Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[F:36][C:37]([F:43])([F:42])[CH2:38][CH2:39][CH2:40]Br>CN(C=O)C.O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:40][CH2:39][CH2:38][C:37]([F:43])([F:42])[F:36])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-(benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (3.7 g, 9.61 mmol) in 40 mL of anhydrous DMF at 0° C. was added potassium tert-butoxide (1.6 g, 14.4 mmol) in one portion. The reaction mixture was stirred 20 m. and 4,4,4-trifluoro-1-bromobutane (Lancaster; Windham, N.H.; 2.6 g, 13.4 mmol) was added. The reaction mixture was warmed to room temperature over 30 min. and the n diluted with 100 mL of water and 200 mL of methylene chloride. The layers were separated. The organic layer was extracted with water and dried over sodium sulfate. Purification of the crude product by silica gel column chromatography (0-3% ethyl acetate/methylene chloride) gave 1.52 g (32%) of an off white foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COCN[C:11](=[O:29])[C@@H:12]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>O1CCCC1>[C:14]([NH:13][C@@H:12]([CH:11]=[O:29])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: COCNC(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C=O)CCc1ccccc1
Temperature: -35 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A cold (−40° C.) solution of lithium aluminum hydride (25.2 mL of a 1M solution) in tetrahydrofuran (165 mL), under nitrogen, is treated with a solution of N-Boc-D-homophenylalanine methoxymethylamide (6.76 g) in tetrahydrofuran (20 mL) at such a rate as to keep the temperature between −36 to −38° C. After the addition, the temperature is allowed to rise to 7° C. after which the reaction mixture is cooled to −35° C. The mixture is quenched with 2.75 M KHSO4 solution and the mixture is stirred for 1 h while warming to 25° C. The aqueous layer is separated and extracted thrice with ether. The combined organics are washed successively thrice with 10% citric acid, water, saturated bicarbonate and brine, dried (MgSO4) and concentrated. The viscous clear residue solidifies under vacuum to give the title compound (5.32 g): 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.88 (m, 1H), 2.22 (m, 1H), 2.71 (t, J=7.6 Hz, 2H), 4.24 (m, 1H), 5.18 (bd, 1H, NH), 7.20 (m, 3H), 7.27 (m, 2H), and 9.54 (s, 1H).
Reaction SMILES: BrC1C=C2C(C(CC([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=O)=CN2)=CC=1.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41](=[O:47])[NH:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[C:35]2[CH2:48][C:49]([OH:51])=O>>[C:43]([NH:42][C:41]([C:36]1[NH:37][C:38]2[C:34]([C:35]=1[CH2:48][C:49]([NH:30][C:15]([NH2:14])=[N:16][CH2:17][C:18]1[CH:19]=[C:20]([Cl:29])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:22]([Cl:24])[CH:23]=1)=[O:51])=[CH:33][C:32]([Br:31])=[CH:40][CH:39]=2)=[O:47])([CH3:44])([CH3:46])[CH3:45]
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Reactant: CC(C)(C)NC(=O)c1[nH]c2ccc(Br)cc2c1CC(=O)O
Product: CC(=O)Nc1c(Cl)cc(CN=C(N)NC(=O)Cc2c(C(=O)NC(C)(C)C)[nH]c3ccc(Br)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetic acid (preparation I) in step 24 (A), the title compound was prepared. 1H-NMR (500 MHz, CD3OD) δ ppm 1.51 (s, 9 H) 2.20 (s, 3 H) 4.13 (s, 2 H) 4.54 (s, 2 H) 7.37 (m, 4 H) 7.84 (s, 1 H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[F:31][C:32]([F:36])([F:35])[CH2:33]I.Cl>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]([CH2:33][C:32]([F:36])([F:35])[F:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: FC(F)(F)CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 505.2 %

