Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]2=[N:4][CH:3]=1.NC1C(Cl)=NC=CN=1.BrCC(OC)OC>>[Cl:11][C:10]1[C:5]2[N:6]([CH:2]=[CH:3][N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: Clc1nccn2c(Br)cnc12
Agent: COC(CBr)OC
Agent: Nc1nccnc1Cl
Product: Clc1nccn2ccnc12

Procedure:
The starting materials are either commercially available or can be synthesized by methods known in the art. Compounds of formula Ia where X is N can be synthesized starting from the known 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (4). Lumma, Jr., W. C.; Randall, W. C.; Cresson, E. L.; Huff, J. R.; Hartman, R. D.; Lyon, T. F. J. Med. Chem. 1983, 26, 357-363. Meurer, L. C.; Tolman, R. L.; Chapin, E. W.; Saperstein, R.; Vicario, P. P.; Zrada, M. M.; MacCoss, M. J. Med. Chem. 1992, 35, 3845-3857. In accordance to Scheme 1 below, 2-amino-3-chloropyrazine (1) can be reacted with 2-bromo-1,1-dimethoxy-ethane (2) to give 8-chloro-imidazo[1,2-a]pyrazine (3) which can be brominated to give 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (4). Compound 4 can be reacted with an appropriate amine (HNR1R2) either in excess or in the presence of another base, such as diisopropyl ethyl amine, in an appropriate solvent, such as ethanol or butanol, between room temperature to reflux to give compound 5. Compound 5 can than be condensed with 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (6) in the presence of a suitable palladium catalyst to give intermediate 7.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8]([NH:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][C:8]2=[O:9])=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: O=C(NCCCl)Nc1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(2-chloroethyl)urea (0.1 g, 0.333 mmol) in THF (6.66 ml) was added sodium hydride (8.00 mg, 0.333 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched by the addition of a solution of saturated ammonium chloride and the product was extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The product was a beige solid which was pure and did not need any further purification (63 mg, 72%): mp 167-170° C.; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J=2.2 Hz, 1H), 8.56 (dd, J=4.7, 1.4 Hz, 1H), 8.33 (s, 1H), 7.99 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.40 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 5.00 (s, 1H), 4.14-4.07 (m, 2H), 3.68-3.58 (m, 2H); ESIMS m/z 264 ([M+H]+).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31](=O)[C:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)([CH3:34])[CH3:33].C(N(CC)CC)C>CN1CCCC1=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=3)([CH3:34])[CH3:33])[CH:30]=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: COc1cccc(C(C)(C)C(=O)C=CN(C)C)c1
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cccc(C(C)(C)c2ccnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)c1
Reaction time: 2.5 h

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate, 1-dimethylamino-4-(3-methoxy-phenyl)-4-methyl-pent-1-en-3-one and triethylamine using 1-methyl-pyrrolidinone as the solvent. The reaction was performed in a microwave at 200° C. for 2.5 h. The title compound was isolated as a brown viscous oil in 44% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C@@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:9](=[O:13])[C@@H:10](O)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:14][C@H:15]([C:16]([F:17])([F:18])[F:19])[O:20][C@H:10]([CH3:11])[C:9]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)C(=O)N(Cc1ccccc1)C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1O[C@@H](C(F)(F)F)CN(Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A solution of (S)—N-benzyl-2-hydroxy-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide (4-3) in THF (200 ml) was cooled to 0° C. To this was added NaH (60% dispersion in mineral oil, 1.05 g, 26.3 mmol) portionwise as a solid. After 1 hr the cooling bath was removed and the mixture allowed to warm to rt. After an additional hour the mixture was quenched with brine. The mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (4-4) as a clear oil which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Reactant: OCCCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCCCO
Temperature: 0 °C

