Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@@:15]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH:40]=[CH2:41])=[CH:34][CH:33]=4)[CH:25]=3)([O:22][CH3:23])[O:14]2)(=O)=O)=CC=1.N1C(C)=CC(C)=CC=1C>CS(C)=O>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:26]2[CH:25]=[C:24]([C@:15]3([O:22][CH3:23])[O:14][C@H:13]([CH:12]=[O:11])[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@H:16]3[OH:21])[CH:29]=[CH:28][C:27]=2[Cl:30])=[CH:33][CH:34]=1)[CH:40]=[CH2:41]
Reactant: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: CS(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 150 °C

Procedure:
To a solution of ((2R,3S,4S,5R,6S)-6-(3-(4-(allyloxy)benzyl)-4-chlorophenyl)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 7.49 mmol) in dry DMSO (30 mL), was added collidine (6.95 mL, 52.44 mmol) and the mixture was heated at 150° C. for 45 min. After the completion of the reaction as monitored by TLC, the reaction mixture was used as such for the next step.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][N:17]=[C:16]([O:19][CH2:20][CH2:21][NH2:22])[C:15]=3[CH:23]=2)=[CH:7][CH:6]=1.CS([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)(=O)=O.C(N(CC)CC)C>C(O)C>[F:25][C:3]([F:2])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][N:17]=[C:16]([O:19][CH2:20][CH2:21][NH:22][C:30]4[N:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:15]=3[CH:23]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ncccn1
Reactant: NCCOc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc(-c2ccc3onc(OCCNc4ncccn4)c3c2)cc1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethanamine hydrochloride (57 mg, 0.152 mmol) and 2-(methylsulfonyl)pyrimidine (96 mg, 0.608 mmol) were dissolved in 2 mL ethanol in a microwave vial. Triethylamine (0.1 mL) was added and the mixture was heated at 120° C. for one hour in the microwave. All volatiles were removed under vacuum and the residue was purified on 12 g silica gel with 0-100% ethyl acetate in hexane to give the title compound (40 mg, 0.096 mmol). MS: 417 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([OH:22])=O)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:25]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[OH:33])[CH2:26]1.Cl.C1C2(CCNC[C@H]2O)C1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OS([O-])(=O)=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:30]3[CH2:31][CH2:32][C:27]4([CH2:25][CH2:26]4)[C@H:28]([OH:33])[CH2:29]3)=[O:22])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O[C@@H]1CNCCC12CC2
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 0.070 g (0.20 mmol) of 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) in 1.5 ml of DMF was treated with 0.045 ml (0.28 mmol) of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2), 0.054 ml (0.40 mmol) of triethylamine and at 0° C. with 0.081 g (0.22 mmol) of HATU. Over night, the suspension was naturally warmed to RT, poured on aqueous 10% KHSO4 solution and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried (Na2SO4) and evaporated to give after purification with flash chromatography (SiO2, dichloromethane/methanol 99:1 to 96:4) 0.069 g (70%) of the titled compound as white foam. MS: 483.2 (MH+, 2Cl).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([CH2:8][CH2:9][CH3:10])[O:4]1.OC1COC(CCC)OC1>[Pd].OCC(CO)O>[CH2:5]([O:6][CH2:7][CH:3]([OH:4])[CH2:2][OH:1])[CH2:8][CH2:9][CH3:10]
Reactant: CCC[C@@H]1OC[C@@H](CO)O1
Agent: [Pd]
Agent: CCCC1OCC(O)CO1
Solvent: OCC(O)CO
Product: CCCCOCC(O)CO
Temperature: 200 °C
Reaction time: 2 h

Procedure:
16.6 g of an equimolar mixture of cis/trans-4-hydroxymethyl-2-propyl-1,3-dioxolane and 5-hydroxy-2-propyl-1,3-dioxane were combined with 100 g of glycerin (glycerol) in a 300 mL stainless steel autoclave. 2.0 g of 5% Pd/C catalyst were added and the autoclave was sealed. The reactor was heated to 200° C. The reactor was then brought to an operating pressure of 6.89 MPa and stirring commenced at 750 rpm. Pressure was maintained through the duration of the experiment. After 2 h, the autoclave was cooled and remaining gas vented. The autoclave was opened, its contents filtered, and the filtrate analyzed by gas chromatography (GC). 76% conversion of the acetal mixture was observed. Upon analysis of the results, the mixture was found to demonstrate 26.1% selectivity to 2-butoxy-1,3-propanediol, 71.7% 3-butoxy-1,2-propanediol, and the balance n-butanol.
Reaction SMILES: C(=O)=[O:2].CC(C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:18][C:19]1[N:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:27]([CH3:28])=[C:23]2[N:22]=[C:21]([CH3:36])[C:20]=1[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:18][C:19]1[N:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:27]([CH3:28])=[C:23]2[N:22]=[C:21]([CH3:36])[C:20]=1[CH:37]([OH:2])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)Cc1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reactant: O=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reaction time: 0.33 h
Yield: 51.9 %

