Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2Cl)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.9 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-chlorobenzene-1-sulfonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a brown solid. MS (ESI+) for C18H19ClN2O3S m/z 379 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[C:7]2[OH:20])([O-:3])=[O:2].[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](=[O:25])[O:20][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH3:22]
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(O)c2c1
Reactant: CCN(CC)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cc(-c2ccccc2)nc2ccc([N+](=O)[O-])cc12
Yield: 77.7 %

Procedure:
The procedure is as in Example 70, starting with 6-nitro-2-phenyl-4-hydroxyquinoline (6 g) in tetrahydrofuran (60 cc), N,N-diethylcarbamoyl chloride (6.1 g), triethylamine (6.3 cc) and 4-dimethylaminopyridine (1.3 g). The residue is recrystallized twice in ethyl acetate. 6-Nitro-2-phenyl-4-quinolyl diethylcarbamate (6.4 g), m.p. 140° C., is thereby obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH:25]([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([CH:25]([F:26])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Product: FC(F)c1nnc2ccc(N3CCCN(Cc4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzyl-1,4-diazepane and 6-chloro-3-difluoromethyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 1 to give 6-(4-benzyl-1,4-diazepan-1-yl)-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[C:16]([O:19][C:20]([CH3:26])([CH2:22][CH2:23][CH:24]=O)[CH3:21])(=[O:18])[CH3:17].C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Ti](Cl)(Cl)(Cl)Cl>[C:16]([O:19][C:20]([CH3:26])([CH2:22][CH2:23][CH2:24][N:8]1[CH2:7][C@@H:6]2[CH2:12][O:13][CH2:14][CH2:15][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[CH3:21])(=[O:18])[CH3:17]
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CC(=O)OC(C)(C)CCC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 200 mg, 0.882 mmol) and 2-methyl-5-oxopentan-2-yl acetate (55.8 mg, 0.353 mmol) were combined in a 25 mL pear flask to give an orange suspension. Titanium(IV) chloride in DCM (1M, 0.971 mL, 0.971 mmol) was added at room temperature to give a deep-red suspension, which was stirred at room temperature for 1 hour before being cooled to 0° C. Sodium triacetoxyborohydride (281 mg, 1.324 mmol) was added at 0° C. in portions. The thick suspension slowly turned into a thinner, orange one with gas evolution. UPLC showed the reaction proceeded more than half-way after about 20 minutes. The reaction mixture was carefully quenched with brine, and was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted a second time with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C17H25ClN4O3, 369.17; found 396.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:30]>C(O)C.O1CCCC1>[Na+:30].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C([O-])CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the ester of Example 5, Step 2, (15 g) in ethanol (200 ml) and tetrahydrofuran (200 ml) was added 2N NaOH (35 ml). The reaction was stirred at room temperature overnight and the product filtered The solid was stirred for 2 hours at room temperature in ethanol (100 ml) and filtered to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[S:24][C:25]([CH2:28]Cl)=[CH:26][CH:27]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:28][C:25]2[S:24][C:23]([Cl:22])=[CH:27][CH:26]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: ClCc1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(Cl)s2)c1C(=O)OC
Yield: 99.3 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.4 g, 6.8 mmol) in acetone (70 mL) and potassium carbonate (2.8 g, 20 mmol) was added 2-chloro-5-chloromethyl-thiophene (0.83 mL, 7.1 mmol) and refluxed for two hours. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(5-chloro-thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (2.3 g, 100% crude yield). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Br[Zn][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:23]([C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Zn]Br
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Product: CCCCc1cc(O)cc2nc(-c3ccc(O)cc3)oc12

Procedure:
The title compound was prepared in substantially the same manner as described in Example 35, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and bromo(butyl)zinc. The desired product was obtained as a white solid, m.p. 125–127° C.; MS m/e 282 (M−H)+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH2:17])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:17][CH2:11][C:12]1[O:16][CH:15]=[CH:14][CH:13]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN=C=S
Reactant: NCc1ccco1
Solvent: c1ccccc1
Product: CCCCCCCNC(=S)NCc1ccco1

Procedure:
To a mixture of 3.1 grams (0.02 mole) of n-heptyl isothiocyanate and 25 milliliters of benzene was added 1.77 milliliters (0.02 mole) of furfuryl amine. The mixture was refluxed for 30 minutes on a steam bath and then evaporated under vacuum to yield 1-n-heptyl-3-furfuryl thiourea. The product was cooled and 4.1 grams (0.02 mole) of bromoethylamine hydrobromide and 25 milliliters of ethanol 2B was added. The resulting mixture was refluxed on a steam bath overnight. The solid product was removed by filtration and air dried. A yield of 5.2 grams of solid, melting point 140°-145° C., was obtained. Structure of the product was confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br-:13].[Br-].O1CCOCC1>O1CCOCC1>[Br:13][CH:10]([CH3:11])[C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[O:12]
Reactant: CCC(=O)c1cc(F)cc(F)c1
Reactant: [Br-]
Solvent: C1COCCO1
Product: CC(Br)C(=O)c1cc(F)cc(F)c1
Yield: 102.1 %

