Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27]O)[C:14]=2[CH3:29])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:50]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27][Br:50])[C:14]=2[CH3:29])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CO)c2C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CBr)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A stirred, cooled (ice bath) solution of [4-(5-tert-butyl-3-hydroxymethyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 147, 0.15 g, 0.37 mmol) and triphenylphosphine (0.125 g, 0.48 mmol) in anhydrous dichloromethane (5 mL) was treated with N-bromo succinimide (0.085 g, 0.48 mmol) under argon and the resulting reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with dilute, aqueous sodium bicarbonate solution and extracted with diethyl ether. The organic phase was washed with water (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that on flash column chromatography over silica gel (230–400 mesh) using 4–5% ethyl acetate in hexane as the eluent afforded the title compound (0.12 g, 69%) as a colorless oil. It was used as such for the next step.
Reaction SMILES: [CH:1]([C@:4]1([C:24]([OH:26])=O)[CH2:8][CH2:7][C@@H:6]([N:9]([C@H:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[O:22][CH3:23])C(=O)C(F)(F)F)[CH2:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[OH:33][C@H:34]1[C@@H:38]2[NH:39][CH2:40][C@H:35]1[N:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2.CCN(CC)CC.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[OH:33][C@H:34]1[C@@H:38]2[N:39]([C:24]([C@@:4]3([CH:1]([CH3:2])[CH3:3])[CH2:8][CH2:7][CH:6]([NH:9][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH:17]4[O:22][CH3:23])[CH2:5]3)=[O:26])[CH2:40][C@H:35]1[N:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2NC[C@@H]1[C@H]2O
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)O)(C(C)C)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1COCCC1NC1CC[C@@](C(=O)N2C[C@@H]3[C@@H](O)[C@H]2CN3C(=O)OC(C)(C)C)(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 250.2 %

Procedure:
To a solution of the (1S,3R)-1-isopropyl-3-(2,2,2-trifluoro-N-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-yl)acetamido)cyclopentanecarboxylic acid (0.95 g, 2.5 mmol) in CH2Cl2 (5 mL) under N2 at 0° C. is added oxalyl chloride (623 mg, 4.98 mmol) and DMF (3 drops). The mixture is allowed to warm to RT and stir for 2 hr, It was then concentrated. The acid chloride was redissolved in DCM (10 ml), cooled to 0° C., and treated with (1R,4R,7S)-tert-butyl 7-hydroxy-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (534 mg, 0.249 mmol), followed by Et3N (0.1 ml, 0.75 mmol). The resulting mixture was warmed to RT and stirred for 2 hrs. The solution was then washed with NaHCO3 (1×5 ml), and brine (1×5 ml). The organic layer was then dried over MgSO4, filtered and concentrated, purified by chromatography (100% EtOAc-60% MeOH/EtOAc) to yield crude intermediate which was dried and concentrated. Then it was dissolved in EtOH (2 ml) and treated with NaOH (3 ml, 7.5 mmol) overnight. The reaction mixture was then purified by chromatography (100% EtOAc-100% MeOH) to yield desired product (300 mg, 25%). LC/MS (M+H)=482.3230 exp, 482.3334 obs; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.67 (dd, J=6.95, 3.66 Hz, 3H) 0.80 (dd, J=6.59, 2.93 Hz, 3H) 1.22 (br. s., 1H) 1.35-1.41 (m, 12H) 1.43-1.48 (m, 2H) 1.55-1.68 (m, 2H) 1.85-1.93 (m, 1H) 1.95-2.04 (m, 1H) 2.16-2.28 (m, 1H) 2.66-2.80 (m, 1H) 2.97-3.02 (m, 1H) 3.03-3.10 (m, 2H) 3.17-3.29 (m, 5H) 3.37-3.47 (m, 1H) 3.47-3.58 (m, 1H) 3.61-3.74 (m, 1H) 3.81-3.89 (m, 1H) 3.94-4.04 (m, 2H) 4.24 (br. s., 1H) 5.65-5.77 (m, 1H)
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:27]1(=O)[CH2:30][CH2:29][CH2:28]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.CC(C)=O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]3([C:5]#[N:6])[CH2:30][CH2:29][CH2:28]3)=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=C1CCC1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC3(C#N)CCC3)cc2)CC1
Reaction time: 15 h
Yield: 84 %

Procedure:
Trimethylsilyl cyanide (0.3 g, 3 mmol) was added dropwise to a mixture of 43a (0.415 g, 1.5 mmol), cyclobutanone (0.21 g, 3 mmol) and sodium sulfate (1 g) in dichloromethane (5 ml). The mixture was stirred for 15 hours. After filtration to eliminate sodium sulfate, the medium was concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane:acetone, 75:25) to yield 43b (0.448 g, 1.26 mmol, 84%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[C:27]1[CH2:54][CH2:55][OH:56])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[CH:13]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=2)[C:28]([CH2:36][CH2:37][S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:45][CH:46]=2)(=[O:39])=[O:40])=[C:27]1[CH2:54][CH2:55][O:56][S:2]([CH3:1])(=[O:4])=[O:3])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