Procedure:
To a cold (−78° C. dry ice/acetone) stirred solution of 0.91 M KHMDS in THF (32 ml, 29.1 mmol) in additional THF (100 ml) was added ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.3 g, 21.94 mmol) in THF (100 ml), by dropwise addition over 30 min. The mixture was stirred for 20 min, and then a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (7.45 g, 28.5 mmol) in THF (50 ml) was added. The reaction was stirred for 2.5 hrs at −78° C. The orange reaction mixture was quenched with sat. NH4Cl (100 mL), diluted with EtOAc (300 mL), washed with water (200 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to give a yellow solid. The crude residue was loaded onto a flash silica gel column and eluted with 10%-30% EtOAc in hexanes. Product fractions were pooled and concentrated under reduced pressure, affording ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5.4 g, 11.40 mmol, 51.9% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.89-7.84 (m, 1H), 7.74 (dt, J=7.2, 1.6 Hz, 1H), 7.44-7.36 (m, 2H), 5.73 (s, 1H), 4.32-4.26 (m, 2H), 3.65 (br. s., 1H), 2.63 (s, 3H), 2.51 (s, 3H), 1.24 (t, J=7.02 Hz, 3H). LCMS (M+H)=394.06.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][C:13]([OH:15])=[O:14])=[N:8][C:7]=2[CH:28]=1)#[N:2].CO.[CH2:31]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][C:13]([O:15][CH3:31])=[O:14])=[N:8][C:7]=2[CH:28]=1)#[N:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2o1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-3-(5-cyanobenzo[d]oxazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoic acid (Example 148-B) (60 mg, 0.160 mmol) in DCM (639 μl) were added MeOH (16.17 μl, 0.400 mmol), DMAP (3.91 mg, 0.032 mmol) and DCC (52.8 mg, 0.256 mmol) successively. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with a saturated solution of ammonium chloride, diluted with DCM and water and passed through a phase separator. The organic layer was concentrated to give crude product that was purified via FCC with Heptane/AcOEt (100/0 to 0/100) to obtain the title compound. (ESI+) m/z 390.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>>[Br:18][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([F:10])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(F)cccc1Cl
Product: N#Cc1c(F)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-fluorobenzonitrile (15.6 g, 100 mmol) was dissolved in trific acid (75 mL) at 0° C., then NBS (17.8 g, 100 mmol) was added. The reaction was warmed up to room temperature and stirred overnight. The reaction mixture was poured into ice and extracted with DCM (2×). DCM layers were washed with NaHCO3 and brine. The DCM was dried over Na2SO4 then filtered and concentrated. The product was purified by chromatography through a 330 g ISCO Redi-Sep column with 10-20% ethyl acetate/hexane solvent system to yield 3-bromo-2-chloro-6-fluorobenzonitrile.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(O)CCCCBr
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCBr)OCc1ccccc1
Yield: 95.9 %

Procedure:
This compound was prepared from 5-bromopentanoic acid (1.81 g; 10.0 mmol), benzyl alcohol (1.62 g; 15.0 mmol), and p-toluenesulphonic acid (50 mg) in toluene (100 mL) using Procedure B. 2.60 g (96%) product was obtained (clear oil). The product was used in 8c without further purification.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C@H:15]2[CH2:28][C:29](=O)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:10]=[CH:11][C:12]=1[Cl:13].[C:37]([NH2:40])(=[S:39])[CH3:38].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C1(C)C=CC=CC=1.C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:16][C@H:15]2[CH2:28][C:29]2[N:40]=[C:37]([CH3:38])[S:39][C:30]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CCOC(=O)CC(=O)C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(N)=S
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(C)nc1C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.4 %

