Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[F:14][C:15]1[CH:20]=[C:19]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert. butylate were dissolved in 90 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 ml) was carefully added dropwise and the mixture was stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EE (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The residue obtained was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EE in cyclohexane) and produced 5.9 g (44.9%) of product.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.[CH:20]1[N:24]([CH2:25][O:26][CH:27]([CH2:30]O)[CH2:28][OH:29])[C:23]2[N:32]=[C:33]([NH2:37])[N:34]=[C:35]([OH:36])[C:22]=2[N:21]=1.C(O)(C)C>[Pd].CO>[CH3:16][CH:14]([C@H:13]([NH2:12])[C:17]([O:19][CH2:30][CH:27]([O:26][CH2:25][N:24]1[C:23]2[NH:32][C:33]([NH2:37])=[N:34][C:35](=[O:36])[C:22]=2[N:21]=[CH:20]1)[CH2:28][OH:29])=[O:18])[CH3:15].[ClH:1]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CC(C)[C@H](N)C(=O)OCC(CO)OCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
Hydrochloric acid (2.6 g) and 10% palladium on carbon (1.1 g, 50% wet) were added to a solution of mono-benzyloxycarbonyl-L-valine ganciclovir (10 g) in aqueous methanol (Methanol:Water::50 mL:8 mL) at ambient temperature. The reaction mass was flushed with nitrogen twice and hydrogenated at about 35° C. to 40° C. at hydrogen pressure of about 0.5-1 kg/cm2 for about 1 hour. The reaction mass was filtered and washed with methanol (10 mL). Methanol was distilled out completely under reduced pressure at about 30° C. to 35° C. The residue was dissolved in water (8 mL) and stirred to obtain clear solution. Iso-propanol (56 mL) was added slowly over a period of about 1 hour. The reaction mass was cooled to about 0 to 5° C., maintained for about 1 hour, filtered, washed with 10% aqueous iso-propanol (10 mL) followed by washing with iso-propanol (10 mL) and dried to obtain valganciclovir hydrochloride (6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)Cc1ccc(Br)cc1
Yield: 57.9 %

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv), dimethylamine (13.20 g, 96.80 mmol, 1.20 equiv, 33%) and potassium carbonate (13.36 g, 96.81 mmol, 1.20 equiv) in ethanol (200 mL) was stirred overnight at 50° C. The solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 200 mL of water and extracted with 3×200 mL of dichloromethane. The combined organic layer was washed with 3×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (20:1) to give 10 g (58%) of (4-bromophenyl)-N,N-dimethylmethanamine as a yellow oil. LC-MS: (ES, m/z): 255 [M+CH3CN+H]+, 214 [M+H]+, 169.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:10]([NH2:13])(=[S:12])[CH3:11]>N1C=CC=CC=1>[CH3:11][C:10]1[S:12][C:2]2[C:3](=[O:9])[CH2:4][CH2:5][CH2:6][C:7]=2[N:13]=1
Reactant: O=C1CCCC(=O)C1Br
Reactant: CC(N)=S
Solvent: c1ccncc1
Product: Cc1nc2c(s1)C(=O)CCC2
Temperature: 100 °C
Yield: 42.7 %

Procedure:
To a stirred solution of 2-bromocyclohexane-1,3-dione (8 g, 42 mmol) in pyridine (50 mL), was added thioacetamide (3.2 g, 42.5 mmol). The reaction mixture was heated at 100° C. for 16 hours. The solvent was then removed under reduced pressure the residue poured in water (250 mL). The reaction mixture was extracted with dichloromethane (3×100 mL). The organic extract was dried using anhydrous sodium sulfate, concentrated under reduced pressure. The crude product was purified by flash column chromatography (Silica gel, gradient from 100% dichloromethane to 2% methanol in dichloromethane) to give the pure desired product (3 g, 42%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 3.01 (t, J=6.0 Hz, 2H), 2.74 (s, 3H), 2.60 (t, J=4 Hz, 2H), 2.20 (quintet, J=4 Hz, 2H); LCMS [M+H]: 168.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred suspension of 3-methyl-4-nitrobenzoic acid (100 g, 0.55 mole) in methanol (400 mL) was added thionyl chloride (36 g, 0.30 mole), over a period of 1 hour (the temperature of the reaction mixture rising to about 35°-40° C.). The mixture was heated to reflux for 1.5 hours, then cooled to 50°-55° C. and maintained at this temperature for 30 minutes prior to cooling to ambient temperature. Water (100 mL) was added over 30 minutes, with cooling applied to maintain the temperature at 20°-25° C. Filtration was followed by washing of the solid with water (100 mL twice), and drying at 40° C. under vacuum, to afford 103 g (95%) of methyl 3-methyl-4-nitrobenzoate as a yellow solid; mp 83°-85° C.; NMR (250 MHz, CDCl3): 2.62 (s, 3H, ArCH3), 3.98 (s, 3H, CO2CH3), 8.01 (m, 3H).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]>CN(C)C=O.C(Cl)Cl>[Cl:9][CH:10]=[C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]
Reactant: [O-]c1ccccc1
Reactant: C=CC(C)(C)C=C(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(C)(C)C(=CCl)Oc1ccccc1
Yield: 84.1 %

