Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][NH:10][C:11](=[O:12])[CH:5]2[CH2:4][NH:3][CH2:2]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=4[CH2:9][NH:10][C:11](=[O:12])[CH:5]3[CH2:4]2)=[CH:20][CH:19]=1
Reactant: O=C1NCc2ccccc2N2CCNCC12
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1NCc2ccccc2N2CCN(Cc3ccc(F)cc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3,4,4a,6,7-Hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one (680.0 mg, 3.13 mmol, Example 2A) was dissolve in methanol (15 mL). 4-Fluorobenzaldehyde (653.5 mg, 5.27 mmol) was added to the reaction and stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (565.3 mg, 9.00 mmol) was then added, and the reaction was stirred at ambient temperature for 17 hours. The reaction was then diluted with 1 MNaOH (50 mL) and extract with dichloromethane (3×50 mL). The organic layers were combined, and purified by silica gel chromatography (ethyl acetate, Rf 0.40) to give the title compound: 1H NMR (400 MHz, benzene-d6) δ ppm 1.93 (td, J=11.0, 2.8 Hz, 1H), 2.42 (t, J=10.6 Hz, 1H), 2.49-2.51 (m, 1H), 2.60 (dt, J=11.0, 2.6 Hz, 1H), 2.85 (td, J=11.2, 2.9 Hz, 1H), 3.02-3.10 (m, 2H), 3.30 (d, J=13.2 Hz, 1H), 3.50 (dt, J=10.7, 2.3 Hz, 1H), 3.75 (dd, J=10.4, 2.8 Hz, 1H), 4.51 (dd, J=13.6, 4.0 Hz, 1H), 6.72-6.73 (d, J=8.1 Hz, 1H), 6.75 (dd, J=7.3, 1.5 Hz, 1H), 6.81-6.84 (m, 3H), 7.02-7.09 (m, 3H); MS (DCI/NH3) m/z 326 (M+H)+.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[O:12])=[CH:6][CH:5]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][CH:33]=2)=O)=O)=[CH:24][CH:23]=1.O>C(O)C.ClCCl>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:12])[C:13]([C:14]3[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=3)=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=3)[C:30]=2[C:32]2[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][CH:37]=2)=[CH:6][CH:5]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: O=C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=C1C(c2ccc(Br)cc2)=C(c2ccc(Br)cc2)C(c2ccc(Br)cc2)=C1c1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A solution of potassium hydroxide (230 mg, 4.1 mmol) in ethanol (5 cm3) was added to a solution of (13) (3.01 g, 8.2 mmol) and 4,4′-dibromobenzil (3.01 g, 8.2 mmol) in ethanol (45 cm3) at 70° C., and the reaction was stirred at 70° C. for 4 hours. Water (200 cm3) and dichloromethane (200 cm3) were added, and the layers were separated. The organic layer was washed with brine (200 cm3) and dried over magnesium sulfate. The solvent was removed to leave a dark purple solid. The crude product was passed through a plug of silica, and then recrystallised from a dichloromethane/ethanol mixture to give (14) as a dark purple crystalline solid (3.87 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][N:10]([CH3:20])[CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([OH:19])[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:13]=2[CH2:12][CH2:11][N:10]([CH3:20])[CH2:9]1
Reactant: CN1CCc2ccc(O)cc2C(c2ccccc2F)C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CN1CCc2cc([N+](=O)[O-])c(O)cc2C(c2ccccc2F)C1
Temperature: 0 °C

Procedure:
5.0 g 5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 90 ml of a mixture of acetic acid and cooled in ice-water bath 0° C. Under stirring was added 1,7 ml fuming nitric acid and the mixture was stirred in the cold for 1 h. The reaction mixture was neutralized (pH 7.9) and the precipitate was extracted with ethyl acetate, dried and evaporated. After column chromatography (kieselgel/CH2Cl2 : CH3OH 95: 5) was isolated yellow crystals. M.p. 90°-94° C. (dec). NMR: C5H 4.61d; C6H g 41% 6 s and C9H 7.88 s ppm. respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Br[C:11]1[C:12](N)=[N:13][CH:14]=[C:15]([Br:17])[N:16]=1.C[N:20](C=O)C>>[Br:17][C:15]1[N:16]=[C:11]([NH2:20])[C:12]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:13][CH:14]=1
