Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH:14]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][C@H:20]([CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:14][C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[O:19][C@H:20]([CH2:28][CH3:29])[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)[C@@H](CC)Oc1cccc(C=O)c1
Reactant: COc1ccc(OCCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(CNCCCOc2ccc(OC)cc2)c1
Temperature: 25 °C

Procedure:
3-(4-Methoxyphenoxy)propylamine (34 mg) was dissolved in methanol (3 mL), and a solution (2 mL) of n-butyl (R)-2-(3-formylphenoxy)butyrate (50 mg) in methanol was added thereto under stirring at room temperature. The mixture was further stirred at 80° C. for 12 hours. Subsequently, an aqueous solution (0.5 mL) of sodium borohydride (7 mg) was added to the solution at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and chloroform was added to the concentrated product. The formed organic layer was washed with water. The washed organic layer was dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby yield 81 mg of a pale yellow, oily substance. The entirety of the substance was employed in the following reaction without any further treatment.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:14]23)[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][CH2:23][N:17]4[CH2:16][C@@H:15]4[CH2:24][NH:25][CH2:26][C@@H:14]34)[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@@H]2C1
Reactant: Clc1ccc(Br)cc1Cl
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)cc1Cl

Procedure:
Using 3,4-dichlorobromobenzene and following the procedures described in EXAMPLE 72, (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate was converted into the title compound of EXAMPLE 73 as a tan solid. 1H NMR (300 MHz, CDCl3) δ 1.25 (br s, 1H), 1.95 (m, 2H), 2.00 (m, 1H), 2.70 (m, 4H), 2.90 (t, 1H, J=9.7 Hz), 3.10-3.50 (m, 5H), 3.54 (t, 1H, J=9.7 Hz), 5.34 (br s, 1H), 6.42 (s, 1H), 6.51 (m, 1H), 6.59 (s, 1H), 6.83 (d, 1H, J=2.6 Hz), 7.16 (d, 1H, J=8.7 Hz). LRMS (ES)+: 374 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=[O:4].F[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:20][C:19]1[CH:21]=[CH:22][C:16]([O:12][C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])[CH:11]=[CH:10][CH:9]=2)=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Nc1cccc(O)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cccc(NC(=O)C(F)(F)F)c2)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(3-hydroxyphenyl)acetamide (5.0 g, 24.4 mmol) and 4-fluoro-3-nitroaniline (3.8 g, 24.4 mmol) in N,N-dimethylformamide (100 mL) was added cesium carbonate (8.0 g, 24.5 mmol), and the mixture was stirred at 120° C. for 16 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the filtrate was diluted with ethyl acetate (250 mL), washed successively with water (250 mL) and saturated brine (250 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→70/30), and the obtained solution was concentrated under reduced pressure to give the title compound (3.03 g, 36%) as a yellow powder.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH:8](=[C:2]1[CH2:3][CH2:4][CH2:5][C:6](=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccccc1
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Reaction time: 2 h

