Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][C:22]1([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:22]([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:31])([F:32])[F:30])([CH3:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC1(CNC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(CNC(=O)C(F)(F)F)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 91.5 %

Procedure:
A mixture of 0.7 g (2.6 mmoles) of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 0.92 g (3.96 mmoles) of 3-methyl-3-trifluoroacetamidomethylazetidine hydrochloride and 1.6 g of triethylamine are heated under reflux for 2 hours in 12 ml of pyridine. The mixture is evaporated, water is added, the product is filtered, and 1.05 g (90%) of 1-cyclopropyl-6-fluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 265°-72° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.Cl.NO.CO[CH:21](OC)[N:22](C)C>>[CH2:12]([O:11][C:9]([C:8]1[CH:21]=[N:22][O:7][C:6]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: NO
Product: CCOC(=O)c1cnoc1-c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of ethyl (4-bromobenzoyl)acetate (1.19 g, 4.39 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was stirred at 100° C. for 1 hour. The mixture was concentrated, and the residue was dissolved in EtOH (10 mL). Hydroxylamine hydrochloride (0.454 g, 6.57 mmol) was added, and the reaction was stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O, and the organic layer was separated, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:14][C:13]=1[CH3:22].CC1NC(C2C(C)=CC(C)=C(C=2)C(OC)=O)=C(C)N=1.Cl.[NH:43]1[CH2:46][CH:45]([C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=2)[CH2:44]1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>CCOC(C)=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([N:43]2[CH2:46][CH:45]([C:47]3[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=3)[CH2:44]2)=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:14][C:13]=1[CH3:22]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(N3CCCC3)nc2C)c1
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: COC(=O)c1cc(-c2[nH]c(C)nc2C)c(C)cc1C
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(N2CCCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1, except methyl 4-methyl-3-(4-methyl-2-(pyrrolidin-1-yl)-1H-imidazol-5-yl)benzoate (compound 197.3) was used in place of methyl 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 1.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 426 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH2:29][CH3:30]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][O:25][CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CCNCCOC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1)CCOC

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and N-(2-methoxy-ethyl)-ethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine as yellowish oil, MS: 476 (MH+, 1Br).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=[N:14]2)[CH2:9]1)=O)(C)(C)C.Br[C:28]1[CH:29]=[C:30]([C:35]2[N:36]=[CH:37][C:38]3[C:43]([CH:44]=2)=[C:42]([Cl:45])[CH:41]=[CH:40][C:39]=3[F:46])[C:31]([NH2:34])=[N:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:53]>C(Cl)Cl.CCOCC.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.COCCOC.O>[ClH:45].[ClH:53].[ClH:45].[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([F:46])=[C:38]2[C:43]=1[CH:44]=[C:35]([C:30]1[C:31]([NH2:34])=[N:32][CH:33]=[C:28]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[CH:17]=3)[CH:29]=1)[N:36]=[CH:37]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Nc1ncc(Br)cc1-c1cc2c(Cl)ccc(F)c2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cnn([C@@H]3CCNC3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A solution of (R)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.0804 g, 0.221 mmol), 5-bromo-3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine (0.065 g, 0.18 mmol), potassium carbonate (0.0815 g, 0.590 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol) in previously degassed DME/Water (4:1) (2.05 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil. This material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3] resulting in (R)-3-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=508.9/510.8 (76/24) [MH+]. This compound was dissolved in DCM (2.0 mL) and charged with 1.0 M of HCl in Et2O (1.1 mL) and stirred at 40° C. for 5 h then at rt for an additional 16 h. The solid that formed was filtered off and washed with diethyl ether (3×), yielding the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.23-2.36 (m, 1H), 2.39-2.49 (m, 1H), 3.33-3.48 (m, 1H), 3.51-3.62 (m, 2H), 3.62-3.82 (m, 2H), 5.14-5.28 (m, 1H), 7.66 (t, J=9.2 Hz, 1H), 8.11 (dd, J=8.4, 4.8 Hz, 1H), 8.17 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.54 (d, J=11.7 Hz, 2H), 8.67 (br. s., 1H), 9.41 (br. s., 1H), 9.54 (br. s., 1H), 9.68 (s, 1H) MS (ES+): m/z=408.88/410.77 (76/24) [MH+]. HPLC: tR=1.84 min (ZQ2, polar—5 min).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].S(O[CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:32][CH2:31]2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Yield: 54.2 %

