Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([OH:19])=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([Cl:22])=[O:19])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc2sc3cccc(C(=O)O)c3c(=O)c2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc2sc3cccc(C(=O)Cl)c3c(=O)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.21 g (0.78 mmoles) of 7-methyl-9-oxo-9H-thioxanthene-1-carboxylic acid are suspended in 30 ml of toluene containing 2 drops of DMF and 0.35 g of thionyl chloride. After stirring for 1 hour at 80° C. the mass is cooled to room temperature obtaining a yellow solution of 7-methyl-9-oxo-9H-thioxanthene-1-carbonyl chloride.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1.C(#N)CO.CCOCC>O>[O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1
Reactant: NCCN1CCCOCC1
Agent: N#CCO
Solvent: CCOCC
Solvent: O
Product: N#CCN1CCCOCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
1,4-Oxazepane (292) (Turner, S. R. et al., PCT Int. Appl. WO 2000 040561, 2000) (4.95 g, 49.0 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 5.3 mL, 53.8 mmol) at 5° C. and stirred at 70° C. for 1 h. More aqueous glycolonitrile (55%, 0.96 mL, 6.13 mmol) was added and the mixture stirred for 30 min, cooled to 20° C. and Et2O (100 mL) and water (50 mL) were added. The aqueous layer was extracted with Et2O (4×30 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 293 (3.24 g, 47%) as a pale yellow oil: 1H NMR δ 3.80-3.84 (m, 2H, H-5), 3.74-3.77 (m, 2H, H-3), 3.60 (s, 2H, CH2CN), 2.79-2.84 (m, 4H, H-2, H-7), 1.92-1.99 (m, 2H, H-6); HRMS calcd for C7H12N2O (M+) m/z 140.0950, found 140.0947.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:51][CH3:52])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:51][CH3:52])=[C:31]([C:36]([CH2:39][S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=3)(=[O:41])=[O:42])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(OC)c2)ccc(Br)c1OC
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(OC)c2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-methoxy-6-(3-methoxybenzenesulphonylmethyl)benzoate (Intermediate 101) and furan-3-yl boronic acid.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29]>ClCCl.N1C=CC=CC=1>[NH2:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:29])=[O:30])=[O:13])(=[O:29])=[O:30]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 23 °C
Reaction time: 144 h
Yield: 19.6 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-aminobenzenesulfonamide (2.00 g, 11.6 mmol) in 16 mL of pyridine. The reaction mixture was stirred for 6 days at 23° C. under nitrogen atmosphere. The crude product was recrystallized from acetonitrile to yield 0.70 g of the title compound, mp 150°-151° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=1[F:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: Nc1ccc(F)cc1F
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (5.0 g) and 2,4-difluoroaniline (2.02 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate, which is then treated with 60% sodium hydride as in Reference Example 22 to give ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.6 g), as pale yellow prisms (recrystallized from dichloromethane - n-hexane), m.p. 156°-157.5° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[CH2:13][CH2:14][N:15]([CH:27]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:28](=[O:31])[NH:29][OH:30])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C(O)C.O>[OH2:3].[CH:32]1([CH:27]([N:15]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:14][CH2:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:38])[C:28](=[O:31])[NH:29][OH:30])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)C1CCN(C(=O)CCN(C(C(=O)NO)C2CCCCC2)S(=O)(=O)c2ccc(OC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCC(C(=O)O)CC2)C(C(=O)NO)C2CCCCC2)cc1
Reaction time: 0.25 h
Yield: 164.9 %

Procedure:
To a solution of 1-{3-[(cyclohexylhydroxycarbamoylmethyl)(4-methoxybenzenesulfonyl) amino]propionyl}piperidine-4-carboxylic acid ethyl ester (0.62 grams, 1.16 mmol) (Example 17) in ethanol (45 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.24 grams, 5.72 mmol). After stirring for 3 hours at room temperature ethanol-washed Amberlite IR-120 plus ion exchange resin (6 grams) was added. Stirring was continued for 15 minutes and then the mixture was filtered. The filtrate was concentrated in vacuo to give 1-{3-[(cyclohexylhydroxycarbamoylmethyl)-(4-methoxy-benzenesulfonyl)amino]propionyl}-piperidine-4-carboxylic acid monohydrate as a white solid (0.52 grams, 88%). MS: 526 (M+1). Analysis calculated for C24H35N3O8S·H2O: C, 53.05; H, 6.86; N, 7.73. Found: C, 53.53; H, 7.15; N, 7.70.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].[H-].[Na+].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C)C=O>[C:1]([N:3]=[C:4]1[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#CN=C1NCCS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCSC1=NC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.1 %