Procedure:
Sulfuryl chloride (0.094 mL, 1.16 mmol) was added to a solution of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-(4-ethoxy-2,4-dioxobutyl)-1,4-oxazepane-4-carboxylate (500 mg, 1.05 mmol) in toluene (5 mL). The reaction mixture was stirred at room temperature for 45 min, and concentrated under reduced pressure. To the residue were added ethanol (5 ml) and thioacetamide (87 mg, 1.16 mmol), and the mixture was stirred at 80° C. for 1.5 hr. To the reaction mixture were added triethylamine (0.294 mL, 2.11 mmol) and di-tert-butyl dicarbonate (0.291 ml, 1.26 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (358 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[C:15](OCC1C=CC=CC=1)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][OH:16]
Reactant: O=C(OCc1ccccc1)c1cccc2cc(-c3nccs3)[nH]c12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of benzyl 2-(1,3-thiazol-2-yl)-1H-indole-7-carboxylate (1.39 g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.200 g), and the mixture was stirred at room temperature for 1 hr. Lithium aluminum hydride (0.600 g) was added to the reaction solution, and the mixture was stirred at room temperature for 4 hr. Sodium sulfate-decahydrate (7.80 g) was added to the reaction mixture, and the mixture was stirred for 30 min and diluted with ethyl acetate. The obtained suspension was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=15:85-70:30) to give the title compound (0.564 g, yield 59%) as colorless crystals.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[NH:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([O:26][C:24]([C:22]1[CH:23]=[N:19][N:20]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:21]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 60 °C
Reaction time: 11 h
Yield: 68 %

Procedure:
tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate described in Production Example 13-1 (2.7 g, 9.67 mmol) and commercially available ethyl 4-pyrazole carboxylate (1.49 g, 10.6 mmol) were dissolved in N,N-dimethylformamide (30 mL), 50-72% oily sodium hydride (570 mg) was added at 0° C., and the mixture was heated and stirred at 60° C. for 11 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added for partition. The organic layer was washed with water twice and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, the resultant residue was dissolved in dichloromethane, the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1-1:3-0:1), and the target fraction was concentrated under vacuum to obtain the title compound (2.11 g, 68%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH:28]1([CH2:34][NH2:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:34][NH:35][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NCC1CCCCC1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCC2CCCCC2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and C-cyclohexyl-methylamine. The crude product was used without further purification (84%, oil). HPLC-MS: m/z=367.3 (M+1); Rt: 4.28 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.I[CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCI
Reactant: COc1cccc(OC)c1
Product: CCCCc1c(OC)cccc1OC
Yield: 71 %

Procedure:
1,3-Dimethoxybenzene (15.0 g, 109 mmol) was alkylated with 1-iodobutane as described above for the preparation of Example 10(A) except that the final reaction mixture was not refluxed. Purification via silica gel chromatography (ethyl acetate/hexane) provided 15.0 g (71%) of the title intermediate product as a yellow oil: NMR (CDCl3) 7.18 (t, J=8.2 Hz, 1H), 6.59 (d, J=9.7 Hz, 2H), 3.84 (s, 6H), 2.70 (t, J=8.7 Hz, 2H), 1.50 (hextet, J=6 Hz, 2H), 1.44 (quintet, J=6 Hz, 2H), 0.98 (t, J=8.2 Hz, 3H); MS-FD m/e 194 (p).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.[O:29]=[C:30]([OH:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[O:29]=[C:30]([O-:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Solvent: O
Solvent: CCO
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
A solution of 3.93 gm of m-AMSA and 5.15 gm of D-gluconic acid-water solution (38% w/w) in 305 ml of specially denatured 3A anhydrous ethanol at 70°-80° C. is filtered with suction. The filtrate is cooled to 30°-35° C. and 100 ml of anhydrous diethyl ether is added with stirring. After chilling to 0°-5° C. with stirring, the mixture is stored about 16 hours at 5° C. The product is collected, washed with specially denatured 3A anhydrous ethanol and anhydrous diethyl ether (3:1) at 5° C., then with several portions of anhydrous ether and dried under reduced pressure at 50°-55° C. to give 3.95 gm of m-AMSA D-gluconate. The salt obtained by this process retains a small amount (about 1% of ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][NH:49][CH3:50])=[CH:44][CH:43]=2)[CH:41]=[CH:40][N:39]=[CH:38]1>C1COCC1.C(Cl)Cl>[N:37]1([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][N:49]([CH3:50])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:46][CH:47]=2)[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: CNCc1ccc(-n2ccnc2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-n4ccnc4)cc3)co2)c(C)c1
Reaction time: 2 h