Procedure:
To 3',5'-difluoropropiophenone (56.0 g. 0 33 mole) was added a solution of dioxane dibromide (81.8 g. 0.33 mole) in dioxane (500 ml) The reaction mixture was worked up as in Example 1 to yield crude 2-bromo-3',5'-difluoropropiophenone (83.9 g).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[S:19](=[O:28])(=[O:27])[NH:18]2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[C:34]([CH3:39])=[N:35][O:36][C:37]=1[CH3:38]>>[CH3:39][C:34]1[C:33]([CH2:32][N:18]2[CH:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=3[CH3:29])[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[S:19]2(=[O:28])=[O:27])=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1c(C2NS(=O)(=O)c3cc(F)ccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1noc(C)c1CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccc(F)cc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 13, step e) and chloromethyl-3,5-dimethyl-isoxazole. 1H NMR (DMSO-d6) δ 13.1 (bs, 1H), 7.99 (dd, J=2.4, 7.5 Hz, 1H), 7.47 (dt, J=2.1, 8.8 Hz, 1H), 7.14-6.74 (m, 4H), 5.93 (s, 1H), 5.01 (s, 2H), 4.02 (d, J=15 Hz, 1H), 3.98 (d, 1H, J=15 Hz, 1H), 2.40 (s, 3H), 2.04 (s, 3H), 1.71 (s, 3H); MS: ESI (negative): 482 (M−H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Cl:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][C:15]([C:17]2[S:21][C:20]([Br:22])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1>CS(C)=O>[Br:22][C:20]1[S:21][C:17]([C:15]2([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:24][CH:23]=3)[CH2:4][O:16]2)=[CH:18][CH:19]=1
Reactant: O=C(COc1ccc(Cl)cc1)c1ccc(Br)s1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ccc(OCC2(c3ccc(Br)s3)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g (0.05 mol) of 80% strength sodium hydride are added in portions to a suspension of 11 g (0.05 mol) of trimethylsulphonium iodide in 100 ml of dimethyl sulphoxide under a nitrogen atmosphere, and the mixture is stirred for a further 30 minutes at room temperature. A solution of 15.5 g (0.046 mol) of 2-bromo-thien-5-yl 4-chlorophenoxymethyl ketone in a small amount of dimethyl sulphoxide is then added dropwise, and the mixture is heated to 6O° C. for 1 hour. The reaction mixture is then poured onto water, and extracted with methylene chloride. The organic phase is washed several times with water, dried over magnesium sulphate and evaporated down. Crude 2-(2-bromo-thien-5-yl)-2-(4-chlorophenoxymethyl)-oxirane is obtained as a viscous oil, which is directly reacted further. ##STR9##
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O.O.NN>CO>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCCCO
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCCCCCCCCCCCO

Procedure:
To a suspension of N-(14-hydroxytetradecyl)phthalimide in 100 ml of methanol was added 0.87 g of hydrazine monohydrate and the mixture was heated under reflux for 3 hours. The reaction solution was distilled under reduced pressure and the residue was diluted with a 1N aqueous solution of sodium hydroxide and then extracted twice with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then distilled under reduced pressure. Chromatography over silica gel afforded the title compound as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=1[OH:28])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:49]1[C:58]2[C:53](=[C:54]([CH2:59][CH2:60]O)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][CH:50]=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=1[O:28][CH2:60][CH2:59][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[CH:52]=[CH:51][CH:50]=[N:49]2)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1cccc2ncccc12
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
To a methylene chloride solution of 3-(4-carbamoyl-2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester at room temperature was added triphenylphosphine (0.25 g, 0.95 mmol), 2-quinolin-5-yl-ethanol (0.11 g, 0.66 mmol) and diethyl azodicarboxylate (0.17 ml, 1.12 mmol). The reaction was stirred at room temperature for 3 days. The reaction was then concentrated under reduced pressure. The crude residue was chromatographed [silica gel with a gradient of 100% ethyl acetate to 10% (1:9 NH4OH/ethanol) in ethyl acetate] to give 3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a white foam (0.27 g, 69%). 1H NMR(300 MHz, DMSO) 8.90 (d, 1H), 8.73 (d, 1H), 8.08 (s, 1H), 7.93 (d, 1H), 7.62 (m, 8H), 4.43 (m, 3H), 3.71 (m, 2H), 3.47 (bs, 3H), 2.77 (bs, 3H), 2.54 (dd, 1H), 2.34 (dd, 1H), 1.31 (s, 9H). MS(APCI) m/z 585.1 (M−H), 587.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:21]=[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:20])[C:14]2=[N:13]1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:21]=[C:15]2[CH:16]=[N+:17]([O-:30])[CH:18]=[C:19]([F:20])[C:14]2=[N:13]1
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
2-(2,6-Dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (4.78 g, 14.62 mmol) was dissolved in DCM (90 mL) and a solution of meta-chloroperbenzoic acid (3.78 g, 21.93 mmol) in DCM (60 mL, which had been pre-dried over anhydrous sodium sulfate and passed through a phase separator), was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 4 hours. Another portion of meta-chloroperbenzoic acid (1.26 g, 7.30 mmol) in DCM (20 mL, dried as above) was added and the reaction mixture was stirred for a further 1.25 hour at room temperature. The resultant mixture was sequentially washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and brine. The combined aqueous extracts were further extracted with DCM and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether (×3) and the solid was collected by filtration and dried under reduced pressure to afford the title compound as a pale yellow solid (4.20 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 8.64 (d, J=1.4 Hz, 1H), 8.42 (s, 2H), 8.20 (d, J=2.3 Hz, 1H), 8.02 (dd, J=5.4, 1.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][C:34]=1[O:43][CH2:44][CH3:45])[CH3:30].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>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])=[CH:35][C:34]=1[O:43][CH2:44][CH3:45])[CH3:30]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OCC
Yield: 80 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with 4-carboxymethyl-2-ethoxy-benzoic acid ethyl ester (Aldrich, 50.4 mg, 0.20 mmol), in the presence of HATU (91.0 mg, 0.24 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) at rt for 2 hrs to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-ethoxy-benzoic acid ethyl ester (52.6 mg, 37.6%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][C:37]=1[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:47][S:44]([C:37]3[CH:38]=[C:39]([CH2:42][CH3:43])[CH:40]=[CH:41][C:36]=3[Cl:35])(=[O:46])=[O:45])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: CCc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.38 mmol, prepared as described in Example 1 Step C) in a 1:1 mixture of t-butanol (5 mL) and dichloromethane (5 mL) was added 4-(dimethylamino)pyridine (138 mg, 1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol). The reaction mixture was stirred for 15 min, 2-chloro-5-ethylbenzenesulfonamide (74 mg, 0.34 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (100 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×50 mL), and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 84 mg of the title compound, a compound of the present invention, as a solid, m.p. 214-215° C. 1H NMR (CDCl3) δ 10.12 (br s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.53 (s, 1H), 7.40 (s, 2H), 2.77 (q, 2H), 1.30 (t, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+].O>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:3]1[C:2]([N:4]2[CH2:5][CH2:11][O:14][CH2:2][CH2:3]2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ncccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ncccc1N1CCOCC1

Procedure:
To a solution of 3-bromo-2-nitropyridine (207 mg, 1 mmol) in DMSO (2 mL) was added at room temperature under stirring and under an atmosphere of nitrogen morpholine (95.8 mg, 95.8 μL, 1.1 mmol), tetrabutyl ammonium iodide (18.5 mg, 50.0 μmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction was stirred at 80° C. over night. Water was added and the aqueous phase was extracted twice with diethyl ether. The combined organic layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow oil (57 mg, 27%) after column chromatography on silica gel using a gradient from heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent.
Reaction SMILES: Cl[CH:2]([S:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:8][S:7][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)SC
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C(SC)c1ccccc1

Procedure:
In a round-bottom glass flask equipped with a magnetic stir bar methyl 2-chloro-2-(methylthio)acetate (1.3 g, 1 equiv) was dissolved in benzene (20 mL) and aluminum chloride (3.36 g, 2.8 equiv) added in one portion and heated to reflux for 3 hours. The mixture was then cooled and washed with H2O, brine, and dried over MgSO4. The organic layer was concentrated under reduced pressure to yield a yellow oil that was used without further purification (0.56 g, 35%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]4([OH:23])[CH2:22][NH:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:24]=1.[CH:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1>>[Br:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]4([OH:23])[CH2:20][N:21]([C:29]([CH:26]5[CH2:28][CH2:27]5)=[O:30])[CH2:22]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:24]=1
Reactant: O=C(O)C1CC1
Reactant: NC(=O)c1nc2n(c1C1(O)CNC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1C1(O)CN(C(=O)C3CC3)C1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with tert-butyl 3-oxoazetidine-1-carboxylate similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-3-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L then deprotected with 4N HCl in dioxane (5 eq) at room temperature to provide 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with cyclopropane carboxylic acid similar to as described in Example 2 with non-critical modifications to afford crude 10-bromo-3-(1-(cyclopropanecarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was then reacted with 2-Methyl-3-butyne-ol via General Procedure F to afford 7.9 mg (71.8%) 3-[1-(cyclopropanecarbonyl)-3-hydroxy-azetidin-3-yl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.