Procedure:
To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15 mL) was added ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL, 0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. After completion of starting material (by TLC), diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×30 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (300 mg) as liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[N:21][N:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH3:13][N:12]([CH3:14])[C:11]1[CH:15]=[CH:16][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([C:19]4[N:18]([CH3:17])[CH:22]=[N:21][N:20]=4)=[CH:29][CH:28]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: Cn1cnnc1-c1ccc(N)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CN(C)c1ccc(-c2ccnc(Nc3ccc(-c4nncn4C)cc3)n2)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-(2-chloropyrimidin-4-yl)-N,N-dimethylaniline (50 mg, 0.2 mmol) [obtained from 4-(dimethylamino)phenylboronic acid and 2,4-dicholorpyrimidine by following procedure B], 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (45 mg, 0.25 mmol), Davephos (3 mg, 0.006 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), NaO′Bu (30 mg, 0.28 mmol) and DME (1.0 mL) was placed in a sealed tube and heated to 140° C. in a microwave for 30 min. The reaction mixture was cooled, filtered through a pad of Celite, washed with ethyl acetate and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford 4-(4-(dimethylamino)phenyl)-N-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyrimidin-2-amine. 1H NMR (DMSO-d6, 400 MHz) δ 10.00 (s, 1H), 9.06 (s, 1H), 8.47 (d, 1H), 8.12-8.08 (m, 4H), 8.78 (d, 2H), 7.38 (d, 1H), 6.84 (d, 2H), 3.88 (s, 3H), 3.03 (s, 6H). MS (ESI) 372 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=3)=[CH:9][O:10][C:4]=2[C:3]=1[O:18][C@@H:19]([C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=1[Cl:29])[CH3:20].[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[S:15][C:14]([CH2:16][OH:17])=[CH:13][CH:12]=3)=[CH:9][O:10][C:4]=2[C:3]=1[O:18][C@@H:19]([C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=1[Cl:29])[CH3:20]
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3ccc(C=O)s3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccc(CO)s3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A solution of 5-{6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-3-yl}-thiophene-2-carbaldehyde (6.0 mg, 0.013 mmol), sodium borohydride (2.5 mg, 0.067 mmol) and MeOH (1 mL) was stirred at 0° C. for 1 h. The material was concentrated in vacuo and redissolved in DMF (0.5 mL) for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 4.76 (s, 2H), 6.54 (q, J=6.8 Hz, 1H), 7.01 (d, J=3.5 Hz, 1H), 7.19-7.27 (m, 2H), 7.41 (dd, J=9.0, 4.9 Hz, 1H), 7.86 (s, 1H), 8.22 (s, 1H). MS (ES+): m/z 452.90 (100) [MH+]. HPLC: tR=3.27 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH:7]=[CH2:8])[CH3:2].B1C2CCCC1CCC2.C([O-])(O)=[O:27].[Na+]>O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH2:7][CH2:8][OH:27])[CH3:2]
Reactant: C=CC(CC(=O)OCC)c1cnc(C)nc1
Reactant: O=C([O-])O
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(CCO)c1cnc(C)nc1
Reaction time: 18 h

Procedure:
To a stirred solution of 2-4 (422 mg, 1.92 mmol) in TBF was added 5.75 mL of 9-BBN (0.5 M/THF). After 18 hours, a slurry of NaBO3 (2.35 g) and NaHCO3 (2.42 g) in H2O (10 mL) was added and the mixture stirred vigorously for 1 hour. The mixture was extracted with CHCl3, washed with brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 3% EtOH/EtOAc) to give 2-5 as a clear oil.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[C:6]1([C@@H:12]([NH2:14])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH:1](=[N:14]/[C@H:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13])\[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: C[C@H](N)c1ccccc1
Solvent: ClCCl
Product: CCC/C=N/[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.7 %

