Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1)=[O:2].S(Cl)(Cl)=O.CN(C)C=O.[NH2:23][C:24]1[CH:29]=[C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:26][C:25]=1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCCl.CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([NH:23][C:24]2[CH:29]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=[CH:26][C:25]=2[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:13])=[CH:7][CH:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)/C=C/c1ccc(C=O)cc1
Temperature: 67 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A suspension of (E)-3-(4-formylphenyl)acrylic acid 93 (1.046 g, 5.94 mmol) in 1,2-dichloroethane (30 mL) was treated with neat thionyl chloride (SOCl2) (0.9 mL, 12.3 mmol) and stirred at 67° C. then dimethyl formamide (0.3 mL) was slowly added; and the reaction mixture was allowed to stir at 67° C. for 30 min, cooled to room temperature, concentrated, diluted with dry benzene (40 mL) and concentrated again. The yellow residue was stored under vacuum for 3 h then suspended in pyridine (25 mL) and treated with amine 4 (1.113 g, 3.83 mmol) and 4-dimethylamino pyridine (DMAP) (156 mg). The suspension was stirred at room temperature for 3 days, diluted with H2O (10 mL) then stirred for additional 5 h. The solution was diluted with DCM, washed with 5% KHSO4, saturated NaHCO3, dried over MgSO4, filtered and concentrated to provide title compound 94 (0.415 g, 24% yield) after purification by flash chromatography (eluent: 30% to 50% AcOEt in hexanes). LRMS: 448.2 (calc) 471.0 (M+Na, obs)
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[F:23][C:24]([F:37])([F:36])[S:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[F:36][C:24]([F:23])([F:37])[S:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)=[CH:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccc(S(=O)(=O)C(F)(F)F)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-[(trifluoromethyl)sulfonyl]benzylamine hydrochloride gave the title compound as an oil. HPLC (Condition A), Rt: 4.36 min (HPLC purity: 43.4%).
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[CH2:6]([NH:13][C:14]([C:16]1[S:17][C:18]([N:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]2=[O:29])=[CH:19][C:20]=1[CH3:21])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:14]([C:16]1[S:17][C:18]([N:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:24][C:23]2=[O:29])=[CH:19][C:20]=1[CH3:21])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCC1CC1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-n2ccc(OCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 62 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use cyclopropylmethyl bromide in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a colorless solid in 62% yield: mp 175-177° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=6.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.35-7.20 (m, 6H), 6.24 (dd, J=8.0, 2.7 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.88 (d, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.27-1.14 (m, 1H), 0.63-0.54 (m, 2H), 0.37-0.29 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 166.5, 162.4, 161.0, 139.6, 138.8, 137.2, 134.9, 128.2, 127.2, 127.1, 126.6, 120.4, 102.5, 96.6, 73.1, 42.3, 15.5, 9.5, 3.1; MS (ES+) m/z 395.2 (M+1).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:9]1[N:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH3:17])[N:10]=1.C(OCCCC)CCC>>[F:15][C:13]1[CH:12]=[C:11]([O:16][CH3:17])[N:10]=[C:9]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:14]=1
Reactant: COc1cc(F)nc(F)n1
Reactant: CCCCCCN
Solvent: CCCCOCCCC
Product: CCCCCCNc1nc(F)cc(OC)n1
Reaction time: 1 h

Procedure:
15.6 g (0.154 mol) of n-hexylamine were added at 0° to 2° C. to a stirred mixture of 10.4 g (0.071 mol) of 2,4-difluoro-6-methoxypyrimidine in 60 ml of methyl t.-butyl ether within 15 minutes. After 1 hour at 0° C., 4 hours at 25° C. and working up as in B 2-3, 9.6 g (60% of theory) of the title compound of nD23 =1.4938 were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C:17]1([CH3:29])[CH:22]=[CH:21][C:20]([S:23]([CH2:26][N+:27]#[C-:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[H-].[Na+]>CS(C)=O.C(OCC)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N+:27]([C:26]([S:23]([C:20]1[CH:19]=[CH:18][C:17]([CH3:29])=[CH:22][CH:21]=1)(=[O:24])=[O:25])([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:15])([CH3:16])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)#[C-:28]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(CCCCBr)COC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: [C-]#[N+]C(CCCCC(C)(C)COC1CCCCO1)(CCCCC(C)(C)COC1CCCCO1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 112.8 %