Procedure:
z,z,z-Octadeca-6,9,12-trienoyl chloride (2 g) was added dropwise to a solution of 1,5-dihydroxypentane (3.5 g), triethylamine (0.94 ml) and 4-(N,N-dimethylamino)pyridine (0.2 g) in methylene chloride (50 ml) with stirring at 0° C. under nitrogen. On completion of reaction as evidenced by tic the reaction mixture was washed with dilute hydrochloric acid and water, dried and purified by column chromatography yielding 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-hydroxypentane as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:15](O)=[O:16])[CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)C2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of (4-methyl-3-nitrophenyl)amine (304 mg) in DMF (3 mL) were added cyclopropanecarboxylic acid (258 mg), HATU (1.14 g) and iPr2NEt (1.55 g) successively, and the mixture was stirred at room temperature for 16 hr under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (15 mL) and the resulted mixture was washed with 1 M HCl (15 mL×2), saturated aqueous NaHCO3 (15 mL×2) and brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc-hexane (1:2) to give N-(4-methyl-3-nitrophenyl)cyclopropanecarboxamide (413 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C@@:18]([CH2:23][C:24]([OH:26])=[O:25])([C:20]([OH:22])=[O:21])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[C:24]([CH2:23][C@:18]1([C:20]([OH:22])=[O:21])[O:17][N:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH2:19]1)([OH:26])=[O:25]
Reactant: O=C(O)C[C@@]1(C(=O)O)CC(c2cccc(OCc3ccccc3)c2)=NO1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@@]1(C(=O)O)CC(c2cccc(O)c2)=NO1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (5R)-3-(3-(benzyloxy)phenyl)-5-(carboxymethyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (75.0 g), 10% Pd/C (containing about 55% water, 7.5 g), and THF (750 mL) was stirred at room temperature for 15 hours under a hydrogen atmosphere. To the reaction mixture, methanol (150 mL) was added, then the catalyst was filtered and washed with methanol (375 mL). The filtrate was concentrated under reduced pressure to obtain (5R)-5-(carboxymethyl)-3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid as a crude product.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>C(O)(C)C>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:23][CH:20]([CH3:22])[CH3:21])=[N:5][N:6]=1
Reactant: CC(C)N
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Solvent: CC(C)O
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)C)s1

Procedure:
7 g (0.025 mole) of 2-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-1,3,4-thiadiazole and 2.9 g (0.05 mole) of isopropylamine are mixed in 100 ml of isopropanol and the mixture is refluxed for 7 hours. On cooling, a precipitate forms; this is recrystallized from toluene, together with the solid residue obtained from concentrating the mother liquor. 5.1 g (61% of theory), melting point 156°-157°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][N:13]1[CH2:19][CH:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:16]=2[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:12][N:13]1[CH2:19][CH:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:16]=2[CH2:15][CH2:14]1)=[O:6]
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(N)CC2
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(NC(=O)c1cc(Cl)cc(Cl)c1)CC2
Reaction time: 1 h
Yield: 61.4 %

Procedure:
3,5-Dichlorobenzoyl chloride (1.7 g) was added to a solution of 3-amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine (2.1 g) in 100 ml dichloromethane containing sodium bicarbonate (3 g). After one hour, the mixture was filtered and concentrated. The solid residue was eluted through silica with 10% ethyl acetate in dichloromethane to yield 2.4 g of light tan solid, mp 182°-184°. This solid was recrystallized from acetonitrile to yield 2 g of white crystals, mp 184°-185°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(CC2C(O)=CC(=O)N2c2ccc(C#N)c(Cl)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C[C@H]2[C@@H](O)CC(=O)N2c2ccc(C#N)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a mixture of 2-chloro-4-[2-(4-cyanobenzyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (300 mg) and acetic acid (0.54 mL) in acetonitrile (10 mL) was added sodium borohydride (81 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 162 mg, 54%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[C:8]#[C:9][CH3:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:28][N+:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:37][CH2:36]2)=[CH:31][C:30]=1[O:38][CH2:39][C:40]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=1[F:47].O>CN(C=O)C>[CH2:13]([O:12][C:7]([C:8]1[C:9]([CH3:10])=[N:28][N:29]2[C:30]([O:38][CH2:39][C:40]3[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=3[F:47])=[CH:31][C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:34]=12)=[O:11])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1ccc(C2CC2)cc1OCc1c(F)cccc1F
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
468 mg (3.4 mmol) of potassium carbonate were added to a mixture of 264 μl (2.3 mmol) of ethyl but-2-ynoate and 540 mg (1.1 mmol) of 1-amino-4-cyclopropyl-2-[(2,6-difluorobenzyl)oxy]pyridinium 2,4,6-trimethylbenzenesulphonate (Example 147A) in 10 ml of DMF. The reaction mixture was stirred at room temperature for 2 h and then poured into 25 ml of water precooled to 5° C. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2cccc(C#N)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccc(C(=O)O)cn2)c1
Temperature: 40 °C
Yield: 73.6 %

