Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:29]1[CH:30]=[C:31]([C:36]2[O:37][C:38]3[C:39]([N:44]=2)=[N:40][CH:41]=[CH:42][CH:43]=3)[C:32]([NH2:35])=[N:33][CH:34]=1.[CH3:45][N:46]([CH3:67])[CH2:47][CH2:48][NH:49][C:50](=[O:66])[C:51]1[CH:56]=[CH:55][C:54](B2OC(C)(C)C(C)(C)O2)=[CH:53][CH:52]=1>O1CCOCC1.O>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:54]2[CH:55]=[CH:56][C:51]([C:50]([NH:49][CH2:48][CH2:47][N:46]([CH3:45])[CH3:67])=[O:66])=[CH:52][CH:53]=2)=[CH:30][C:31]=1[C:36]1[O:37][C:38]2[C:39]([N:44]=1)=[N:40][CH:41]=[CH:42][CH:43]=2
Reactant: Nc1ncc(Br)cc1-c1nc2ncccc2o1
Reactant: CN(C)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(-c2cnc(N)c(-c3nc4ncccc4o3)c2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The following conditions were used. Tris(dibenzilideneacetone)dipalladium (47.2 mg), tricyclohexylphosphine (28.9 mg) and potassium phosphate (656 mg) were added to a degassed solution of 5-bromo-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (300 mg, 1.03 mmol), N-(2-dimethylaminoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (361 mg, 1.13 mmol) in 1,4-dioxane (2 ml) and water (0.400 ml) under nitrogen atmosphere. The suspension was stirred at 90° C. for 4 hours. The mixture was filtered and the solvent was removed. The mixture was adsorbed on silica gel, the crude product was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane follow by 10% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)-N-(2-dimethylaminoethyl)benzamide after stirring overnight in acetonitrile. NMR Spectrum: (DMSO-d6) 2.19 (s, 6H), 2.42 (t, 2H), 3.35-3.42 (m, 2H), 7.50 (dd, 1H), 7.84 (d, 2H), 7.91 (bs, 2H), 7.95 (d, 2H), 8.26 (dd, 1H), 8.45 (t, 1H), 8.56 (dd, 1H), 8.61 (d, 1H), 8.73 (d, 1H); Mass spectrum: M+H+ 403
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: O=C1C=CC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C=CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (1.41 g, 14.4 mmol) in tetrahydrofuran (24 mL) is treated with 3,4-dihydro-2H-pyran (2 mL) and pyridinium p-toluenesulfonate (500 mg, PPTS). The reaction is stirred at room temperature for 18 hours. The reaction mixture is then diluted with ethyl acetate (25 mL) and washed with 50% saturated brine (2×30 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The resulting crude brown oil is purified by filtration through a plug of silica gel (25 g, 33% ethyl acetate/hexane) to provide the title compound as a yellow oil (2.00 g, 76%); 1H NMR (CDCl3) δ 7.46 (2×dd, 1 H, J=16.3, 5.7 Hz), 6.2 (m, 1H), 4.9 (m, 1 H), 4.80 (d appt, 1 H, J=23.8, 2.9 Hz), 3.9 (m, 1 H), 3.6 (m, 1 H), 2.73 (2×dd, 1 H, J=18.4, 6.2 Hz), 2.35 (2×d, 1 H, J=18.4 Hz), 1.8 (m, 1 H), 1.6 (m, 4 H); IR (neat) νmax 2944, 2870, 2855, 1723, 1348, 1202, 1182, 1152, 1128, 1078, 1032 cm-1 ; MS (CI) m/e (% relative intensity) 183 (M+H+, 28), 85(100).