Procedure:
To a solution of 2-(6-bromo-2,2-dimethyl-hexyloxy)-tetrahydro-pyran (13.0 g, 44.33 mmol) and p-toluenesulphonylmethyl isocyanide (4.33 g, 22.17 mmol) in anhydrous DMSO (50 ml) and anhydrous diethyl ether (50 ml) was added sodium hydride (60% dispersion in mineral oil, 2.13 g, 53.20 mmol) at rt under N2 atmosphere. After solidification of the reaction mixture, additional anhydrous DMSO (50 ml) was added. After stirring for 5.5 h at room temperature, tetrabutylammonium iodide (1.64 g, 4.43 mmol) was added and the mixture stirred for additional 22.5 h at rt. The reaction mixture was carefully hydrolyzed with water (10 ml), diluted with water (200 ml), and extracted with diethyl ether (200 ml). The organic layer was washed with saturated NaCl solution (100 ml), dried over MgSO4, and concentrated in vacuo to give crude 2-[7-isocyano-2,2,12,12-tetramethyl-13-(tetrahydro-pyran-2-yloxy)-7-(toluene-4-sulfonyl)- tridecyloxy]-tetrahydro-pyran (15.5 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>[OH-].[Na+]>[CH2:19]([O:18][C:16]([NH:1][C:2]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:17])[CH3:20]
Reactant: Nc1cc(S(N)(=O)=O)ccc1C(=O)O
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1cc(S(N)(=O)=O)ccc1C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 2-amino-4-sulfamoylbenzoic acid (1.32 g) in 2N sodium hydroxide (6 ml) was added dropwise ethyl chloroformate (1.9 ml) and 2N sodium hydroxide on an ice bath. After stirring for 3 hours, the reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate. Combined organic extracts were washed in turn with water and brine, dried over magnesium sulfate and evaporated to give an amorphous of 2-ethoxycarbonylamino-4-sulfamoylbenzoic acid (1.99 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 59.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.46 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[P:8](Cl)([Cl:11])([Cl:10])=[S:9]>CCOCC>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[P:8]([Cl:11])([Cl:10])=[S:9])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: S=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)N(C(C)C)P(=S)(Cl)Cl
Temperature: 25 °C
Yield: 37.7 %

Procedure:
A solution of diisopropylamine (72 mL, 0.512 mole) in 75 mL of anhydrous ether was added dropwise to a cold (ice bath) solution of 106 mL (1.02 moles) of thiophosphoryl chloride in 300 mL of anhydrous ether under an argon atmosphere. The resultant slurry was allowed to slowly warm to room temperature. After filtering to remove isopropylamine hydrochloride, the filtrate was concentrated under vacuum to provide a red oil (45.2 g, 75.4%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[C:10]([C:9]1[CH:12]=[C:5]([CH:6]=[CH:7][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[CH2:4][O:3][C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccnc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH:26]1([NH:31][C:2]2[N:7]3[N:8]=[C:9]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCC1
Reactant: CC(=O)c1c(-c2ccncc2)nn2c(Cl)cccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
To a solution of 1-[7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.68 g, 2.5 mmol) in toluene (10 mL) was added successively rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (100 mg, 0.15 mmol), cesium carbonate (1.2 g, 3.8 mmol), cyclopentylamine (1.5 mL, 12.5 mmol), and palladium (II) acetate (25 mg, 0.1 mmol). The resulting mixture was stirred at 90° C. for 24 hours, at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ethyl acetate and water were added to the reaction mixture. The phases were separated, and the aquous phase again extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (1:1 hexanes-ethyl acetate) to give 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.64 g, 80%) as a yellow foam. 1H NMR (CDCl3): δ 8.80 (d, 2H), 7.65 (d, 1H), 7.60 (d, 2H), 7.50 (t, 1H), 6.20 (d, 1H), 6.06 (d, 1H), 4.0 (m, 1H), 2.26 (s, 3H), 1.6–2.2 (m, 8H); MS m/z 321 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O.C(O)(C(F)(F)F)=O.O.C(O)(C(F)(F)F)=O.CC#N>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:27]([CH2:33][O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[CH:28]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: Nc1ccc(Oc2ccccc2)c(COC2CCCCO2)c1
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)c(COC4CCCCO4)c3)c2c1C
Reaction time: 0.13 h

Procedure:
Compound 394 was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (160 mg, 0.61 mmol) and 394D (180 mg, 0.60 mmol) by a route analogous to that used for the preparation of compound 388D. It has a retention time 7.69 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M−H)+=525.4
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[CH3:20][C:16]1[CH:15]=[C:14]([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)c1
Agent: [Pd]
Product: Cc1cccc(-c2cccc3c2OC(CN)C3)c1
Yield: 71 %