Reactant: Oc1cccnc1
Reactant: CN(C)C=O
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(Br)cnc1Oc1cccnc1
Temperature: 170 °C

Procedure:
A solution of pyridin-3-ol (0.045 g, 0.47 mmol), sodium hydride (12 m g, 0.47 mmol) in DMF (2 ml) is stirred at room temperature for 20 minutes. 3,5-Dibromo-pyrazin-2-ylamine (0.1 g, 0.39 mmol) is added and the reaction is heated at 170° C. for 15 minutes in a microwave. The solvent is concentrated in vacuo and the residue is purified using flash chromatography (SiO2, DCM/MeOH) to afford 6-bromo-3-(pyridin-3-yloxy)-pyrazin-2-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 8.47 (1H, dd), 7.78 (1H, s), 7.75 (1H, dt), 7.51 (1H, dd), 6.89 (2H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>C(Cl)Cl>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
3-Nitrobenzoyl chloride (2 g, 10.77 mmol) was loaded into a round bottomed flask, placed under a N2 atmosphere and dissolved in anhydrous DCM (10 mL). The mixture was cooled to 0° C. and N,N-dimethylethylenediamine (0.98 mL, 8.98 mmol) was added to the reaction. The reaction was allowed to warm to RT and left to stir for 18 h. After 18 h the reaction had given a precipitate which was isolated by filtration and washed with DCM to give 2.28 g of a white solid, which was partitioned between DCM and a saturated aqueous NaHCO3 solution. The organic layer was removed under reduced pressure and the aqueous layer was then re-extracted DCM. The organic layers were combined, dried over Na2SO4 and the solvent was removed under reduced pressure to afford the title compound as a yellow solid.
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.[C:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:13]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:21]=[CH:20][C:16]([C:17]([O:22][CH:26]2[CH2:2][CH:3]3[CH2:4][CH:25]2[CH:24]=[CH:23]3)=[O:18])=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccncc1
Product: O=C(OC1CC2C=CC1C2)c1ccc(-c2ccccc2)cc1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
28 g (253.9 m mol) of norbornene alcohol (with an endo form/exo form molar ratio of 8/1) was measured into a 500 mL flask equipped with a dropping funnel, and the air inside the system was replaced with nitrogen. 41 mL (507.8 m mol) of pyridine was then added dropwise and stirred well until dissolved. Subsequently, with the temperature of the reaction system maintained at 4±2° C. by cooling in an ice bath, a solution of 50 g (230.8 m mol) of 4-phenylbenzoyl chloride dissolved in 200 mL of dry THF (tetrahydrofuran) was gradually dropped into the reaction solution with constant stirring, and following completion of the addition, stirring was continued for 1 hour with the reaction vessel still in the ice bath, and then for 1 hour at room temperature, and then for a further 30 minutes under reflux. Following cooling of the reaction mixture to room temperature, the generated pyridine salt was removed by filtration through filter paper, and the reaction mixture was well washed with distilled water. The solvent was then removed by heating under reduced pressure, and the product crystals were repeatedly recrystallized from n-hexane to yield 63 g of white crystals of 5-(4-biphenylcarbonyloxy)bicyclo[2.2.1]hept-2-ene (monomer). Analysis of the product crystals by HPLC revealed a purity of 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:5]([C:6]([C:8]2[C:16]3[C:11](=[C:12]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[C:4]([Cl:26])[CH:3]=1.N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5]([C:6]([C:8]2[C:16]3[C:11](=[C:12]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[C:23]([Cl:25])[CH:24]=1)(=[O:35])[CH3:34]
