Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[O+][O-].[CH3:4][C@@H:5]([C@@H:13]1[C@@:17]2([CH3:32])[CH2:18][CH2:19][CH2:20]/[C:21](=[CH:22]\[CH:23]=[C:24]3\[CH2:25][C@@H:26]([OH:31])[CH2:27][CH2:28][C:29]\3=C)/[C@@H:16]2[CH2:15][CH2:14]1)/[CH:6]=[CH:7]/[C@@H](C(C)C)C.N1C=CC=CC=1.[BH4-].[Na+].[CH3:41][OH:42]>>[CH3:7][CH2:6][C@@H:5]([C@@H:13]1[C@@:17]2([CH3:32])[CH2:18][CH2:19][CH2:20]/[C:21](=[CH:22]\[CH:23]=[C:24]3[CH2:29][C@@H:41]([OH:42])[C:27](=[CH2:28])[C@H:26]([OH:31])[CH2:25]3)/[C@@H:16]2[CH2:15][CH2:14]1)[CH3:4]
Reactant: CO
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]12
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: C=C1[C@H](O)CC(=C/C=C2\CCC[C@]3(C)[C@@H]([C@@H](C)CC)CC[C@@H]23)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
Ozone was passed through a solution of vitamin D2 (3 g, 7.6 mmol) in methanol (250 mL) and pyridine (2.44 g, 2.5 mL, 31 mmol) for 50 minutes at −78° C. The reaction mixture was then flushed with oxygen for 15 min to remove the residual ozone, and the solution was treated with NaBH4 (0.75 g, 20 mmol). After 20 minutes, the second portion of NaBH4 (0.75 g, 20 mmol) was added, and the mixture was allowed to warm to room temperature. The third portion of NaBH4 (0.75 g, 20 mmol) was then added and the reaction mixture was stirred for 18 hours. The reaction was quenched with water (40 mL), and the solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×80 mL), and the combined organic phases were washed with 1M aq. HCl, saturated aq. NaHCO3, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel with hexane/ethyl acetate (75:25) to give (20S)-de-A,B-20-(hydroxymethyl)pregnan-8β-ol 1 (1.21 g, 75% yield) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[NH:6][C:5]3=[O:12])=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)C(=O)NC2=O)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-isoindole-1,3-dione and (4-benzyl-piperidin-1-yl)-oxo-acetic-acid (Example 5b) according to the method described in Example 1c. Melting Point: 239-241° C. (diethylether)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C>[N:19]1([CH2:18][CH2:17][O:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCCN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
97% NaH (3.56 g, 0.14 mol) was suspended in DMF (100 ml) and methyl 4-hydroxyphenylacetate (10 g, 0.06 mol) was added. The reaction mixture was stirred for 0.5 hours, then N-(2-chloroethyl)morpholine hydrochloride (11.2 g) was added and the reaction mixture was stirred at room temperature for about 2 days, and then was heated on a steam bath for 2 hours. The reaction mixture was cooled, filtered and the filtrate was stripped. The residue was partitioned between water and ether, the layers were separated and the aqueous layer was extracted with ether. The organic layers were combined, washed with brine, and dried over MgSO4, filtered and concentrated to afford 11.59 g (69%) of methyl 4-[2-(4-morpholinyl)ethoxy]phenylacetate.
