using chromatography to give the title compound as a yellow solid, 0.39 g (28%). 1H NMR (d6-DMSO) δ 0.50 (m, 2H), 0.69 (d, 2H, J=4.0 Hz), 2.69 (m, 1H), 6.29 (d, 1H, J=8.0 Hz), 7.34 (t, 2H, J=8.0 Hz), 7.47 (d, 1H, J=4.0 Hz), 7.69 (m, 3H), 8.11 (d, 1H, J=4.0 Hz), 8.56 (br 5,1H) MS (ES+) m/z 370 (M++H).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1

Procedure:
A solution of 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg), 2-chloro-5-nitropyridine (56 mg) and potassium carbonate (52 mg) in dimethylformamide (1.0 ml) was stirred at 120° C. for 2 hrs. After cooling the mixture water (10 ml) was added and the precipitated product was filtered, washed with water and 2-propanol and dried under reduced pressure. Yield is 60 mg and mp 163-170° C. 1H NMR (DMSO-d6) δ=4.16 (dd, J=8.5, 11.6 Hz, 1H), 4.47 (dd, J=11.6, 2.6 Hz, 1H), 5.28 (dd, J=2.6, 8.5 Hz, 1H), 6.75 (dd, J=2.6, 8.8 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 7.39-7.52 (m, 5H), 8.60 (dd, J=2.8, 9.1 Hz, 1H), 9.05 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:6]#[N:7])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:8]([CH2:10]N)[OH:9]>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:1]([C:6]1[O:9][CH2:8][CH2:10][N:7]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: NCCO
Reactant: CC(C)CCC#N
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Product: CC(C)CCC1=NCCO1
Temperature: 115 °C
Reaction time: 48 h

Procedure:
A mixture of about 50.g grams (0.515 mole) isoamyl cyanide, about 31.5 grams (0.515 mole) ethanolamine, and about 3.2 grams (0.012 mole) cadmium acetate dihydrate is heated to about 115 degrees C. to about 125 degrees C. and stirred under nitrogen for about two days. The product is distilled under vacuum and the fraction boiling at about 81 degrees C. to about 84 degrees C. at about 29 mmHg is collected.
Reaction SMILES: [C:1]([C:5]1[O:14][C:8]2[N:9]=[CH:10][NH:11][C:12](=O)[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>>[C:1]([C:5]1[O:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([Cl:17])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc2c(=O)[nH]cnc2o1
Product: CC(C)(C)c1cc2c(Cl)ncnc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A mixture of 6-tert-butylfuro[2,3-d]pyrimidin-4(3H)-one (1.0 g) and POCl3 (10 mL) was stirred at 55-65° C. for 3 h. The reaction mixture was poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with aq. NaHCO3 solution, water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (90:10) as eluents to give the product as a white color solid (800 mg, 73%), mp 72-74° C. 1H NMR (400 MHz, CDCl3): δ 8.69 (1H, s), 6.48 (1H, s), 1.42 (9H, s).