Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:49]([N:51]([CH2:56][CH3:57])[C:52](=[O:55])[CH:53]=[CH2:54])[CH3:50].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:49]([N:51]([CH2:56][CH3:57])[C:52](=[O:55])/[CH:53]=[CH:54]/[C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:7]=1)[CH3:50]
Reactant: C=CC(=O)N(CC)CC
Reactant: O=C(c1ccc(Br)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)/C=C/c1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 85 °C
Yield: 55.1 %

Procedure:
To a screw cap seal tube is added 0.83 g (2.0 mmol) of the product from Example 2, 0.25 g (0.82 mmol) of tri-o-tolylphosphine, 0.30 g (2.3 mmol) of N,N-diethyl acrylamide, 0.045 g (0.21 mmol) of palladium acetate, 40 mL of acetonitrile and 4 mL of triethylamine. The solution was purged with nitrogen then capped and heated to 85° C. for 15 hours. At the end of this time, the solution was concentrated, then taken up in 100 mL of water:ethyl acetate (1:2). The organic layer was separated and the water layer extracted once with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4) and concentrated. The residue subjected to column chromatography on silica. Elution first with 60% ethyl acetate:hexane followed by ethyl acetate:hexane:isopropanol (60:35:5) yielded 0.52 g of product (55%) which was crystallized from chloroform:acetone:hexane mp 159°-163° C. (soft).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=O)(C)(C)C>>[CH:14]1([N:8]2[C:6]3[N:7]=[C:2]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]5)=[CH:37][CH:36]=4)[N:3]=[CH:4][C:5]=3[C:10]([C:11](=[O:13])[CH3:12])=[CH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CC(=O)c1cn(C2CCCC2)c2nc(Cl)ncc12
Product: CC(=O)c1cn(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cc3)ncc12

Procedure:
1-[7-cyclopentyl-2-(4-piperazin-1-yl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanone is prepared from 1-(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone and 4-(4-Aminophenyl)-piperazine-1-carboxylic acid tert-butyl ester using a method similar to that for the preparation of Example 202. [M+H+] 405.2.
Reaction SMILES: [OH:1]O.[C:3]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:3]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N+:11]=1[O-:1])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: OO
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1ccc(Cl)c[n+]1[O-]
Temperature: 0 °C
Yield: 65 %

Procedure:
Thirty-one percent aqueous hydrogen peroxide (1.0 ml) was added to a solution of N-t-butyl-5-chloro-2-pyridinecarboxamide obtained in Example 40 (0.35 g, 1.65 mmol) in trifluoroacetic acid (5 ml), and heated under reflux for 1.5 hours. The reaction mixture was added portionwise into an ice-cooled 1N aqueous NaOH and extracted three times with ethyl acetate and the extracts were dried over MgSO4. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1 to 2/1) to give the title compound (0.24 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][N:15]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:13])[CH:19]=1)=[N:1]2
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: Cc1cc(C=O)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)ccn1
Temperature: 115 °C

Procedure:
To a solution of 2-amino-4,6-difluoro-benzamide (0.71 g, 4.10 mmol) and 2-methyl-pyridine-4-carbaldehyde (0.50 g, 4.10 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (58.5 wt %, 1.00 g, 5.70 mmol) and p-TSA (0.16 g, 0.08 mmol). The reaction mixture was heated at 115° C. for 30 hours, then cooled to room temperature. The solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane) to afford 5,7-difluoro-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one as a light yellow solid. Yield: 0.30 g (26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1

Procedure:
24.5 g of 2-(4'-chlorophenylsulphonyl)-5-nitro-pyridine is dissolved in 300 ml of ethanol, and the solution, after the addition of 3 g of Raney nickel, hydrogenated at a temperature of between 20°and 35° C until the reaction ceases. Raney nickel is filtered of under nitrogen by suction. The solvent is evaporated off under vacuo to obtain 2-(4'-chlorophenylsulphonyl)-5-amino-pyridine, which is further processed in the crude state.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][C@@H:2]1[C:11](Cl)=O.[O-2].[Mg+2].S1C=CC=C1.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][NH:27][C:26]1=[O:31]>C(OCC)(=O)C.[Pd].CO.[Rh]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][C@@H:2]1[CH2:11][NH:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][NH:27][C:26]1=[O:31]
Reactant: NCCCN1CCCNC1=O
Reactant: O=C(Cl)[C@H]1CCc2ccccc2O1
Agent: [Pd]
Agent: [Rh]
Agent: [Mg+2]
Solvent: CO
Solvent: c1ccsc1
Solvent: CCOC(C)=O
Product: O=C1NCCCN1CCCNC[C@H]1CCc2ccccc2O1
Reaction time: 8 h

