Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)[OH:38]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH:37]([OH:38])[C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=539.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[S:18][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:20]([C:19]2[S:18][C:17]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:16][C:15]=2[CH3:14])=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)piperazine (3.72 g), 4-methyl-2-(4-pyridyl) -5-thiazolecarboxylic acid (4.4 g), triethylamine (2.5 g) and HOBt (2.7 g) in DMF (60 ml), was added WSC hydrochloride (4.217 g) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and to the residue were added dichloromethane and sodium bicarbonate aqueous solution. The organic layer was separated, washed with water and brine, dried and concentrated. The residue was purified with silica gel chromatography (dichloromethane:methanol=50:1) to give colorless crystals of the title compound (6.49 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9])[CH3:2].C(O)(C)C.CCOCC>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[CH3:2]
Reactant: CCC1CCCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCC1CCCCC1=O
Yield: 91.3 %

Procedure:
2-Ethylcyclohexanol (1.6 moles, 204 g 226 ml) was stirred in 3.2 l of acetone at 0° C. and treated with 8N Jones reagent (prepared from 106.8 g of CrO3 suspended in 92 ml of concentrated sulfuric acid and diluted to 400 ml with water) until the orange color persisted (~430 ml). Isopropanol was then added to turn the solution green again after which it was poured into 2 l of ether. The product was washed with 6×500 ml of brine, dried over MgSO4 and stripped of solvent. Short path distillation (b.p. 80°-85° C. at 25 mm) afforded 184 g (1.46 moles, 91%) of 2-ethylcyclohexanone as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N1CCN2CCN(C(C)C)P1N(C(C)C)CC2)(C)C.[N+:37]([CH2:40][CH3:41])([O-:39])=[O:38]>[N+](C)([O-])=O>[N+:37]([CH:40]([CH3:41])[CH:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:39])=[O:38]
Reactant: CC[N+](=O)[O-]
Reactant: O=CCOc1ccccc1
Agent: CC(C)N1CCN2CCN(C(C)C)P1N(C(C)C)CC2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C[N+](=O)[O-]
Product: CC(C(O)COc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 81 %

Procedure:
2-Phenoxyacetaldehyde (1.36 g, 10 mmol) was added to a suspension of anhydrous magnesium sulfate (2.65 g, 22 mmol) in nitroethane (7.0 mL) under an argon atmosphere. After 5 min a solution of 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (0.30 g, 1.0 mmol) in nitromethane (3.0 mL) was added. The mixture was vigorously stirred for 5 days at r.t., filtered through celite and concentrated. Purification by column chromatography (SiO2, dichloromethane/t-butyl methyl ether) gave the subtitle compound as an oil (1.7 g, 81%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[O:9]=[C:5]1[NH:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][NH:1][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: O=C=Nc1ccccc1
Reactant: NCCN1CCNC1=O
Solvent: c1ccccc1
Product: O=C(NCCN1CCNC1=O)Nc1ccccc1
Reaction time: 4 h

Procedure:
To a mixture of 6.5 g of commercially available 1-(2-aminoethyl)-2-imidazolidone and 50 ml benzene was added 5.5 ml of phenyl isocyanate. The strongly exothermic reaction was moderated by cooling to 25°. The mixture was stirred at 25° for 4 hr. It was cooled in ice and the mixture was filtered. The solid product was crystallized from 250 ml of acetone to give 6.8 g of white 1-[2-(2-oxo-1-imidazolidinyl)-ethyl]-3-phenylurea, mp 162- 164°.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([N+:22]([O-])=O)[C:8]([S:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][CH:10]=1.C(O)(=O)C>C(OCC)(=O)C.[Fe]>[NH2:22][C:7]1[C:8]([S:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][CH:10]=[C:5]([Cl:4])[CH:6]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ncc(Cl)cc1N
Reaction time: 4.5 h
Yield: 85 %

Procedure:
To an ethanol solution (6 ml) of tert-butyl 2-[(5-chloro-3-nitropyridin-2-yl)thio]-2-methylpropanoate (442 mg) were added at room temperature acetic acid (6 ml) and iron powder (418 mg), followed by stirring for 4.5 hours. The reaction solution was diluted with ethyl acetate, followed by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were added saturated sodium hydrogen carbonate and ethyl acetate, followed by filtration through Celite, and then the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 2-[(3-amino-5-chloropyridin-2-yl)thio]-2-methylpropanoate (342 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([N:13]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH2:46]>C(Cl)Cl.N1C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH:46][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:13]([CH:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18]
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Yield: 83.7 %

