Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.Cl.[O:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:30][NH:29][CH2:28]2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:29]3[CH2:30][CH:27]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:28]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CC(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.173 g, 0.65 mmol), 3-(tetrahydropyran-4-yl)azetidine hydrochloride (0.138 g, 0.78 mmol) and 4 Å molecular sieves (0.9 g) in DCE (7 mL). The reaction mixture was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.274 g, 1.29 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 2-Chloro-9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine as a white foam (0.117 g, 45%). LCMS (Method A): RT=2.40 min, [M+H]+ 407.2
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C[O-].[Na+].[C:17](=[O:19])=[O:18]>CN(C)C(=O)C>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[C:17]([OH:19])=[O:18])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O
Temperature: 90 °C
Yield: 23 %

Procedure:
This acid was prepared according to the procedure of W. H. Meek et al. J. Chemical and Engineering Data, 14(3), 388, (1969). To a solution of 2,6-diisopropylphenol (Aldrich cat. #D12660-8) (37.0 ml, 0.20 mol) in anhydrous N,N-dimethylacetamide (150 ml) was added sodium methoxide (16.2 g, 0.30 mol). Carbon dioxide was passed through the mixture throughout the subsequent reaction period. The mixture was heated with stirring and the solvent was slowly distilled out during 2 hours of the period until the pot temperature reached to 180° C.. The mixture was allowed to continue stirring at 180° C. for another 1.5 hours and then cooled to 90° C. The flow of carbon dioxide was discontinued and water (400 ml) was added. The mixture, after further cooled to room temperature, was washed with toluene (4×60 ml) and then treated with conc. hydrochloric acid in an ice-water bath to pH 3. The resulting mixture was extracted with diethyl ether (2×150 ml); the ether extract was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 3,5-diisopropyl-4-hydroxybenzoic acid (10.4 g, 23%). Rf 0.5 (silica gel, 50% diethyl ether/hexane). MS (CI, CH4): m/z 223 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][C:39](=[O:40])[N:38]([CH3:42])[CH3:37])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OC(=O)N(C)C)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 65 °C

Procedure:
To a suspension of the product of Example 57 in CHCl3 was added TEA (84 μL, 0.6 mmol) and dimethylcarbamoyl chloride (56 μL, 0.6 mmol). The resulting suspension was heated to 65° C. overnight with shaking. Solvent was removed under vacuum to give a crude, which was purified by chromatography on silica gel, eluting by MeOH-DCM (5:95) to afford the title compound (38.6 mg). 1H-NMR indicated one isomer. 1H-NMR (DMSO-d6): δ 97.73 (1H, d), 7.28–7.39 (7H, m), 7.14 (1H, d), 6.97 (1H, dd), 6.63 (1H, dd), 5.12 (2H, s), 4.98(1H, t), 3.78 (3H, s), 3.05 (6H, m), 2.91 (3H, s), 0.99 (3H, t); MS (ESI): 585 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][NH:22][C:23](SC)=[CH:24][N+:25]([O-:27])=[O:26]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[CH:24][N+:25]([O-:27])=[O:26])[N:8]=1
Reactant: NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine (0.31 g.) 1-methylamino-1-methylthio-2-nitroethylene (0.15 g.) and acetonitrile (5 ml.) was heated under reflux for 6 hours and then left at room temperature for 18 hours. The yellow crystalline precipitate was collected to give 1-(2-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]ethylamino)-1-methylamino-2-nitroethylene (0.26 g.), m.p. 154°-157° after recrystallisation from ethanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]#N)[CH2:12][CH2:11]2)=[N:2]1.C[O-:19].[Na+].[C:21](O)(=[O:23])C>CO>[CH3:21][O:23][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH2:11][CH2:12]1)=[O:19]
Reactant: N#CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: CC(=O)O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1CCC(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-(1H-indazol-3-yl)piperidine-1-carbonitrile (7.9 g, 0.024 mole) in methanol (15 ml) was added 4.9 ml of 25% solution of sodium methoxide in methanol. The solution was stirred at ambient temperature for 16 hours, made neutral to pH paper with glacial acetic acid, and extracted with ether. The aqueous solution was made basic with concentrated NH4OH, and extracted thrice with CH2Cl2 (35 ml). The organic extracts were combined, washed (H2O), dried (MgSO4) and the solvent removed in vacuo to yield 6.6 g of an oil. The oil was triturated with hexane and the resultant solid collected (5.4 g). Recrystallization from CH3CN (twice) yielded 3.5 g (56.8%) of 4-(1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester having a melting point of 153°-155° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2/[CH:23]=[N:24]/[OH:25])=[C:5]([CH3:26])[O:4][N:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=[N:24][OH:25])=[C:5]([CH3:26])[O:4][N:3]=1.[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=[N:24][OH:25])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1/C=N/O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C=NO
Product: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.1 %