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[OH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[C:17](=[O:26])[C:16]=1[I:27]>CO>[I:27][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19]2[C:24]([C:15]=1[O:14][CH3:1])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CCCCCC
Reactant: Cn1c(=O)c(I)c(O)c2ccccc21
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COc1c(I)c(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1M hexane solution of trimethylsilyldiazomethane (10 ml) and methanol (5 ml) were added to 4-hydroxy-3-iodo-1-methyl-2(1H)-quinolinone (500 mg) and stirred at room temperature for one hour. The reaction solution was concentrated and purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (479 mg).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)CN(CCCC)[C@@H:10]1COCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C@H:43]1[C@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46][NH:45][C@@H:44]1[CH2:56][O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O=CC(CO)O.C([BH3-])#N.[Na+]>CO>[CH2:35]([O:42][C@H:43]1[C@H:47]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:46][N:45]([CH2:10][CH:9]([OH:8])[CH2:13][OH:14])[C@@H:44]1[CH2:56][O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: CCCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: O=CC(O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OCC(O)CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Yield: 72 %

Procedure:
The title compound was synthesized as described for compound 10 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.5 g, 1.2 mmol), methanol (30 ml), glyceraldehyde (0.134 g, 1.5 mmol) and sodium cyanoborohydride (0.094 g, 1.5 mmol). Purification of the crude product on silica gel (Eluent: Ethyl acetate) afforded (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine (0.424 g, yield: 72%) as an oil.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=1[O:29][C:30]([F:33])([F:32])[F:31].[C:34]([NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:41]=1)([CH3:37])([CH3:36])[CH3:35].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:50]2[CH2:49][CH2:48][N:47]([CH2:46][C:42]3[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=3)[C:39]([NH:38][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:53])[CH2:52][CH2:51]2)=[O:26])=[CH:22][C:21]=1[O:29][C:30]([F:33])([F:32])[F:31]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(OC(F)(F)F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (5.76 g, 92 mmol, 5.38 mL) was added dropwise to a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (1 g, 4.6 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.3952 g, 5.1 mmol) and triethylamine (1.37 g, 13.8 mmol, 1.886 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.36 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[N+:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[OH:31])([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.O>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([O:31][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (1.0 g, 3.35 mmol) in butanone (35 mL) was added 2-nitro-4-chlorophenol (0.64 g, 3.69 mmol), potassium carbonate (0.93 g, 6.7mmol) and potassium iodide (0.56 g, 3.35 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was then cooled, diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an orange oil. Chromatography on silica gel gave the title compound (1.35 g).
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: OB(O)c1ccccc1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=c1cc(N2CCOCC2)oc2c(-c3ccccc3)csc12
Temperature: 130 °C
Yield: 2 %

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (50 mg, 0.16 mmol), phenylboronic acid (29 mg, 0.24 mmol), cesium carbonate (103 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol), and dimethoxyethane (1 mL). The reaction mixture was magnetically stirred and heated via microwave irradiation for 15 minutes at 130° C. Upon cooling to room temperature, the reaction was concentrated in vacuo and purified using high-pressure liquid chromatography to give 5-morpholino-3-phenyl-7H-thieno[3,2-b]pyran-7-one (6) (10 mg, 3.2 μmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:12]([CH3:13])=[CH:11][C:5]2[N:6]=[C:7]([CH2:9][SH:10])[NH:8][C:4]=2[CH:3]=1.[N+:14]1([O-])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OC(=O)C)(=O)C>[CH3:13][C:12]1[C:2]([CH3:1])=[CH:3][C:4]2[N:8]=[C:7]([CH2:9][S:10][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[NH:6][C:5]=2[CH:11]=1
Reactant: Cc1cc2nc(CS)[nH]c2cc1C
Reactant: [O-][n+]1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc2nc(CSc3ccccn3)[nH]c2cc1C

Procedure:
A solution of 3.84 g (0.02 mole) of 5,6-dimethyl-2-mercaptomethylbenzimidazole and 1.9 g (0.02 mole) of pyridine N-oxide in 50 ml of acetic anhydride is heated to 100° C. for 4 hours. The acetic anhydride is evaporated off, the residue taken up with acetone and the mixture filtered and concentrated to a volume of 20 ml. From this solution, 2.6 g (48%) of 5,6-dimethyl-2-(2-pyridylthiomethyl)benzimidazole crystallize. The product thereby obtained is identical to that obtained by Method A, and the data for the identification appear in Tables 1 and 2.
