Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][C:40]1[N:41]([C:46]2[N:47]=[C:48]([CH2:53][CH2:54][CH3:55])[NH:49][C:50]=2[CH:51]=[O:52])[C:42]([CH3:45])=[CH:43][CH:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:39][C:40]1[N:41]([C:46]2[N:47]=[C:48]([CH2:53][CH2:54][CH3:55])[N:49]([CH2:25][C:22]3[CH:21]=[CH:20][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4[N:8]([C:7]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:9]=[N:10][N:11]=4)=[CH:24][CH:23]=3)[C:50]=2[CH:51]=[O:52])[C:42]([CH3:45])=[CH:43][CH:44]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(C=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(-n2c(C)ccc2C)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(triphenylmethyl)-5-[4'-(bromomethyl)-biphenyl-2-yl]tetrazole (Example 12, 9.66 g, 17.34 mmol), 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1H-imidazole-5-carboxaldehyde (Example 49, 4.0 g, 17.4 mmol), and cesium carbonate (13 g, 40 mmol) in DMF (30 mL) was stirred under an atmosphere of dry nitrogen at room temperature overnight. The reaction mixture was poured over water (750 mL) and the resulting precipitate was collected by filtration. The solid was taken up in ethyl acetate and extracted with water, adjusting the pH of the aqueous layer to pH 8-9 by the addition of sodium bicarbonate. The organic layer was dried over MgSO4 and evaporated to give the crude product as a mixture of regioisomers which were separated by flash chromatography (silica; 3:1 hexane/EtOAc).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:12]2[CH:22]=[C:23]([OH:28])[C:24]([OH:27])=[C:25]([Cl:26])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl-].O.CN([CH:36]=[O:37])C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[C:12]2[CH:22]=[C:23]([OH:28])[C:24]([O:27][CH2:10][C:11]3[CH:25]=[CH:24][C:23]([O:37][CH3:36])=[CH:22][CH:12]=3)=[C:25]([Cl:26])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(O)c(O)c2Cl)C(c2ccc(O)cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COc2c(O)cc3c(c2Cl)CCN(C(=O)OC(C)(C)C)CC3c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
10.0 g of 3-t-butyloxycarbonyl-6-chloro-7, 8-dihydroxy-1-(4'-hydroxyphenyl) 2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 100 ml of DMF. To this was added 1.25 g of a 50% sodium hydride mineral oil dispersion under an argon atmosphere. The reaction was stirred at ambient temperature for 15 minutes and 3.59 g of 4-methozybenyl chloride was added. The reaction was stirred for 16 hours at ambient temperature then poured into a large volume of water. The mixture was then extracted with ethyl acetate. The extracts were washed with water dried over magnesium sulfate and concentrated to yield an oil. The crude product was dissolved in 100 ml. of acetonitrile and the solution washed with several portions of petroleum ether. The acetonitrile solution was concentrated and seeded with crystals of the product. The solution was allowed to stand in a freezer overnight with a resultant of white solid. Additional solid was obtained after concentration of the mother liquor. The solid (5.57 g) was heated for 10 minutes in 100 ml of dichloromethane on a steam bath. The suspension was filtered and the solid washed with warm dichloromethane to yield 3-t-butyloxycarbonyl-6-chloro-8-hydroxy-7-(4-methoxybenzyloxy)-1-(4 -hydroxyphenyl)-2,3,4,5 tetrahydro-1-H-3-benzazepine, M.P. 190°-192° C.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]2[N:38]=[C:37]([CH2:39][OH:40])[NH:36][C:35]=2[CH:41]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[OH:40][CH2:39][C:37]1[NH:36][C:35]2[CH:41]=[C:31]([NH:30][C:18]3[N:17]=[CH:16][C:15]4=[CH:14][CH:13]=[C:12]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]4[N:19]=3)[CH:32]=[CH:33][C:34]=2[N:38]=1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc4nc(CO)[nH]c4c3)nn12)S(C)(=O)=O

Procedure:
N-{2-[2-(2-Hydroxymethyl-3H-benzoimidazol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide was prepared from trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1061. Product isolated as a yellow solid (32 mg, 31%). m.p.=250-256° C.; LCMS (m/e) 464 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.5-12.01 (m, 1H), 9.28-9.21 (m, 1H), 8.98-8.92 (m, 1H), 8.12-8.00 (m, 1H), 7.94-7.89 (m, 0.5H), 7.68-7.60 (m, 2H), 7.60-7.31 (m, 3H), 7.27-7.21 (m, 0.5H), 7.01-6.95 (m, 1H), 6.95-6.89 (m, 1H), 5.65-5.54 (m, 1H), 4.67-4.60 (m, 2H), 3.09-3.03 (m, 3H), 2.92-2.86 (m, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[SH:30][CH2:31][C:32]([NH:34][CH3:35])=[O:33]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([S:30][CH2:31][C:32]([NH:34][CH3:35])=[O:33])=[N:3][C:4]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: CNC(=O)CS
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: CNC(=O)CSc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.4 g) and 2-mercapto-N-methylacetamide (0.1 g). The intermediate product containing the SEM (2-[trimethylsilyl]ethoxymethyl) group was purified by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.05 g.
Reaction SMILES: [N:1]1[C:9]2[C@H:8]([NH:10]C(=O)C)[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>C(Cl)(Cl)Cl>[N:1]1[C:9]2[C@@H:8]([NH2:10])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N[C@@H]1CCc2cccnc21
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N[C@H]1CCc2cccnc21
Reaction time: 2 h
Yield: 42 %

Procedure:
Following the general procedure, 6,7-dihydro-5H-[1]pyrindin-7-ylamine (271 mg, 2.02 mmol), CALB (81 mg) and EtOAc (6.5 mL) were stirred for 7 hours. The conversion determined from 1H NMR by integration of the peaks at 5.17 ppm (CHNHAc) and 4.21 ppm (CHNH2) was 55%. Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished (R)-N-(6,7-dihydro-5H-[1]pyrindin-7-yl)acetamide ((194 mg, 41%). The two enantiomers of the acetamide could not be resolved by GC nor HPLC, and hence the % ee had to be determined indirectly. A small sample of the acetamide was treated with 1N HCl to convert it to the amine, and the resulting amine was resolved by chiral GC (chiral GC method: 85° C. for 120 min, ramp rate 5° C./min to 210° C., final time 5 min; (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) to give % ee of 79%; [α]D=−41° (c 1.49, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.75-1.89 (m, 1H), 2.07 (s, 3H), 2.80-2.98 (m, 3H), 5.19-5.27 (m, 1H), 6.32 (br s, 1H), 7.14 (dd, 1H, J=7.5, 5.0 Hz), 7.55 (d, 1H, J=7.5 Hz), 8.39 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 23.6, 28.3, 33.9, 55.7, 123.0, 133.3, 137.2, 148.2, 148.4, 162.7, 171.0. The unreacted (S)-6,7-dihydro-5H-[1]pyrindin-7-ylamine (was isolated in 42% yield (113 mg) and 99% ee (chiral GC, (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) and displayed spectra identical to the starting material: 1H NMR (CDCl3, 300 MHz) δ 1.68-1.88 (m, 1H), 2.50-2.61 (m, 3H), 2.75-2.86 (m, 1H), 2.92 (ddd, 1H, J=13.2, 9.0, 3.0 Hz), 4.32 (dd, 1H, J=7.8, 7.8 Hz), 7.08 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (d, 1H, J=7.8 Hz), 8.40 (d, 1H, J=4.8 Hz). The dark color of the amine after purification by column chromatography prevented determination of its optical rotation.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H][H]>CO>[C:8]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)C1=C(N)CCCC1
Reactant: [H][H]
Solvent: CO
Product: CCOC(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 10 mL test tube were charged diacetato{(S)-2,2′-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl}ruthenium (II) (12.9 mg), and ethyl 2-aminocyclohexene-1-carboxylate (50 mg), and the mixture was set on a pressurization apparatus. Argon substitution was performed, and dehydrated methanol for organic synthesis (2.5 ml) was injected with pressure. Thereafter, hydrogen (1 MPa) was charged in and the mixture was stirred at 25° C. for 18 hr. After completion of the reaction, the reaction mixture was analyzed by HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:32][CH2:31][C:21]3[N:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:24][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1sc(-c2ccccc2)nc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield {6-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-indol-1-yl}-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:15][C:13]3[O:14][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:17])[F:18])[CH:5]=4)=[CH:11][CH:12]=3)[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: O=Cc1ccc(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cccc(OC(F)(F)F)c4)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[3-(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-])=O)[CH:8]=2)[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO.C1COCC1>[NH2:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1c(C)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc2ccc(N)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
10% palladium on carbon (0.22 g) was added to a solution of the product of Step 1 (1.05 g, 3.25 mmol) and ammonium formate (2.05 g, 32.5 mmol) in MeOH/THF mixture (1:1, 125 ml) under N2. The resulting mixture was stirred for 30 min at room temperature, filtered through Celite bed and filtrate evaporated to dryness. The residue was diluted to 50 ml with CH2Cl2, washed with H2O, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title product as a heavy oil (0.91 g, 98%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J=8.9 Hz, 1H), 7.44(m, 3H), 7.31(m, 2H), 7.13 (dd, J=2.5, 8.9 Hz, 1H), 6.61(d, J=2.5 Hz, 1H), 3.78(broad s, 2H), 3.53(s, 3H), 2.67(s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C1(O)C=CC=CC=1.[CH3:22][O:23][C:24](=[O:28])[CH:25](Br)[CH3:26]>>[CH:6]([C:5]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]([O:1][CH:25]([CH3:26])[C:24]([O:23][CH3:22])=[O:28])=[C:3]([O:13][CH3:14])[CH:4]=1)=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1c(OC)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-3-methoxy-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a dark oil: 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.95 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.80 (d, J=1.8 Hz, 1 H), 5.15 (q, J=6.8 Hz, 1H), 3.95 (s, 3H), 3.63 (s, 3H), 1.50 (d, J=6.8 Hz, 3H). ESI-MS: m/z 284.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17]([N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[CH:2]1[CH3:1])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1NCCCC1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C(O)CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a solution of 1.4 g (9.232 mmol) 2-methyl-piperidin-3-ol (CAS: 4766-56-7) in 9.8 ml dichloromethane under argon at room temperature, was added 2.57 ml (18.46 mmol) triethylamine. The mixture was stirred for 15 minutes and then cooled to 0° C. 1.37 ml (9.232 mmol) benzyl chloroformate was added dropwise. The reaction mixture was allowed to come to room temperature and the stirring was continued overnight. The mixture was extracted three times with water and the combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 30) to provide 800 mg (34.8%) of the title compound as a colorless oil. MS (m/e): 272.4 (M+Na+)
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34](=[O:48])[C@@H:35]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][C:37](O)=[O:38])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([O:43][C:41]([NH:40][C@@H:35]([CH2:36][C:37]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:38])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol) in DCM (5 mL) was added (S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (0.118 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction was stirred at rt for 18 hours. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 25% ethyl acetate in petroleum ether to provide the purified product (37 mg, 68%) as an off-white semi solid. LC-MS (Method A) RT=2.55 min, (M+H)+=654.4. 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.34 (m, 2H), 7.20-6.98 (m, 6H), 4.82-4.53 (m, 1H), 4.43-4.24 (m, 2H), 4.11 (d, J=14.1 Hz, 1H), 3.58 (t, J=8.8 Hz, 1H), 3.48-3.39 (m, 1H), 3.22-3.07 (m, 3H), 3.02 (dd, J=16.1, 6.5 Hz, 1H), 2.87 (dd, J=15.8, 7.8 Hz, 1H), 2.78-2.63 (m, 2H), 2.38-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.03 (m, 1H), 1.98-1.86 (m, 1H), 1.78 (br. s., 1H), 1.74-1.58 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ −180.707.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(#N)C>[CH2:20]([O:19][C:15]([NH:16][NH:17][C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)NN