Procedure:
To a suspension of 10 g 3 Å MS in CH2Cl2 (150 mL) under N2 at rt was added butyraldehyde (4.96 mL, 55 mmol) followed by (S)-(−)-1-phenylethylamine (6.45 mL, 50 mmol). The mixture was stirred at rt for 1.5 h, filtered over celite and the solvent removed under reduced pressure to give 9 g of the crude imine, which was used in the next step without further purification.
Reaction SMILES: C(OC([C:8]1([CH2:11][CH2:12][N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][C:15](OC(C)(C)C)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Li].S(=O)(=O)(O)O.C(OC(C1N(CC2C=CC=CC=2)CCC2(CC2)C=1O)=O)(C)(C)C.[OH-].[Na+].C([O-])(O)=O.[Na+].[ClH:75]>C1COCC1.CCOC(C)=O>[ClH:75].[CH2:22]([N:13]1[CH2:12][CH2:11][C:8]2([CH2:10][CH2:9]2)[C:15](=[O:16])[CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)CN(CCC1(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Agent: CC(C)(C)OC(=O)C1=C(O)C2(CCN1Cc1ccccc1)CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CN(Cc2ccccc2)CCC12CC2
Temperature: 2 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
10.8 g (24.4 mmol, 1 eq.) 1-[2-(benzyl-tert-butoxycarbonylmethyl-amino)-ethyl]-cyclopropanecarboxylic acid tert-butyl ester were dissolved in 35 ml THF. 50 ml (2.05 eq.) 1 M lithium hexamethyldisilazanide solution in THF were added dropwise over 2.5 h maintaining the temperature between 20° C. and 25° C. After 2 h at RT (IPC by HPLC), the reaction mixture (containing the lithium salt of 6-benzyl-4-hydroxy-6-aza-spiro[2.5]oct-4-enc-5-carboxylic acid tert-butyl ester) was cooled to −10° C. (ice EtOH cooling bath) and 75 ml 1 M aq. sulfuric acid solution were added (temperature increased to 2° C.). The reaction mixture was warmed to RT and the THF removed under reduced pressure at 40° C. The resulting reaction mixture was heated to 40° C. for 1 h, was stirred 15 h at RT and an additional 3 h at 40° C. to complete the reaction (IPC by GC; intermediate 6-benzyl-4-hydroxy-6-aza-spiro[2.5]oct-4-ene-5-carboxylic acid tert-butyl ester is hydrolyzed and decarboxylation follows). The reaction mixture was cooled to 0° C. and was neutralized to pH 7.4 by addition of 10 ml 2 M aq. sodium hydroxide solution and 50 ml 1M aq. NaHCO3 solution were added, setting the pH to 9.4. The crude solution was extracted with TBME and EtOAc. The organic phases were combined, dried over sodium sulfate and filtered over a plug of SiO2. The solution was concentrated under reduced pressure (45° C./20 mbar) to give 4.56 g of the crude product as free base. The crude oil was dissolved in 8 ml EtOAc, cooled to 0° C. and 5.1 ml HCl solution (4.3 M in EtOAc) were added dropwise (exotherm 2° C. to 18° C.). The reaction mixture was stirred overnight at RT (gummy crystals) and filtered. The filter cake was washed with 10 ml EtOAc and dried under reduced pressure until constant weight to give 4.54 g of the title compound as off-white crystals (74% yield).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:26][CH:25]=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:28][CH:29]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: CNC(=O)Nc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CNC(=O)Nc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 100 °C
Yield: 24.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.149 g, Example 33), N-(4-bromophenyl)-N′-methyl urea (0.225 g) 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.028 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 100° C. for 2 hours. After cooling, the solution was concentrated under reduced pressure. The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1). The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1). The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution. The HPLC fractions were concentrated under reduced pressure, the residue dissolved in ethanol, filtered and concentrated under reduced pressure to give the title compound as a solid (0.050 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([O:38][CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:4]=3)=[CH:34][C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOC(=O)c1cc(=O)c2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Yield: 28.2 %

Procedure:
A mixture of 3.47 g of 2-((3-chloromethylphenoxy)methyl)-quinoline, 3.04 g of 2-carbopropoxy-6-hydroxy-4-oxo-4H-1-benzopyran, 1.69 g of potassium carbonate and 1 ml of dimethylformamide is refluxed in 50 ml of acetone for 41 hours. The mixture is concentrated in vacuo and the residue is dissolved in water. This solution is neutralized with diluted hydrochloric acid and the resulting solid is filtered off and purified by flash silica gel chromatography in propanol-dimethylformamide to give 1.71 g of 2-carbopropoxy-6-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H1-benzopyran as a white solid having an m.p. of 109°-10° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH:11]=1)([O-])=O.C>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH:11]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1[N+](=O)[O-])cc1[nH]c3ccccc3c21
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccccc1-c1cc2[nH]c3ccccc3c2c2c1C(=O)NC2=O
Reaction time: 4 h

Procedure:
0.5 g (1.51 mmole) 1,2,3,6-tetrahydro-4-(2-nitrophenyl)-1,3-dioxopyrrolo[3,4-c]carbazole (Example 2g) in 30 ml dimethylformamide are hydrogenated at room temperature with 0.27 g palladium on active charcoal (10%). After 4 hours, the catalyst is filtered off and the solution evaporated in a vacuum. The residue is stirred up with ethyl acetate, the crystals filtered off, and recrystallized from methanol. One obtains 4-(2-aminophenyl)-1,2,3,6-tetrahydro-1,3-dioxopyrrolo[3,4-c]carbazole in the form of yellow crystals of the mp >300° C.
Reaction SMILES: [NH3:1].CO.C([O:6][C:7](=O)[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)([F:10])[F:9])C>>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]([F:10])([F:9])[C:7]([NH2:1])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: CCOC(=O)C(F)(F)c1cccc(Cl)c1
Solvent: CO
Product: NC(=O)C(F)(F)c1cccc(Cl)c1
Reaction time: 13 h
Yield: 95 %