Procedure:
4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid (3.62 g, 10 mmol) and oxalyl chloride (3.8 mL, 30 mmol) were stirred in DCM dry (120 mL) and a few drops of dry DMF at room temperature for 2 hours Volatiles were evaporated and the residue dissolved in dry pyridine (50 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (2 gr, 7.72 mmol) in dry pyridine (20 mL) was added to the cooled reaction mixture under nitrogen atmosphere. The resulting mixture was allowed to react overnight at room temperature, then the solvent removed under reduced pressure. The residue was taken-up with EtOAc and washed with acqueous NaHCO3 sat.sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using AcOEt/Hexane 7:3 as the eluant, affording 3.9 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)=O)cc1-n1nc2ccccc2n1

Procedure:
The crude reaction product 2(2-hydroxy-5-acetylphenyl)2H-benzotriazole (2H5A) is then o-acetylated with an acetic anhydride/pyridine mixture, and after reflux, 2(2-acetoxy-5-acetylphenyl)2H-benzotriazole (2A5A) was produced. The 2(2-acetoxy-5-acetylphenyl)2H-benzotriazole (2A5A) is a key intermediate in the process, and in purified form served as the starting material for the two carbinols.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:6])=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: BrBr
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 96.2 %

Procedure:
A stirred suspension of 2,6-dinitroaniline (5 g, 27.3 mmol) in glacial acetic acid (50 mL) was added bromine (1.5 mL, 30 mmol) dropwise and heated at 120° C. for 2 h. After cooling to ambient temperature, the resultant mixture was poured into water (50 mL). The precipitate solid was collected by filtration and washed with water then dried in-vacuo. The solid was re-dissolved in EtOAC, washed with water and saturated brine. The organic layer was collected and concentrated in-vacuo to give the desired product (6.88 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (br s, 2H), 8.58 (s, 2H).
Reaction SMILES: [Li]CCCC.CCCCCC.C(=O)=O.Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C@@H:36]1[N:40]2[CH:41]=[N:42][CH:43]=[C:39]2[C:38](=[O:44])[CH2:37]1)[C:31]#[N:32]>C1COCC1.CC(C)=O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C@@H:36]1[N:40]2[CH:41]=[N:42][CH:43]=[C:39]2[C@@:38]([OH:44])([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH2:37]1)[C:31]#[N:32]
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2C[C@](O)(c3ccc(OC(F)(F)F)cc3)c3cncn32)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a solution of a 1.6 M n-BuLi solution in hexane (0.428 ml, 0.684 mmol) cooled in a dry ice and acetone bath was added a solution of 1-bromo-4-(trifluoromethoxy)benzene (0.046 ml, 0.311 mmol) in 1 mL THF. The yellow crude was stirred at −78° C. for 1 hr. This crude was cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (75 mg, 0.311 mmol) in THF (1 mL) cooled to −78° C. The crude was slowly warmed to room temperature over 5 hrs. The crude was quenched with NH4Cl and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was first purified via preparation plate using 5% (2M NH3 in MeOH)/CH2Cl2. The product was further purified using HPLC to give 19.8 mg of the entitled product as the major diastereomer. MS 404.2 (M+H); LCMS condition A, retention time 1.38 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.94 (d, 1H), 3.26 (dd, 1H), 5.71 (d, 1H), 6.72 (br. s., 1H), 7.03-7.17 (m, 3H), 7.27-7.39 (m, 3H), 7.40-7.52 (m, 2H).
Reaction SMILES: [OH2:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Br:11]Br.OO>ClC1C=CC=CC=1>[Br:11][C@@H:3]1[CH2:2][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[OH:1]
Reactant: C1=Cc2ccccc2C1
Reactant: BrBr
Reactant: O
Agent: OO
Solvent: Clc1ccccc1
Product: O[C@@H]1c2ccccc2C[C@H]1Br
Temperature: 63 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
160 ml of water and 60.0 g of indene (95 mol%; 0.49 mol) were put into a 500-ml 4-mouthed flask, and mixed as they were heated to 63° C. 40.1 g of bromine (0.25 mol) was added dropwise at 60°-63° C., requiring 30 minutes. On standing, 2 layers separated; the lower layer (organic layer) was transparent pale orange and no crystals could be observed. On mixing for a further 1 hour 15 minutes at 60° C., crystals of trans-2-bromoindan-1-ol were seen in the organic layer. Then 23.55 g of hydrogen peroxide (35 wt %; 0.24 mol) was added dropwise, requiring 25 minutes. After mixing for 3.5 hours at the same temperature, mixing was continued during air cooling overnight. 80 ml of chlorobenzene was added to the reaction mixture which included sticky semi-crystals, and mixed for 30 minutes. The slurry was filtered under decreased pressure at 18° C., and the cake was washed with a small quantity of chlorobenzene, and dried under decreased pressure. 52.14 g of white crystals of trans-2-bromoindan-1-ol (yield 49.9%) was obtained.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)C(C)(C)C)cs2)ccc1-n1cnc(C)c1
Yield: 98.8 %

