Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH:7]=[C:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=O)[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(OC([S-])=[S:36])C.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH:7]=[C:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=[S:36])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1
Reactant: CCOC(=S)[S-]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: [K+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)C(=S)N[C@H]1C[C@@H]2c3c(Br)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
At -20° C., 6.29 g of 3-(12-bromo-6-methyl-8α-ergolinyl)-1,1-diethylurea (15 mmol) is dissolved in a mixture of 4.13 g of freshly distilled phosphorus oxychloride (45 mmol) and 50 ml of anhydrous methylene chloride, and the temperature is allowed to rise to +10° C. within 4 hours. The mixture is agitated overnight at room temperature, then for another 2 hours at 40° C., and subsequently the solvent is distilled off under vacuum. The residue is dissolved in 50 ml of anhydrous acetonitrile, cooled to -10° C., combined with 7.2 g of potassium ethylxanthate (45 mmol) and stirred for 20 hours at room temperature. The solvent is extensively distilled off, then the mixture is divided between ethyl acetate and saturated sodium carbonate solution, the organic phase is dried with sodium sulfate, and evaporated. The residue is crystallized from ethyl acetate, thus obtaining 5.03 g (77%) of 3-(12-bromo- 6-methyl-8α-ergolinyl)-1,1-diethylthiourea.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].CO[C:12]1C(OC)=C[C:15]2[NH:16][C:17](CCCNC)=N[C:14]=2[CH:13]=1>>[Cl:1][C:2]1[C:3]2[N:9]=[C:12]([CH2:13][CH2:14][CH2:15][NH:16][CH3:17])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: Nc1cccc(Cl)c1N
Product: CNCCCc1nc2c(Cl)cccc2[nH]1

Procedure:
Prepared from 3-chloro-benzene-1,2-diamine (J. Med. Chem. 1981, 24(1), 93-101) in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].O.O.[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Yield: 99 %

Procedure:
To a solution of ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (0.16 g, 0.39 mmol) in tetrahydrofuran (8 mL), and water (2 mL) was added lithium hydroxide monohydrate (0.08 g, 1.99 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 17 hours. The organic solvent was removed in vacuo and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was filtered and dried to afford the title compound in 99% yield (0.15 g): MS (ES+) m/z 385.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=3)[C@@H:27]([NH:38][C:39]3[N:44]=[CH:43][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:41][N:40]=3)[CH2:26][C@H:25]2[CH2:51][CH3:52])=O)=CC=1)([O-])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:7][O:8][C:22]([N:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:35])([F:37])[F:36])=[CH:31][CH:32]=2)[C@@H:27]([NH:38][C:39]2[N:44]=[CH:43][C:42]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[CH:41][N:40]=2)[CH2:26][C@H:25]1[CH2:51][CH3:52])=[O:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
Hydroxyacetic acid tert-butyl ester (70 mg) and sodium hydride (60%; 21 mg) were added to a solution of the compound obtained in Example 21 (1) above (200 mg) in tetrahydrofuran (3 ml) and the mixture was stirred at 50° C. for an hour. The reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→3:2) to give the titled compound (183 mg). MS (m/z): 566 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25]1([C:31](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:8][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
L-Tyrosine tert-butyl ester* was reacted at room temperature in DMF, in the presence of triethylamine, with an equimolar amount of triphenylmethylchloride. Through mixing of the DMF phase with the 4-fold amount of ice the raw product is precipitated and recrystallized from ethanol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)[N:15]=1
Reactant: O=C1Cc2cc(C(=O)CBr)ccc2N1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2ccc3c(c2)CC(=O)N3)cs1
Temperature: 25 °C

Procedure:
A solution of 5-(α-bromoacetyl)oxindole (5 g) and thiourea (1.67 g) in absolute EtOH (250 ml) is refluxed for 30 minutes. The reaction mixture is cooled to RT, filtered, and washed with absolute EtOH affording the desired product. The free base is converted to its methanesulfonate salt by the procedure previously described in Example 12, affording the desired product, M.P.=244°-246° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: COCCN
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Product: COCCNc1ccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)cc1[N+](=O)[O-]