Reactant: Nc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a solution of N-[3-(4-amino-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (0.2 g, 0.5 mmol) in dichloromethane (10 mL), pyridine (0.081 g, 1 mmol) was added followed by addition of acetyl chloride (0.044 g, 0.56 mmol) at 0° C. After stirring at 0° C. for about 0.5 hour, the reaction was kept at room temperature for about 2 hours. Dichloromethane was evaporated; water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel (100-200 mesh) column chromatography. Elution with 2.5% methanol in dichloromethane afforded N-{3-[4-(acetylamino)-2,6-dichlorobenzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (0.06 g, 27%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CCOCC>[CH3:30][S:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CSC(CCCCO)CCCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CSC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.094 g (0.29 mmol) ethyl 8-hydroxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate in 1.5 mL methylene chloride is cooled to 0° and then 0.1 mL of triethylamine is added followed by 0.027 mL methanesulfonyl chloride. The reaction is stirred at 0° C. for 1 hour and diluted with ether. The ether layer is washed with saturated sodium bicarbonate, water, brine, then dried, filtered and evaporated to yield ethyl 8-methanesulfonyloxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; NMR (CDCl3): delta 3.2 (s,2H), 3.1 (s,3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.C([O-])(=O)C.[Na+].[Br:35]Br.ClCCl>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[C:5]([Br:35])=[C:4]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:3]=1
Reactant: BrBr
Reactant: N#Cc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(Oc2ccc(Nc3nc(N)nc(-c4ccccc4)c3Br)cc2)ccn1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 4-[4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-phenoxy]-pyridine-2-carbonitrile (Example 8, 200 mg, 0.53 mmol) and sodium acetate (146.6 mg, 459.8 mmol) in acetic acid (4 mL) at rt was added bromine (84 mg, 0.53 mmol). The reaction was allowed to stand for 2 h after which time dichloromethane (20 mL) was added followed by water (20 mL). The phases were separated and the organic layer was washed with a saturated aqueous bicarbonate solution. The combined organic extracts were dried over MgSO4 and then evaporated under vacuum. The crude material was purified by column chromatography eluting with a gradient of 0 to 60% AcOEt/Hexanes to give 4-[4-(2-Amino-5-bromo-6-phenyl-pyrimidin-4-ylamino)-phenoxy]-pyridine-2-carbonitrile as an orange solid (200 mg, 83%). 1H NMR (DMSO d6) δ 8.58 (d, J=5 Hz, 1H, 8.50 (Br, 1H), 7.90-7.86 (m, 2H), 7.67 (d, J=2 Hz, 1H), 7.54-7.51 (m, 2H), 7.47-7.41 (m, 3H), 7.20-7.16 (m, 3H), 6.57 (Br, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[OH2:10].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Yield: 197.2 %

Procedure:
A solution of 2-chlorophenylacetic acid (10.0 g, 58.6 mmol) in concentrated sulfuric acid (40 mL) was cooled to −10° C. and slowly reacted with a solution of fuming nitric acid (2.80 mL, 66.7 mmol) in concentrated sulfuric acid (7.2 mL). After 2.5 hours the reaction was slowly poured over ice water (400 mL), filtered over a coarse filter frit, washed once with cold water, and dried on the frit overnight giving the title compound (13.5 g, 98%) as a white solid. Integration of the proton NMR spectrum showed the product contained about 0.2 equivalents of 2-chlorophenylacetic acid, but thin-layer chromatography showed this to be inseparable from the product. 1H NMR (300 MHz, CDCl3/CD3OD) δ 8.25 (d, 1H, J=2.7 Hz), 8.13 (dd, 1H, J=8.7 Hz, 2.7 Hz), 7.61 (d, 1H, J=8.8 Hz), 3.89 (s, 2H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].[O:23]=[C:24]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:28]2[CH2:40][CH2:41][C:42](=[O:43])[C:27]=2[C@@H:26]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[NH:25]1.[O:52]=[S:53]1(=[O:60])[CH2:58][CH2:57][CH:56]([NH2:59])[CH2:55][CH2:54]1>CN(C)C1C=CN=CC=1.C(#N)C>[C:48]([C:47]1[CH:46]=[CH:45][C:44]([C@H:26]2[N:25]([C:11]([NH:59][CH:56]3[CH2:57][CH2:58][S:53](=[O:60])(=[O:52])[CH2:54][CH2:55]3)=[O:12])[C:24](=[O:23])[N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[C:28]3[CH2:40][CH2:41][C:42](=[O:43])[C:27]2=3)=[CH:51][CH:50]=1)#[N:49]
Reactant: N#Cc1ccc([C@H]2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCS(=O)(=O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc([C@@H]2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)(=O)CC2)cc1
Temperature: 25 °C

Procedure:
N,N-Diisopropylethylamine (137 μL, 0.81 mmol), 4-dimethylaminopyridine (27 mg, 0.22 mmol) and 4-nitrophenyl chloroformate (45 mg, 0.22 mmol) is added to a solution of (R)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 1A, 80 mg, 0.20 mmol) in acetonitrile (2.0 mL), and the mixture is stirred at room temperature over night. 1,1-Dioxotetrahydro-2H-thiopyran-4-amine (74 mg, 0.40 mmol) is added, and the mixture is stirred for 1 h and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 72 mg; ESI mass spectrum [M+H]+=573; Retention time HPLC: 1.01 min (Z018_S04).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][CH:8]=[C:9]2[C:14](=[O:15])OC(C)(C)OC2=O)=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][O:24][CH3:25])#[N:2].C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[C:1]([C:3]1[CH:20]=[C:19]2[C:6](=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][O:24][CH3:25])[NH:7][CH:8]=[CH:9][C:14]2=[O:15])#[N:2]
Reactant: COCCOc1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1C#N
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: COCCOc1cc2[nH]ccc(=O)c2cc1C#N
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
5-((4-Cyano-3-(2-methoxyethoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (840 mg, 2.4 mmol) was added in portions to a mixture of biphenyl (8 ml) and phenyl ether (22 ml) at 250° C. and the mixture stirred at that temperature for 30 minutes. The mixture was allowed to cool, hexane was added and the solid product collected by filtration and recrystallised from methylene chloride/methanol/hexane to give 6-cyano-7-(2-methoxyethoxy)-1,4-dihydroquinolin-4-one (230 mg, 38%).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O)N.[CH3:12][C:13]1[CH:14]=[C:15]([N:22]=[C:23]=[S:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20].OCCN.Cl.Cl[CH2:31][C:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[OH:20][CH2:7][C:8]1([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:6]1.[CH3:12][C:13]1[CH:14]=[C:15]([N:22]=[C:23]2[S:24][CH2:31][C:32]3([CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:37]2)[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: NC1(CCl)CCCC1
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: Cc1cc(N=C=S)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: NCCO
Product: Cc1cc(N=C2NC3(CCCC3)CS2)ccc1[N+](=O)[O-]
Product: NC1(CO)CCCC1

Procedure:
3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(3-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4]nonane.