Procedure:
A mixture of (−)-(R)-3,4-dihydro-2H-1-benzopyran-2-carbonyl chloride (0.2 mol) and magnesium oxide (40 g) in ethyl acetate (350 ml) was hydrogenated at 25° C. with palladium on activated carbon (10%) (5 g) as a catalyst in the presence of a solution (4%) of thiophene in methanol (5 ml). After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was collected in a mixture of potassium acetate (7 g) in methanol (200 ml). A mixture of 1-(3-aminopropyl)-tetrahydro-2(1H)pyrimidinone (0.2 mol) in methanol (200 ml) was added and the mixture was hydrogenated (16 hours at 25° C.; 16 hours at 50° C.) with rhodium on activated carbon (5%, 3 g) as a catalyst in the presence of a solution (4%) of thiophene in methanol (3 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in water, treated with 50% NaOH, and extracted with DCM. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stood overnight in 2-propanone (500 ml). The supernatant was decanted off and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH NH3) 95/5). The desired fractions were collected and their solvent was evaporated, yielding (R)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl]amino]propyl]tetrahydro-2(1H)-pyrimidinone (comp. 2).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH3:11])[C:8]=1[CH2:9][OH:10].I[CH3:13]>C1COCC1.CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH3:11])[C:8]=1[CH2:9][O:10][CH3:13]
Reactant: Cn1ncc(Br)c1CO
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCc1c(Br)cnn1C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
NaH (60%, 58 mg) was added to a solution of (4-bromo-1-methyl-1H-pyrazol-5-yl)methanol (Preparation 149, 97 mg, 1.03 mmol) in THF/DMF (8/4 mL). After stirring for 15 minutes, iodomethane (439 mg, 3.09 mmol) in THF (1 mL) was added. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulphate and concentrated in vacuo to afford the title compound (142 mg, 67%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1)=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and cis-2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.080 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.315 mL, 0.315 mmol). The reaction was stirred for 6 h at 25° C., the urea byproduct was filtered off and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-2-{(5-fluoro-pyridin-2-ylmethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.085 g, 0.146 mmol, 48.7%), as a white solid. LC-MS (ESI) calcd for C24H28FN5O7S2 581.14, found 582.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:13]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=S)NC(=O)c2ccccc2)nc1
Yield: 82 %

Procedure:
A solution of ethyl 6-amino-nicotinate (830 mg, 5 mmol) and benzoyl isothiocyanate (830 mg, 5.1 mmol) in acetone was refluxed for 2 h. The mixture was concentrated to thin slurry and methanol was added. The solid was filtered, washed with methanol and dried to afford ethyl 6-(3-benzoyl-thioureido)-nicotinate (1.35 g, 82%). 1H NMR (CDCl3) δ 13.34 (s, 1H), 9.04 (m, 3H), 8.38 (s, 1H), 7.93 (m, 2H), 7.66 (m, 3H), 4.42 (q, 2H, J=7.6 Hz), 1.41 (t, 3H, J=7.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.Cl.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH2:10][NH:9][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)=[CH:12][CH:13]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2cncc(Cl)n2)cc1
Temperature: 90 °C
Yield: 32 %

Procedure:
A stirred suspension of 2,6-dichloropyrazine (500 mg, 3.36 mmol), methyl 4-(aminomethyl)benzoate.HCl (744 mg, 3.69 mmol) and i-Pr2NEt (2.05 mL, 11.75 mmol) in a mixture of anhydrous THF/DMF (10 mL/2 mL) under nitrogen was heated at 90° C. for 24 h. The mixture was allowed to cool down to room temperature, was poured into saturated aqueous NH4Cl and extracted with AcOEt. The organic layer was washed with H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 20/80→30/70) to afford the title compound 62 (300 mg, 1.08 mmol, 32% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.18 (t, J=6.0 Hz, 1H), 7.97 (s, 1H), AB system (δA=7.95, δB=7.49, JAB=8.5 Hz, 4H), 7.75 (s, 1H), 4.58 (d, J=5.9 Hz, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[NH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])=[CH:3][CH:2]=1.[OH:15]P(O)(O)=O>[O-]S([O-])(=O)=O.[Cu+2]>[C:12]([NH:14][C@H:8]([C:9]([OH:15])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:13])[NH2:11]
Reactant: O=P(O)(O)O
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: NC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
The assay of the D-hydantoinase activity was conducted by incubating a reaction mixture containing 120 mg/dl D-5-benzylhydantoin (BH), 50 mM KPB (pH 8.0) and an enzyme solution at 37° C. for 30 minutes, adding 9 volumes of 1.1 mM CuSO4, 11.1 mM H3PO4, centrifuging at 20,000 G for 10 minutes to remove the pellet, and then quantifying the resultant N-carbamylphenylalanine (N-Car-Phe) by HPLC. One unit of the enzyme activity was defined as an enzymatic activity capable of producing 1 μmol of N-carbamylphenylalanine per 1 minute under the condition described above.
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCCNC(OC(C)(C)C)=O)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:56])[CH2:31][C:32]1[C:33](=[O:55])[N:34]([CH2:53][CH3:54])[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][NH:45]C(OC(C)(C)C)=O)[CH:36]=2>>[CH3:28][O:29][C:30](=[O:56])[CH2:31][C:32]1[C:33](=[O:55])[N:34]([CH2:53][CH3:54])[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][NH2:45])[CH:36]=2
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCNC(=O)OC(C)(C)C)cc21
Agent: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCN)cc21

