Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=2)[C:11](O)=[O:12])=[N:6][CH:7]=1.Cl.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@H:36]([NH2:38])[CH3:37])=[N:34][CH:35]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@H:36]([NH:38][C:11](=[O:12])[C:10]2[CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:9]=2)[CH3:37])=[N:34][CH:35]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Reactant: C[C@@H](N)c1ccc(F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)cn3)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoic acid (11.7 g, 27.1 mmol) in N,N-dimethylformamide (150 mL) were added (1R)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride salt (7.5 g, 35.2 mmol), EDC (7.78 g, 40.6 mmol), HOAT (1.84 g, 13.5 mmol) and triethylamine (26.4 mL, 189 mmol). The reaction mixture was heated to 50° C. After 2 h, the mixture was cooled to ambient temperature and water was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane—*40% dichloromethane/acetone) gave the title compound (10.67 g). HRMS 482.1999 (M+1). NMR (400 MHz, CDCl3): δ 8.57 (ddd, J=4.8, 1.8, 1.0 Hz, 1H); 8.49 (d, J=2.1 Hz, 1H); 8.45-8.39 (m, 3H); 8.16 (t, J=1.6 Hz, 1H); 7.71-7.66 (m, 2H); 7.59-7.52 (m, 3H); 7.37 (td, J=8.3, 2.8 Hz, 1H); 7.30 (dd, J=8.6, 4.4 Hz, 1H); 7.21 (ddd, J=7.6, 4.9, 1.2 Hz, 1H); 5.87 (dd, J=10.7, 7.1 Hz, 1H); 5.41-5.31 (m, 1H); 3.92-3.78 (m, 2H); 2.36 (s, 3H); 1.55 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:17])([O-])=O.[H][H]>CN(C)C=O.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:17]
Reactant: [H][H]
Reactant: O=C(O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1cccc2c(=O)c(C(=O)O)c[nH]c12
Yield: 74.2 %

Procedure:
A solution of 15.0 g (64 mmol) of 1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid [J. Amer. Chem. Soc., 68, 1264 (1946)] in 300 ml of dimethylformamide is hydrogenated using 1 g of Raney nickel catalyst at 51 psi and 23° until the required amount of hydrogen uptake is obtained. The catalyst is filtered off and the filtrate is concentrated to 50 ml and ethanol is added. The solid is collected by filtration and washed with ethanol and ether to give 9.7 g of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19]O.C(N(CC)CC)C.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>C(Cl)Cl>[CH3:45][S:42]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][S:42]([CH3:45])(=[O:44])=[O:43])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(CCCCO)CCCCCCCCN(CCCCO)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCCCCCCCN(CCCCS(C)(=O)=O)C(=O)OC(C)(C)C)CCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cool to 0° C. a mixture containing 3.0 gm of the product of Step F, 3.3 ml of triethylamine and 70 ml of CH2Cl2. In a dropwise fashion add 1.22 ml of mesylchloride in 10 ml of CH2Cl2, and stir the resulting mixture at 0° C. for 11/2 hours. Pour the mixture into 100 ml of CH2Cl2, wash with 200 ml of 1N AcOH, 100 ml of water, 100 ml of sat'd sodium bicarbonate, dry over MgSO4 and remove the solvent in vacuo. Flash chromatograph the residue, eluting from silica gel with 60% EtOAc/hexane to obtain 3.5 gm of the desired product. Rf is 0.39.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[CH2:35]1[CH2:40][CH2:39][CH:38]([C:41](=[O:46])[CH2:42][C:43](=O)[CH3:44])[CH2:37][CH2:36]1>>[CH:38]1([C:41](=[O:46])/[CH:42]=[C:43](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:44])[CH2:39][CH2:40][CH2:35][CH2:36][CH2:37]1
Reactant: CC(=O)CC(=O)C1CCCCC1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)C1CCCCC1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 428 mg (0.89 mmol) of Intermediate 45 (as the TFA salt) and 150 mg (0.89 mmol) of Intermediate 33 to yield 245 mg (53% yield) of Example 43 as a solid beige-colored glass: TLC (DCM/MeOH (4:1): Rf=0.69; 1H NMR (DMSO-d6, 400 MHz) δ10.79 (d, 1H, J=9.0), 7.89 (m, 2H), 7.50-7.41 (m, 3H), 7.05 (d, 2H, J=8.4), 6.77 (d, 2H, J=8.4), 4.7 (s, 1H), 4.12 (t, 2H, J=6.5), 3.9 (br s, 1H), ), 3.04 (dd, 1H, J=13.6, 4.0), 2.87 (t, 2H, J=6.5), 2.64 (dd, 1H, J=13.6, 8.9), 2.32 (s, 3H), 1.9 (m, 1H), 1.6 (m, 4H), 1.5 (s, 3H), 1.25-1.05 (m, 4H): low resolution MS (ES+)m/e 517.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1N>C(O)C.[Ni]>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: Cc1c(N)cc([N+](=O)[O-])c2ccccc12
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(N)c2ccccc12
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To a solution of 1-methyl-4-nitro-naphthyl-amine (4.0 g, 21 mmol) in ethanol (300 mL) was added Raney-Nickel (4 scoops). The mixture was stirred under H2 (1 atm) for 16 h. The reaction was filtered through a pad of Celite and concentrated. Purification by silica gel flash column chromatography (EtOAc:Hexanes=15:85) provided product (3.2 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].CO.C[O-].[Na+]>>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(CBr)OC
Reactant: Fc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(CSc1ccc(F)cc1)OC
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
In a nitrogen stream, 4-fluorobenzenethiol (2.5 ml, 23.4 mmol) and 2-bromo-1,1-dimethoxyethane (3.0 ml, 25.7 mmol) were added to a sodium methoxide methanol solution (0.5 M, 74.9 ml, 37.4 mmol) under cooling with ice and the reaction mixture was stirred at the same temperature for 10 minutes, and then heated and refluxed for five hours. The reaction mixture was concentrated under reduced pressure, and added with cold water. The mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution, and then dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (4.52 g, 89%).