CH3SO2Cl (2 eq) and Et3N (2.5 eq) were added to a solution of ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 eq) in CH2Cl2 (0.02M) at 0° C. under N2. After 1 hour the reaction was warmed to room temperature. After an additional hour water was added and extracted with CH2Cl2 and washed with brine and dried over sodium sulfate. Removed solvent to obtain ethyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (white solid) in 98% yield.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][S:11][CH2:12]Cl.C(N(CC)CC)C>>[C:1]([O:9][CH2:10][S:11][CH3:12])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CSCCl
Reactant: CCCCCCC(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting heptanoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 80°-81° C./2 mm Hg, nD20 1.4591.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]=[CH:7][CH:3]([CH2:4]2)[CH2:2]1.[CH2:8]=[CH:9][CH:10]=[CH2:11]>CC1C=CC(O)=CC=1>[CH:3]12[CH2:4][CH:5]([CH:1]3[C:2]1=[CH:11][CH2:10][CH2:9][CH2:8]3)[CH2:6][CH2:7]2
Reactant: C=CC=C
Reactant: C1=CC2CCC1C2
Agent: Cc1ccc(O)cc1
Product: C1=C2C3CCC(C3)C2CCC1
Temperature: 200 °C
Yield: 145.8 %

Procedure:
A 400 ml autoclave was charged with bicyclo[2,2,1]-2-heptene (152 g, Aldrich), 4-methylphenol (1 g, Aldrich), and butadiene (110 g). The mixture was heated at 200° C. for 10 hours. The reaction mixtures from four identical reactions were combined and distilled at atmosphere to give starting bicyclo[2,2,1]-2-heptene (307 g). Further distillation at reduced pressure afforded octahydro-1,4-methanonaphthalene (349 g with 97-98% purity, bp 47° C./0.05 Torr, yield 73%, based on consumed bicyclo[2,2,1]-2-heptene) and about 120 g of product with lower purity (bp 47° C./2 Torr to 58° C./0.16 Torr).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:19](=[O:26])[NH:20][NH:21][C:22]=2[CH:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]([O:30][CH2:31][C@H:32]1[O:37][C@H:36](Br)[C@H:35]([O:39][C:40]([CH3:42])=[O:41])[C@@H:34]([O:43][C:44]([CH3:46])=[O:45])[C@H:33]1[O:47][C:48]([CH3:50])=[O:49])=[O:29].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:40]([O:39][C@@H:35]1[C@@H:34]([O:43][C:44](=[O:45])[CH3:46])[C@@H:33]([O:47][C:48](=[O:49])[CH3:50])[C@@H:32]([CH2:31][O:30][C:28](=[O:29])[CH3:27])[O:37][C@H:36]1[O:26][C:19]1[C:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[C:22]([CH:23]([CH3:24])[CH3:25])[NH:21][N:20]=1)(=[O:41])[CH3:42]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(CCOCc2ccccc2)cc1
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCOCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-{[4-(2-benzyloxyethyl)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:27][NH:28][C@@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=2)[NH:32][C:31]([CH3:45])([CH3:44])[CH2:30]1)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C(C)(C)C)(C)C.C(Cl)Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>O>[CH3:44][C:31]1([CH3:45])[CH2:30][C@H:29]([NH:28][CH2:27][C@@H:9]([OH:8])[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=2)[NH:32]1
Reactant: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C)CC(C)(C)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C)CC(C)(C)N2
Reaction time: 8 h

Procedure:
To a solution of tert-butyl(2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-1-(3-fluorophenyl)butan-2-ylcarbamate (0.231 g, 0.360 mmol) in DCM (1.20 ml, 0.360 mmol) was added tetrabutylammonium fluoride (1.44 ml, 1.44 mmol). The resulting solution was stirred overnight. The mixture was transferred to a sep. funnel containing EtOAc and H2O. The aqueous layer was washed 4× with EtOAc. The proganic layers were combined, dried over MgSO4, filtered and concentrated. The crude mixture was purified by the MPLC. MS m/z: 528 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.N(C1C=CC=C(C)C=1)=[C:11]=[S:12].CCOCC>ClC1C=CC(Cl)=CC=1.CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11]([SH:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: Cc1cccc(N=C=S)c1