Reaction SMILES: [CH2:1]([N:11]([C:30](=O)[CH3:31])[CH2:12][CH2:13][N:14]([C:27](=O)[CH3:28])[CH2:15][CH2:16][N:17]([C:24](=O)[CH3:25])[CH2:18][CH2:19][NH:20][C:21](=O)[CH3:22])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:11]([CH2:30][CH3:31])[CH2:12][CH2:13][N:14]([CH2:27][CH3:28])[CH2:15][CH2:16][N:17]([CH2:24][CH3:25])[CH2:18][CH2:19][NH:20][CH2:21][CH3:22])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CC(=O)NCCN(CCN(CCN(C/C=C(\C)CCC=C(C)C)C(C)=O)C(C)=O)C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNCCN(CC)CCN(CC)CCN(CC)C/C=C(\C)CCC=C(C)C
Yield: 62.6 %

Procedure:
To a chloroform solution (200 ml) containing triethylenetetramine (60 g) was added dropwise with stirring a chloroform solution (100 ml) containing geranyl bromide (20 g) at room temperature, and the mixture was further stirred at room temperature for 3 hours. After the completion of the reaction, the reaction liquid was concentrated under reduced pressure to remove the chloroform therefrom, and the concentrate was extracted with ethyl acetate. The extract was washed with a 10% aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a concentrate (21 g). The concentrate was dissolved in benzene (100 ml), charged with acetic anhydride (30 ml) and sodium acetate (10 g) and then heated under reflux for 4 hours with stirring. The reaction liquid poured in a 10% aqueous sodium hydroxide solution (300 ml) and then extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate (23.5 g) was treated by chromatography with an ethanol-ethyl acetate mixture over a column packed with alumina (250 g) to obtain an oily N-geranyl-N,N',N",N'"-tetraacetyltriethylenetetramine (9.3 g). The thus obtained N-geranyl-N,N',N",N'"-tetraacetyltriethylenetetramine (9.3 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and thereto was added in small portions lithium aluminum hydride at room temperature with stirring. The mixture was stirred at room temperature for 1 hour and then heated under reflux with stirring for 3 hours. After cooling, the reaction liquid was charged with a 20% aqueous sodium hydroxide solution (5 ml), filtered to separate insolubles therefrom and then the filtrate was concentrated under reduced pressure. The concentrate was extracted with isopropyl ether, washed with water and saturated saline, dried over anhydrous sodium sulfate and the concentrated under reduced pressure to obtain as an oily product N-geranyl-N,N',N",N'"-tetraethyltriethylenetetramine (5.1 g) represented by the following formula. ##STR8## Given below are measured values of physical properties of the title compound.
Reaction SMILES: [Na].[C:2]([O-:8])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[CH3:9][C:10](O)([CH:12](Br)[CH2:13][C:14](Br)([Br:16])[Br:15])[CH3:11]>C(O)C>[C:4]([CH:3]1[CH:12]([CH:13]=[C:14]([Br:16])[Br:15])[C:10]([CH3:11])([CH3:9])[O:8][C:2]1=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)CC(=O)[O-]
Reactant: CC(C)(O)C(Br)CC(Br)(Br)Br
Agent: [Na]
Solvent: CCO
Product: CC(=O)C1C(=O)OC(C)(C)C1C=C(Br)Br
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 23 g of sodium in 1,000 ml of ethanol was added dropwise to 251 g (0.5 mol) of the acetoacetate of 2-methyl-3,5,5,5-tetrabromopentan-2-ol at 0° C. and the mixture was subsequently stirred at 0° C. for 4 hours, then allowed to come to room temperature and concentrated somewhat under reduced pressure. Working up was carried out as in Example 4. 125 g of 2-acetyl-3-(2',2'-dibromovinyl)-4-methyl-γ-valerolactone were obtained, which was processed as described in Example 2.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([SH:29])[S:28][C:24]=2[CH:23]=1)([CH3:20])[CH3:19]>ClCCl.N1C=CC=CC=1>[C:1]([CH2:3][C:4]([N:21]([CH:18]([CH3:20])[CH3:19])[C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([SH:29])[S:28][C:24]=2[CH:23]=1)=[O:6])#[N:2]
Reactant: CC(C)Nc1ccc2nc(S)sc2c1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Cyanoacetic acid (1.63 g, 19.17 mmol) was suspended in anhydrous dichloromethane (40 ml). A catalytic amount of N,N-dimethylformamide (0.1 ml) was added and the mixture cooled to 0° C. under an atmosphere of Argon. After 20 minutes stirring at 0° C., oxalyl chloride (1.67 ml, 19.17 mmol) was slowly added to the reaction mixture, which was then allowed to warm to ambient temperature. This mixture was added slowly, after stirring 1 hour, to a 1 M solution of 6-isopropylamino-1,3-benzothiazole-2-thiol (2.16 g, 9.57 mmol) in anhydrous pyridine. After 2 hours the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and 1 M aqueous citric acid. The resulting precipitate was collected by filtration, combined with the organic extract and concentrated in vacuo. The residue was triturated with diethyl ether to yield 2.32 g (83%). 1H NMR (DMSO-d6) δ=0.98 (m, 6H), 3.43 (s, 2H), 4.75 (sep, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.63 (s, 1H), 13.94 (s, 1H); ESIMS: m/z 290 (M-H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl.O.