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester is replaced with [7-(2-tert-butoxycarbonylaminoethoxy)-1-ethyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])OC1=O.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>COCCOC>[NH2:1][C:6]1[CH:7]=[CH:8][S:9][C:5]=1[C:4]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:10]
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2sccc2N)CC1
Yield: 41.6 %

Procedure:
A solution of 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (3.1 g) and 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (3.9 g) in 1,2-dimethoxyethane (50 ml) was stirred at ambient temperature for 5 hours. The solvent was removed in vacuo and the residue purified by flash chromatography over silica eluting with ether. Appropriate fractions were combined and the solvent evaporated to give 3-amino-N-(1-tert-butoxycarbonyl-4-piperidylmethyl)thiophene-2-carboxamide as a colourless solid (2.57 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([Cl:18])[N:11]=1.CCCCCC>C(Cl)(Cl)Cl>[Cl:18][C:12]1[N:11]=[C:10]([NH:9][C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[S:8])[C:15]([O:16][CH3:17])=[CH:14][CH:13]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(Cl)nc1N
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=S)Nc1nc(Cl)ccc1OC
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Ethoxycarbonyl isothiocyanate (3.7 mL, 4.1 g, 31.5 mmol) was added slowly with stirring to a solution of 2-amino-6-chloro-3-methoxypyridine (5.0 g, 31.5 mmol) in chloroform (40 mL) and the mixture was stirred overnight. The solvent was removed by evaporation and the residue obtained was mixed with hexane. The resulting slurry was filtered and the solids collected were washed with a small amount of ether and dried to obtain 8.3 g of the title compound as a man powder melting at 184°-185° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]=[C:10]([CH2:12]O)[S:11][C:7]=2[CH:6]=1)=[O:4].P(Br)(Br)[Br:17].O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]=[C:10]([CH2:12][Br:17])[S:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc2nc(CO)sc2c1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(CBr)sc2c1
Temperature: 120 °C
Yield: 38.4 %

Procedure:
To a solution of 2-Hydroxymethyl-benzothiazole-6-carboxylic acid methyl ester (0.08 g, 0.40 mmol) in 5 ml of toluene and 1 ml of DMF was added PBr3 (0.06 ml, 0.60 mmol). The reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.044 g, 36%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)COCC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.Cl[C:58]1[N:66]=[C:65]2[C:61]([N:62]=[CH:63][N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])=[C:60]([NH:79][CH2:80][CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[N:59]=1.[N:94]1([C:101]2[CH:106]=[CH:105][CH:104]=[CH:103][N:102]=2)[CH2:99][CH2:98][CH:97]([NH2:100])[CH2:96][CH2:95]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:82]1([CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:80][NH:79][C:60]2[N:59]=[C:58]([NH:100][CH:97]3[CH2:98][CH2:99][N:94]([C:101]4[CH:106]=[CH:105][CH:104]=[CH:103][N:102]=4)[CH2:95][CH2:96]3)[N:66]=[C:65]3[C:61]=2[N:62]=[CH:63][N:64]3[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1
Reactant: NC1CCN(c2ccccn2)CC1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate Example 1 (Step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine. (MH+ 331.7)
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15]C(=O)OCC)=[S:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13](=[S:14])[NH2:15])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NC(=S)N1CCN(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=S)N1CCN(c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
Ethyl (4-phenyl-1-piperazinyl)carbothioylcarbamate (13 g, 44 mmol) was added to conc. hydrochloric acid (44 mL) and the mixture was stirred at 80° C. for 2 h. The reaction mixture was made basic with 8N aqueous sodium hydroxide solution and the crystals were collected by filtration. The crystals were washed with water and dried to give the title compound (6.1 g, yield 63%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:14]([O:28][CH3:29])=[C:15]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([OH:26])[CH:20]=2)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].Cl[C:36]1[N:41]=[CH:40][N:39]=[C:38]([C:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)=[O:43])[CH:37]=1.O>CN(C)C=O>[C:7]([C:11]1[CH:12]=[C:13]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:14]([O:28][CH3:29])=[C:15]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[O:26][C:36]2[N:41]=[CH:40][N:39]=[C:38]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]3)=[O:43])[CH:37]=2)=[O:27])[CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ncn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(NC(=O)c2ccc(C)c(Oc3cc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)ncn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
75 mg potassium-tert-butoxide are added at ambient temperature under an argon atmosphere to 225 mg N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-hydroxy-4-methyl-benzamide in 3 ml N,N-dimethylformamide. After ten minutes 210 mg tert-butyl 4-(6-chloro-pyrimidin-4-carbonyl)-piperazine-1-carboxylate are added, and the reaction mixture is stirred for six days at ambient temperature. For working up the reaction mixture is mixed with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (50:50→20:80).