Procedure:
2-(Cyanoimino)thiazolidine (6.35 g, 49.9 mmol), prepared by the procedure of Neidlein and Reuter, Arch. Pharm. (Weinheim, Ger.) 305, 731 (1972), was added to a suspension of sodium hydride (2.04 g, 51 mmol, pre-washed with hexane)in dimethylformamide (100 mL) at ambient temperature, resulting in heat and gas evolution. After stirring the mixture 30 minutes, tert-butyl bromoacetate (10.0 g, 51.3 mmol) was added and the resulting mixture was stirred 2.5 hours at ambient temperature. After removing the solvent in vacuo, the residue was partitioned between saturated sodium bicarbonate and methylene chloride and the aqueous phase extracted with additional methylene chloride (2×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Subsequent recrystallization from methylene chloride/hexane (1:4) afforded 9.04 g (75%) of the title compound as a white crystalline solid. m.p. 143°-144° C. TLC (ethyl acetate) Rf =0.44. 1H NMR (CDCl3, 300 MHz) d 1.48 (s, 9H), 1.48 (s, 9H), 3.43 (t, 2H), 3.98 (t, 2H), 4.08 (s, 2H). MS (DCl/NH3) m/e 242 (M+H)+. Anal calcd for C10H15N3O2S.0.25 H2O: C, 48.86; H, 6.36; N, 17.09. Found: C, 48.71; H, 5.98; N, 16.93.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[O:20]([C:28]1[CH:43]=[CH:42][C:31]([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1)[Si](C(C)(C)C)(C)C>CN(C=O)C.O>[OH:20][C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:36][CH:35]=2)=[O:33])=[CH:42][CH:43]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)n(C)c1=O
Yield: 109.7 %

Procedure:
A solution of 1,3-dimethylxanthine (742 mg), potassium carbonate (569 mg) and 4-(4-t-butyldimethylsiloxybenzoyl)benzyl bromide (2292 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:3) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (1763 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-])=O.C(OC(NC1C=CC(CC(O)=O)=CC=1)=O)(C)(C)C>>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:31]([C:29]2[O:30][C:26]([C:23]3[CH:24]=[CH:25][C:20]([NH2:17])=[CH:21][CH:22]=3)=[CH:27][CH:28]=2)=[O:32])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Product: CC(C)(C)c1cc(NC(=O)c2ccc(-c3ccc(N)cc3)o2)cc(C(C)(C)C)c1O
Yield: 56 %

Procedure:
The experimental protocol used is the same as that described for intermediate 40.1, 2,6-di-t-butyl-4-aminophenol and 5-(4-nitrophenyl)-2-furan carboxylic acid replacing thiazolidine and 4-(t-butoxycarbonylamino)-benzeneacetic acid respectively. The expected compound is obtained in the form of a colourless oil with a yield of 56%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[S:21])#[N:8]
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1COCCO1
Product: Cc1sc(NC(=S)NC(=O)c2ccccc2)c(C#N)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (1.52 g, 10.0 mmol) in 1.4-dioxane (20 mL) was added benzoylisothiocyanate (1.63 g, 10.0 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitation was collected by filtration, washed with EtOAc/Hexanes (1:4), and dried under vacuum overnight to give N-(3-Cyano-4,5-dimethylthiophen-2-ylcarbamothioyl)benzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ2.23 (s, 3H), 2.31 (s, 3H), 7.58-7.54 (m, 2H), 7.68-7.66 (m, 1H), 7.94 (d, J=7.2 Hz, 2H), 9.13 (bs, 1H). MS 316 (MH+).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([O-:21])=[O:20]
Reactant: COC(=O)c1ccccc1O
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Oc1ccccc1[N+](=O)[O-]

