Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17].C(OCC)C>ClCCl>[O:12]=[CH:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]
Reactant: CC(C)COC(=O)/C=C/CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)COC(=O)/C=C/C=O
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a suspension of pyridinium chlorochromate (100 g, 0.463 mol) in dichloromethane (350 ml), a solution of isobutyl (E)-4-hydroxycrotonate (50 g, 0.316 mol) in dichloromethane (150 ml) was added. The internal temperature gradually rose to 40° C. and stirring was continued for 2 hours without cooling. Diethyl ether (0.9 l) was added and the supernatant was decanted from the black gum. The insoluble residue was washed twice 300 ml portions of diethyl ether. The combined organic solutions were passed through a short pad of Florisil and the solvent was removed by distillation, to yield 45.3 g (91.6%) of the title compound, as a pale yellow oil, Rf=0.5 (silica gel plates, cyclohexane-ethyl acetate 6:4). NMR (CDCl3): deltaH =9.80 (ABX, 1H, CHO), 6.98 and 6.75 (ABX, JAB =15 Hz, 2H, CH=CH). MS (E.I., 70 eV, 1.5 mA) m/z=155 (M--H)+, 85 (M--C3H3O2)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:23][C:24]1[C:29](F)=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34].O>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([O:22][C:29]2[C:28]([F:31])=[C:27]([F:32])[C:26]([F:33])=[C:25]([F:34])[C:24]=2[F:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(F)c(F)c(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)c(F)c1F
Reaction time: 20 h
Yield: 14.53 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 4.0 g) in 75 ml of dimethylformamide was added a solution of 22.69 g of 1-benzyl-4-hydroxy-4-phenyl piperidine in 100 ml of dimethylformamide. The mixture was heated with a heat gun to initiate evolution of gas. When evolution had ceased, the mixture was cooled to ice bath temperature and 18.61 g of hexafluorobenzene was added, dropwise, and the reaction was allowed to proceed for 20 hours. The reaction mixture was then poured into 500 ml of iced water and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% ethyl acetate/dichloromethane) to yield 5.36 g, (14.53%) of 1-benzyl-4-(2,3,4,5,6,-pentafluorophenoxy)-4-phenyl piperidine, m.p. 80°-83° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:25][CH3:26])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2].[S:27](Cl)([Cl:30])(=[O:29])=[O:28]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:25][CH3:26])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.34 g (0.96 mmol) of 2-(2-ethoxyphenyl)-5-ethyl-7-cyclopentyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 16A). This gives 0.43 g (98%) of sulphonyl chloride as a colourless foam which is directly reacted further.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]#[C:11][CH2:12][N:13]1[C:21]2[C:20](Cl)=[N:19][CH:18]=[N:17][C:16]=2[CH:15]=[CH:14]1)(C(C)(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[NH2:27].O>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]2[C:21]3[N:13]([CH2:12][C:11]#[C:10][CH2:9][OH:8])[CH:14]=[CH:15][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Solvent: CC(C)O
Solvent: O
Product: OCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
5-(4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (408.3 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421.0 mg) was added, and the mixture was stirred at 80° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (6 mL), a 1.0 M solution (2 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) and crystallized from hexane/ethyl acetate to give the title compound (425 mg) as white crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.CN(CC)C.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(OCC)(=O)C>C(Cl)Cl>[CH3:17][C:16]([Si:13]([CH3:15])([CH3:14])[O:7][C@H:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)([CH3:19])[CH3:18]
Reactant: O=C1C=C[C@@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C=CC(=O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 1-L round bottomed flask was charged (4S)-4-Hydroxy-2-cyclopenten-1-one (32) (20 g, 204 mmol, prepared described in Khanapure, S.; Najafi, N.; Manna, S.; Yang, J.; Rokash. J. J. Org. Chem., 1995, 60, 7448) in DCM (200 mL) followed by N,N-dimethylethylamine (47.7 g, 653 mmol), tert-butyldimethylsilyl chloride (46.1 g, 306 mmol) and a catalytic amount of 4-N,N-dimethylaminopyridine (1 g). The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ethyl acetate (200 mL) and the organic layer washed with water (200 mL), aqueous HCl (1 N, 2×100 mL), brine (100 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a crude product (42 g, ˜98% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:23]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:30](=[O:31])[CH2:29][CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Reactant: O=C(Cl)CCc1cccnc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2cccnc2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 3′-amino-5-formyl-6-methoxy-N-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](OCC)(OCC)(OCC)[CH3:13]>>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:12]([CH3:13])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(I)cc1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2ccc(I)cc2)o1
Temperature: 130 °C