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(OC)=[O:2].[Cl-].[Mg+2].[Cl-].[CH3:22][Mg]Br.[Cl-].[NH4+]>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:2])[CH3:22]
Reactant: C[Mg]Br
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
In 7 ml of THF, was dissolved 295 mg of 2-carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane. After addition of 138 mg of anhydrous magnesium chloride, the mixture was refluxed for 10 minutes. To the mixture cooled to -70° C., was added dropwise an ether solution of 1.36 equivalents of methylmagnesium bromide. After having been stirred for 15 minutes at -70° C., the reaction mixture was admixed with saturated aqueous ammonium chloride solution and ether and brought to room temperature. The mixture was extracted with ether and the ether layer was dried. The ether layer was freed from the solvent by distillation in vacuo and the residue was purified by alumina column chromatography to obtain 199 mg (72%) of 2-acetyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ(ppm)=1.5-2.2 (4H, multiplet), 1.9 (3H, singlet), 2.4-3.3 (3H, multiplet), 3.5-3.9 (2H, multiplet), 4.1 (1H, singlet), 6.1-7.1 (5H, multiplet).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[C:39]([O:43][C:44]([N:46]1[CH2:49][CH:48]([NH2:50])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:50][CH:48]1[CH2:47][N:46]([C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH2:49]1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Yield: 98.6 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 90 mg, 0.209 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (115 μL, 1.043 mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (53.9 mg, 0.313 mmol), and BOP (166 mg, 0.376 mmol). This was stirred overnight before EtOAc was added. The solution was washed with brine, 1N HCl, and sat. NaHCO3 solution. The organic layer was dried and concentrated to give single enantiomer tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)azetidine-1-carboxylate (120.6 mg, 0.206 mmol, 99% yield): LCMS=586.4 [M+H]+. A portion of this tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)azetidine-1-carboxylate (118 mg, 0.202 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL). This was stirred for 1 h and then concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B% over 10 min, product retention time=10.5 min, 20 mL/min, 220 nM) to give single enantiomer N-(azetidin-3-yl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide-TFA (30 mg, 0.046 mmol, 22.60% yield): LCMS=486.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.25 (2 H, m), 7.65-7.78 (4 H, m), 7.54-7.65 (3 H, m), 5.18 (1 H, s), 4.71 (1 H, t, J=7.81 Hz), 4.16-4.32 (4 H, m). HPLC Peak RT=8.3 min (Analytical Method A).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[CH:5][C:6]([O:14][CH:15]([CH3:17])[CH3:16])=[C:7]2[OH:13]>C(OCC)C.O.C(O)(C)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([O:14][CH:15]([CH3:16])[CH3:17])[C:7]2=[O:13]
Reactant: CC(C)Oc1cc(O)c2c(F)cc(F)cc2c1O
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC1=CC(=O)c2c(F)cc(F)cc2C1=O
Reaction time: 0.75 h
Yield: 80.6 %

Procedure:
A solution of 0.55 g (2.1 mM) of 5,7-difluoro-1,4-dihydroxy-2-isopropoxy-naphthalene in 20 mL of diethyl ether was added over 0.05 hours to a stirred, room temperature solution of 4.05 g (25 mM) of ferric chloride in 46 mL of water and 12 mL of isopropanol. The mixture was stirred for 0.75 hours and then extracted with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and concentrated to give 0.44 g of tan solid which was recrystalized from 3 mL of warm acetic acid and a few drops of water. After cooling to room temperature, the solid was filtered off, washed with acetonitrile and then water before vacuum drying at room temperature to give 0.057 g of yellow solid. mp 172.0°-173.2°; 1H NMR (CDCl3): δ=7.68 (dd, 1H), 7.15 (m, 1H), 6.09 (s, 1H), 4.55 (m, 1H), 1.45(d, 6H).
