Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: CC(=O)C(C)NC(C)(C)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2ccc(Cl)c(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 4.0 g of 2-fluorophenylacetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by an evaporator, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with a 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was concentrated by an evaporator, and then subjected to silica gel chromatography to obtain 2.5 g of 1-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH2:13])=[N:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[N+:14]([C:4]1[CH:3]=[C:2]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:7]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[N:6][C:5]=1[NH2:13])([O-:16])=[O:15]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Nc1nc(-c2ncco2)c(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1nc(-c2ncco2)c(-c2ccncc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 20 h
Yield: 64.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 5-bromo-3-nitro-6-(1,3-oxazol-2-yl)pyridin-2-amine (0.141 g, 0.49 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.203 g, 0.99 mmol), dioxane (5 mL) and a 2M aqueous solution of cesium carbonate (0.74 mL, 1.48 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex [PdCl2dppf.DCM] (0.024 g, 0.03 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 95° C. After 20 hours, the mixture was cooled and partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The aqueous phase was filtered through Celite® and the pH was adjusted to 5-6 with solid sodium hydroxide. The suspension was cooled in an ice bath and the precipitate was filtered, washed with water and dried to give the title compound (0.090 g, 65%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[CH2:26][C:27]#[N:28])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:30][OH:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[OH:31][NH:30][C:27](=[NH:28])[CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:10]2[C:9]3[CH:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:17]=[CH:18]1
Reactant: NO
Reactant: N#CCc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N=C(Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21)NO

Procedure:
The title compound is prepared in analogy to Example 67 starting from 300 mg (0.832 mmol) of [2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)phenyl]-acetonitrile (Example 64), 346 mg (0.499 mmol) hydroxylamine hydrochloride in 7 ml DMF, and 465 mg sodium carbonate in 2.5 ml water. The compound is isolated as colorless powder. mp: 253-254° C.; MS: 394 (M+1); HPLC: tret=6.57 min (Grad 1).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:67](=[NH:80])([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:74]1([C:67]([C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)=[N:80][C:2]2[CH:18]=[CH:17][C:5]([O:6][C:7]3[N:11]([CH3:12])[C:10]4[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=4[N:8]=3)=[CH:4][CH:3]=2)[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(Oc2ccc(N=C(c3ccccc3)c3ccccc3)cc2)nc2ccccc21
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a suspension of 2-(4-bromophenoxy)-1-methyl-1H-benzimidazole (1.0 g), Pd2(dba)3 (0.076 g), sodium tert-butoxide (0.48 g) and xantphos (0.19 g) in dioxane (10 mL) was added benzophenone imine (0.83 ml), and the mixture was stirred at 100° C. under Ar atmosphere for 6 h. After stirring at room temperature overnight, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residual crystals were washed with AcOEt to obtain N-(diphenylmethylidene)-4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (0.81 g) as pale yellow crystals.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]1[N:30]=[C:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[O:28][N:27]=1)C1C=CC=CC=1.Cl>ClCCl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][C:29]2[O:28][N:27]=[C:26]([C:10]3[N:11]=[C:12]4[CH:19]=[CH:18][C:17]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])[N:30]=2)=[CH:37][CH:36]=1
Reactant: O=c1c(OCc2ccccc2)c(-c2noc(Cc3ccc(F)cc3)n2)nc2ccc(N3CCOCC3)cn12
Agent: Cl
Solvent: ClCCl
Product: O=c1c(O)c(-c2noc(Cc3ccc(F)cc3)n2)nc2ccc(N3CCOCC3)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of the product of example 22 (40 mg, 0.078 mmol) in dichloromethane (5 ml) was added FeCl3 (38 mg, 0.234 mmol), and the mixture was stirred at room temperature for 30 min. Then 1M HCl (8 ml) was added and the mixture was extracted with dichloromethane three times. The combined extracts were washed with water and brine, dried and evaporated into dryness. The residue was recrystallized from CH2Cl2/MeOH to give the titled products (10 mg, yield 30.3%).
Reaction SMILES: [N:1]1([C:6]2[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:15]/[N:16]=[C:17](\Cl)/[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:7]3[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][C:6]3([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[O:15][N:16]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)N1CC=C(N2CCCC2)CC1
Reactant: O/N=C(\Cl)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(N3CCCC3)ON=C(c3ccncc3)C2C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1-(4-(Pyrrolidin-1-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (1.2 g, 6.176 mmol) (synthesis: see below) was dissolved in methylene chloride (10 ml) and the solution was cooled to 0° C. under an inert gas. (Z)-N-Hydroxyisonicotinimidoyl chloride (1.45 g, 9.264 mmol), dissolved in methylene chloride (5 ml), and triethyl-amine (2.1 ml, 14.82 mmol), dissolved in methylene chloride (5 ml), were added, stir for 15 h, during this allow to warm to room temperature. The mixture was diluted with methylene chloride (30 ml) and washed water (20 ml) and citric acid (10%, 20 ml). The aqueous phase was neutralized with sodium bicarbonate and extracted with methylene chloride and the combined organic phases were washed with saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25% eq.) 100/10/1. The yield was 0.64 g (33%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([O:30]CC3C=CC=CC=3)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1>CO.[C].[Pd]>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Agent: [Pd]
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
Benzyl 5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate (3.58 g, 6.66 mmol) synthesized in Example (97d) was dissolved in methanol (100 mL), and a 10% palladium carbon catalyst (2.00 g) was added, followed by stirring at room temperature for 3 hours under hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, followed by washing with tetrahydrofuran. The solvent was distilled off under reduced pressure to afford the desired compound (2.56 g, 86%) as a white solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:9]2[CH2:23]OS(C)(=O)=O.O>CS(C)=O>[C:1]([CH2:23][CH:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH3:4])[CH:7]=2)[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:10]1)#[N:2]
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C2
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(CC#N)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C