Procedure:
116 g (1 mol) of sodium phenolate and 82.5 g (0.5 mole) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene in 500 ml of dimethylformamide were heated under reflux for 8 hours. The solution was diluted with methylene chloride and extracted by shaking with dilute sodium hydroxide solution. After the methylene chloride phase had been dried over sodium sulphate, the solvent was stripped off in vacuo. The residual crude product was distilled in vacuo. 93.6 g (84% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene of boiling point 80° to 90° C./0.5 mm Hg were obtained. ##STR26##
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([S:22]([NH:1][C:2]2[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1cnc(N)c(I)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To a solution of 2-amino-3-iodo-5-methylthiopyridine (7.63 g) in pyridine (30 ml), benzenesulfonyl chloride (7.9 ml) was added at 15 to 30° C. under nitrogen atmosphere and the mixture was stirred at 60° C. for 15 hours. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. A solution of the resulting crude bis(benzenesulfonyl) product in a mixture of methanol/dioxane (1:1, 200 ml) was added a 1N aqueous potassium hydroxide solution (64 ml) at 15 to 30° C. and the mixture was stirred at 60° C. for 1 hour. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:chloroform=1:50) to obtain 6.4 g (56%) of the desired product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 117.5 mg (43%) of the desired product as a creme solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[Br:38][CH2:39][C:40]([O:51][CH2:52][CH3:53])([O:48][CH2:49][CH3:50])[C:41](=[N:45][O:46][CH3:47])[C:42](Cl)=[O:43].O>C(OCC)(=O)C>[Br:38][CH2:39][C:40]([O:51][CH2:52][CH3:53])([O:48][CH2:49][CH3:50])[C:41](=[N:45][O:46][CH3:47])[C:42]([NH:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12)=[O:43]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Yield: 100.6 %

Procedure:
To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.4 g) and trimethylsilylacetamide (9.8 g) in ethyl acetate (80 ml) was added 4-bromo-3,3-diethoxy-2-methoxyiminobutyryl chloride (syn isomer) (5.0 g) at -20° C. with stirring, and the stirring was continued at -20° to -5° C. for an hour. To the reaction mixture were added ethyl acetate and water, and the separated ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (10.1 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.05 g, 10 mmol) were mixed in 1,2-dichloroethane (35 mL) and then treated with NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under a N2 atmosphere overnight. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (3×30 mL). The organic layers were combined and dried over NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2/DMA=1/1 (DMA=CH2Cl2/MeOH/30% NH3=80/19/1) to afford 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][Li]>O1CCCC1.CCOCC>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A solution of 3-(phenyl)pyridine (1.55 g, 10 mmol) in tetrahydrofuran (10 ml) was stirred at −78° C. and treated with methyllithium (1.4 M, 7.5 mL, 10 mmol) in ether. The resulting yellow solution was stirred for 1 h, allowed to warm to 0° C., stirred 1 h, quenched with saturated ammonium chloride, and extracted with ether. The combined organic phase was washed with water and with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed (silica gel, 25% ethyl acetate/hexane) to give the title compound (0.36 g).
Reaction SMILES: O[Li].O.C([C@@H]1COC(=O)N1[C:17](=[O:35])[C@@H:18]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1.C[O:37]C1C=C(OC)C=CC=1C=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:23]([O:22][C:21]([NH:20][CH2:19][C@H:18]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:17]([OH:35])=[O:37])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=S([O-])[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
35% 11202 (0.240 mL, 2.91 mmol) was added to a solution of LiOH—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes, and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The ice bath was allowed to slowly warm, and the reaction mixture was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added. The mixture was stirred for 5 minutes, and then warmed to room temperature and stirred an additional 20 minutes. The reaction mixture was then transferred to a separatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M-BOC+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12].O>O1CCCC1>[CH3:8][N:9]([CH2:10][CH2:11][OH:12])[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: CNCCO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCO)c1ncccn1