Procedure:
10% of the crude (E)-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (1.2 mg, 0.003 mmol) from step (e) was dissolved in CH2Cl2 (4 mL) and BBr3 (1 M solution in DCM, 0.4 mL, 0.37 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and DCM were added and the phases were separated. The organic phase was purified on preparative HPLC to give E4 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (0.58 mg, 3% over three steps). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 341.16 (M+H), 339.25 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.84 s 1H, 7.14 m 2H, 6.85 m 2H; (missing m 2H under H2O); 2.18 s 3H, 1.85 s 3H, 1.75 m 2H, 0.99 t (7.6 Hz) 3H.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[S:30][C:7]2[NH:8][C:9]([C:11]([NH:13][CH:14]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:24][C:25]([O:27]C)=[O:26])[C:15]3=[O:29])=[O:12])=[CH:10][C:6]=2[CH:5]=1>O.C1COCC1>[C:25]([CH2:24][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH:14]([NH:13][C:11]([C:9]2[NH:8][C:7]3[S:30][C:4]([Cl:3])=[CH:5][C:6]=3[CH:10]=2)=[O:12])[C:15]1=[O:29])([OH:27])=[O:26]
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 2 h
Yield: 88.4 %

Procedure:
LiOH (1.41 g, 33.6 mmol) in H2O (16.5 mL) was added to a stirring solution of 2-chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 1; 7.00 g, 16.8 mmol) in THF (88 mL) and the reaction was stirred for 2 h. The reaction was quenched by addition of 1M aqueous HCl (200 mL) and EtOAc (400 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The resultant white foam was triturated with hot Et2O (100 mL) cooled, filtered and dried to afford the title compound (6.00 g, 89%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Yield: 107.6 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (3.64 g, 10 mmol) and trimethylsilylacetylene (4.2 mL, 30 mmol) according to the general procedure F. Obtained as a green oil (3.6 g).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[CH:17]1[CH:32]=[CH:31][C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=O)[NH:25][C:19]=2[CH2:18]1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[S:2])[NH:25][C:19]=2[CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NC2=C(C=CC(C(F)(F)F)C2)Sc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2c(c1)NC(=S)c1ccccc1S2
Yield: 70.7 %

Procedure:
Phosphorus pentasulphide (0.6 g, 2.5 mmol) was added to a stirred solution of 8-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one (0.295 g, 1 mmol) in pyridine (10 ml). The mixture was heated under reflux for 6 hr and then at room temperature overnight. A further 0.3 g of phosphorous pentasulphide was added and the reaction mixture refluxed for 6 hr and then left at room temperature overnight before hot water (40 ml) added. Filtration and recrystallisation from toluene then ethanol gave he title compound as fine yellow needles (0.22 g, m.p. 232°-233° C. Rf 0.76, petrol/EtOAc 2:1).
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[C:29]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccccc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC[C@@H](C)OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (725 mg, 2.76 mmol), benzoic acid (338 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (649 mg, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-benzoyloxyoctane as a colorless liquid substance (490 mg, yield: 91%/(S)-2-octanol).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[CH3:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1>>[CH3:4][CH:3]1[CH2:2][NH:1][C:10]2([CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[O:5]1
Reactant: CN1CCC(=O)CC1
Reactant: CC(O)CN
Product: CC1CNC2(CCN(C)CC2)O1
Reaction time: 8 h

Procedure:
A mixture of 1-amino-2-propanol (9.2 ml, 1.2 mmol) and 1-methyl-4-piperidone (11.5 ml, 1.0 mmol) was heated under reflux for 2 h and left overnight at room temperature. The reaction mixture was distilled under reduced pressure (˜15 mm Hg). The title compound was collected at 82-95° C. 1H NMR (CDCl3, 300 MHz) δ 4.02 (m, 1H, OCH), 3.25 (dd, J=11.9, 6.3 Hz, 1H, CHH), 2.68 (dd, J=11.9, 6.6 Hz, 1H, CHH), 2.4-2.6 (m, 4H-piperidine), 2.1 (s, 3H, NCH3), 1.65-1.81 (m, 4H-piperidine), 1.21 (d, J=6.1 Hz, 3H, CH3CH) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)cc3OC)nc2n(CCC)c1=O
Yield: 23.8 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.04 g (14.60 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.26 g (yield 24%) of Compound 25 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 130.3 %