Procedure:
Potassium cyanide (5.52 g; 85 mmol) is suspended in 50 ml of DMSO and the solution is heated to 80° C. The compound obtained in Step H (6.3 g; 17 mmol), dissolved beforehand in 50 ml of DMSO, is progressively added to the preceding solution, and then the reaction mixture is heated again at 80° C. for 30 minutes. The solution is poured into 150 ml of water and extracted three times with dichloromethane. The organic phase is then dried over magnesium sulphate, filtered and evaporated. The dark red oil obtained is purified by chromatography on silica gel (eluant:cyclohexane with the progressive addition of ethyl acetate until the proportions 8/2 are reached) and the solid obtained is recrystallised from cyclohexane to yield the title product in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C@:6]2([C@@H:11]([O:12][C:13]([CH3:15])=[O:14])[C@:10]3([OH:31])[CH2:16][C@@:17]45[S:28]S[S:26][C@@:21]([CH2:29][OH:30])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[C@@H:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:33])[CH3:32].S(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:1][CH:2]1[O:7][C:6]2([CH:11]([O:12][C:13]([CH3:15])=[O:14])[C:10]3([OH:31])[CH2:16][C:17]45[S:28][S:26][C:21]([CH2:29][OH:30])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[CH:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:33])[CH3:32]
Reactant: CC(=O)O[C@H]1[C@]2(O)C[C@]34SSS[C@](CO)(C(=O)N3[C@@H]2C[C@@]12OC(C)C(C)(C)C2=O)N(C)C4=O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1C2(CC3N4C(=O)C5(CO)SSC4(CC31O)C(=O)N5C)OC(C)C(C)(C)C2=O
Reaction time: 0.25 h

Procedure:
Sirodesmin C (5.0 mg.) in dry pyridine (0.1 ml.) was treated with thionyl chloride (0.01 ml.) for 10 minutes at 0°C., then added to iced-water (5 ml.) and left for 15 minutes. The solution was adjusted to pH 2 with 2N.sulphuric acid, then extracted with chloroform (3 × 5 ml.). The extracts were dried over sodium sulphate, then concentrated to yield Sirodesmin A as an oil (4.3 mg.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>CN1CCCC1=O>[O:24]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1=[O:25]
Reactant: O=C(O)CCCC/C=C\CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: O=C1CCCC/C=C\CCCCCCCCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1CCCCC=CCCCCCCCCCO1
Temperature: 112.5 °C
Reaction time: 10 h

Procedure:
25 g of potassium carbonate were suspended in 300 ml of N-methyl pyrrolidone. 30 g (0.09 mol) of crude 6Z-16-bromohexadec-6-enoic acid in 200 ml of N-methyl- pyrrolidone were added dropwise while stirring at 110-115° C. within 10 hours. After usual work up 18 g of crude product were obtained, and after chromatography 12 g (53%) of Z-oxacycloheptadec-7-en-2-one were obtained having the following characteristics: Z/E=93/7;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([OH:18])[C:15]3[C:10](=[C:11]([CH3:21])[C:12]([O:19][CH3:20])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C([O:24][C:25]([C:27]12[CH2:44][CH:43]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:45])[C:35](=[O:46])[N:34]1[CH:30]([CH2:31][CH:32](O)[CH2:33]1)[C:29](=[O:48])[NH:28]2)=[O:26])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:32]3[CH2:31][CH:30]4[N:34]([C:35](=[O:46])[N:36]([CH3:45])[CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH:43]5[C:27]([C:25]([OH:26])=[O:24])([NH:28][C:29]4=[O:48])[CH2:44]5)[CH2:33]3)[C:15]3[C:10](=[C:11]([CH3:21])[C:12]([O:19][CH3:20])=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(O)nc(-c3ccc(F)cc3)nc2c1C
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(F)cc3)nc2c1C