Procedure:
Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.90 g, 2.27 mmol) with sodium azide (0.44 g, 6.84 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (10%, 0.060 g) generally according to the procedure described for Example 1 afforded 0.444 g (71%) of (±)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C. (dec); Anal. calcd. for C16H17NOHCl.0.2H2O: C, 68.79; H, 6.64; N, 5.01. Found: C, 68.54; H, 6.57; N, 4.9.
Reaction SMILES: [NH2:1][C:2](=[N:13][NH:14][C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=O)[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C>[C:7]1([S:4]([CH2:3][C:2]2[N:1]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[NH:14][N:13]=2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1ccco1
Solvent: CCO
Product: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
105 g (0.34 mol) Furan-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide were heated at 200° C. for 20 minutes. The molten mass was then cooled, dissolved in 250 ml hot ethanol and stirred overnight at room temperature. The precipitated crystals were filtered off and dried to yield 65.7 g (66%) 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole as white crystals with mp. 185-186° C., MS m/e (%): 290 (M+H+, 100).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15])=O.[C:16]([CH2:18][C:19]([NH:21][NH2:22])=[O:20])#[N:17]>C(O)C>[C:16]([CH2:18][C:19]([NH:21][N:22]=[CH:1][C:3]1[C:12]([CH3:13])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15])=[O:20])#[N:17]
Reactant: Cc1c(C=O)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: N#CCC(=O)NN
Solvent: CCO
Product: Cc1c(C=NNC(=O)CC#N)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
A suspension comprising 20.4 grams (0.1 mole) of 2-formyl-3-methylquinoxaline-1,4-dioxide (m.p. of 180°-182° C.) and 9.9 grams (0.1 mole) of cyanoacetylhydrazine in 200 ml of ethanol was stirred for 4 hours at room temperature. The separated product was sucked off and washed with ethanol, so yielding 22.2 grams (78% of theoretical) of crude material. Upon crystallization from dimethylformamide, yellow crystals melting at a temperature within the range of 255°-260° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([F:11])[CH:3]=1.[CH:12]1([CH2:15][CH:16]=O)[CH2:14][CH2:13]1.[OH-].[Na+]>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:16]/[CH2:15][CH:12]2[CH2:14][CH2:13]2)/[C:7]#[N:8])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=CCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: N#C/C(=C\CC1CC1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (3.39 g, 20.0 mmol) and cyclopropyl-acetaldehyde (Aldrich) (1.68.0 g, 20.0 mmol) in iPrOH (25 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight under reduced pressure to afford (Z)-2-(4-chloro-2-fluoro-phenyl)-4-cyclopropyl-but-2-enenitrile (2.36 g, 50.0%) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH2:12])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH2:12])=[S:34]
Reactant: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 128.8 %

Procedure:
A suspension of 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrobenzamide (54.1 g; 0.15 mol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (LAWESSON's reagent) (28 g; 0.075 mol) in toluene (250 cc) is prepared. It is heated to 100° C., with stirring, and the heating is continued for 1 hour at this temperature. The toluene is removed by evaporation and the residue is purified by chromatography. This gives a yellow solid of 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrothiobenzamide (36.4 g; yield 65%) melting at 152° C. and having the formula: ##STR21##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:31][CH:30]=[CH2:29])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride and the solution was stirred for 30 minutes at room temperature. To this was further added 3.6 g of allyl bromide, and the mixture was reacted for 2 hours at room temperature. Then, the solvent was distilled off from the resulting mixture under reduced pressure to leave a residue, to which was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.9 g of 1(m-nitrophenyl)-3 -allylquinazoline- 2,4(1H, 3H)-dione as light brown needles, melting at 165°-166° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>O>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:14](=[O:15])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:32]3[CH2:33][C@@H:28]4[CH2:34][C@H:31]3[CH2:30][O:29]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:23]([F:26])([F:25])[F:24]
Reactant: Cc1ccncc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccncc1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 120 °C
Yield: 74.2 %

Procedure:
140 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 126 μl (0.90 mmol) of triethylamine are added. The tube is sealed and heated at 120° C. in an oil bath for 2 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.Br.NC(N)=[S:14]>O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][SH:14])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(I)cc1
Reactant: NC(N)=S
Agent: Br
Solvent: O
Product: SCCc1ccc(I)cc1
Yield: 27 %

Procedure:
104 g of p-iodophenethyl alcohol was combined in solution with 216 g of hydrobromic acid (48%) and 36 g of thiourea in 100 ml of water and reacted in accordance with the procedure outlined in Example I(a). Vacuum distillation at 91°-95° and 0.2 mm Hg gave a 27% yield of p-iodophenethyl thiol having a refractive index of n25D = 1.6411, an ALD of 0.56 ml/Kg and a formula of C8H8IS.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][CH:15]3[C:10]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.N1C=CC=CC=1.Cl.CON>C(O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][CH:15]3[C:10]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3cccnc3)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NC1=NC2(c3cccnc3)CN(c3ncc(F)cn3)CC2CS1
Temperature: 70 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
To a stirred solution of N-[6-(5-fluoropyrimidin-2-yl)-7a-(3-pyridyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (110 mg, 0.210 mmol) in ethanol (10 mL) are added pyridine (187 μL 2.31 mmol) and O-methylhydroxylamine hydrochloride (143 mg, 1.68 mmol). The mixture is heated at 70° C. with stirring for 17 hours. The solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (62 mg, 89%). ES/MS (m/e): 331 (M+1).