Procedure:
This compound was prepared from the compound of Example 15 and 2-methoxyethanamine (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=512.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14][CH:15]=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[C:19]([CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14][CH:15]=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:20]
Reactant: [C-]#N
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CC#N)O2
Yield: 84.6 %

Procedure:
A solution of N-(2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl)formamide (20 g) and sodium cyanide (17 g) in dimethyl sulfoxide (100 mL) was stirred under argon gas at 100° C. for 13 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/diisopropyl ether to provide 14 g of the title compound. Yield 86%.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:8](=[C:9]([CH3:15])[C:10]=1[CH2:11][C:12]([CH3:14])=[CH2:13])[N:7]([CH:16]=[O:17])[C:6]([CH3:19])([CH3:18])[CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:26](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:26][CH2:13][C:12]1([CH3:14])[O:1][C:2]2=[C:3]([CH3:20])[C:4]3[CH2:5][C:6]([CH3:19])([CH3:18])[N:7]([CH:16]=[O:17])[C:8]=3[C:9]([CH3:15])=[C:10]2[CH2:11]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(C)c2c(c(C)c1O)CC(C)(C)N2C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)C(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-2,2,4,7-tetramethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (1.90 g, 6.95 mmol) in dichloromethane (20 ml) and methanol (10 ml) were added calcium carbonate (0.90 g, 9.0 mmol) and benzyltrimethylammonium dichloroiodate (2.66 g, 7.64 mmol), and stirred for 15 minutes at room temperature. The reaction mixture was filtered and concentrated under reduced pressure. To the residue was added a 5% aqueous solution of sodium hydrogen sulfite (15 ml), and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 2.40 g of the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH:12]1[N:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:23])[CH2:15][CH2:14][CH:13]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1[F:32].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[CH2:35]([CH:15]1[CH2:14][CH:13]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=2[F:32])[CH:12]([CH3:11])[N:17]([CH2:18][C:19]([F:22])([F:20])[F:21])[C:16]1=[O:23])[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CC1C(c2cc(F)cc(F)c2F)CCC(=O)N1CC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1CC(c2cc(F)cc(F)c2F)C(C)N(CC(F)(F)F)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled, stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.0 mL, 2.0 mmol) in THF (10 mL) at −78° C., was added a solution of (5S,6R & 5R,6S)-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one (0.50 g, 1.54 mmol) in THF (10 mL) dropwise, keeping the internal temperature of the reaction mixture below −65° C. The resulting mixture was stirred at −78° C. for 30 min, then a cold (−78° C.) solution of allyl bromide (0.242 g, 2.0 mmol) in THF (10 mL) was added dropwise, keeping the internal temperature of the reaction mixture below −65° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction was quenched by the addition of a saturated solution of sodium chloride (20 mL) and partitioned between water (50 mL) and EtOAc (200 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (50 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 40:60, to give the title compound. MS: m/z=366.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([NH:14][C:15](=[O:42])[C@@H:16]([C@@H:21]([C:31](=[O:41])[NH:32][O:33]CC2C=CC=CC=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([NH:14][C:15](=[O:42])[C@@H:16]([C@@H:21]([C:31](=[O:41])[NH:32][OH:33])[CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH:18]([CH3:19])[CH3:20])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(Cc2ccccc2)C1=O)[C@H](CC=Cc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(Cc2ccccc2)C1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 47.6 %