Procedure:
96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 25 mg (0.2 mmol) pivaloylchloride were suspended in methylene chloride (2 ml) and 101 mg (1 mmol) triethyl amine was added at room temperature. The reaction was stirred over night, diluted with methylene chloride, washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure to yield 90 mg (99%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-2,2-dimethyl-propionamide as a light yellow solid. MS ISP (m/e): 456.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.37 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 7.22 (d, 1H), 7.05-6.99 (m, 2H), 6.44 (s, 1H), 4.95 (m, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.73 (m, 2H), 1.65 (m, 1H), 1.14 (s, 9H), 0.91 (d, 3H), 0.87 (d, 3H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(O)[CH3:21])=[CH:16][CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:21])=[CH:18][CH:19]=1
Reactant: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared starting from 1.00 g (5.64 mmol) of the compound from Example 8A and 1.41 g (5.64 mmol) of the compound from Example 182A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. was for only 4 h. 1.31 g (56% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][C:11](C(O)=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN([C:20]([O:24]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][CH:51]1[CH2:54][N:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:52]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][CH:11]=[CH:15][C:16]=2[C:20]([NH:50][CH:51]2[CH2:52][N:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54]2)=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2cccnc2-c2cccc(F)c2)C1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 6-(3-fluorophenyl)nicotinic acid (0.50 g, 2.30 mmol) in DMF (10 mL) was added HBTU (0.96 g, 2.53 mmol) and DIPEA (0.52 mL, 2.99 mmol). After 1 hr at room temperature, tert-butyl 3-aminoazetidine-1-carboxylate was added and the reaction stirred overnight. The solvent was removed and the residue was partitioned between ethyl acetate and sodium bicarbonate (aqueous saturated). The organic layer was washed with brine (2×), dried (MgSO4), filtered and concentrated to give the desired product, tert-butyl 3-(2-(3-fluorophenyl)nicotinamido)azetidine-1-carboxylate (630 mg, 74%). LC/MS (M+H)=372.2 observed, 372.17 expected
Reaction SMILES: F[B-](F)(F)F.[OH:6][C@H:7]([CH2:13][C:14](=[O:16])[O-:15])[CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10].N1C(C)=CC(C)=[CH:19][C:18]=1[CH3:25].Cl[CH:27](Cl)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][P:42]([O-:44])[O-:43].I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[OH-:6].[CH3:11][N+:9]([CH3:12])([CH3:10])[CH2:8][CH:7]([O:6][P:42]([OH:44])([O:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27])=[O:43])[CH2:13][C:14](=[O:15])[O:16][CH2:25][CH:18]=[CH2:19]
Reactant: [O-]P([O-])OCCCCCCCCCCCCCC(Cl)Cl
Reactant: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Reactant: Cc1cc(C)nc(C)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C=CCOC(=O)CC(C[N+](C)(C)C)OP(=O)(O)OCCCCCCCCCCCCCC
Product: [OH-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3.6 gm of the tetrafluoroborate salt of the allyl ester of L-carnitine and 4.5 gm of collidine in 25 ml of acetonitrile is added 5.7 gm of dichlorotetradecylphosphite in 25 ml of acetonitrile. The reaction mixture is stirred at room temperature for 17 hours, and then a solution of 4 gm of sodium metaperiodate in 20 ml of water is added. After stirring at room temperature for two hours, the reaction mixture is filtered through Celite; and the filtrate is concentrated under vacuum. The resulting residue is flash chromatographed on silica gel, initially with a 50/30/5 ratio of methylene chloride/methanol/ concentrated ammonium hydroxide and then with a 50/30/8 ratio of the same solvent system. Subsequent flash chromatography on LiChroprep RP-8 silica gel eluting initially with water and then with methanol gave N,N,N-trimethyl-4-oxo-4-[(2-propenyl)oxyl]-2-[{hydroxy(tetradecyloxy)phosphinyl}oxy]-1-butanaminium hydroxide, inner salt as an amorphous solid (31P NMR=0.108 ppm).
Reaction SMILES: [C:1](=[S:3])=[S:2].[OH-].[K+].[NH2:6][C:7]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=1[CH2:9]O>C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:7]2[NH:6][C:1](=[S:3])[S:2][CH2:9][C:8]=2[CH:11]=1
Reactant: Nc1ccc(Cl)cc1CO
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=C1Nc2ccc(Cl)cc2CS1
Yield: 102.4 %