Procedure:
To a solution of NH3 in MeOH (2 M, 50 mL, 100 mmol) was added (3-chlorophenyl)difluoroacetic acid ethyl ester (4.78 g, 20.4 mmol), as prepared in the preceding step. The homogeneous yellow solution was allowed to sit at room temperature for 13 h, and was then concentrated to provide 3.99 g (95%) of the title compound as a yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 8.41 (br, 1H), 8.09 (br, 1H), 7.68-7.60 (m, 2H), 7.59-7.52 (m, 2H).
Reaction SMILES: C[O:2]C1C=C(NC(=O)C(O)=O)C=CC=1C1OC=NC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=[O:46])[CH2:35][C:36](NC2C=CC=C(C)C=2)=[O:37])[CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=[O:46])[CH2:35][C:36]([OH:37])=[O:2])[CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1
Reactant: COc1cc(NC(=O)CC(=O)Nc2cccc(C)c2)ccc1-c1cnco1
Reactant: COc1cc(NC(=O)C(=O)O)ccc1-c1cnco1
Product: COc1cc(NC(=O)CC(=O)O)ccc1-c1cnco1

Procedure:
56A was prepared from 55 by a route analogous to that used for the preparation of 5A. LC/MS: ret. timeA=2.611 min., MS (M+H)+=277. 56B. Preparation of N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl) propanediamide
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2nonc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2nonc2c1

Procedure:
5-Bromo-2,1,3-benzoxadiazole (10 g, 50.3 mmol) was dissolved in toluene (300 mL) and treated with lithium chloride (6.39 g, 151 mmol), Pd(Ph3P)4 (2.90 g, 2.51 mmol), and allyltributylstannane (18.66 ml, 60.3 mmol). Degassed and refluxed the mixture under N2 for 3 hrs. The reaction mixture turned black. Poured the reaction mixture into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried, and evaporated to dryness. The residue was chromatographed through 120 g ISCO Redi-Sep column and eluted with 0-10% ethyl acetate/hexane to yield 5-(prop-2-en-1-yl)-2,1,3-benzoxadiazole.
Reaction SMILES: O.[CH2:2]([O:4][C:5](=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3].CC[O-].[Na+].[C:20]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CCCCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCC(Cc1ccccc1-c1ccccc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Into a 3 neck flask, equipped with water cooler, were added 43.8 mL (0.22 mol) of diethyladipate and 220 mL THF. 16.3 g (0.24 mol, 1.1 equivalents) of NaOEt were added in small portions, at 20° C., and the reaction mixture was stirred at 60° C. for 16 hours. After cooling to 20° C., 48.6 g (0.20 mol) of 2-phenyl-benzyl bromide was added dropwise. The reaction mixture was stirred at 60° C., for 16 hours, to give 2-(2-phenyl-benzyl) adipic acid diethylester as a viscous oil, in a yield of 92%.
Reaction SMILES: Cl.S(=O)(=O)(O)[OH:3].[CH2:7]([CH:9]([CH:15]([N+:17]([O-:19])=[O:18])[CH3:16])[CH2:10][CH:11]([OH:14])[C:12]#[N:13])[CH3:8]>CCOCC.O>[CH2:7]([CH:9]([CH:15]([N+:17]([O-:19])=[O:18])[CH3:16])[CH2:10][CH:11]([OH:14])[C:12]([NH2:13])=[O:3])[CH3:8]
Reactant: O=S(=O)(O)O
Reactant: CCC(CC(O)C#N)C(C)[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCC(CC(O)C(N)=O)C(C)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of conc. hydrochloric acid (2.4 ml) and conc. sulfuric acid (0.38 ml) was added to a solution of 4-ethyl-2-hydroxy-5-nitrohexanenitrile (1 g) in ether (2 ml) at 0° C. with stirring. The resulting mixture was allowed to stand at room temperature overnight, diluted with cold water, and then extracted with ethyl acetate. The extract was washed with successively with water and 5% aqueous sodium bicarbonate, dried over magnesium sulfate and then evaporated to dryness in vacuo to give 4-ethyl-2-hydroxy-5-nitrohexanamide (0.46 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:28]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(OC(=O)NCCCC(N1CCC(N2N=C(C3C=CC(OC)=C(OC)C=3)[C@@H]3[C@@H](CC=CC3)C2=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([N:41]1[CH2:42][CH2:43][CH:38]([N:29]2[N:28]=[C:27]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=3)[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30]2=[O:37])[CH2:39][CH2:40]1)=[O:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: CC(C)(C)OC(=O)NCCSCCC(=O)O
Agent: COc1ccc(C2=NN(C3CCN(C(=O)CCCNC(=O)OC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CCSCCNC(=O)OC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 12 mmol of 3-(2-tert-butoxycarbonylamino-ethylsulfanyl)-propionic acid and 10 mmol of compound 5c as described for compound 5b. M. p. 132-134° C.