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH:23]([C:25]([OH:27])=O)[O:22][C:21]3=[O:28])=[CH:16][CH:15]=2)[NH:10]1.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[O:8]=[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:24][CH:23]([C:25]([N:29]4[CH2:34][CH2:33][CH:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[O:27])[O:22][C:21]3=[O:28])=[CH:18][CH:19]=2)[NH:10]1
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Reactant: O=C(O)C1CN(c2ccc(-c3noc(=O)[nH]3)cc2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C1CCN(C(=O)C2CN(c3ccc(-c4noc(=O)[nH]4)cc3)C(=O)O2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.03 g of N-methylmorpholine are added to a solution of 2.91 g of 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid [obtainable according to Example 3], 2.77 g of tert-butyl piperidine-4-carboxylate, 2.02 g of 1-hydroxybenzotriazole and 2.86 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 20 ml of DMF, and the mixture is stirred at room temperature for 5 h. 200 ml of water are subsequently added dropwise with intensive stirring, the crystalline precipitate formed is separated off and taken up in 90 ml of dichloromethane, and the mixture is dried over Na2SO4. The solution is concentrated in vacuo, and the resulting oil is triturated with diethyl ether to give tert-butyl 1-{3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonyl}piperidine-4carboxylate, m.p. 171°-175°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].[ClH:10].[CH3:11][N:12]([CH2:14][CH2:15][Cl:16])[CH3:13].C(O)C>CC(C)=O>[ClH:16].[Cl-:10].[CH3:11][N:12]([CH3:13])[CH2:14][CH2:15][N+:3]1[C:2]([CH3:1])=[C:6]([CH2:7][CH2:8][OH:9])[S:5][CH:4]=1
Reactant: Cc1ncsc1CCO
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1c(CCO)sc[n+]1CCN(C)C
Product: [Cl-]

Procedure:
To a mixture of 4-methyl-5-thiazole ethanol (16.0 g) and dimethylaminoethyl chloride hydrochloride (14.4 g) was added ethanol (10 ml. The mixture was heated under reflux for about 20 hours. Ethanol (10 ml) and acetone (100 ml) were added, and the mixture was stirred to give pale yellow powdery crystals, which were collected by filtration, washed with acetone containing a small amount of ethanol and dried under reduced pressure.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Si]([O:39][S:40]([C:43](F)(F)F)(=O)=[O:41])(C)(C)C.O=O>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[O:25][S:40]([CH3:43])(=[O:41])=[O:39])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CCN(CC)CC
Product: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirring mixture of 4 (3.58 g, 8.72 mmol) and Et3N (6.1 ml, 43.6 mmol) was added Me3SiOSO2 CF3 (2.56 mL, 13.0 mmol) at 0° C. under positive pressure of dry Ar. The mixture was stirred for 30 min at the same temperature, and then partitioned between CH2Cl2 and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in DMSO (12 mL). To this solution was added Pd(OAc)2 (98 mg, 0.44 mmol), and the mixture was stirred for 36 h under positive pressure of O2. The mixture was partitioned between EtOAc and brine. The organic layer was dried (Na2SO4), evaporated, and chromatographed on a silica gel column (hexane/EtOAc=5/1) to give 5 (3.13 g, 88%) as a white solid.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:3][NH:4][C@H:5]([CH3:16])[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.C(N(CC)CC)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH3:4].[CH2:33]([NH:40][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([CH2:6][C@H:5]([NH:4][CH2:3][C@H:2]([OH:1])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)[CH3:16])[CH:8]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C[C@H](Cc1cccc(C(=O)O)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Cc1cccc(C(=O)NCc2ccccc2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.4 %

Procedure:
To a solution of 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) (116 mg, 0.22 mmol) in DMF (2 ml) was added triethylamine (62 μl, 0.45 mmol), benzylamine (29 μl, 0.27 mmol), HOBt (33 mg, 0.25 mmol) and WSCDl (47 mg, 0.25 mmol) and the resulting solution stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate solution (5 ml) and dichloromethane/methanol (95/5) (10 ml). The aqueous layer was separated and extracted with further dichloromethane/methanol (95/5) (4×10 ml). The combined organic layers were dried (sodium sulfate), filtered and evaporated in vacuo. The resulting oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90:10:1, by volume) to give the title compound as a white foam (70 mg). 1H NMR (400 MHz, CD3OD): δ=7.70-7.68 (1H, d), 7.66 (1H, s), 7.38-7.29 (6H, m), 7.26-7.21 (1H, m), 7.21 (1H, s), 7.03-7.01 (1H, d), 6.69-6.67 (1H, d), 4.64-4.61 (1H, m), 4.61 (2H, s), 4.58 (2H, s), 3.05-2.98 (1H, m), 2.92-2.86 (1H, dd), 2.84-2.79 (1H, dd), 2.75-2.71 (1H, dd), 2.68-2.63 (1H, dd), 1.10-1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 435, [M+Na]+ 457, [M−H]− 433. CHN analysis: found C, 69.79; H, 6.96; N, 6.37; C26H30N2O4+0.7H2O requires C, 69.84; H, 7.08; N, 6.26.