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1Cl
Solvent: CC#N
Product: CCOC(=O)NNc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Temperature: 24 °C
Yield: 85 %

Procedure:
To a solution of 0.58 g (~2.3 mmol) 2,6,7-trichloroquinoxalin-3(4H)-one in 25 ml of acetonitrile was added 0.27 g (~2.6 mmol) of ethyl carbazate. The reaction mixture was refluxed for 3 h. Cooling to 24° C. gave the title compound (0.62 g; 84%) as a precipitate. M.p. >300° C. decomp.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OCCN2CCCC2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (2.15 g, 10.42 mmol) and triethylamine (3.27 mL, 23.4 mmol) in 100 mL methylene chloride at 0° C. was added cyclohexanecarbonyl chloride (1.46 mL, 10.94 mmol), dropwise. The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with 50 mL methylene chloride. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated to afford the title compound of Step A. MS 317.2 (M+1)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O[Li].O.Cl>C1COCC1.O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:22][CH:23]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2ccc(CO)cc2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C#Cc2ccc(CO)cc2)cc1
Reaction time: 1.5 h

Procedure:
Ethyl 2-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenoxy)acetate (54.0 mg, 0.174 mmol) was dissolved in THF (1 mL), and LiOH.H2O (10.9 mg, 0.261 mmol) in water (0.5 mL) was added. The mixture was stirred for 1.5 h. and 3% HCl (0.5 mL) was added until pH<1. Water (10 mL) was added, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was white/yellow and solid (48.0 mg, 98%). Rf=0.04 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6): □ 4.52 (s, 2H, CH2OH); 4.73 (s, 2H, OCH2); 5.26 (s, 1H, CH2OH); 6.95 (d, 2H, J=8.7 Hz, Ph); 7.35 (d, 2H, J=7.8 Hz, Ph); 7.48 (m, 4H, Ph); 12.99 (s, 1H, COOH). 13C-NMR (DMSO-d6): □ 62.0 (CH2OH); 64.0 (OCH2); 87.7 (CC); 88.3 (CC); 114.3, 114.4, 120.3, 126.1, 130.5, 132.3, 142.6, 157.5 (Ph); 169.4 (COO). EI-MS: m/z calculated for C17H14O4 [M]+ 282; [C15H11O2]+ 223; [C8H8O3]+ 152. found 282, 223, 152.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCNC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3 grams of (3-Amino-propyl)-carbamic acid tert-butyl ester in 15 ml of dimethylformamide was added 3 grams of N-benzyloxycarbonyl glycine, 4.7 mL of N-methylmorpholine and 5.06 grams of TBTU. The reaction was cooled to 0 degrees C. for 30 minutes then allowed to stir at room temperature overnight. The volatiles were removed under reduced pressure and the resulting material was dissolved in ethyl acetate and washed with 10% citric acid. The aqueous was extracted an additional two times with ethyl acetate, combined and washed with water, saturated aqueous sodium bicarbonate, water, brine and dried over MgSO4. The volatiles were removed under reduced pressure and the resulting material was crystallized from EtOAc/hexane affording 4.55 grams of the desired product as a tan solid. LRMS found 388.3=(M+Na)+
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][N:34]2[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN1CCN(CCCN)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-Carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCI, m/z): 483 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: C1CCNC1
Product: O=C(O)c1c(CC(=O)N2CCCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with pyrrolidine at 22° C. to give the title compound as a white solid. MS: 429.3 ([M−H]−).