Procedure:
A mixture of 2-chloropyrimidine (10 g) and 2-methylaminoethanol in dry tetrahydrofuran (100 ml) was boiled under reflux for 3 hours. The solution was cooled, water (200 ml) was added, the mixture extracted with dichloromethane, the organic extracts were dried (MgSO4), filtered and evaporated to dryness. The residual oil was used in Preparation 5 without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.Cl.[NH2:14][C@@H:15]1[CH2:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]1.C(N(CC)CC)C.[OH-].[Na+]>C(O)C(C)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][C@@H:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Temperature: 80 °C
Reaction time: 13 h
Yield: 74 %

Procedure:
2.07 g of N-(2-amino-4,6-dichloro-5-pyrimidinyl)formamide were heated to 80° C. in 40 ml of isobutanol (white suspension). A solution of 1.97 g of (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride, 3.8 g of triethylamine and 15 ml of isobutanol was added to the mixture. The mixture was stirred at 80° C. for a further 13 h. 10 ml of 1N NaOH were added to the clear solution at 20° C., followed by evaporation to dryness. The residue underwent flash chromatography (silica gel 60 column, length 8 cm, diameter 6.5 cm, eluent ethyl acetate/ methanol 95/5). After evaporating off the eluent and drying the residue, 2.1 g of title compound were obtained. The yield was 74%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccnc(Cl)n1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction mixture of 2-chloropyrimidine-4-carboxylic acid, 9.A (avialable from Anichem LLC, 1.00 g, 6.3 mmol), 1,3-dicyclohexylcarbodiimide (1.4 g, 6.9 mmol) and ethanol (0.32 g, 6.9 mmol) in DCM (10 ml) was stirred at room temperature overnight. The solid was filtrated off. DCM (80 ml) was added and washed with brine (30 ml) and dried over MgSO4. The solvent was evaporated. The crude product was purified by Cobi-Flash silica gel column to give 9.B. 0.74 g, yield, 63%. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=4.7 Hz), 7.95 (1H, d, J=4.7 Hz), 4.51 (2H, q, J=7.4 Hz), 1.45 (3H, t, J=7.0 Hz). MS ESI (pos.) m/e: 187.0 (M+H)+.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(O)(=O)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CO
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 184.6 %

Procedure:
(i)(a) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) was heated under reflux for 10 hours. Following cooling to 15°-20°, the solid which crystallised was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (45.5 g.), m.p. 189°-192°.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.O>CS(C)=O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]=[O:22])=[CH:16][CH:15]=1
Reactant: OCCc1ccc(F)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: O=CCc1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 672 mg of o-iodoxybenzoic acid in methyl sulfoxide (5 mL) was added 250 μL of 2-(4-fluorophenyl)ethanol and stirring was continued for 3 h. Water (20 mL) was added and the reaction mixture filtered, the filtrate was extracted with ether (3×20 mL), washed with brine (10 mL), dried over magnesium sulfate, and concentrated to give 2-(4-fluorophenyl) ethanal as an unstable oil. The material was immediately dissolved in acetonitrile (3.5 mL) at 0° C. and 264 μL of bromotrimethylsilane and 142 μL of methyl sulfoxide were added. After stirring for 1 h, water (10 mL) was added and the reaction mixture was extracted with ether (3×20 mL), washed with brine (10 mL), dried over magnesium sulfate, and concentrated to give the title compound (220 mg) as an unstable oil which was used immediately without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O
Yield: 70 %

Procedure:
Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, (20 g) and beta-alanine (9 g) dissolved in 3:2 v/v water/ethanol (500 ml) containing NaOH (10 g) to provide a solution with a pH of at least 13. The solution is refluxed for 15 minutes whereupon it turns from a light orange to an intense red colour. The solution is acidified to pH 7.0 and the ethanol is removed by rotary evaporation. The resulting aqueous solution is washed twice with ethylacetate (100 ml). This solution is then subjected to rotary evaporation until the volume is reduced to 100 ml and this reduced volume of solution is acidified to pH 3.0 to give a white precipitate, which is filtered off to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one in 70% yield, m.p. 156°-157° C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH2:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1.CCN(CC)CC>ClCCl>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:12][CH2:13][C:14]2([C:17]#[N:18])[CH2:16][CH2:15]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: N#CC1(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
TsCl (7.25 g, 38 mmol) was added in one portion to a stirred solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (3.1 h, 32 mmol) in dichloromethane (75 mL) at 0° C. Et3N (4.1 g, 40 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was diluted with dichloromethane, washed with water, 0.5 N NaOH, brine. The organic extract was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 18A (6.43 g, 81% yield) as a white solid.