Reaction SMILES: Cl.[C:2]([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])(=[O:6])[C:3]([CH3:5])=[CH2:4].O.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].C(=O)(O)[O-].[Na+]>CC(C)=O>[C:2]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:17]1[N:19]=[C:20]([Cl:21])[N:13]=[C:14]([Cl:15])[N:16]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=C(C)C(=O)NCCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(=O)NCCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of 71.6 g (0.4 mole) of 3-methacrylamidopropylamine hydrochloride in 400 ml. of water being stirred at 0°-5° C. was added dropwise a solution of 79 g (0.4 mole) of cyanuric chloride in 400 ml of acetone. To this mixture was then added in portions 67.2 g (0.8 mole) of sodium bicarbonate over the course of 1 hr. The mixture was stirred at room temperature for an additional hour and then 2 l of water was added. The product was collected by filtration and dried in vacuo at room temperature to yield 75.8 g. The product was recrystallized from 600 ml of ethyl acetate to give 53.2 g (46%) (mp 138°-140° C.).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[N:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13]([N:12]([C:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[NH:11][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH3:17]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)NN(C(=O)OCC)C1(C(=O)OC)CCCC1=O
Reaction time: 0.5 h
Yield: 130.9 %

Procedure:
To a solution of methyl 2-oxocyclopentanecarboxylate (15.6 mg, 0.11 mmol) and (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (4.1 mg, 0.01 mmol) in toluene (1 mL) was added diethyl azodicarboxylate (45.5 μL, 0.10 mmol) at room temperature. After stirring for 0.5 hr, the reaction mixture was concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=3/1) to give the title compound (41.4 mg, yield: 92%).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH3:27])=[O:17])[CH:8]=[CH:7]2>CC(O)=O>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH3:27])=[O:17])=[CH:10]2
Reactant: Cc1oc2ccccc2c1C(=O)NCc1ccc2cc(O)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
Bromine (83 μL, 1.61 mmol) in 15 mL of glacial HOAc was added under nitrogen dropwise over 3 h to a solution of 2-methyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (537 mg, 1.62 mmol), prepared in the previous step, in 60 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue partitioned between 20% MeOH in methylene chloride and 5% NaHCO3. After separating the organic layer the aqueous layer was extracted three times with 20% MeOH in methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 2-methyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (690 mg, 100%) as a brown solid, mp 179-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:8]([CH:23]=[O:24])=[CH:7]2.O1CCCC1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]([F:22])([F:20])[F:21])[C:8]([CH2:23][OH:24])=[CH:7]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of 8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde (0.3036 g, 0.8584 mmol) in tetrahydrofuran (4.292 mL, 0.8584 mmol) at 0° C. was added sodium borohydride (0.04871 g, 1.288 mmol) and the mixture was stirred at 0° C. After 1 h of stirring at 0° C., the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), and the organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)-quinolin-3-yl)methanol as a light-yellow syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (1 H, s), 8.10 (1 H, dd, J=8.2, 1.2 Hz), 8.01 (1 H, dd, J=8.8, 5.3 Hz), 7.95 (1 H, dd, J=7.6, 1.4 Hz), 7.53-7.69 (3 H, m), 5.55 (1 H, br. s.), 4.25-4.56 (2 H, m); LC-MS (ESI) m/z 356.0 [M+H]+. The light-yellow syrupy solid was carried on crude without purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (1.50 g), ethyl 8-oxo-8-phenyloctanoate (2.54 g), acetic acid (0.830 ml), sodium acetate (793 mg) and ethanol (40 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate (2.02 g, yield 76%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][CH2:16][C:17]#[N:18].F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[C:16]([CH2:17][NH:18][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])#[N:15]
Reactant: N#CCN
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#CCNC(=O)c1ccc2ncccc2c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a solution of quinoline-6-carboxylic acid (500 mg, 2.9 mmol) and amino acetonitrile hydrochloride (320 mg, 3.4 mmol) in N,N-dimethylformamide (10 mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (1.5 g, 3.48 mmol) and triethylamine (1.2 mL, 8.7 mmol), and the solution was stirred at 60° C. for 10 minutes. Ethyl acetate and water was added to the reaction solution, which was then partitioned, the organic layer was washed twice with water. Silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purified by NH silica gel column chromatography (ethyl acetate), and the title compound (420 mg, 2.0 mmol, 68.9%) was obtained as a light brown solid.