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (53 mg, 0.15 mmol) was dissolved in THF (0.5 mL) and CDI (24 mg, 0.15 mmol) added. The reaction was stirred for 2 h prior to addition of 1-[4-(1H-imidazol-1-yl)phenyl]-N-methylmethanamine (25 mg, 0.135 mmol). The reaction was stirred at ambient temperature for 3 days, and diluted with DCM (1 mL) and washed with 2M aqueous K2CO3 (1 mL). The organic layer was dried over MgSO4, the solvent removed in vacuo and a portion of the crude product purified using prep method A.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][N:3]12.[Cl:16]N1C(=O)CCC1=O>O1CCCC1>[Cl:16][C:15]1[N:3]2[N:2]([CH3:1])[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=1
Reactant: Cn1c2ccccc2c(=O)c2cccn21
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1c2ccccc2c(=O)c2ccc(Cl)n21
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 5-methylpyrrolo[1,2-b]cinnolin-10(5H)-one (5.0 g) in 180 mL of tetrahydrofuran at 0° C. was treated with N-chlorosuccinimide (3.4 g) all at once and the mixture was stirred at ambient temperature. After 36 h the solution was concentrated and the residue taken up in chloroform. This solution was washed with two 100 ml portions of water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, dichloromethane) to give 2.83 g of an off-white powder, mp 88.5°-90.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[O:19][C:18]([C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([C:3]5[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[NH:10][C:11]=4[CH:17]=3)=[N:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: O=C(NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Clc1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cc1
Reaction time: 0.33 h

Procedure:
To a 20 mL microwave vial was added 0.500 g (1.09 mmol) of 4-Chloro-benzoic acid N′-[2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carbonyl]-hydrazide, 13 mL of THF, and 0.5187 g (2.18 mmol) of Burgess Reagent. The suspension was placed in the microwave at 150° C. for 20 min. The crude solution was concentrated and the residue was purified by silica gel column chromatography (ACN/DCM, 1:9 to 6:4) to give of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.67 (m, 1H) 7.68-7.74 (m, 4.5H) 7.78-7.81 (m, 0.6H) 7.94 (d, J=8.46 Hz, 0.5H) 8.02-8.10 (m, 1H) 8.17-8.22 (m, 2H) 8.33 (d, J=1.01 Hz, 0.4H) 8.49-8.52 (m, 0.6H) 13.36 (d, J=10.36 Hz, 1H). MS (m/z) 442.9 M (+1), tR=1.49, Meth 10
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])=[C:4]([CH2:19][N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21](=[O:24])[O:22][CH3:23])[CH:3]=1.CCCCCON=O.[I:48]I.CCOC(C)=O.CCCCCC>C(Cl)(Cl)Cl.C(Cl)Cl>[F:38][C:36]([F:39])([F:37])[C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=1)[CH2:25][N:20]([CH2:19][C:4]1[CH:3]=[C:2]([I:48])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=1[O:17][CH3:18])[C:21](=[O:24])[O:22][CH3:23]
Reactant: II
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(N)ccc1-c1cc(C(C)C)ccc1OC
Agent: CCCCCON=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(I)ccc1-c1cc(C(C)C)ccc1OC

Procedure:
To a solution of the methyl [(4-amino-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl][3,5-bis(trifluoromethyl)benzyl]carbamate from Example 9 (0.31 g, 0.56 mmol) in chloroform (10 ml), n-amyl nitrite (0.11 ml, 0.84 mmol) and iodine (0.28 g, 1.1 mmol) were added. The mixture was heated to and maintained at reflux for 2 h. TLC analysis (5:95 EtOAc/hexane) showed completion of the reaction. The mixture was diluted with methylene chloride (20 ml) and washed with saturated sodium thiosulfate solution, brine. The light yellow solution was dried over sodium sulfate. The title compound was obtained by flash column chromatography using 5:95 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.74 (s, 1H), 7.67 (dd, J=8.0, 2.0 Hz, 1H), 7.47 (m, 1H), 7.31 (dd, J=8.0, 2.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.91 (dd, J=4.0, 2.5 Hz, 1H), 6.87 (d, J=8.5 Hz, 1), 4.20-4.48 (m, 4H), 3.78 (s, 3H), 3.70 (s, 3H), 2.92 (m, 1H), 1.23 (s, 3H), 1.21 (s, 3H), LC-MS (M+1) 666.0 (4.74 min).