Procedure:
(75) Cyclohexanone (10 mmol) and benzaldehyde (20 mmol) were used. The reaction stirred for 2 hours. A solid formed and was filtered. Recrystallization from ethanol yielded 2.01 g (73.4%) of bright-yellow flakes: mp 118.1-119.0° C. (lit. mp 116-117° C., Smith, et al., Can. J. Chem., 1973, 51, 1458-1470). 1H NMR (250 MHz) δ 7.83 (s, 2H), 7.50-7.32 (m, 10H), 2.95 (t, 4H), 1.80 (p, 2H); 13C NMR (62.7 MHz) 190.5, 137.1, 136.4, 136.1, 130.5, 128.8, 128.5, 28.6, 23.2 ppm.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([CH3:20])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1Br.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:12]1[C:13]([CH3:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Cc1cc(C)c(Br)c(C)c1
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(P(C(C)(C)C)C(C)(C)C)c(C)c1
Temperature: 73 °C
Yield: 90 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 20 ml of tetrahydrofuran, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride and 0.05 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) chloride were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 14.9 g (0.075 mol) of mesityl bromide and 2.2 g (0.090 mol) of metallic magnesium in 100 ml of tetrahydrofuran was dropwise added over a period of 1 hour at 50° C. After the dropwise addition was completed, stirring was conducted under reflux at 73° C. for 4 hours. After the temperature of the reaction solution was returned to room temperature, 40 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, a small amount of MeOH was added, and the whole system was cooled to −30° C. to precipitate solids. The solids were filtered off to obtain 11.9 g (purity: 97.5%) of the aimed di-tert-butyl(2,4,6-trimethylphenyl)phosphine as white solids. The yield was 88.0%. Melting point: 36-37° C.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:27])[C@H:12]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:28]([O:35][C:36](=[O:64])[C@H:37]([CH2:60][CH2:61][S:62][CH3:63])[NH:38]C(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)NC(OC(C)(C)C)=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36](=[O:64])[C@H:37]([CH2:60][CH2:61][S:62][CH3:63])[NH:38][C:11](=[O:27])[C@H:12]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](Cc1cccs1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-β-(2-thienyl)-L-alanine 2,4,5-trichlorophenyl ester is substituted for the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 5 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-β-(2-thienyl)-L-alanyl-L-methionine benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:39][C:40]([OH:42])=O)[CH:25]=[CH:26][C:27]=1[N:28](C1C=CC=CC=1C)[C:29]([NH2:31])=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:40](=[O:42])[CH2:39][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([NH:31][C:4]2[CH:3]=[CH:13][CH:12]=[CH:11][C:5]=2[CH3:6])=[O:30])=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COc1cc(CC(=O)O)ccc1N(C(N)=O)c1ccccc1C
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 180.7 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (290 mg, 1.08 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetic acid (502 mg, 1.05 mmol) in DMF (7 mL) was added Et3 N (250 μl, 1.79 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (40:1, v/v) as an eluent to give 550 mg (93%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) δ 1.11–1.18 (m, 3 H), 1.37–1.41 (m, 3 H), 2.30 (s, 3 H), 3.47–3.53 (m, 2 H), 3.61–3.75 (m, 7 H), 3.84 (s, 3 H), 4.03–4.27 (m, 2 H), 4.33–4.39 (m, 2 H), 6.34–8.07 (series of m, total 12 H).
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44]C(C)C)=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)C[CH2:7]1)=[O:5].O.[OH-].[Na+].O1CCO[CH2:58][CH2:57]1>C(OCC)(=O)C>[CH3:1][N:2]([CH3:52])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH2:44])=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:58][CH2:57][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CCC2
Temperature: 120 °C

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (110 mg, 0.156 mmol) was dissolved in 1,4-dioxane (6 mL) and transferred to a 20 ml microwave vessel. Water (2 mL) and a solution of 6M NaOH (2 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluorobenzamide (53 mg, 0.096 mmol) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.94 (m, 2 H), 2.12 (br. s., 6 H), 2.68 (br. s., 2 H), 3.24 (s, 2 H), 3.70 (t, J=5.95 Hz, 2 H), 3.84 (s, 3 H), 6.29 (d, J=1.10 Hz, 1 H), 6.83 (br. s., 1 H), 6.98 (br. s., 1 H), 7.38-7.51 (m, 2 H), 8.12 (br. s., 3 H), 8.42 (br. s., 1 H), 9.83 (br. s., 1 H), 11.37 (d, J=1.01 Hz, 1 H). (ESIMS (M+H)+=551)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)/C=C/c1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of ester 9 (4.9 g, 18.0 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (5 g, 36.0 mmol) and benzyl bromide (3.38 g, 19.8 mmol). The reaction mixture was stirred overnight at room temperature, filtered and the solvent was removed under reduced pressure. The resulting crude reaction product was suspended in water and extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered, and the volatiles were removed in vacuo to give 6.06 g of bromoaryl 10 as a white solid. Yield 93%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.94 (d, J=15.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.38-7.25 (m, 5H), 7.14 (d, J=3.0 Hz, 1H), 6.81 (dd, J1=9.0 Hz, J2=3.0 Hz, 1H), 6.29 (d, J=15.9 Hz, 1H), 5.00 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 166.2, 158.0, 142.8, 136.1, 135.1, 133.9, 128.6, 128.2, 127.4, 121.1, 118.3, 116.1, 113.6, 70.2, 60.6, 14.2; HRMS (EI) m/z: calcd for C18H17BrO3: 360.0361. found: 360.0361; mp: 72-74° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C@H:15]([CH3:24])[CH2:16][NH:17]C(=O)C(F)(F)F)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:17][CH2:16][C@H:15]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[C:3]([NH:2][CH3:1])=[O:4])[CH3:24]
Reactant: CNC(=O)c1ncnc2c([C@H](C)CNC(=O)C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1ncnc2c([C@H](C)CN)cccc12