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.N1C=CC=CC=1>[NH2:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCc1ccc(N)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(2-aminoethyl)aniline hydrochloride salt (10.0 g, 78 mmol) was dissolved in dioxane (200 mL) followed by the addition of 5 M HCl (14.6 ml) and water (25 ml). The solution was cooled in an ice bath and was treated quickly with benzenesulfonyl chloride (10.3 ml, 81 mmol). Pyridine (10 ml) was added and the solution stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in water (300 ml) and washed with 3 portions of diethylether. The aqueous solution was treated with 80 ml of 5 N sodium hydroxide and was washed again with 3 portions of diethylether. The aqueous phase was adjusted to a pH of approximately 9 by the addition of 40 ml of 5N HCl. The solids were collected and dried. NMR, MS, EA.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][N:19]=[C:13]2[CH2:12]1)=[O:10].C1C(=O)N([Br:27])C(=O)C1>CN(C)C=O>[Br:27][C:17]1[N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])=[O:10])[CH2:12][C:13]2=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccc(F)cc1Cl)N1CCn2ccnc2C1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1Cl)N1CCn2c(Br)cnc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-[(2-Chloro-4-fluorophenyl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I21) (300 mg, 1.073 mmol) was dissolved in N,N-dimethylformamide (DMF) (2 mL) and treated with NBS (200 mg, 1.126 mmol). The solution was stirred at 25° C. for 16 h. The solvents were removed in vacuo and the residue purified by MDAP (High pH method) to afford desired product in 210 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:9][CH2:8][C@H:4]2[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]2)=[O:21])[CH2:25][CH2:26]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Reactant: CN1CCO[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@H](COC(=O)N2CCN(c3ccc(F)cc3F)CC2)C1
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
(S)-(4-Methylmorpholin-2-yl)-methanol (Intermediate 10; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12, 330 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and the solvents were removed in vacuo to give [(2S)-4-methylmorpholin-2-yl]methyl 4-(2,4-difluorophenyl)-piperazine-1-carboxylate (104 mg, 38%) as a colourless gum.
Reaction SMILES: C(C(O)=O)(F)(F)F.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19]([CH2:20][O:21][C:22](=[O:24])[CH3:23])=[CH:18][C:17]([CH2:25][O:26][C:27](=[O:29])[CH3:28])=[N:16]2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>O>[C:27]([O:26][CH2:25][C:17]1[CH:18]=[C:19]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[NH:15][N:16]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1cc(COC(C)=O)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cc(COC(C)=O)[nH]n1
Reaction time: 1 h

Procedure:
To a solution of 90 ml. of CF3CO2H and 15 ml. of H2O, cooled to -20° was added, in portions, 10 g. (0.022 mol) of the end product of Example 20. After the addition was complete, the solution was stirred at -15° to -20° for 1 hour, poured into excess saturated K2CO3 solution and extracted with EtOAc. The organic phase was dried (MgSO4), concentrated and the residue chromatographed on silica gel to give the end product as a pale yellow oil. The analytical sample was obtained as a colorless oil by bulb to bulb distillation: bp 175 (0.05 mm).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22].Cl>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][N:7]1[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CSCCN1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CSCCN1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of thiomorpholin-3-ylcarboxylic acid ethyl ester (5.05 g) in methylene chloride (120 mL) were added dimethylaminopyridine (352 mg), triethylamine (4.9 mL) and 3-nitrobenzoyl chloride (5.62 g) in ice bath and then the mixture was stirred at room temperature overnight. 2N hydrochloric acid was added to the reaction mixture, which was extracted with methylene chloride. The extract was wash with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (5.91 g) having the following physical data.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[N:10]=[CH:11][C:12]3[CH:17]=[CH:16][S:15][C:13]=3[N:14]=2)[CH2:3][CH2:2]1.[Br:18]Br>C(Cl)Cl>[Br:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:10]=[CH:11][C:12]=2[CH:17]=1
Reactant: BrBr
Reactant: c1cc2cnc(CCN3CCOCC3)nc2s1
Solvent: ClCCl
Product: Brc1cc2cnc(CCN3CCOCC3)nc2s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-morpholinoethyl)thieno[2,3-d]pyrimidine (1.0 g, 3.79 mmol) in DCM (50 mL) at 0° C. was added a solution of bromine (1.2 eq) in DCM (3 mL) dropwise. The resulting solution was stirred at 0° C. for 30 min. The reaction mixture was quenched with saturated solution of NH4Cl. The layers were separated, and the aqueous layer was extracted with DCM (3×25 mL). Organic layers were combined, washed with brine (2×30 mL), dried over MgSO4, filtered and concentrated to provide the title compound (0.910 g). MS (ES+): 345 (M+H)+.