Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].C(N(C(C)C)CC)(C)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][S:21](=[O:23])(=[O:22])[N:20]([CH3:25])[CH3:19]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccccc1OS(=O)(=O)N(C)C
Yield: 5.4 %

Procedure:
A solution of 24.8 g (0.2 mole) of guaiacol (Aldrich) and 34.9 g (0.27 mole) of diisopropylethylamine (Hunig's base, Aldrich) in 200 ml of toluene was added to a solution of 29 ml (0.27 mole) of dimethylsulfamoyl chloride (Aldrich) in 75 ml of toluene and the stirred reaction mixture was heated at reflux for 12 hr. The reaction mixture was successively washed with four 300 ml portions of 6N hydrochloric acid solution, 400 ml of water, three 200 ml portions of 20% sodium hydroxide solution, 400 ml of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure to give a brown, viscous oil that solidified upon standing. The solid was recrystallized from ethyl ether-petroleum ether and was collected by filtration. The filtrate was evaporated under reduced pressure and the viscous, brown oil was purified by chromatography (4.5×90 cm glass column, 5.30 g of silica gel, ethyl acetate-hexanes, 1:8). Fractions containing the desired compound were combined and the solvents evaporated under reduced pressure to yield 2.5 g (5%) of the title compound as a light yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-(trifluoromethyl)phenol (4.37 g) in N,N-dimethylformamide (40 ml) were added potassium carbonate (3.75 g) and benzyl bromide (2.59 ml), and the mixture was stirred for 12 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) gave benzyl 4-bromo-2-(trifluoromethyl)phenyl ether (3.37 g). To a stirred solution of the obtained benzyl 4-bromo-2-(trifluoromethyl)phenyl ether (2.05 g) in diethyl ether (20 ml) was added 1.46M tert-butyl lithium solution in pentane (11.4 ml) at −100° C., and the mixture was stirred for 5 minutes. An excess amount of ethylene oxide was added to the reaction mixture, and the mixture was gradually allowed to warm up to −50° C. After a saturated aqueous ammonium chloride solution was added to the reaction mixture, the resulting mixture was allowed to warm up to room temperature and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) gave 4′-benzyloxy-3′-(trifluoromethyl)phenethyl alcohol (1.46 g).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2C3N=C(C(N)=O)SC=3CC[O:38]C=2C=1.N(CCO)N>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][CH2:20][OH:38])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCCO
Product: OCCn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with 2-hydrazino-ethanol to give 2-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-ethanol. MS(ESI+) 393.0/395.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[F:29][C:25]1[CH:24]=[C:23]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(-c3cccc(F)c3)sc2C(=O)O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
5-(3-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (25 mg, 0.060 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (0.8 mL) and then LiOH 1N (0.3 ml, 0.300 mmol) was added. After 3 hours of stirring at room temperature, solvents were removed and then partitioned between 10 ml of H2O acidified to pH 4 and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (Na2SO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 20 mg (83%) of 5-(3-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (Compound 5).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cl:16][CH2:17][C:18]#[N:19]>Cl.O1CCOCC1>[NH2:19][C:18](=[N:1][C:2]1[C:3]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:17][Cl:16]
Reactant: COC(=O)c1sc2ccc(Br)cc2c1N
Reactant: N#CCCl
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ccc(Br)cc2c1N=C(N)CCl

Procedure:
A suspension of EXAMPLE 1A (7.2 g, 25.16 mmol) in 4N hydrochloric acid in dioxane (70 mL) was treated with 2-chloroacetonitrile (3.18 mL, 50.32 mmol) at ambient temperature for 3 hours. The white solid was collected by filtration and dried to give the title compound as the hydrochloride salt. LCMS (APCI) m/z: 362(M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].C([Mg]Br)C.[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22](Cl)=[O:23]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1)=[O:23]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(C#N)cc23)C1(C)C
Yield: 17 %

Procedure:
A mixture of 5-cyanoindole (1.42 g, 10 mmol), ethylmagnesium bromide (1.0 M solution in THF, 11 mL, 11 mmol), zinc chloride (1.0 M solution in Et2O, 11 mL, 11 mmol) and the product of Example 1A (10 mmol) in 30 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.45 g, 1.7 mmol, 17% yield). MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([CH:20]1[CH:24]([OH:25])[CH:23]=[CH:22][C:21]1=O)[CH2:16][CH2:17][CH2:18][CH3:19]>COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.C1(C)C=CC=CC=1>[CH2:15]([C:20]1[C:24](=[O:25])[CH2:23][CH:22]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC1C(=O)C=CC1O
Reactant: Sc1ccccc1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC1=CC(Sc2ccccc2)CC1=O
Reaction time: 5 h
Yield: 104.5 %

Procedure:
Into the same flask as used in Example 1, thiophenol (10 g), triethylamine (2 g), quinine (0.2 g), 2-n-pentyl-3-hydroxy-4-cyclopentenone (16.8 g) and toluene (30 g) were charged, and the mixture was stirred under a nitrogen stream at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 50 to obtain 2-n-pentyl-4-phenylthio-2-cyclopentenone (24.7 g). Yield, 95%. nD20 1.5706.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 59 %

Procedure:
Compound 2b (800 mg, 1.84 mmol) was subjected to Suzuki coupling conditions with compound 1f using the reaction conditions described in Example 1, Step G to obtain compound 2c as a yellow solid (500 mg, 59% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H21N7O: 460.2 (M+H). found: 460.3.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+]=[N-].P(C)(C)C>O1CCCC1>[NH2:1][CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Agent: CP(C)C
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 7-[(3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (527.5 mg, 1.6 mmol) in tetrahydrofuran (5 ml) under N2 was added 1M PMe3 in THF (3.2 ml, 3.2 mmol) and the reaction was stirred overnight. The reaction was quenched by the addition of H2O (1 ml), and stirred for 15 mins before being concentrated under reduced pressure. The crude material was purified by silica flash column chromatography, eluting with 2.5 to 20% 2M NH3 in MeOH in DCM to afford the title compound (376.9 mg, 78%) as a colorless gum: MS (ESI+) for C15H21N5O2 m/z 304.0 [M+H]+; LC purity 99% (ELS) (ret. time, solvent front); 1H NMR (500 MHz, MeOD) δ 7.26 (d, J=3.6 Hz, 1H), 8.07 (s, 1H), 6.61 (d, J=3.6 Hz, 1H), 4.97-5.06 (m, 1H), 4.90-4.97 (m, 1H), 4.55 (dd, J=7.3, 5.8 Hz, 1H), 2.82-2.91 (m, 1H), 2.70-2.81 (m, 1H), 2.39 (dt, J=12.6, 6.5 Hz, 1H), 2.26 (dt, J=12.6, 6.2 Hz, 1H), 1.93-2.10 (m, 1H), 1.54 (s, 3H), 1.25-1.35 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[C:33]1([C:32]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]#[C:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[CH:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#C[Si](C)(C)C)ccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
To a solution of {1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (84 mg, 0.16 mmol) in MeOH (0.8 mL) and CH2Cl2 (1.3 mL) was added a 4 molar solution of HCl in dioxane (0.8 mL, 3.1 mmol, 20 equiv) and the resulting solution was stirred at room temperature for 18 h with monitoring by UPLC-MS and the resulting solution was concentrated under reduced pressure. The remaining material (84 mg) was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 1 min., gradient to 95% CH2Cl2: 5% MeOH over 10 min.; 95% CH2Cl2: 5% MeOH for 5.2 min.). The resulting partially purified material (48 mg) was triturated with diisopropyl ether to give 1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (18 mg, 24%). The resulting diisopropyl ether solution was concentrated under reduced pressure. The remaining material was triturated with diisopropyl ether to give 1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (20 mg, 30%, 54% total):
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:40])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.19 mmol) of the compound from Example 103 were introduced into 14 ml of dichloromethane at 0° C., 47 mg (0.19 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 74 mg (95% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)cc1C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-4-fluorobenzoic acid (10 g, 64.5 mmol) in N,N-dimethylformamide (100 mL) at −10° C., was added dropwise a solution of N-bromosuccinimide (11.2 g, 62.9 mmol) in N,N-dimethylformamide (50 mL) over 1 hour. After the addition was complete, the mixture was stirred at −10° C. for 1 hour. The reaction was quenched with aqueous sodium bisulfate and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and then with brine, and then dried over sodium sulfate. The sample was concentrated to give the crude product 27 (14.5 g, yield: 96.5%), which was used for the next step without further purification.
Reaction SMILES: O[C:2]1([CH3:22])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.C([SiH](CC)CC)C.B(F)(F)F>ClCCl>[I:13][C:11]1[CH:10]=[CH:9][C:6]2[O:7][CH2:8][CH:2]([CH3:22])[C:3]3[N:4]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=3)[C:5]=2[CH:12]=1
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(C)O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2C
Yield: 16.7 %

Procedure:
To a solution of ethyl 4-hydroxy-9-iodo-4-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (2.3 g, 5.55 mmol, 1.00 equiv) in dichloromethane (50 mL) was added triethylsilane (9.7 g, 83.42 mmol, 15.00 equiv) and boron trifluoride diethyletherate (7.8 g, 10.00 equiv) at room temperature. After 1 h at room temperature the resulting mixture was diluted with 30 mL of dichloromethane, washed with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:9) to give 370 mg (17%) of the titled compound as a light yellow solid; LC-MS (ES, m/z) 399 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8]>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](C(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrate (0.59 mL, 12.2 mmol) was added in one portion to a stirred mixture of tert-butyl trans-4-(4-{[methoxy(oxo)acetyl]amino}phenyl)cyclohexanecarboxylate (4.0 g, 11.1 mmol) in EtOH (50 mL) and the reaction mixture was stirred at room temperature for 3 h. EtOH (25 mL) was added and the mixture was filtered to give the title compound (Intermediate 79) (3.7 g, 92%) as a solid; 1H NMR δ 1.4 (9H, s), 1.4-1.5 (4H, m), 1.8-1.9 (2H, m), 1.9-2.0 (2H, m), 2.15-2.3 (1H, m), 2.4-2.55 (1H, m), 4.5 (1H, s), 4.6 (2H, s), 7.2 (2H, d), 7.7 (2H, d), 10.45 (1H, s); MS m/e (M−H)− 360.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2([NH:16]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C@H:10]([CH2:24][OH:25])[CH2:9]1)[C:2]1[CH:7]=CC=C[CH:3]=1.[NH2:26][C:27]1[C:36]([F:37])=C(F)C(C)=C2[C:28]=1[C:29](=[O:46])[C:30]([C:43]([OH:45])=[O:44])=[CH:31][N:32]2[CH:40]1[CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)C.CS(C)=O.[OH-].[Pd+2].[OH-]>[NH2:26][C:27]1[C:36]([F:37])=[C:1]([N:8]2[CH2:12][C@@H:11]([C:13]3([NH2:16])[CH2:14][CH2:15]3)[C@H:10]([CH2:24][OH:25])[CH2:9]2)[C:2]([CH3:7])=[C:3]2[C:28]=1[C:29](=[O:46])[C:30]([C:43]([OH:45])=[O:44])=[CH:31][N:32]2[CH:40]1[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1c(N2C[C@@H](CO)[C@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
Trans-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-hydroxymethylpyrrolidine (1.10 g, 3.18 mmol) was dissolved in ethanol (50 ml), and the solution was mixed with palladium hydroxide (500 mg) and stirred for 1.5 hours at room temperature under a hydrogen atmosphere. The reaction suspension was subjected to celite filtration (ethanol washing) and the solvent was evaporated. The resulting residue and 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (471 mg, 1.60 mmol) were dissolved in dimethyl sulfoxide (20 ml) and, under a nitrogen atmosphere, the solution was mixed with triethylamine (5 ml) and stirred at 150° C. for 19 hours. After evaporating the solvent, the resulting residue was mixed with 10% citric acid aqueous solution (50 ml) and extracted with chloroform (50 ml×2), and the extract was dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting residue was mixed with concentrated hydrochloric acid (5 ml) and stirred for 1 hour. This was mixed with water (50 ml) and washed with chloroform (50 ml×2). The aqueous layer was adjusted to pH 12.00 with a sodium hydroxide aqueous solution and washed with chloroform (50 ml×2). Finally, the aqueous layer was adjusted to pH 7.40 with 1 N hydrochloric acid and extracted with chloroform (300 ml×5). The extract was dried over anhydrous sodium sulfate, the solvent was evaporated and then the resulting residue was recrystallized from ethanol to obtain 165 mg (38%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([OH:42])=O)=[CH:9]1)[CH2:5][O:6][CH3:7].F[P-](F)(F)(F)(F)F.[N:50]1(OC(N(C)C)=[N+](C)C)[C:54]2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN.C1COCC1>CN(C=O)C.O>[CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([NH:50][CH3:54])=[O:42])=[CH:9]1)[CH2:5][O:6][CH3:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C(COC)COC)cn1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NC)cn3C(COC)COC)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(1,3-Dimethoxypropan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4, 0.112 g, 0.18 mmol) was suspended in DMF (1 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.105 g, 0.28 mmol) was added, followed by diisopropylethylamine (0.097 mL, 0.55 mmol). The reaction mixture was stirred for 15 min at RT. A 2.0 M solution of methylamine in THF (0.2 mL, 0.40 mmol) was added and the mixture was stirred at RT for 2 d. Water was added and the solid precipitate was purified by column chromatography (silica, 95:5 methylene chloride/methanol). The solid was further purified by trituration with CH2Cl2 and hexanes.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=3)[CH2:22]2)=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COc1ccc2c(c1)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc2c(c1)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 31.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (3.7 g), 1,2,3,4-tetrahydro-7-methoxyisoquinoline (2.7 g; Daniel J. Sall and Gary L. Grunewald, J. Med. Chem. 1987, 30, 2208-2216) and potassium carbonate (6.7 g) in isopropanol (150 ml) was stirred under reflux for 48 h. The mixture was evaporated to dryness, and the residue was extracted with dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was then purified by column chromatography elating with dichloromethane/methanol (99:1) to give the title compound (1.6 g) as an orange solid, MP: 92°-94°. NMR includes signals at d 3.6 (2H,m,N--CH2Ar), 3.7 (3H,s,OCH3).