Procedure:
Methyl salicylate (1.7 mL, 0.0131 mol), 1-chloro-2-nitrobenzene (2.30 mL, 0.01965 mol) and potassium carbonate (3.62 g, 0.0262 mol) were mixed in dimethylformamide (35 mL), under argon, at 150° C. for 16 h. The solvent was evaporated and the crude material was flash chromatographed (silica gel, ethyl acetate/hexane). Concentration in vacuo yielded the title compound. 1H NMR (250 MHz, CDCl3) δ8.0 (m, 4H), 7.58 (m, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.13 (dd, 1H), 6.85 (dd, 2H).
Reaction SMILES: P(Cl)(Cl)[Cl:2].[N:5]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11](=O)[CH:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:6]=[N-:7]>CN(C)C=O.C1(C)C=CC=CC=1>[N:5]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11]([Cl:2])=[C:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Reactant: ClP(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reaction time: 5 h

Procedure:
Phosphorus trichloride (1 mmol) is added to a solution of benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (0.5 mmol) in anhydrous dimethylformamide (2.5 ml) and the mixture is left to stand at room temperature. After 5 hr, the mixture is diluted with toluene, washed with water, 1 N hydrochloric acid, 5% sodium bicarbonate solution, and brine, dried over magnesium sulfate, and filtered. Evaporation of the solvent under vacuum yields benzyl 6-azido-3-chloro-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[N:3]=1.[NH4+:21].[OH-]>[Cl-].[Na+].O>[NH2:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[N:3]=1
Reactant: [NH4+]
Reactant: Brc1cccc(Oc2ccc(CN3CCCC3)cc2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc(Oc2ccc(CN3CCCC3)cc2)n1
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine (20 g) and Cu powder (1 g) in concentrated NH4OH (250 mL, aq) and IpOH (60 mL) was heated at 100° C. in a sealed flask for 48 h. After cooling to RT, brine (300 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residues were filtered through silica gel pad eluting with MeOH/CH2Cl2 (5%). The filtrate was concentrated to dryness, then 50 mL of MeOH was added. After stirring for a while the solid was filtered to give the title compound. MS m/z: 270 (M+1). Calc'd for C16H19N3O-269.3
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:11]([O:15][C:16]([N:18]1[CH:22]2[CH2:23][CH2:24][CH:19]1[CH:20]([CH2:25]OS(C)(=O)=O)[CH2:21]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:25][CH:20]2[CH2:21][CH:22]3[N:18]([C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:19]2[CH2:24][CH2:23]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COS(C)(=O)=O)C2
Reactant: Cc1ncccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1OCC1CC2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 2-methylpyridin-3-ol in DMF was added KOH. The solution was stirred for 30 min at rt, then the title compound from step A was added and the reaction was heated at 80° C. After 5 h, H2O was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgSO4). Purification via silica gel chromatography (0-7% MeOH in DCM) gave the title compound (201 mg, 90%). MS (ESI) mass calcd. for C18H26N2O3, 318.2; m/z found 319.0 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:25][C:24]4[C:23]([F:22])=[CH:30][C:29]([F:31])=[CH:28][C:27]=4[F:32])[CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Reactant: O=Cc1c(F)cc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(N2CCN(Cc3c(F)cc(F)cc3F)CC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 2-furan-2-yl-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine in methylene chloride (see Example 16 above) was added 2,4,6-trifluorobenzaldehyde (28 mg, 0.18 mmol), sodium triacetoxyborohydride (46 mg, 0.22 mmol) and acetic acid (6 μL, 0.1 mmol). The reaction was stirred at room temperature for overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl acetate/hexanes=30:70, 40:60) to afford 2-furan-2-yl-6-[4-(2,4,6-trifluoro-benzyl)-piperazin-1-yl]-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white solid (35 mg, 56%). 1H NMR (300 MHz, CDCl3) δ2.66 (t, J=4.5 Hz, 4H), 3.34 (t, J=4.5 Hz, 4H), 3.73 (s, 2H),5.61 (s, 2H), 6.54 (dd, J=1.8, 3.6 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 7.26 (s, 1H), 7.57 (d, J=1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ46.53, 48.35, 51.56, 95.63, 99.82, 100.10, 100.38, 110.29, 111.73, 134.80, 143.80, 146.00, 146.42, 149.06, 155.13.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[F:11][B-:12]([F:15])([F:14])[F:13].[H+].[N:17]([O-])=O.[Na+]>O>[F:11][B-:12]([F:15])([F:14])[F:13].[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([N+:6]#[N:17])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cc(C)c1[N+]#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
21.2 g (0.104 mol) 4-bromo-2,6-dimethylaniline in 58.0 mL (0.444 mol) tetrafluoroboric acid (48% in water) were diluted with water to form a stirrable suspension. 7.18 g (0.104 mol) sodium nitrite, dissolved in water, were slowly added dropwise to the reaction mixture which was cooled to 0° C. After the addition had ended the mixture was stirred for 1 h at RT. The product precipitated as a solid was suction filtered, washed three times with diethyl ether and dried.
Reaction SMILES: O=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1.[ClH:28].Cl.[NH2:30][CH2:31][CH2:32][O:33][NH2:34].N1C=CC=CC=1>C(O)C>[ClH:28].[ClH:28].[NH2:30][CH2:31][CH2:32][O:33][N:34]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1
Reactant: NCCON
Reactant: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Reaction time: 3 h
Yield: 47.8 %