Procedure:
A solution of 1.1 g of N-(3-benzyl-2,5-dioxo-1-imidazolidinyl)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in 20 ml of methanol was hydrogenated in the presence of 0.100 g of 10% palladium-on-carbon for 3 hours. The mixture was filtered and evaporated and the residue was triturated with diethyl ether to give 0.444 g of N-(3-benzyl-2,5-dioxo-1-imidazolidinyl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[CH3:20])[CH:3]=1.[C:21](Cl)([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]>N1C=CC=CC=1>[C:21]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:12])([F:13])[F:14])=[C:4]([N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[CH3:20])[CH:3]=1)([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1nccn1-c1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1cc(-n2ccnc2C)c(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 14.5 g (~50.7 mmol) of 4-amino-2-(2-methyl-1H-imidazol-1-yl)-5-nitrobenzotrifluoride in 200 ml dry pyridine was added dropwise 11,3 ml (~102 mmol) ethoxalyl chloride, and stirring was continued overnight at room temperature. The reaction mixture was filtered and the filtrate was evaporated to give the title compound as a crude oil (19 g).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:22])[NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH3:28]COC(C)=O.[N+](=C[Si](C)(C)C)=[N-].C(O)(=O)C>CO>[CH3:28][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:22])[NH:14][CH2:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1OC
Temperature: 23 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
Combined ethyl 5-hydroxy-1-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (0.6 g, 1.603 mmol), EtOAc (30 mL), and MeOH (10 mL) then added (diazomethyl)trimethylsilane, 2.0 M solution in hexanes (2.60 mL, 5.21 mmol) at 23° C. over 20 minutes. The reaction mixture was stirred at 23° C. for 1 hour, quenched with acetic acid (0.206 mL, 3.61 mmol), and the mixture was stirred for 2 hours at 23° C. The reaction mixture was concentrated to give an orange-brown oil which was purified by medium pressure chromatography using an eluent of 100% EtOAc on a 25 g silica gel column (Single Step™) to give the title compound (408 mg, 65.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.27 (m, 2 H) 1.31 (t, J=7.07 Hz, 3 H) 1.62 (dd, J=12.88, 2.02 Hz, 2 H) 1.81 (ttd, J=11.13, 11.13, 7.31, 7.31, 3.79 Hz, 1 H) 3.20 (t, J=6.44 Hz, 2 H) 3.27 (td, J=11.68, 2.15 Hz, 2 H) 3.85 (dt, J=9.35, 2.27 Hz, 2 H) 4.14 (s, 3 H) 4.27 (q, J=7.07 Hz, 2 H) 7.79 (dd, J=8.34, 0.76 Hz, 1 H) 8.03 (s, 1 H) 8.38-8.43 (m, 1 H) 8.78 (t, J=5.81 Hz, 1 H) 8.98 (dd, J=2.53, 0.76 Hz, 1 H). MS m/z [M+H]+ 389.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][NH2:14].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:14][CH3:13]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2,4-Dimethoxybenzaldehyde (5.0 g) was dissolved in methanol (60 mL), and a 40% methanol solution (9.3 mL) of methylamine was added at room temperature. The mixture was stirred at room temperature for 1 hr, and sodium borohydride (1.37 g) was added by small portions under ice-cooling. The mixture was stirred at room temperature for 3 hr, treated with 1 mol/L hydrochloric acid under ice-cooling, and methanol was evaporated under reduced pressure. The residue was diluted with ethyl acetate, basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→2:1) to give the title compound as a colorless oil (yield 4.41 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]CC(F)(F)F)=[CH:15][CH:14]=3)[C:9](SCCC)=[N:8][C:7]=2[N:29]=1.[F:30][C:31]([F:35])([F:34])[CH2:32][OH:33].[H-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:32][C:31]([F:35])([F:34])[F:30])=[CH:15][CH:14]=3)[C:9]([O:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[N:8][C:7]=2[N:29]=1
Reactant: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OCC(F)(F)F)nc2n1
Temperature: 25 °C

Procedure:
7-Methoxy-2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (350 mg) and 2,2,2-trifluoroethanol (592 μl) were dissolved in tetrahydrofuran (3 ml), and sodium hydride (60% in oil, 165 mg) was added thereto at room temperature. The reaction mixture was heated under reflux for 3 days, and allowed to be cooled to room temperature, and poured into 0.5M hydrochloric acid (10 ml). The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white solid was purified by silica gel column chromatography (ethyl acetate/hexane) and then (NH, ethyl acetate/hexane) to give the white title compound (63 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:17][CH:16]([OH:18])[CH2:15][CH:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]3)[CH:5]=[CH:6][C:7]=1[F:8].CO>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(NC1=NC2(c3ccc(F)c(Br)c3)CC(O)CC2CS1)c1ccccc1
Solvent: CO
Solvent: CC#N
Product: O=C(NC1=N[C@@]2(c3ccc(F)c(Br)c3)C[C@H](O)C[C@H]2CS1)c1ccccc1
Yield: 34.9 %