Solvent: Clc1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Sc1nnc2ccc(Br)cn12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To the suspended solution of 5-Bromo-2-hydrazinylpyridine (1.85 g, 10 mmol) in a mixture of 1,4-dichlorobenzene and NMP (5:1, 10 ml) was added isothiocyanato-3-methylbenzene (1.5 g 10 mmol). The mixture was stirred at rt for 5 min, 70° C. for 15 min, and then heated under microwave condition at 200° C. for 1.5 h. The mixture was poured into Ether (20 mL). Solid was filtered and the washed with ether to give title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][C:19]3[CH:33]=[CH:32][C:22]4[CH2:23][CH2:24][N:25]([CH2:28][CH2:29]SC)[CH2:26][CH2:27][C:21]=4[CH:20]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.O[O:35][S:36]([O-:38])=O.[K+].[CH3:40]O>O>[CH3:40][S:36]([CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][C:22]2[CH:32]=[CH:33][C:19]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:20][C:21]=2[CH2:27][CH2:26]1)(=[O:38])=[O:35]
Reactant: COc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CCSC)CC4)nc12
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CCS(C)(=O)=O)CC4)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To [8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.256 g, 0.664 mmol) in N,N-dimethylformamide (10 mL) under an atmosphere of nitrogen was added potassium carbonate (0.275 g, 1.99 mmol), 2-chloroethyl methyl sulfide (0.0982 mL, 0.996 mmol), followed by sodium iodide (0.0996 g, 0.664 mmol) was heated at 70° C. overnight and cooled to room temperature. The reaction was diluted with ethyl acetate, washed with water several times, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using Prep TLC plates (5% methanol in dichloromethane) and concentrated to give [8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-[3-(2-methylsulfanyl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-amine (0.173 g, 57%). MS=460 (MH)+. 314b) To [8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-[3-(2-methylsulfanyl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-amine (0.173 g, 0.376 mmol) in methanol (5 mL) was added oxone (0.694 g, 1.13 mmol) in water (2.5 mL) and was stirred at room temperature for 2 hours and concentrated. The reaction was partitioned between dichloromethane/1N sodium carbonate, washed with water/brine, dried over sodium sulfate, and concentrated. The product was purified using Prep TLC plates (5% methanol in dichloromethane) and concentrated to give [3-(2-methanesulfonyl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-[8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-amine (0.025 g, 14%). MP=91-94° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.75 (d, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 7.32 (s, 1H), 7.18 (d, 1H), 7.05 (m, 3H), 3.75 (s, 3H), 3.28 (m, 2H), 3.18 (s, 3H), 2.85 (m, 2H), 2.75 (m, 4H), 2.58 (m, 4H): MS=492 (MH)+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([Cl:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[Cl:28][C:23]1[CH:22]=[C:21]([S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:26]=[CH:25][C:24]=1[S:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(O)Cc1cc(S)cc(C(F)(F)F)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Sc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from step (iii) and the product from example 3 step (i).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25].C1(C)C=CC=CC=1.Cl.[NH:36]1[CH2:50][CH2:49][CH2:48][C@@H:37]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>ClCCl>[C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:24]([N:36]3[CH2:50][CH2:49][CH2:48][C@H:37]3[C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])=[O:25])[C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CN(C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)C1=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a slurry of dried (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (0.44 g, 2 mmoles) in 10 ml of dry dichloromethane under argon at -10° C. was added triethylamine (0.3 g, 3 mmoles) followed by 4 ml of 12.5% phosgene in toluene (5 mmoles). After stirring for 1.5 hours at -10° C., the solvent was evaporated, and the residue taken up in dichloromethane (10 ml) and chilled to -10° C. To this was added 0.48 g (2 mmoles) of D-proline, phenylmethyl ester, hydrochloride followed by 0.4 g (4 mmoles) of triethylamine. The mixture was stirred at -10° C. for 30 minutes, then quenched and washed with 10% monobasic potassium phosphate. The organics were washed with brine, dried (sodium sulfate), and chromatographed on silica (LPS-1) in 1:1 hexane:ethyl acetate. The pure product fractions (Rf=0.23 on silica, same system) were evaporated to give 0.42 g of a thick oil.