Procedure:
Quinazolinol derivative (92) (141 mg, 0.5 mmol) was coupled to compound 51 (170 mg, 0.45 mmol) as described in example 52, which gave the crude ethyl ester of the title compound. The crude ester was purified by flash chromatography on silica gel eluted with 5→15% MeOH in diethyl ether, the afforded residue was dissolved in dichloromethane and filtered to remove traces of silica, which gave the ethyl ester of the title compound (135 mg, 46%). The ethyl ester was then hydrolyzed as described in example 52, which gave the title compound (125 mg, 100%)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C@@H:3]([OH:22])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:6]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.[N-]=C=O>C1(C)C=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C@@H:3]([O:22][C:33](=[O:34])[NH:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=2)[CH2:6]1
Reactant: O[C@@H](CN1CCO[C@H](c2ccc(F)c(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCO[C@H](c2ccc(F)c(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(S)-1,1,1-Trifluoro-3-((R)-2-(4-fluoro-3-(trifluoromethyl)phenyl)morpholino)propan-2-ol (427 mg, 1.18 mmol) was mixed with 1-chloro-4-isocyanatobenzene (180 mg, 1.17 mmol) in toluene (5 mL). The mixture was stirred at 90° C. for 2 h. TLC indicated still significant amount of the starting material. So a second batch of 1-chloro-4-isocyanatobenzene (180 mg, 1.17 mmol) was added and the mixture was further stirred at 95° C. for 2 h. TLC indicated still significant amount of starting material. A second batch of isocyanate was added and the mixture was stirred at 90° C. for 2 h. The mixture was concentrated and the residue was extracted with ethyl acetate and water, washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was purified through ISCO flash column chromatography (ethyl acetate in hexanes 0% to 40% gradient in 16 min). The desired fraction was concentrated to give (4-chlorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(4-fluoro-3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester a colorless oil, which was dissolved in ether and 1N HCl in ether (1 mL) was added. Solvent was evaporated and the residue was dissolved in ether. Hexane was added and solvents were evaporated to give a white solid 241 mg. LC/MS indicated 13% des-fluoro ((M+H)+=497 m/e) and 87% desired compound ((M+H)+=515 m/e).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@H:15]([C@H:18]1[C@@H:21]([C:22]#[CH:23])[N:20]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:19]1=[O:32])[CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[Si:6]([O:14][C@H:15]([C@H:18]1[C@@H:21]([C:22]#[CH:23])[N:20]([C@@H:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])[C:19]1=[O:32])[CH2:16][CH3:17])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C#C[C@@H]1[C@H]([C@@H](O)CC)C(=O)N1[C@H](C)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#C[C@@H]1[C@H]([C@H](CC)O[Si](C)(C)C(C)(C)C)C(=O)N1[C@H](C)c1ccccc1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
Imidazole (554 mg, 8.14 mmol) and tert-butyldimethylsilyl chloride (1.13 g, 7.52 mmol) were added to a solution of the compound (1.61 g, 6.26 mmol) prepared in Example 3 in N,N-dimethylformamide (7 ml) at room temperature in an argon atmosphere. After stirring overnight at this temperature, the mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of potassium hydrogensulfate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate=20/1) to obtain 2.157 g (yield 93%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O-:2].[Li+].[CH2:4]([N+:8]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH3:7].[O:21]=[C:22]1[CH:25]([N:26](Cl)[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:24][N:23]1[S:38]([O-:41])(=[O:40])=[O:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO.CN(C)C=O>[CH2:17]([N+:8]([CH2:4][CH2:5][CH2:6][CH3:7])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH3:20].[CH3:1][O:2][C:25]1([NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:24][N:23]([S:38]([O-:41])(=[O:40])=[O:39])[C:22]1=[O:21]
Reactant: O=C(OCc1ccccc1)N(Cl)C1CN(S(=O)(=O)[O-])C1=O
Reactant: C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC1(NC(=O)OCc2ccccc2)CN(S(=O)(=O)[O-])C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirring solution of lithium methoxide (667 mg) in anhydrous methanol (10 ml) at -78° C. is added a solution of 2-oxo-3-[N-chloro-N-[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt (0.94 g) in dry dimethylformamide (10 ml). After stirring the mixture at -78° C. for 1 hour, it is poured into 0.5M monobasic potassium phosphate solution and extracted with methylene chloride (three 150 ml portions). The combined extracts are dried (sodium sulfate) and solvent is removed in vacuo to given an oil (0.83 g). The desired product is obtained by chromatographing the oil on silica gel (100 g) and eluting with 4-5% methanol in methylene chloride to give an oil (513 mg): λmax (neat) 1767, 1720 cm-1 ; NMR (CDCl3) δ 3.40 (S, OCH3), 3.03 (ABq, J=6.5 Hz, H4), 5.08 (S, CH2), 6.00 (S, NH), 7.27 (S, aromatic).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[OH:21])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][CH3:6].[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:37]([O:36][C:35]([N:18]1[CH2:19][CH2:20][C@H:15]([CH2:14][O:13][C:10]2[N:11]=[N:12][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:9]=2)[C@H:16]([OH:21])[CH2:17]1)=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCCCc1nnc(OC[C@H]2CCNC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-3-ol dihydrochloride (1.14 mmol, 0.50 g) in DCM and saturated NaHCO3 (1 M, 1:1, v/v), was added di-t-butyl carbonate (3.42 mmol, 0.75 g). The reaction was stirred for 1 hour at room temperature. The reaction was allowed to settle and the layers were separated. The organic layer was dried and the crude product was purified by flash chromatography to give (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.50 g).