Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Br[CH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CC#N>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:3][C:4]([N+:16]([O-:18])=[O:17])=[C:5]([C:10]2([C:14]#[N:15])[CH2:11][CH2:12][CH2:13]2)[CH:6]=1
Reactant: BrCCCN1CCCC1
Reactant: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of 1-(4-(hydroxyl)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (0.73 g, 2.93 mmol), from Step 3, in MeCN (20 mL) was added potassium carbonate (1.215 g, 8.79 mmol) and 1-(3-bromopropyl)pyrrolidine hydrochloride (1 g, 4.4 mmol) and stirred at 100° C. for 3 hours. The reaction mixture was concentrated, and extracted with dichloromethane. The combined organic extracts were washed with brine. The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-20% methanol/dichloromethane) afforded 0.63 g (59%) of 1-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)cyclobutanecarbonitrile. 1H NMR (400 MHz, METHANOL-D4) δ 7.65 (s, 1H), 6.94 (s, 1H), 4.14 (t, J=6.1 Hz, 2H), 3.97 (s, 3H), 2.87 (ddd, J=8.6, 5.3, 2.5 Hz, 2H), 2.77-2.67 (m, 2H), 2.68-2.52 (m, 6H), 2.42 (dd, J=14.6, 6.3 Hz, 1H), 2.13-2.01 (m, 2H), 2.01-1.89 (m, 1H), 1.84 (dt, J=6.6, 3.2 Hz, 4H). MS (ESI) m/z 360 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][C:12](=[O:17])[CH2:13]3)=[CH:6][CH:5]=1>CO.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][CH:12]([OH:17])[CH2:13]3)=[CH:18][CH:19]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CC2CCC(C1)N2Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium borohydride (95 mg, 1.50 mmol) was added to a solution of 8-(4-bromobenzyl)-8-azabicyclo-[3.2.1]octan-3-one (0.22 g, 0.75 mmol) in methanol (10 mL) and the reaction mixture was stirred for 30 minutes. The reaction was diluted with water (10 mL) and extracted into DCM (3×20 mL). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as an off-white solid (200 mg, 90%). 1H NMR (CDCl3, 300 MHz): 7.43 (dd, J=8.3, 2.0 Hz, 3H), 7.29-7.23 (m, 2H), 3.60-3.45 (m, 2H), 3.23-3.10 (m, 2H), 2.16-1.40 (m, 8H). LCMS (Method B): RT=1.90 min, M+H+=296/298.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:22])[CH2:20]O)=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:22][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:20][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCC(O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C2COC(CBr)(c3ccc(Cl)cc3)O2)cc1

Procedure:
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 9 parts of 1-(p-chlorophenyl)-1,2-ethanediol, 0.5 parts of p-toluenesulfonic acid and 80 parts of benzene is stirred and refluxed for 2 days with water-separator. The reaction mixture is cooled and washed successively twice with a sodium hydrogen carbonate solution and once with water. The organic phase is dried and evaporated. The residue is triturated in petroleum ether and cooled on ice. The precipitated product is filtered off, crystallized from methanol, stirred in acetonitrile while cooling on ice, filtered off again and washed once more with acetonitrile, yielding 2-(bromomethyl)-2,4-bis(p-chlorophenyl)-1,3-dioxolane.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[CH:27][C:28]=1[F:29].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:25]5[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(F)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,4-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (60 ml), washed with water and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (85 mg) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([C:14]([O:16]C(C)(C)C)=[O:15])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc2c(ccn2CC2CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc2c(ccn2CC2CC2)cn1
Temperature: 50 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2A, 1.1 g, 4.0 mmol) in DCM (5 ml) and TFA (5 ml) was stirred at 50° C. for 15 h. The mixture was concentrated in vacuo to give 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (2B, 0.9 g, 4.0 mmol) as a brown oil. The material was used for next reaction without further purifications. ESI-MS: m/z 217.1 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=O)=[CH:19][CH:18]=1>CS(O)(=O)=O>[CH3:29][C:25]1([CH3:30])[C:26](=[O:28])[C:19]2[C:20](=[CH:21][CH:22]=[C:17]([S:16][CH3:15])[CH:18]=2)[NH:23][C:24]1=[O:31]
Reactant: CSc1ccc(NC(=O)C(C)(C)C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CSc1ccc2c(c1)C(=O)C(C)(C)C(=O)N2
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Phosphorus pentoxide (4.49 g, 0.032 mol) was added to a stirred solution of N-(4-methylthiophenyl)-2,2-dimethylmalonamic acid (5.0 g, 0.020 mol) in methanesulfonic acid (35 ml). The reaction mixture was warmed to 70° C. and stirred for 90 mins. The product mixture was then cooled to room temperature and poured over ice. The product was extracted with ethyl acetate (2×200 ml). The organic extracts were combined, washed with water (200 ml), saturated sodium hydrogen carbonate solution (200 ml), dried (MgSO4) and concentrated in vacuo to give 3,3-dimethyl-6-methylthio-2,4(1H,3H)-quinolinedione as a yellow solid. Mp 152° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12](C(O)=O)=[C:8]3[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC([O-])=O.[Na+].[I:31]Cl.O>C(O)(=O)C>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([I:31])=[C:8]3[CH:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)cc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)n3ncc(I)c3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (example C.28 step 6) (1.03 g, 2.97 mmol) in acetic acid (40 mL) was refluxed for 20 h. Cooled to 23° C., added NaOAc (325 mg, 3.95 mmol) and ICl (2M in HOAc, 1.85 mL, 3.7 mmol) and the mixture was stirred at 23° C. for 2 h. Poured into water, filtered precipitate off, washed with water, dissolved in TBME, washed with sat. NaHCO3-sol.+little sat. Na2SO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light red solid (1.257 g, 99%). MS (ISP) 429.2 [(M+H)+].
Reaction SMILES: O[CH:2]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=1[CH3:32])[CH2:3][CH3:4]>C(OCC)(=O)C.CCCCCC>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[C:9]3[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:6]([CH3:32])=[C:5]([CH2:2][CH2:3][CH3:4])[C:13]=3[O:12][CH2:11]2)=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: CCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 86 %

Procedure:
Using a diastereo mixture of N-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in the synthesis in Examples 30 and 31, the title compound was synthesized in the same manner as in Example 23. Yield: 86%. Melting point: 145-148° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH2:27]O)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(CCO)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of (2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzenesulfonyl}-ethanol (prepared as in Example 91, 600 mg, 1.5 mmol) and triethylamine (0.42 ml, 3.0 mmol) in dichloromethane (15 mL) at 0° C. was added a solution of methanesulfonyl chloride (0.18 ml, 2.2 mmol) in dichloromethane. The mixture was stirred at 0° C. for 30 min. The reaction was quenched with a water (20 mL). The mixture was extracted with dichloromethane (2×50 mL), washed with brine (3×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/dichloromethane) afforded 2-[2-cyclopentyl-1-(4-ethenesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (380 mg, 66%) as a solid: LC/MS m/e calcd for C22H24N2O2S [M+H]+ 381.51, observed 381.0.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCc1ccccc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 108 %

Procedure:
40 g (205 mmol, 1 eq.) tert-butyl bromoacetate were dissolved in 200 ml acetonitrile. The solution was cooled to 0-5° C. and 47 g benzylamine (2.14 eq.) in solution in 90 ml acetonitrile were added over 15 min. After 5 min, the reaction mixture was warmed to room temperature and stirred for 3 h (IPC by GC). The resulting suspension was filtered and evaporated to constant weight to give 49 g of a yellow oil. The oil was dissolved in 200 ml heptane and washed 3 times with 50 ml aq. sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated to give 35.8 g of the crude product. Distillation under high vacuum afforded 27.2 g of the titled product (95% pure by GC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23](C1CCCCN1)[CH:22]=[CH:21]2>ClCCl.CO>[N:24]1([C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][CH:27]=[C:18]([NH:17][C:14](=[O:16])[C:13]#[C:12][C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=4[Cl:1])[CH:19]=3)[N:24]=2)[CH2:25][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc2nc(C3CCCCN3)ccc2c1
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc2nc(N3CCCCC3)ccc2c1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 6-amino-2-piperidin-2-ylquinoline. Yield: 170 mg (37.1% of theory); melting point: 176° C.-179° C.; C24H19ClF3N3O (M=457.88); calc.: molecular ion peak (M+H)+: 456/458; found: molecular ion peak (M+H)+: 456/458; Rf value: 0.62 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:2].[Na+].[I-:28]>CO>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[CH2:5][C:6]1[C:7]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[C:21]([I:28])[CH:22]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:26]
Reactant: [I-]
Reactant: CCN(CC)C(=O)Cc1c(-c2ccc(O)cc2)nn2c(C)cc(C)nc12
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(=O)Cc1c(-c2ccc(O)c(I)c2)nn2c(C)cc(C)nc12
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 3 (100 mg, 0.28 mmol) in MeOH (15 mL) was added NaI (52 mg, 0.35 mmol) and chloroamine-T hydrate (80 mg, 0.35 mmol). The reaction mixture was stirred for 1 h and then concentrated under vacuum. The residue was purified by column chromatography (CH2Cl2/MeOH, 20:1 (v/v), as eluent) to yield 4 (60 mg, 45% yield). 1H NMR (CD3OD, 400 MHz) δ 1.16 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 2.57 (s, 3H), 2.76 (s, 3H), 3.44 (q, J=7.2 Hz, 2H), 3.59 (q, J=7.2 Hz, 2H), 3.97 (s, 2H), 6.80 (s, 1H), 6.92 (d, J=8 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 8.01 (s, 1H). ESI MS m/z: [M+H]+. C20H24IN4O2: calculated 479.1. found 479.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(N)cc3)ncnc2n1
Yield: 74.9 %