Reaction SMILES: C1(SC)C=CC=CC=1.C([O:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[CH2:20][NH:21][C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)=[O:23])C1C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[CH2:20][NH:21][C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)=[O:23]
Reactant: O=C(NCc1cccc(OCc2ccccc2)c1)c1ccc2ncccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(NCc1cccc(O)c1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
Thioanisole (1.7 mL, 14 mmol) was added to a mixture of quinoline-6-carboxylic acid 3-benzyloxybenzylamide (1.3 g, 3.6 mmol) and trifluoroacetic acid(8 mL) on an ice bath, and the solution was stirred for 4 hours at room temperature. The solvent was evaporated in vacuo, then water, an aqueous solution of saturated sodium bicarbonate, ethyl acetate and tetrahydrofuran were added to the residue for extraction, the organic layer was washed with brine, then, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, recrystallized from ethyl acetate-methanol, and the title compound (0.64 g, 2.3 mmol, 64%) was obtained as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28].[CH3:32][OH:33]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([C:23]([C:26](=[O:30])[C:27]([O:33][CH3:32])=[O:28])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C1CCc2cc3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reactant: CO
Solvent: ClCCl
Product: COC(=O)C(=O)c1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.9 g of the product of Step 9 in 50 mL of CH2Cl2 was added 0.42 mL of oxalyl chloride at 0° C. After stirring for 1 h at 0° C., 4 mL of MeOH was added and the mixture was stirred for another hour and quenched with 30 mL of saturated aqueous solution of NaHCO3. The mixture was extract with 50 mL of CH2Cl2 and the extract was dried over Na2SO4. After filtration, the filtrated was concentrated to give 1.2 of the title product as a solid. 1H NMR (500 MHz, acetone-d6) d 8.11 (m, 2H), 7.92 (m, 1H), 7.45-7.52 (m, 3H), 7.28-7.34 (m, 2H, 4.70 (m, 1H), 7.32 (m, 1H), 4.12 (t, 1H), 3.97 (s, 3H), 3.48-3.55 (m, 1H), 3.08-3.07 (m, 1H), 3.00 (s, 3H), 2.10 (m, 1H), 1.76 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:28])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:21]=3)[CH:18]=2)=[C:9]([C:29](O)=[O:30])[CH:8]=[N:7]1>>[N:22]1([C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:11]([C:10]4[N:6]([CH3:5])[N:7]=[CH:8][C:9]=4[C:29]([CH:4]4[NH:1][CH2:2][CH2:3]4)=[O:30])=[O:28])=[CH:18][N:17]3[N:19]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: Cn1ncc(C(=O)C2CCN2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using azetidine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light yellow solid (99 mg, 53%). MS: m/z=411 (M+H+). Ames test negative.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:10][CH:9]=1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32].O>ClCCl>[CH3:34][S:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH:14]=[CH:13][CH:12]=2)[CH:17]=1)(=[O:33])=[O:32]
Reactant: CC(=O)NCCc1cccc2ccc(OCCCCCO)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCc1cccc2ccc(OCCCCCOS(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a 250 ml round-bottomed flask, dissolve the compound obtained in Step B (3.15 g, 10 mmol) in 50 ml of dichloromethane and add triethylamine (1.6 ml; 12 mmol). Cool in an ice/salt bath at 0° C, and then add mesyl chloride (0.93 ml; 12 mmol) dropwise with stirring using a magnetic stirrer. Allow the reaction mixture to return to room temperature and stir for 5 hours. Add 100 ml of water and extract the aqueous phase 3 times with dichloromethane. Wash the organic phase with 3×20 ml of an aqueous 1M hydrochloric acid solution and then with water, dry over magnesium sulphate and evaporate under reduced pressure. Purify the resulting oil by chromatography over silica gel (eluant: acetone/cyclohexane (3/7)). Colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C:19]([O:22][C:23]([N:25]1[CH2:31][C:30]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:29]=2[O:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:16][CH:15]([CH3:17])[CH2:14][O:13][C:11]([N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH2:27][CH2:26][N:25]([C:23]([O:22][C:19]([CH3:20])([CH3:18])[CH3:21])=[O:24])[CH2:31][C:30]=4[CH:32]=3)[CH:3]=2)[N:8]=[CH:9]1)=[O:12]
Reactant: CC(C)COC(=O)n1cnc2ncc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc21
Temperature: 95 °C
Yield: 45.6 %

Procedure:
A flask was charged with isobutyl 6-bromo-1H-imidazo[4,5-b]pyridine-1-carboxylate (2.00 g, 6.82 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (2.00 g, 6.82 mmol), dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.14 g, 0.17 mmol), and diisopropylethylamine (3.50 g, 27.2 mmol) in dry dioxane (60 mL) and the mixture heated to 95° C. for 24 hours. The resulting mixture was diluted with ethyl acetate (100 mL) then washed with water (50 mL), 10% aqueous citric acid (50 mL) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, 1:1) to give 1,1-dimethylethyl 7-(1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazo[4,5-b]pyridine-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.45 g, 46% yield) as a brown oil. MS (EI) for C25H30N4O5: 467 (MH+).