Procedure:
A mixture of methyl 6-(3-cyanophenyl)nicotinate (300 mg, 1.26 mmol) and 2 M lithium hydroxide solution (1.89 mL) in tetrahydrofuran (30 mL) was heated at 40° C. overnight. The tetrahydrofuran was evaporated off, water (5 mL) was added and the reaction mixture was acidified to pH 6 with 2N aqueous HCl. The precipitated solid was filtered off and dried under vacuum to give 6-(3-cyanophenyl)nicotinic acid (208 mg). 1H NMR (400 MHz, DMSO-d6) ppm 7.74 (t, J=7.8 Hz, 1H), 7.96 (m, 1H), 8.23 (m, 1H), 8.36 (m, 1H), 8.49 (m, 1H), 8.55 (m, 1H), 9.15 (m, 1H), 13.5 (broad s, 1H) LCMS 225 (M+1) ELSD 1.33 minutes.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[Cl:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:34].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[Cl:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(Cl)c3Cl)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(Cl)c2Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 166.1 %

Procedure:
Compound 60-4 (770 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:20][CH:19]([OH:21])[C:16]([CH2:22][CH2:23][CH3:24])([CH2:17][O:18]2)[CH2:15][O:14]3)=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[CH3:1][S:2]([O:21][CH:19]1[C:16]2([CH2:22][CH2:23][CH3:24])[CH2:15][O:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)([O:18][CH2:17]2)[CH2:20]1)(=[O:4])=[O:3]
Reactant: CCCC12COC(c3ccc(Cl)cc3)(CC1O)OC2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC12COC(c3ccc(Cl)cc3)(CC1OS(C)(=O)=O)OC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methanesulphonyl chloride (164 μl) was added to a stirred solution of 1-(4-chlorophenyl)-8-hydroxy-4-n-propyl-2,6-dioxabicyclo[2,2,2]octane (500 mg.) in dry pyridine (2.0 ml.). The mixture was stirred at room temperature for 6 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with 1N hydrochloric acid solution. The ethereal extracts were then washed with saturated aqueous sodium hydrogen carbonate solution. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH2:18][CH3:19])[N:17]=[C:4]2[CH:3]=1.[SH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:18]([C:16]1[N:17]=[C:4]2[CH:3]=[C:2]([S:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])=[CH:25][CH:26]=3)[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]2[CH:15]=1)[CH3:19]
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Reactant: CCc1cn2c(Nc3cc(C)[nH]n3)nc(Cl)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cn2c(Nc3cc(C)[nH]n3)nc(Sc3ccc(NC(=O)C4CC4)cc3)cc2n1
Temperature: 160 °C

Procedure:
7-chloro-2-ethyl-N-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidin-5-amine 0.22 mmol, 0.06 g) was dissolved in DMF (1 mL). N-(4-mercaptophenyl)cyclopropanecarboxamide (0.24 mmol, 0.046 g) and K2CO3 (0.24 mmol, 0.033 g) was added. The reaction mixture was heated to 160° C. using a microwave reactor for 20 minutes. The mixture was then concentrated and purified by LC-MS to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83-0.84 (m, 4H) 1.25 (t, J=7.45 Hz, 3H) 1.79-1.86 (m, 1H) 2.12 (s, 3H) 2.73 (q, J=7.24 Hz, 2H) 5.80 (s, 1H) 6.65 (s, 1H) 7.58 (d, J=8.59 Hz, 2H) 7.81 (d, J=8.59 Hz, 2H) 8.31 (s, 1H) 10.55 (s, 1H) 10.97 (s, 1H) 12.30 (s, 1H); ESI-MS: m/z calc'd for C22H23N7OS 433.53; found 434.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:23]1[C:27]2[CH:28]=[CH:29][C:30](B(O)O)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:3]=[C:4]([C:9]4[N:13]5[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]5=[N:11][CH:10]=4)[CH:5]=[CH:6][C:7]=3[F:8])=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc5c(c4)OCO5)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and benzo[1,3]dioxole-5-boronic acid were coupled in the same way as in Example 30 to give 2-{3-[3-(benzo[1,3]dioxol-5-yl)-4-fluorophenyl]-8-fluoroimidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (8 mg, 4%): m/z (ES+) 409 [MH+].
Reaction SMILES: [CH2:1]([C:7](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Zn].C(O)(=O)C>[CH2:1]([C:7]([CH:8]([OH:9])[CH:8]([OH:9])[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCC(=Cc1ccccc1)C(O)C(O)C(=Cc1ccccc1)CCCCCC