Reaction SMILES: [Li][CH2:2][CH2:3]CC.[C:6]([O:11][CH2:12][CH3:13])(=[O:10])[CH:7]([CH3:9])[CH3:8].[CH2:14](Br)C#C>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH3:8][C:7]([CH3:14])([CH2:9][C:2]#[CH:3])[C:6]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [Li]CCCC
Reactant: C#CCBr
Reactant: CCOC(=O)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C#CCC(C)(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of n-BuLi (199 mL, 498 mmol) as 2.5M in hexane was added slowly to a stirred solution of DIPA (74.3 mL, 521 mmol) in anhydrous THF (500 mL), at −75° C. and under nitrogen. The solution was stirred for 20 minutes, and a solution of ethyl isobutyrate (64 mL, 474 mmol) in THF (100 mL) was added dropwise to the solution over 1.5 hours. The solution was warmed to 0° C. and recooled to −75° C., then a solution of propargyl bromide (53.6 mL, 498 mmol) as 80% in PhMe was added dropwise. The reaction solution was slowly warmed to 22° C. and stirred for 20 hours, then quenched with water (150 mL). The water layer was extracted with ether (2×200 mL). The combined organic layer was washed with water (150 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 eluting with 0 to 25% EtOAc in hexane, to give the title product. 1H NMR (500 MHz, CDCl3) δ 4.12 (q, J=7.1 Hz, 2H); 2.41 (s, 2H); 1.98 (s, 1H); 1.25 (s, 6H); 1.23 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: CN(C)CCO.[Li]CCCC.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CCCCCC.O>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:17]1[N:12]=[C:13]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:14]=[CH:15][CH:16]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc(N2CCOCC2)nc1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCOCC2)n1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
To a solution of 2-dimethylaminoethanol (0.46 mL, 4.56 mmol) in hexane (7.0 mL, HPLC grade) cooled at −5° C. was added drop wise n-BuLi (1.60 M, 5.70 mL, 9.12 mmol) under nitrogen atmosphere. After 30 min at 0° C., 4-pyridin-2-yl-morpholine (0.25 g, 1.52 mmol) in hexane (2.0 mL) was added drop wise. After stirring the reaction mixture for 1 h at 0-5° C., the reaction medium was cooled to −78° C. followed by drop wise addition of tributyl tin chloride (1.03 mL, 3.70 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then allowed to stir at 0-5° C. for 2 h. The reaction mixture was then allowed to come to room temperature. After the completion of reaction (TLC monitoring), the reaction mass was cooled to 0° C. and water was added slowly. The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness. The crude residue was purified over silica gel (230-400 M) using EtOAc-Hexane (2:98) to provide the compound as yellow oil (0.050 g, 7.20%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([CH2:22][NH2:23])=[N:18][CH:19]=[CH:20][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:23][CH2:22][C:17]2[C:16]([CH3:15])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, C-(3-methyl-pyridine-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave 4-[(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.89-1.93 (m, 5H), 2.30 (s, 3H), 2.68-2.71 (m, 1H), 2.73-2.87 (m, 2H), 3.90 (s, 2H), 4.02-4.04 (m, 2H), 7.06-7.10 (m, 1H), 7.41-7.44 (m, 1H), 8.38 (d, 1H, J=3.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and N′,N′-dimethylethane-1,2-diamine (7.3 mg, 0.12 mmol). The title compound was obtained as a solid (5.8 mg, 14.8% yield). MS m/z: 421.90, 423.90 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][N+]([O-])=O)=[CH:27][CH:26]=1>C(#N)C>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:31]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:36])[F:37])=[CH:26][CH:27]=2)=[CH:32]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)cc1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CC#N
Product: FC(F)(F)c1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1

Procedure:
The title compound (0.23 g) was prepared from 0.50 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 274 μL of benzylamine, and 0.55 g of 1-trifluoromethyl-4-(2-nitro-vinyl)-benzene, using acetonitrile as the solvent. MS (ESI): exact mass calculated for C21H19F3N2, 356.16; m/z found, 357.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.65-7.63 (m, 2H), 7.54-7.52 (m, 2H), 7.36-7.27 (m, 4H), 7.20-7.18 (m, 2H), 5.17 (s, 2H), 4.40 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Cl)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-chlorophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:15][CH:16]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH:17]([CH3:19])[CH3:18])(=[O:14])[CH3:13]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:15][CH:16]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH:17]([CH3:19])[CH3:18])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl acetate (306 mg, 1.12 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 40 (89 mg, 28% yield) as an oily solid after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.83-0.95 (br. m, 8H), 1.18-1.37 (m, 3H), 1.65-1.73 (br. m, 2H), 1.84-1.97 (br. m, 3H), 2.02 (s, 3H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.78-2.84 (m, 2H), 6.41 (d, J 5.2 Hz, 1H), 7.39 (t, J 6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[ClH:11].[CH2:12]([N:19]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[ClH:3].[CH2:12]([N:19]1[CH2:25][CH2:24][C:23]([Cl:11])=[C:22]([CH:9]=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Agent: Cl
Solvent: ClCCl
Product: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
77 mL phosphoroxychloride was added to 62 mL DMF at 8-18° C. 84 mL dichlormethane was added and 50 g 1-benzyl 4-azepanone hydrochloride. The reaction was stirred over night at RT. The mixture was added to 300 mL ice water and extracted with dichlormethane. The organic layer was evaporated to give 23.3 g of the desired product. (M+H)+=287
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 2 mL of dichloromethane was added methanesulfonyl chloride (0.007 mL, 0.091 mmol, 2 eq.) and triethylamine (0.02 mL, 0.137 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 12 mg (51%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81-2.18 (m, 4 H) 2.77-2.94 (m, 3 H) 3.07-3.29 (m, 2 H) 3.42 (br. s., 1 H) 3.82 (d, J=9.89 Hz, 1 H) 4.68 (br. s., 1 H) 6.13 (br. s., 1 H) 7.12-7.65 (m, 8 H) 8.48 (s, 1 H), [M+H]+ 517.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[ClH:1].[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(Nc2cc(C)nc(-c3ccccn3)n2)c(OC)c1
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 2,4-dimethoxyaniline (56 mg, 0.365 mmol) similar to Example 92 and isolated as a purple crystal (52 mg, 64%). 1H NMR (CDCl3): 8.84-8.81 (m, 1H), 8.48-8.44 (m, 1H), 7.86-7.80 (m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 1H), 6.93 (s, 1H), 6.56-6.53 (m, 2H), 6.46 (s, 1H), 3.84 (d, J=0.6 Hz, 3H), 3.83 (d, J=0.9 Hz, 3H), 2.48 (s, 3H).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].N12CCCN=C1CCCCC2>C(O)C>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CNC(N)=S
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Cn1c(S)nc(-c2ccncn2)cc1=O
Yield: 82.8 %

Procedure:
A solution of ethyl 3-oxo-3-pyrimidin-4-yl-propionate (36.10 g, 0.186 mol), N-methylthiourea (25.40 g, 0.282 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (29.11 g, 0.191 mol) in ethanol (150 ml) was refluxed for 21 hrs. After removal of a half amount of ethanol under reduced pressure, hydrochloric acid was added to the solution. The resulting precipitate was collected by filtration, washed with water and then dried. The precipitate was stirred in hot ethyl acetate (1 L), and the precipitate was collected by filtration and dried to give 2-mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (33.91 g, 83%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: O=C(c1ccc(CBr)cc1)c1cccs1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5.9 parts of sodium cyanide in 40 parts of dimethyl sulfoxide is heated to 60° C and there are added at once 11.3 parts of α-bromo-p-tolyl 2-thienyl ketone (exothermic reaction: temperature rises to 100° C). The whole is stirred for 2 hours at 60° C. After cooling, the reaction mixture is poured onto water and the product is extracted three times with 450 parts of chloroform. The combined extracts are washed twice with 200 parts of water, dried and evaporated. The dark-coloured residual tar is extracted several times with ether. The combined ether extracts are stirred with activated charcoal, filtered and evaporated. The residue is triturated in petroleumether (solid carbon dioxide) and the whole is evaporated, yielding 2-[p-(2-thenoyl)phenyl] acetonitrile as a residue.