Procedure:
Racemic N-((4aRS,6RS,7aSR)-7a-(3-bromo-4-fluorophenyl)-6-hydroxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.492 g, 1.09 mmol) is purified by chiral HPLC: Column: Chiralcel OJ-H 3×25 cm; eluent: 75:25 (methanol:acetonitrile); flow: 40 mL/min at UV 225 nm. The second eluting isomer is isolated to provide the enantiomerically enriched title compound (0.171 g, 35%). ES/MS m/e (79Br/81Br) 449, 451 (M+1).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[CH:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[CH:32]=[CH:31][C:24]4[N:25]=[C:26]5[N:30]([C:23]=4[CH:22]=2)[CH2:29][CH2:28][S:27]5)(Br)[C:14]3=[O:37])=[O:11])=CC=1)([O-])=O.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:27]1[C:26]2=[N:25][C:24]3[CH:31]=[CH:32][C:21](/[CH:20]=[C:15]4\[C@@H:16]5[N:13]([C:14]\4=[O:37])[C:12]([C:10]([OH:11])=[O:9])=[CH:18][S:17]5)=[CH:22][C:23]=3[N:30]2[CH2:29][CH2:28]1
Reactant: [H][H]
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CSC21
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCS5)C(=O)N12
Yield: 8.1 %

Procedure:
6-[Acetoxy-(2,3-dihydro-benzo[4,5]imidazo[2,1-b]thiazol-6-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (690 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 32 mg of product (Yield 3%) was collected. MP: >250° C.; H-NMR(D2O): □ 7.08(m, 6H), 7.36(s, 1H), 4.05(m, 2H), 3.90(b, 1H); MS: 358.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][C:12]([CH2:14]Cl)=[CH2:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:16][C:17]1[N:25]=[C:24]([NH2:26])[N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:6]([O:5][P:4]([CH2:9][O:10][CH2:11][C:12](=[CH2:13])[CH2:14][N:21]1[CH:20]=[N:19][C:18]2[C:22]1=[N:23][C:24]([NH2:26])=[N:25][C:17]=2[Cl:16])([O:3][CH2:1][CH3:2])=[O:8])[CH3:7]
Reactant: C=C(CCl)COCP(=O)(OCC)OCC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(COCP(=O)(OCC)OCC)Cn1cnc2c(Cl)nc(N)nc21
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of (2-chloromethyl-2-propenyloxymethyl)-phosphonic acid diethylester (0.285 g, 1.1 mmol), 6-chloro-2-aminopurine (0.25 g, 1.5 mmol) and potassium carbonate (0.24 g, 1.5 mmol) in anhydrous dimethylformamide is stirred 2 days at 20° C. Then the reaction mixture is concentrated in vacuo and the title product is obtained by flash chromatography on silica gel (0.22 g, 51%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([C:14]1[S:18][C:17]([S:19]([OH:22])(=O)=[O:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:7]([C:14]1[S:18][C:17]([S:19]([Cl:25])(=[O:22])=[O:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(Cc2ccccc2)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
Phosphorous pentachloride (2.08 g, 40 mmol) was added to a solution of 5-benzylthiophene-2-sulfonic acid in phosphorous oxychloride (6.0 g, 40 mmol) at 0° C. The reaction mixture was kept at 50° C. for 1 h, cooled to room temperature, then poured onto crushed ice (50 g) and extracted with ethyl acetate (2×30 ml). Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography using 3% ethyl acetate in hexane to give 2-benzylthiophene-5-sulfonyl chloride (0.6 g, 39% yield).