Reaction SMILES: C(OC([NH:8][N:9]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[C:10]1[CH:16]1[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CO.O1CCOCC1>[NH2:8][N:9]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[C:10]1[CH:16]1[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19]1
Reactant: CC(C)(C)OC(=O)Nn1c(C#N)ccc1C1CN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc(C2CN(C(=O)OCc3ccccc3)C2)n1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
To a cooled (0° C.) solution of benzyl 3-{1-[(tert-butoxycarbonyl)amino]-5-cyano-1H-pyrrol-2-yl}azetidine-1-carboxylate (800 mg, 2.02 mmol) in methanol (2.5 mL) was added a solution of 4 M HCL in dioxane (2.5 mL). The reaction was stirred (0° C.) for 15 min, then was allowed to warm to rt. After 4 h, the reaction was recooled (0° C.) and the mixture was made basic (pH 9) with slow addition of 2M aqueous Na2CO3. The mixture was allowed to warm to rt and was extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried (Na2SO4), and evaporated to afford 575 mg (96%) of the desired product, which was used without further characterization.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(N(CC)CC)C.[CH2:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26].S(Cl)(Cl)=O>ClCCl>[CH2:25]([N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[C:11]([C:2]=1[OH:1])=[C:10]([Br:12])[CH:9]=[CH:8][CH:7]=2)=[O:17])[CH3:26]
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Br)cccc21
Reactant: CCNc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(C(=O)c1c(O)c2c(Br)cccc2n(C)c1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To an ice-cold solution of 1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid (9.6 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) and N-ethylaniline (4.2 g, 0.035 mol) in 150 ml of dichloromethane was added dropwise during 0.5 hours a solution of thionyl chloride (3.0 ml, 0.042 mol) in 10 ml of dichloromethane. The stirring was continued at 4° C. for 24 hours. The solvents were evaporated. The residue was dissolved in ethyl acetate, filtered through celite and extracted with 2 M sodium hydroxide. The aqueous phase was washed with ethyl acetate and then acidified with hydrochloric acid to pH 5. On standing a crystalline precipitate was formed which was filtered off, washed with water and dried to give the title compound (8.5 g), yield 69%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([OH:25])[CH:4]=1.N1C=CC=CC=1.[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[S:33]([O:25][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[C:19]2[C:6]=1[C@@:7]1([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]1)(=[O:34])=[O:32]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 29) (0.61 g, 1.69 mmol) in CH2Cl2 (40 mL), pyridine (0.20 g, 2.54 mmol) was added and the mixture was cooled to 0° C. Tf2O (0.62 g, 2.20 mmol) was added dropwise to the reaction mixture and stirred for 1.5 h. The reaction was diluted with CH2Cl2 and washed with water (2×40 mL). The organic layer was separated, dried (Na2SO4) and concentrated giving (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl trifluoromethanesulfonate (Compound No. 32) (0.825 g, 98%) as a yellow foam. 1H NMR (CDCl3): δ 6.58 (d, 2H), 3.75 (s, 3H), 2.90 (m, 3H), 1.80-1.40 (m, 8H), 1.38 (s, 3H), 1.25-1.00 (m, 2H), 0.95 (s, 3H), 0.90 (m, 1H), 0.85 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[CH:5]=1.[CH2:21]([N:23]([CH2:37][CH3:38])[C:24](=[O:36])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH3:22].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]([S:32]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:24]([N:23]([CH2:37][CH3:38])[CH2:21][CH3:22])=[O:36])=[CH:31][CH:30]=3)(=[O:34])=[O:33])[C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1Cl
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)n2c(=O)n(-c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
0.075 g of sodium hydride as a 60% dispersion in oil is added to a solution of 0.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-2H-benzimidazol-2-one in 40 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride is then added and the mixture is stirred for 4 hours at RT. The reaction mixture is poured into iced water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.45 g of the expected product. M.p.=222° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:6].C([C:29]1[C:30]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:31][CH:32]=[CH:33][CH:34]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([S:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:2]([NH:1][C:39]3[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][C:30]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)=[CH:10][CH:11]=1
Reactant: Nc1cc(C(=O)NCc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: O=C(NCc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 26 %

Procedure:
The product of Example 33A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 33A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (26 mg, 26%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 4.41 (d, J=5.88 Hz, 2 H) 6.76-6.96 (m, 1 H) 6.83 (d, J=8.46 Hz, 2 H) 7.20-7.33 (m, 4 H) 7.51 (d, J=8.46 Hz, 2 H) 7.58-7.80 (m, 2 H) 7.82-7.97 (m, 1 H) 8.52-8.69 (m, 1 H) 8.86-9.18 (m, 3 H) 9.94 (s, 1 H) 10.28 (s, 1 H); MS (ESI+) m/z 558/560 (M+H)+.