Procedure:
Carbon disulfide (180 ml, 3.0 moles) was added dropwise to a stirred solution of 84 g (1.5 moles) of potassium hydroxide in 400 ml of absolute ethanol with external cooling. To this mixture was added 157 g (1.0 mole) of 2-amino-5-chlorobenzyl alcohol. The reaction mixture was heated under reflux for 20 hours and the solvent was removed by distillation. The solid residue was stirred with 2000 ml of 10% aqueous potassium hydroxide, and the mixture was filtered to remove neutral impurities. The clear filtrate was made acidic with dil. hydrochloric acid, and the solid which was deposited was collected by filtration to give 221 g (100%) of product. Recrystallization from methanol gave an analytical sample, m.p. 217°-222°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[O:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1.[Br:18][C:19]1[C:28]([O:29][CH:30]([C:38]([O:40][CH3:41])=[O:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH2:42][NH3+:43])=[CH:24]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH:30]([O:29][C:28]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:42][NH:43][C:11]([C:9]3[O:10][C:6]([O:5][C:4]4[CH:3]=[C:2]([Cl:1])[CH:16]=[C:15]([Cl:17])[CH:14]=4)=[CH:7][CH:8]=3)=[O:12])[CH:24]=2)[C:19]=1[Br:18])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
5-(3,5-Dichloro-phenoxy)-furan-2-carbonyl chloride (0.194 g, 0.6655 mmol) was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.30 g, 0.6655 mmol), prepared in the previous step, in 20 mL of methylene chloride at room temperature. Triethylamine (0.186 mL, 1.33 mmol) was then added to the mixture. The reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% NaHCO3. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (0.4079 g, 92%) as a tan oil, MS m/z: 668 [M+H]+.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10]C(C)(C)C)=O)#[N:2].FC(F)(F)C(O)=O.[CH2:22]([C:34]1[CH:42]=[CH:41][C:37](C(O)=O)=[CH:36][CH:35]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:22]([C:34]1[CH:35]=[CH:36][C:37]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[C:1]#[N:2])=[O:10])=[CH:41][CH:42]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCc1ccc(C(=O)N2CCC[C@@H]2C#N)cc1
Yield: 39.3 %

Procedure:
General procedure D was used to deprotect 1.4 mmols of 41 using 14 mL of dichloromethane and trifluoroacetic acid. After previously described recrystallization techniques, the TFA salt of 41 was coupled to 0.4 grams (1.4 mmols) of 4-dodecylbenzoic acid using 0.73 grams (1.4 mmols) of PyBOP and 0.72 grams (5.6 mmols) of N,N-diisopropylethylamine in 14 mL of dichloromethane according to general procedure E. Using previously described work-up and purification techniques (column chromatography, 25% EtOAc in hexanes), yielded 0.2 grams (0.55 mmols, 39%) of the title product as an off-white solid. 1H and 13C NMR data were identical to that of 29.