Procedure:
Cesium carbonate (16.29 g, 50 mmoles, 2 equivalents) was added to a stirred solution of 4-amino-3-nitrophenol (3.85 g, 25 mmoles, 1 equivalent) and tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (10.16 g, 27.5 mmoles, 1.1 equivalent) in anhydrous DMA (25 mls). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. This material was triturated with diethylether to give a solid which was filtered off and washed with ether to give 4.76 g of tert-butyl 4-((4-amino-3-nitrophenoxy)methyl)piperidine-1-carboxylate as a yellow solid (yield=54%). 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.89 (d, 1H), 7.74 (d, 1H), 3.82 (d, 2H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, 1H), 1.54 (m, 2H), 1.38 (s, 9H), 0.98 (m, 2H). MS (EI): 352 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)CC3)cc2)C(=O)O1
Yield: 85 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), with sodiumborohydride (1.2 mmol)) methanol (10 ml) at a temperature 0-25° C. for 2 hours in 85% yield.
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][C:7]3([CH3:15])[CH2:13][NH:14][C:5]([C:6]=23)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>C1COCC1.O1CCOCC1.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>[CH3:15][C:7]12[CH2:13][NH:14][C:5]3[C:6]1=[C:11]([C:2]([CH3:16])=[CH:3][CH:4]=3)[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: O=C([O-])[O-]
Reactant: CC12CNc3ccc(Br)c(c31)NC(=O)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2c3c1NC(=O)CC3(C)CN2

Procedure:
A mixture of (±)-6-bromo-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one from Step B (48 mg, 0.18 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol), potassium carbonate (75 mg, 0.54 mmol), and trimethylboroxine (0.126 mL of a 50 wt. % solution in THF, 0.50 mmol) in 1,4-dioxane (0.9 mL) and H2O (0.1 mL) was heated at 120° C. in a microwave reactor for 40 min. The cooled reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=203 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]([OH:39])[CH2:36][NH:37][CH3:38])=[CH:27]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:37]([CH2:36][CH:35]([OH:39])[C:28]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[NH:26][CH:27]=4)[CH3:38])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1c[nH]c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2c[nH]c3ccccc23)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(1H-indol-3-yl)-2-(methylamino)ethanol (Khim.-Farm. Zh. 1970, 4, 5-9)(73 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred for 48 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (112 mg) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:51])[N:5](C)[C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[N:40]=[C:41]([C@@H:44]6[CH2:48][C@H:47]([CH3:49])[CH2:46][NH:45]6)[NH:42][CH:43]=5)=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:26][C:20]=2[N:19]=1)=[O:11])[CH:7]([CH3:9])[CH3:8].[CH3:52][O:53][C:54]([N:56]([CH3:64])[C@@H:57]([CH:61]([CH3:63])[CH3:62])[C:58]([OH:60])=O)=[O:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4]([NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[N:40]=[C:41]([C@@H:44]6[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]6[C:58](=[O:60])[C@@H:57]([N:56]([CH3:64])[C:54](=[O:55])[O:53][CH3:52])[CH:61]([CH3:63])[CH3:62])[NH:42][CH:43]=5)=[CH:35][CH:34]=4)=[CH:31][CH:32]=3)=[CH:26][C:20]=2[N:19]=1)=[O:11])=[O:51]
Reactant: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6)n5)cc4)cc3)ccc2[nH]1)C(C)C
Reactant: COC(=O)N(C)[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)[C@H](C(C)C)N(C)C(=O)OC)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.9 %

Procedure:
To a solution of methyl {(S)-2-methyl-1-[(2S,4S)-4-methyl-2-(5-{4′-[2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester hydrochloride (68.7 mg, 0.0987 mmol) and (2S)-2-[methoxycarbonyl(methyl)amino]-3-methyl-butanoic acid (18.67 mg, 0.09867 mmol) in DMF (2 mL), cooled in an ice bath is sequentially added HATU (41.25 mg, 0.1085 mmol) and DIPEA (38.26 mg, 51.56 μL, 0.2960 mmol) under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 5 hours, and diluted with water (6 mL). The mixture is extracted with EtOAc (5×6 mL), and the combined organic layers are washed with H2O (3×3 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 10% methanol in CH2Cl2) and is further purified by reverse phase preparative HPLC to give methyl ((S)-1-((2S,4S)-2-(4-(4′-(2-((2S,4S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-3H-benzo[d]imidazol-6-yl)-[1,1′-biphenyl]-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (36 mg, 41%).
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:10]=2)=[O:8])=[CH:5][CH:4]=1.CSC.B(F)(F)F>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:10]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)c2cccc(C(=O)c3ccc(OC)cc3)c2)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: O=C(c1ccc(O)cc1)c1cccc(C(=O)c2ccc(O)cc2)c1
Reaction time: 27 h
Yield: 37.5 %