Procedure:
In a fashion similar to that described in Example 1, α-hexyl-cinnamaldehyde was treated with zinc and acetic acid to provide 2,5-dihexyl-1,6-diphenyl-1,5-hexadiene-3,4-diol.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].Cl.Cl.[NH2:16][O:17][CH2:18][CH2:19][NH2:20].C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:20][CH2:19][CH2:18][O:17][N:16]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: NCCON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (5.5 g.) in ethanol (100 ml.) was added a solution of 2-(aminooxy)ethylamine.dihydrochloride (4.1 g.) in water (50 ml). The resulting mixture was adjusted to pH 4 with an aqueous solution of sodium bicarbonate and stirred for 3 hours at room temperature. The reaction mixture was evaporated to a volume of 100 ml. and cooled. The resulting precipitates were collected by filtration, washed successively with cold-water and ethanol to give the title compound (6.5 g.), mp 213° to 214° C. (dec.).
Reaction SMILES: [C:1]([CH2:3][S:4]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=O)[CH3:16])(=[O:6])=[O:5])#[N:2]>[OH-].[Na+]>[F:13][C:11]1[CH:10]=[CH:9][C:8]2[NH:14][C:15]([CH3:16])=[C:3]([C:1]#[N:2])[S:4](=[O:6])(=[O:5])[C:7]=2[CH:12]=1
Reactant: CC(=O)Nc1ccc(F)cc1S(=O)(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(C#N)S(=O)(=O)c2cc(F)ccc2N1
Temperature: 0 °C

Procedure:
N-(2-Cyanomethylsulfonyl-4-fluoro-phenyl)acetamide (0.21 g) was dissolved in 0.5 M NaOH (3 ml) at room temperature. After 1½ h the mixture was filtered. The filtrate was cooled to 0° C. and 4M HCl (0.5 ml) was added. A white precipitate was isolated by filtration, washed with water (5 ml) and dried to give the title compound as a white solid. Yield 0.17 g (85%); mp 326-327° C. (decomp.); 1H-NMR (DMSO-d6), δ (ppm): 12.07 (s, 1H, NH), 7.95-7.81 (m, 1H, Ar—H), 7.75-7.45 (m, 2H, Ar—H), 2.47 (s, CH3 +DMSO); IR (KBr) ν (cm−1): 3291 (NH), 2214 (C≡N).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.C([O-])(=O)C.[Na+].[I:18]Cl.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(OCC)C>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([I:18])[C:3]=1[NH2:4]
Reactant: ClI
Reactant: Cc1ccc(N)c(F)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)c(N)c(I)c1

Procedure:
A solution of 2-fluoro-4-methylaniline (1.0 g, 8 mmol) (bought from Avocado, Lancaster or Aldrich) in glacial acetic acid (10 ml) was treated with sodium acetate trihydrate (2.2 g, 16 mmol) then iodine monochloride (1.3 g). After 30 min at room temperature aqueous sodium bicarbonate/sodium sulfite and diethyl ether were added, and the organic phase was dried (MgSO4), evaporated and chromatographed on silica eluting with 0 to 30% ethyl acetate in hexane to give the title compound, 370 mg.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([C:13](=O)[CH:14]([CH3:16])[CH3:15])[C:8](OCC)=[O:9]>C(O)C>[CH:14]([C:13]1[NH:5][C:3](=[S:4])[NH:2][C:8](=[O:9])[C:7]=1[CH3:6])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C(C)C(=O)C(C)C
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Product: Cc1c(C(C)C)[nH]c(=S)[nH]c1=O
Yield: 77.5 %

Procedure:
To anhydrous ethanol (110 mL) was added sodium metal (1.16 g, 50.4 mmol) and the mixture was stirred until dissolution was complete. To this solution was added thiourea (1.79 g, 23.5 mmol) and ethyl 2,4-dimethyl-3-oxopentanoate (2.89 g, 16.8 mmol). The reaction mixture was stirred at 85° C. for 20 h then cooled and concentrated. The residue was diluted with water, the pH adjusted to 4 with 1 N hydrochloric acid then extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide 6-isopropyl-5-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2.40 g, 78% yield) as a tan solid that was used without further purification. C8H12N2OS: 185 (MH+).