Procedure:
The product of Example 49D (2.78 g, 4.152 mmol) was treated with trifluoroacetic acid (25 mL) in methylene chloride (25 mL) at room temperature for 30 minutes. The solvents were removed under vacuum by rotary evaporation and the residual oil taken up in ethyl acetate (400 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL), water (2×100 mL), and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with 3% methanol/methylene chloride and dried in vacuo to afford the title compound as a light beige solid (1.77 g, 75%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.32 (d, J=6.99 Hz, 6 H) 3.09-3.31 (m, 1 H) 5.03 (s, 2 H) 6.57 (d, J=8.82 Hz, 2 H) 6.78 (d, J=8.82 Hz, 2 H) 6.83 (d, J=8.82 Hz, 1 H) 7.53 (d, J=8.82 Hz, 2 H) 7.60 (d, J=8.82 Hz, 1 H) 7.75 (d, J=9.19 Hz, 2 H) 7.85 (dd, J=8.46, 2.21 Hz, 1 H) 8.16 (d, J=2.21 Hz, 1 H) 8.62 (s, 1 H) 8.84 (d, J=8.46 Hz, 1 H) 10.00 (s, 1 H) 10.29 (s, 1 H); MS (ESI+) m/z 569/571 (M+H)+, MS (ESI−) m/z 567/569 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([Cl:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:20][C:9]1[C:8]2[C:7](=[O:21])[C:6]3[CH:5]=[C:4]4[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]4=[C:16]([Cl:19])[C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc2c(=O)c3c(Cl)cccc3oc2c(Cl)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2cc3c(=O)c4c(Cl)cccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
A mixture of 2-allyl-4,8-dichloro-3-hydroxy-9-oxo-9H-xanthene (14 g), m-chloroperbenzoic acid (11 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and to the stirred solution, a mixture of chromium trioxide (17 g), water (100 ml) and concentrated sulfuric acid (30 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 5.0 g of 6,11-dichloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 291°-294° C. This compound showed a mass spectrum having a molecular ion peak at m/e 350.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:12]=[CH:11][N:10]([CH3:22])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CI
Reactant: Clc1ccc(-c2nc[nH]c2-c2ccc(Cl)cc2Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4,5-di-(2,4-dichlorophenyl)imidazole (230 mg, 0.65 mmol) from Step B and methyl iodide (0.062 mL, 1.0 mmol) in DMF (5 mL) was added sodium hydride (60% in mineral oil, 52 mg, 1.3 mmol). The reaction was stirred at rt for 3 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (50% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 371 (M+1), 373 (100%, M+3), 375 (M+5); Rt=2.85 min.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(C1SC=C(C2C=CC=C(N)C=2)N=1)=O)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)c1nc(-c2cccc(N)c2)cs1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 4-(3-amino-phenyl)-thiazole-2-carboxylic acid ethyl ester (prepared in two steps from 2-bromo-3′-nitroacetophenone) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.49 (1H, br s), 8.09-8.07 (1H, m), 7.89 (1H, s), 7.63-7.61 (1H, m), 7.56-7.46 (3H, m), 7.40-7.28 (2H, m), 7.05 (1H, d, 7.8), 4.82 (1H, d), 4.62 (1H, d), 4.33-4.20 (2H, m), 2.81-2.77 (1H, m), 2.05-1.69 (6H, m), 1.44-1.16 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 56.05; H, 6.47; N, 9.82%; C32H35N5O5S.C7H17NO5.2.0H2O requires: C, 56.24; H, 6.78; N, 10.09%.
Reaction SMILES: C(O[C:6]([N:8](C)[NH:9][C:10](=[O:12])[CH3:11])=O)(C)(C)C.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>C(Cl)Cl>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[CH3:6][NH:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)NN(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNNC(C)=O
Reaction time: 1 h

Procedure:
To a solution of N'-acetyl-N-methylhydrazinecarboxylic acid tert-butyl ester (0.3 g, 1.59 mmol) in methylene chloride (2 ml) was added trifluoroacetic acid (2 ml) and the mixture was stirred for 60 min. The mixture was concentrated in vacuo and stripped three times with methylene chloride to give 0.32 g (100%) of acetic acid N'-methylhydrazide trifluoroacetic acid as a thin oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=2.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1.C(=O)(O)[O-].[Na+].C(=O)=O>C(O)(=O)C.O>[N+:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]#[N:12])=[C:2]([N:1]3[CH:18]=[CH:22][CH:21]=[CH:20]3)[NH:3]2)=[CH:8][CH:7]=1)([O-:15])=[O:14]
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1c(N)[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(-n2cccc2)[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) is treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution is heated to reflux for 14 h. After cooling to ambient temperature, the solution is poured into water (100 mL), and solid sodium bicarbonate is added until CO2 evolution ceased. The mixture is extracted with EtOAc (2×100 mL), and the extracts are washed with saturated brine, combined, dried over MgSO4, filtered and concentrated. The residual material is separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[OH:12])=[CH:5][CH:4]=[N:3]1>CCCCCC.C(O)C>[CH3:1][N:2]1[C:6]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[OH:12])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1O
Solvent: CCCCCC
Solvent: CCO
Product: Cn1nccc1[C@@H]1CCC[C@H]1O

Procedure:
The (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol prepared in Example 8a was optically resolved with CHIRALPAK IC (Daicel Corp.; hexane/ethanol=8:2) to yield the title compound as a colorless oil.