Procedure:
As shown in step 12-iii of Scheme 12, a solution of (S)—N-methyl-8-(1-(2,2,2-trifluoroacetamido)propan-2-yl)quinazoline-4-carboxamide (200 mg, 0.588 mmol), K2CO3 (406 mg, 2.94 mmol) in MeOH (10 mL) and water (0.5 mL) was heated at 60° C. for 1 hour. The reaction mixture concentrated under reduced pressure and dried under high vacuum to provide (S)-8-(1-aminopropan-2-yl)-N-methylquinazoline-4-carboxamide (compound 2054). LC-MS: 245.09 (M+), which was used in the following reaction as is.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[SH:21].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[S:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Sc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Yield: 300.3 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (10.0 g, 54.77 mmol) in THF (300 mL) was added 2,5-dichlorobenzenethiol (19.6 g, 12.108 mmol) and K2CO3 (37.8 g, 273.85 mmol). The reaction mixture was refluxed for 48 hrs. The solid was filtered and washed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated NaHCO3, H2O, and saturated NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The resulting solid was then triturated with DCM and hexanes, and filtered to yield compound 27 as a yellow solid (11.823 g, 91.0% HPLC purity, 66.4% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.82 (d, J=2 Hz, 1H), 8.00 (m, 3H), 7.80 (d, J=9 Hz, 1H), 7.75 (dd, J1=3 Hz, J2=9 Hz, 1H), 6.97 (d, J=9 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:6]2[O:5][C:4]([NH:7][CH:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])=[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]2=[O:1])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NC(C)c2ccccc2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NC(C)c2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 33 %

Procedure:
To a solution of ethyl 4-oxo-2-[(1-phenylethyl)amino]-4,5-dihydrofuran-3-carboxylate (0.40 g, 1.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.21 g, 1.5 mmol) in ethanol (20 mL), L-proline (0.017 g, 0.15 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.20 g, y. 34%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11]([CH3:21])([CH3:20])[O:10][C:9]2=[O:22])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40]>C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:12]2[C:11]([CH3:20])([CH3:21])[O:10][C:9](=[O:22])[N:8]2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)N(C2CCC(N)CC2)[C@H]1c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccncc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a vial charged with (S)-3-(4-aminocyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.320 g, 1.044 mmol) were added ACN (3.48 mL), DIEA (0.365 mL, 2.089 mmol) and 4-chloro-3-nitropyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.166 g, 1.044 mmol) respectively. The vial was sealed and heated at 80° C. for 2 hours leading to ˜90% conversion to the desired product with starting amine present. Additional chloropyridine (0.2 eq) and DIEA (0.2 eq) were added, and the mixture was heated at 80° C. for an additional 15 hours. The dark mixture was dried under reduced pressure and purified with a 25 g HP spherical silica column ramping DCM:MeOH (90:10) in DCM from 0-50%, then isocratic at 50% (detection at 215 nm) leading to isolation of (S)-4-(4-fluorophenyl)-5,5-dimethyl-3-(4-((3-nitropyridin-4-yl)amino)cyclohexyl)oxazolidin-2-one (0.286 g, 0.668 mmol, 63.9% yield) as an orange/brown oil and as a mixture of cis/trans isomers. m/z (ESI) 429.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 56 %

Procedure:
Upon boiling a solution of 7.6 g 2-nitrobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 142°C (ethanol) is obtained. Yield: 56% of theory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[CH:11]([CH3:13])[CH3:12].ClC1C=C(C=CC=1)C(OO)=[O:38]>ClCCl.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][S:5]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[CH:11]([CH3:13])[CH3:12])=[O:38]
Reactant: COC(=O)CSCCCCN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CS(=O)CCCCN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C(C)C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 600 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}acetic acid methyl ester obtained in Example 36 in 10 ml of dichloromethane was ice-cooled and 329 mg of 70% m-chloroperoxybenzoic acid was added. After stirring under ice cooling for 2 hours, the reaction solution was diluted with an aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 385 mg of the desired compound as a yellowish crystal having a melting point of 128 to 130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([CH2:20][CH2:21][NH2:22])([NH:12]C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:23].C(OCC)C>C(O)(C)C>[ClH:23].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([NH2:12])([CH2:20][CH2:21][NH2:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(CCN)(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)N1CCC(N)(CCN)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.01 g (9.56 mmol) of 4-(2-amino-ethyl)-4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid ethyl ester in 19 ml of isopropanol was added 8 ml of a solution of hydrochloric acid (5.6 N) in isopropanol and the resulting solution was stirred at room temperature for 3 h. The mixture was cooled and diethyl ether was added. The resulting precipitate was filtered. The product was dried to give 2.49 g of pure compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]2[O:12]C(OCC)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:13]=1[OH:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc2c1OC(OCC)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCOc1cccc(O)c1O

Procedure:
A solution of 38 (3.3 g, 15 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.9 mmol) in aqueous MeOH (21 mL, MeOH: H2O 20:1) was stirred at rt for 16 h, then neutralised by the addition of saturated NaHCO3 aq. and the methanol was removed in vacuo. The residue was extracted with t-BuOMe (3×) and the organic phase was dried (Na2SO4) and evaporated to dryness to give 39 compound (2.4 g, 95%) which was used as such in the next step: