Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:34][C:35]([F:46])([F:45])[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]N)=[CH:39][CH:38]=1>>[CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:41]4[C:40](=[CH:39][CH:38]=[C:37]([O:36][C:35]([F:46])([F:45])[F:34])[CH:42]=4)[NH:43][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:17]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl}propanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 592.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.[Li]CCCC.[CH3:35][C:36]([CH3:42])=[C:37]1[CH:41]=[CH:40][CH:39]=[CH:38]1>C1COCC1>[CH:37]1([C:36]([CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)([CH3:42])[CH3:35])[CH:41]=[CH:40][CH:39]=[CH:38]1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Reactant: CC(C)=C1C=CC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(C)(C)C1C=CC=C1)C2(C)C
Temperature: 2 °C
Yield: 68.1 %

Procedure:
In a 200 ml three-necked flask purged with nitrogen, 3.11 g (8.04 mmol, 1 eq) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene was placed at room temperature. Then, 40 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled to 2° C. with an ice bath (light yellow solution). To the solution, 5.2 ml (8.48 mmol, 1.05 eq) of n-BuLi (hexane solution) was dropwise added over a period of 10 minutes, and 10 ml of dehydrated THF was further added. The ice bath was removed, and the mixture was stirred at room temperature for 22 hours (dark red slurry). After the slurry was cooled to 0° C. with an ice bath, a solution of 1.05 ml (8.54 mmol, 1.06 eq) of 6,6-dimethylfulvene in 10 ml of dehydrated THF was dropwise added over a period of 15 minutes (dark red solution). The ice bath was removed, and the solution was stirred at room temperature for 23 hours. The resulting dark red brown solution was poured into 100 ml of a diluted hydrochloric acid solution to perform quenching. After the organic phase was washed with 100 ml of a saturated saline solution, the soluble component was extracted from the aqueous layer with 50 ml of diethyl ether. The soluble component and the dispensed organic phase were together dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellowish orange solid. The solid was purified by silica gel column chromatography (developing solvent: hexane) to obtain a white powder (2.70 g, yield: 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[N:4]=1.O(P(O[C:39]1[N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:42][O:43][CH:44]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[Cl-].[Li+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([C:39]2[N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:42][O:43][CH:44]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C2=COCCN2C(=O)OC(C)(C)C)n1
Yield: 29.7 %

Procedure:
A mixture of 2-methoxy-6-(tributylstannyl)pyridine (552 mg, 1.39 mmol) and tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate (300 mg, 0.69 mmol) were dissolved in THF (6 ml). Lithium chloride (90 mg, 2.1 mmol) and Pd(PPh3)4 (78 mg, 0.069 mmol) were added and the mixture heated at reflux for 18 hours. The mixture was concentrated and purified on silica gel, eluting with 0-10% ethyl acetate/petrol. This gave the title compound as a brown solid (60 mg, 30%); 1H-NMR (CDCl3) 1.26 (9H, s), 3.77 (2H, t), 3.92 (3H, s), 4.19 (2H, m), 6.55 (1H, d), 6.76 (1H, d), 6.80 (1H, s), 7.49 (1H, t); MS ES(+) 293.2 (M++1); HRMS m/z calcd for C15H20N2O4+H+ 293.1501 [M+H+]. Found 293.1512. IR λmax=1701 cm−1.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.CCCCCC.C([Li])CCC.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=O.[Cl-].[Na+]>O1CCCC1>[O:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH3:22])=[CH:30][CH:29]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
2-Trimethylsilyl-1,3-dithiane, 1.92 g, was dissolved in 20 ml of tetrahydrofuran and 6.3 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow under ice cooling. The mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2.33 g of 4-phenoxyacetophenone in 10 ml of tetrahydrofuran was dropwise added under ice cooling followed by stirring at the same temperature for 30 minutes and at room temperature for an hour. After saturated sodium chloride aqueous solution was added, the mixture was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate : hexane =1 : 10) to give 2.7 g of the oily product.
Reaction SMILES: [H-].[Na+].[C:3]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CN(C)C=O>[C:3]([N:11]([CH2:13][CH2:14][O:15][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)[CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CCO)C(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in oil, 1.30 g) was added portionwise to a solution of 2-(N-benzoyl-N-methylamino)ethanol (5.0 g) in dry dimethylformamide (100 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour prior to the addition of 4-fluorobenzaldehyde (5.09 g, 4.4 ml), and the mixture then heated at 80° C. for 15 hours. The solvent was evaporated and the residue dissolved in water (500 ml) and extracted with ethyl acetate (3×500 ml). The combined ethyl acetate layers were washed with water (2×300 ml), brine (300 ml), dried (MgSO4) and evaporated to yield an oil. The oil was triturated with hexane, and the residue chromatographed on silica gel with 1.5% methanol in dichloromethane to afford the title compound as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH2:23])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:1]([NH:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Oc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.6 g of 4-(4-acetamidophenoxy)-3-amino-5-sulfamoylbenzoic acid, 10 ml of water and the sufficient amount of N aqueous sodium hydroxide to reach a pH = 7.4, 1.3 g of benzyl chloride are added while stirring at 30°. The mixture is stirred for 16 hours at room temperature, during which time 4N aqueous sodium hydroxide is added dropwise to keep said pH value. It is filtered, the filtrate acidified with glacial acetic acid and the precipitate formed filtered off, to yield the 4-(4-acetamidophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid which, on recrystallization from aqueous ethanol, melts at 255° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:52](O)[CH2:53][OH:54]>CN(C=O)C.CN(C1C=CN=CC=1)C>[OH:54][CH2:53][CH2:52][O:23][C:22]([C:21]1[C:16]2[N:15]=[C:14]([C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1)=[O:24]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)OCCO)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
50 mg (0.08 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid were dissolved in 4 mL DMF. Subsequently 20 mg DMAP, 34.3 mg (0.16 mmol) DCC and 46 μl (0.83 mmol) ethylene glycol were added. The resulting mixture was stirred for 8 h at 60° C. and then concentrated under removed pressure. The remaining residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give pure 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid 2-hydroxy-ethyl ester as a white amorphous solid. The corresponding dihydrochloride was obtained by treatment with a 0.1 M HCl-solution and following lyophilization. Yield: 22 mg MS (ES+): m/e=572, chloro pattern.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[C:17]([N+:6]([O-:9])=[O:7])=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=1
Reactant: COc1ccc(NC(C)=O)c(C)c1
Reactant: O=[N+]([O-])O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A mixture of tin(IV)chloride (1 9.3 ml) and 69.5% nitric acid (10.3 ml) in methylene chloride (140 ml) was added dropwise to a solution of N-(4-methoxy-2-methylphenyl)acetamide (28 g, 0.14 mol) in methylene chloride (500 ml) cooled to and maintained at −30° C. The reaction mixture was stirred at −30° C. for 1.5 hours, allowed to warm to ambient temperature then poured on to ice/water. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined extracts were dried (MgSO4), the solvent removed by evaporation and the residue purified by column chromatography eluting with petroleum ether/ethyl acetate (2/8) to give N-(4-methoxy-2-methyl-5-nitrophenyl)acetamide (1 7.8 g, 51%)
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1>>[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:64][S:61]([CH:58]2[CH2:60][CH2:59]2)(=[O:63])=[O:62])=[O:38])[CH2:30][CH2:29]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoic acid, and making variations as required to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a white solid (0.034 g, 34%): 1H NMR (300 MHz, DMSO-d6) δ11.78 (s, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.00 (d, J=13.3 Hz, 1H), 4.61-4.55 (m, 1H), 3.11-3.03 (m, 1H), 2.08-1.99 (m, 1H), 1.84-1.73 (m, 2H), 1.68-1.50 (m, 4H), 1.38-1.23 (m, 11H), 1.12-1.07 (m, 5H), 0.92-0.85 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 450.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28])([CH2:22][CH3:23])([CH3:21])[CH3:20]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:19]([CH2:22][CH3:23])([CH3:20])[CH3:21])[CH:25]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: CCC(C)(C)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: CCC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)c1
Yield: 31 %

Procedure:
Method H2 was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-tert-pentylbenzoic acid to afford the title compound as a light pink solid (54 mg, 31%). 1H-NMR (δ, ppm, DMSO-d6): 0.63 (t, 3H, CH3Et, J=7.4 Hz), 1.29 (s, 6H, CH3Me), 1.66 (q, 2H, CH2Et, J=7.4 Hz), 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.90 (dd, 1H, Harom, J=7.4 Hz, J=1.7 Hz), 7.41-7.47 (m, 2H, Harom), 7.56 (d, 1H, Harom, J=7.8 Hz), 7.65-7.66 (m, 2H, Harom), 7.75 (d, 1H, Harom, J=7.7 Hz) 7.81 (d, 1H, HPy,6, J=5.9 Hz), 7.84 (s, 1H, Harom), 10.30 (s, 1H, NHamide), 11.21 (s, 1H, NHurea), 11.39 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 8.89 (CH3Et), 28.03 (CH3), 35.90 (C(CH3)3Et,) 37.66 (CH2Et), 106.38, 110.81, 113.58, 114.28, 116.27, 124.61, 124.89, 127.91, 129.16, 129.98, 134.30, 140.76, 141.22, 144.57, 147.02, 149.24, 154.09, 154.56, 165.97. HRMS (EI): m/z [M+H] calculated for C24H24N4O3: 417.1921, found: 417.1923.
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:19]CCCO)[CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].C(S(NC)(=O)=O)(C(C(C(F)(F)F)(F)F)(F)F)(F)F.O(C)[Na].BrC[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57]>COCCOCCOC>[C:1]([S:14]([N:17]([CH2:19][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57])[CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:8])[F:9])([F:5])[F:6])([F:2])[F:3]
Reactant: CN(CCCCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCCCCCCCCCCCBr
Agent: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CO[Na]
Solvent: COCCOCCOC
Product: CN(CCCCCCCCCCCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C

Procedure:
C4F9SO2N(CH3)(CH2)11OH was prepared using a procedure similar to that described above for preparing C4F9SO2N(CH3)(CH2)4OH. 175.9 g C4F9SO2NHCH3 and 121.4 g 25% NaOCH3 were reacted to produce a solution of C4F9SO2NNaCH3 in about 100 mL diglyme. This solution was treated with 141 g 11-bromoundecanol (available from Aldrich) and heated at 100° C. for 20 hr to form a heavy precipitate. The reaction was quenched in about 600 mL warm water and the resulting lower layer was stripped at 50° C./0.5 mTorr to leave 269.9 g of C4F9SO2N(CH3)(CH2)11OH, a low-melting solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12](OCC)=[O:13])[N:5]=[C:4]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1>CCO.[Ni]>[CH2:21]([O:20][C:18](=[O:19])[NH:17][C:4]1[N:5]=[C:6]2[NH:11][C:12](=[O:13])[NH:8][C:7]2=[C:2]([Cl:1])[CH:3]=1)[CH3:22]
Reactant: CCOC(=O)Nc1cc(Cl)c([N+](=O)[O-])c(NC(=O)OCC)n1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Nc1cc(Cl)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of diethyl 4-chloro-5-nitro-2,6-pyridinedicarbamate (intermediate for the preparation of 1) (500 mg) in EtOH (50 mL) was added Raney Ni (1 g) and stirred for 12 h under hydrogen atmosphere at room temperature. Reaction mixture was filtered on celite and filtrate was concentrated under reduced pressure. Residue was dissolved in 2-propanol (10 mL) and stirred for 60 h under reflux. The reaction mixture was cooled to room temperature and precipitate was filtered. The filtrate was concentrated to give 250 mg of (7-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-carbamic acid ethyl ester as a gray solid. 1H NMR confirmed the structure.
Reaction SMILES: [O:1]1[CH:6]([C:7]([O-:9])=O)[CH2:5][NH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[Li+].[NH2:15][C@@H:16]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:17]([OH:32])[CH2:18][NH:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][CH3:31])[CH:28]=2)[O:23][CH2:22][CH2:21]1>>[CH2:30]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][C@@H:20]2[NH:19][CH2:18][C@@H:17]([OH:32])[C@@H:16]([NH:15][C:7]([CH:6]1[O:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[NH:4][CH2:5]1)=[O:9])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH3:31]
Reactant: O=C([O-])C1CNc2ccccc2O1
Reactant: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@@H](N)Cc1ccccc1)CCO2
Agent: [Li+]
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)C1CNc3ccccc3O1)CCO2

Procedure:
The title compound was prepared using a procedure analogous to that described in Example 35, wherein (±)-lithium 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate was coupled with (2R,3S)-3-amino-1-((S)-6-ethylchroman-4-ylamino)-4-phenylbutan-2-ol to afford the title compound (a 1:1 mixture of epimers at the benzooxazine stereocenter) as a white solid. MS m/z: 502 (M+1).
Reaction SMILES: [C:1]([N:5]=[C:6]([S:19][CH3:20])[NH:7][C:8]1[CH:14]=[C:13]([S:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:9]=1[NH2:10])([O:3][CH3:4])=[O:2].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[NH:10]=[C:9]1[CH:11]=[CH:12][C:13]([S:15][CH2:16][CH2:17][CH3:18])=[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]1[NH:7][C:6](=[N:5][C:1]([O:3][CH3:4])=[O:2])[S:19][CH3:20]
Reactant: CCCSc1ccc(N)c(NC(=NC(=O)OC)SC)c1
Reactant: O=Cc1ccccc1
Solvent: CO
Product: CCCSC1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(3-carbomethoxy-S-methylisothioureido)-4-propylthioaniline (3.13 g.; 0.01 mol) in methanol (25 ml.), cooled to 5° C., there is added benzaldehyde (1.06 g.; 0.1 mol). The mixture is stirred at room temperature for one hour and is filtered. The filter cake is dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([O-])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[CH2:16][CH2:17]1)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccncc1C(=O)[O-]
Reactant: CC(C)N(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccncc1CN1CCC(N(C(=O)OC(C)(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.9 %

Procedure:
A solution of 4-(N-tert-butoxycarbonyl-N-isopropylamino)piperidine (118 g, 0.49 mol) in dichloroethane (600 mL) was stirred at room temperature for 1 hour, and then 4-methoxypyridine-3-carboxylate (63.5 g, 0.46 mol) was added. The resulting solution was stirred at room temperature for 2.5 hours and then cooled to 5° C. in an ice/water bath. Sodium triacetoxyborohydride (124 g, 0.58 mol) in dichloroethane (600 mL) was added and the reaction mixture was stirred at 5° C. for 15 minutes. The ice bath was then removed and reaction mixture was stirred for 4 hours at room temperature. Acetic acid (30 mL) was then added to the reaction mixture and the resulting mixture was stirred for 0.5 hours, and then concentrated to half its original volume. This solution was cooled in a dry ice/acetone bath and 10 N aqueous sodium hydroxide (350 mL) was added. This mixture was stirred for 0.5 hours and then the organic layer was separated and washed with 1 N aqueous sodium hydroxide (400 mL). The aqueous layer was then washed three times with dichloromethane (400 mL) and the combined organic layers were dried over sodium sulfate (40 g). The sodium sulfate was filtered off and washed with dichloromethane (100 mL) and the combined organic layers were concentrated in vacuo to give 177 g of the title intermediate as a yellow oil (>99% yield; 74% purity by GC).