Procedure:
(R)-tert-butyl 2-((S)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)morpholine-4-carboxylate (120 mg, 0.28 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 20 min and a solution of satd aq NaHCO3 was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford methyl 2-((S)-(3-chlorophenyl)((R)-morpholin-2-yl)methoxy)ethylcarbamate (120 mg, 100%), which was used without purification.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[CH2:24]1)(=O)=O.[Cl-].[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[N:36]1([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:25]3[CH2:26][CH2:27][C@@H:23]([N:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=5[CH2:12][O:11][C:10]5[CH:14]=[CH:15][CH:16]=[CH:17][C:9]4=5)[CH2:24]3)=[CH:31][CH:32]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)COc1ccccc1N2[C@@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (132 mg, 3.3 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (10 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (600 mg, 3.0 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 30 minutes. A solution of (S)-3-methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 42 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-pyrrolidinophenethyl)pyrrolidin-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (142 mg, 32%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[N+:15]([O-])=O)[CH3:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[NH2:15])[CH3:2]
Reactant: CCOC(=O)c1cc(SCC)cc(N)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(SCC)cc(N)c1N

Procedure:
1.5 g (5.5 mmol) of 3-amino-5-ethylsulfanyl-2-nitro-benzoic acid ethyl ester was reduced by 2.9 g (16.6 mmol) of Na2S2O4 in 28 mL of ethanol/ethyl acetate/water (3:3:1) at 80° C. for 3 h to produce 2,3-diamino-5-ethylsulfanyl-benzoic acid ethyl ester. LCMS: 241 (M+1)+.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:14](=[O:15])[N:13]2[C:8]([S:9][CH2:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[CH3:16].Br.[C:18]1([C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:18]1([C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[CH2:26][CH2:27][N:28]([CH2:3][CH2:4][C:5]3[C:14](=[O:15])[N:13]4[C:8]([S:9][CH2:10][CH2:11][CH2:12]4)=[N:7][C:6]=3[CH3:16])[CH2:29][CH2:30]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc2n(c(=O)c1CCBr)CCCS2
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2n(c(=O)c1CCN1CCC(=C(c3ccccc3)c3ccccc3)CC1)CCCS2
Yield: 60 %

Procedure:
A mixture of 7.4 parts of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromide, 6.6 parts of 4-(diphenylmethylene)piperidine hydrobromide, 12 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The reaction mixture was cooled, water was added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered off and recrystallized from 2-propanol, yielding 5.5 parts (60%) of 7-[2-[4-(diphenylmethylene)-1-piperidinyl]ethyl]-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]-thiazin-6-one; mp. 176.0° C. (compound 104).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:28])[NH:26][OH:27])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(Cl)[Cl:36]>>[ClH:36].[NH2:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25](=[O:28])[NH:26][OH:27])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[C:29]([N:30]([CH3:31])[CH3:32])=[O:33]
Reactant: ClCCl
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Product: CN(C)C(=O)C(N)Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
The hydroxamate 8 (3.4 g) was dissolved in CH2Cl2 and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×50 mL), decanted, and dried to yield the desired compound 9 as a white amorphous solid (2.9 g, 98%). 1H NMR (DMSO-d6): 10.39 (s, 1H), 7.21 (d, J=8.4 Hz, 4H), 6.95 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 4.55 (m, 1H), 2.95-2.99 (m, 2H), 2.82 (s, 3H), 2.80 (t, J=8.0 Hz, 2H), 2.73 (s, 3H), 2.25 (t, J=8.0 Hz, 2H); LCMS (m/e): Obsd. 372.0, Calcd. 371.43
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[NH2:8][C:9]([NH2:11])=[S:10]>CCO>[CH:4]([C:3]1[N:8]=[C:9]([NH2:11])[S:10][CH:2]=1)([CH3:6])[CH3:5]
Reactant: NC(N)=S
Reactant: CC(C)C(=O)CBr
Solvent: CCO
Product: CC(C)c1csc(N)n1
Yield: 91.4 %

Procedure:
1-Bromo-3-methyl-butan-2-one (10.5 g, 64 mmol, prepared as described in Org. Syn. Coll. Vol. 6, p. 193 (1988)) was added to a stirring slurry of thiourea (4.601 g, 60 mmol) in 20 mL EtOH. The reaction mixture was heated to reflux for 90 minutes, then cooled and concentrated under reduced pressure. The residue was dissolved in water, and the resulting solution was diluted with concentrated aqueous NaOH until pH was adjusted to about 12. The mixture was extracted with diethel ether, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 4-isopropyl-thiazol-2-ylamine (7.8 g) as an oil.