Procedure:
A mixture of 1-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]-1,3-dihydro-2-benzimidazolone (3.85 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.89 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. The solvent was evaporated and the residue was taken up in hot 2-propanol and chilled. The precipitate was collected and recrystallized from 2-propanol and then twice from ethanol/ether to give 1.5 g (29%) of product, mp 175°-180° C. (dec).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@@H:9]2[NH:12][C:11](=[O:13])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14]OS([O-])=O.[K+]>CO>[C:1]1([S:7]([CH2:8][C@@H:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C[C@H](CSc2ccccc2)N1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=C1C[C@H](CS(=O)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 157.4 %

Procedure:
A solution of 4(R)-(phenylsulfanylmethyl)azetidin-2-one (from example 6, step A) (105 mg, 0.543 mmol) in MeOH (3 mL) was treated with an aqueous solution of oxone (167 mg, 0.272 mmol, 3 mL). After stirring at room temperature for 24 h, the reaction mixture was quenched with aqueous Na2S2O3 (10%, 1 mL) and concentrated. The concentrate was diluted with EtOAc (5 mL) and brine (5 mL) and the two layers separated. The aqueous layer was re-extracted three times with CHCl3 (20 mL) and the combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4(R)-(benzenesulfinylmethyl)azetidin-2-one (89.6 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ (1:1 mixture of diastereoisomers) 7.61-7.45 (m, 10H), 6.29-6.14 (bs, 1H), 5.70-5.58 (bs, 1H), 4.16-4.08 (m, 1H), 3.88-3.80 (m, 1H), 3.27-3.05 (m, 4H), 2.92 (dd, J=13.3, 9.2 Hz, 1H), 2.90 (dd, J=13.3, 3.5 Hz, 1H), 2.75-2.67 (m, 1H), 2.66-2.58 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26]Br>C(Cl)(Cl)(Cl)Cl>[Br:26][CH:17]([CH3:18])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:8][C:9]=2[CH:15]=1)=[O:19]
Reactant: BrBr
Reactant: CCC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
1-(2,2-Diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one (the compound of Preparation 42, 4.70 g, 14.23 mmol) was dissolved in carbon tetrachloride (60 mL) and bromine (0.74 mL, 14.36 mmol in 10 mL of carbon tetrachloride) was added dropwise. The reaction was stirred at ambient temperature 30 min and then it was extracted with saturated aqueous bicarbonate solution. The organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to afford 5.58 g (96%) of 2-bromo-1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one as a dark orange oil which had: NMR δ7.68-7.37 (m, 12 H), 6.95 (d, J=8.3 Hz, 1 H), 5.21 (q, J=6.7 Hz, 1 H), 1.88 (d, J=6.6 Hz, 3 H).