Procedure:
To a well-stirred solution of 1,3-bis-(4-methoxybenzoyl)benzene 14 (1.80 g, 5.2 mmol) in dichloromethane (85 mL) was added boron trifluoride dimethyl sulfide complex (BF3.SMe2, 15 mL). The mixture was stirred for 27 h. After the reaction was quenched by water, the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The resulting solid was further purified using flash chromatography (silica gel, hexanes:ethyl acetate, 50:50) to afford the pure 1,3-bis-(4-hydroxybenzoyl)benzene 20 (0.62 g, 1.95 mmol) as a white solid in a 38% yield; 1H NMR (500 MHz, Acetone-d6): δ 9.28 (s, OH), 8.04 (td, J=1.7 Hz, 1.3 Hz, 1H, ArH), 7.98 (dd, J=7.7 Hz, 1.75 Hz, 2H, ArH), 7.80 (ddd, J=9.5 Hz, 4.8 Hz, 2.75 Hz, 4H, ArH), 7.73 (td, J=7.9 Hz, 0.45 Hz, 1H, ArH), 7.00 (ddd, J=9.5 Hz, 4.8 Hz, 2.75 Hz, 4H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([N:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[N:9]2)[CH:7]=1.NC1C=CC=CC=1>Cl.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:17])=[C:6]([N:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[N:9]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1-n1nnc2ncccc21
Agent: [Fe]
Agent: Cl
Solvent: Nc1ccccc1
Product: Nc1ccc(Cl)cc1-n1nnc2ncccc21
Temperature: 25 °C
Yield: 84.1 %

Procedure:
1-(5-Chloro-2-nitrophenyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (10 g, 36.3 mmol) was dissolved in 200 mL concentrated HCl in a 1 L round-bottom flask fitted with a magnetic stir bar. Iron powder (4.2 g, 74.4 mmol) was added in portions to the rapidly stirring solution. The resultant thick yellow slurry was allowed to stir overnight until no visible metallic iron was observed in the reaction vessel. The following day, LCMS analysis indicated complete reduction to the aniline. The mixture was subsequently transferred to a 500 mL Buchner funnel, with the assistance of a small amount of concentrated HCl to rinse out the remaining slurry from the reaction vessel, and the insoluble material was collected by vacuum filtration. The filter cake was then stirred into a thick paste with water (15 mL) and the solids collected by vacuum filtration. The material was again stirred in 15 mL water and filtered, the mother liquors were discarded, and the solid material dried in vacuo. The resultant light brown solid was slurried in 50 mL of 1:1 (v/v) EtOAc:acetonitrile and heated to the boiling point with a heat gun. The mixture was allowed to cool to room temperature and the solids were collected by vacuum filtration. The solids were subsequently washed with a small amount of 1:1 EtOAc:acetonitrile and dried in vacuo to generate 7.5 g 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine (light grey solid, 84% yield): MS (ES) M+H expected 246.0, found 246.0.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[NH:13][C:14](=[O:35])/[C:15](=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)/[CH2:16][CH2:17][CH2:18]Cl)=[CH:6][C:5]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O.C(OCC)(=O)C>CN(C=O)C>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[N:13]2[CH2:18][CH2:17][CH2:16]/[C:15](=[CH:20]\[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)/[C:14]2=[O:35])=[CH:6][C:5]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2CCc3cc(N4CCOCC4)c(F)cc32)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C2\CCCN(C3CCc4cc(N5CCOCC5)c(F)cc43)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Sodium hydride (containing mineral oil at 40%, 19.0 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (6-fluoro-5-morpholin-4-ylindan-1-yl)amide (123 mg) in DMF (3.0 mL) at 0° C., and the reaction solution was stirred for 15 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system, ethyl acetate-methanol system) to obtain 85 mg of (E)-1-(6-fluoro-5-morpholin-4-ylindan-1-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate. Next, the compound (12.0 mg) was fractionated using CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=70:30) to obtain the title optically active substance with a retention time of 13 minutes (Example 973, 4.60 mg; >99% ee) and the title optically active substance with a retention time of 15 minutes (Example 974, 4.70 mg; >99% ee). The physical properties of the optically active substances are as follows.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH:18]([CH3:21])[CH2:19][NH2:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH:18]([CH3:21])[CH2:19][NH:20][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:16])=[O:15]
Reactant: CC(CN)O[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)CS1
Solvent: O=[N+]([O-])O
Product: CC(CNC(=O)[C@@H]1CSC(=O)N1)O[N+](=O)[O-]

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 2.0 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 3.0 g of N-(2-nitrooxypropyl)amine nitrate, to obtain 24 mg of the title compound as pale yellow crystals, melting at 70°-72° C. (after recrystallization from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:34](Cl)(=[O:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][C:34](=[O:45])[O:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (0.15 g, 0.38 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Solid powdered K2CO3 (0.52 g, 3.8 mmol) was added followed by 4-nitrophenyl carbonochloridate (0.11 g, 0.56 mmol). The resulting slurry was stirred at room temperature for 14 h, diluted with DCM (ca. 50 mL) and washed with sat. NaHCO3 (ca. 4×20 mL). The organic portion was dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate as a pale brown oil, (0.20 g, crude quantitative yield). LCMS: 2.26 min [M+1] 560.2 (2 min gradient, MeOH/H2O 0.1% TFA)