Procedure:
Triethyl orthoacetate (10 ml) was added to 4-iodo-benzoic acid hydrazide (Intermediate 14) (0.55 g, 2.1 mmol) and heated under nitrogen at 130° C. for 3 hours. The triethyl orthoacetate was removed in vacuo and the residue partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over magnesium sulfate filtered and the solvent removed in vacuo. The residue was purified by silica SPE cartridge (10 g) eluting with 20:1 cyclohexane/ethyl acetate v:v to 5:1 cyclohexane/ethyl acetate v:v. The desired product was obtained as a white solid (0.31 g, 1.1 mmol).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][CH:33]([CH2:34][CH3:35])[CH2:36][CH3:37])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: CCC(CC)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(CC)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1 ethylpropyl)-3-pyridinecarboxamide (Intermediate 12, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+]([O-])=O)[C:17]=1[C:18]#[N:19])([O-:15])=[O:14]>>[C:18]([C:17]1[C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=[CH:21][C:20]=1[O:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5])#[N:19]
Reactant: COCCNC(=O)C(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COCCNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 55 %

Procedure:
Prepared as in Example 197c from 3-hydroxy-N-(2-methoxyethyl)-2,2-dimethylpropanamide (Example 204d) and 2,6-dinitrobenzonitrile in 55% yield. MS 322 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(Cl)=[S:13].C(OCC)(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[C:12]=[S:13]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1N=C=S

Procedure:
2-trifluoromethylaniline (4.1 ml, 0.0325 mol) is added dropwise at a temperature close to 20° C. and under an argon atmosphere to a mixture containing thiophosgene (2.5 ml, 0.0326 mol) in 43 ml of water. Agitation is carried out for twelve hours then 30 ml of ethyl acetate is added. The organic phase is extracted with water then with a solution of 10% sodium bicarbonate and finally with a solution of salt water. The organic phase is dried over magnesium sulphate and the solvent is evaporated off with a rotary evaporator. The product obtained (6.85 g, 100%) is in the form of a brown oil which is used immediately for the following reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:19])[CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
1-Bromo-4-(1-methylpropylthio)benzene is prepared by the following procedure. To a solution of 4-bromobenzenethiol (4.73 g, 25.0 mmol) in 25 ml of DMF at 70° under N2 is added potassium carbonate (4.15 g, 30.0 mmol). The mixture is allowed to stir for 15 min., after which 3-bromobutane (4.8 ml, 44.0 mmol) is added dropwise. The mixture is stirred at 70° for ca. 5 hours. Water is added to the cooled solution and the aqueous phase is extracted with ether (3X). The combined organic layers are washed with water and with brine and dried and the solvent is removed in vacuo to give, following purification by distillation under vacuum, 1-bromo-4-[1-methylpropylthio)benzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1F)[C:6]([OH:8])=[O:7])#[N:2].O.[NH2:14][NH2:15]>C(O)C>[NH2:2][C:1]1[C:3]2[C:11](=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=2)[NH:15][N:14]=1
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of 3-cyano-4-fluorobenzoic acid (980.0 mg, 5.94 mmol) in ethanol (6 mL), was added hydrazine hydrate (0.89 mL, 17.8 mmol). The reaction was heated at reflux for 3 hours. The reaction was cooled to room temperature and ethanol was removed under reduced pressure. The resultant yellow oil was taken up in water (50 mL) and basified with 1 N aqueous sodium hydroxide (5 mL). The solution was washed once with ethyl acetate (25 mL). The aqueous phase was acidified to pH=3 with 6 N aqueous hydrochloric acid and was allowed to stir at room temperature for 1 hour. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (612 mg, 48%) as a pink solid. +ESI (M+H) 178.1; 1H NMR (400 MHz, DMSO-d6, δ): 8.42-8.47 (m, 1H), 7.76 (dd, J=8.8, 1.6 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH2:34][F:35])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][F:35])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCCF)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cn(C(CCF)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.26 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 445 mg (2.27 mmol) of 2-fluoroethyl trifluoromethanesulphonate and 1.39 ml (1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by column chromatography (120 g silica cartridge, flow rate: 80 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 360 mg (67% of theory)
Reaction SMILES: C([NH:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15]([NH2:17])=[O:16])[NH:12]1)=[O:10])C1C=CC=CC=1>C(O)(=O)C.CO.[Pd]>[NH:12]1[C@H:13]([C:15]([NH2:17])=[O:16])[CH2:14][C@@H:11]1[C:9]([NH2:8])=[O:10]
Reactant: NC(=O)[C@@H]1C[C@H](C(=O)NCc2ccccc2)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)[C@@H]1C[C@H](C(N)=O)N1
Reaction time: 8 h

Procedure:
45.8 mg (196 μmol) of cis-N-benzylazetidine-2,4-dicarboxamide in 10 ml of glacial acetic acid (no reaction occurs in methanol) are hydrogenated in a Parr shaker over 11 mg of 10% Pd/C under a hydrogen pressure of 4 atm for 7 hours. The mixture is filtered through a fluted filter and the catalyst washed with several portions of methanol. Evaporation and drying in vacuo yields a colorless film which crystallizes slowly on addition of a few drops of methanol. After standing in a freezer overnight, the crystals are isolated, washed with a small volume of ethyl acetate/methanol (5:1), and dried in vacuo; yield 16.7 mg (60%). Mp. 215°-218° C. (dec.) after strong shrinking and darkening from approx. 200° C. on (measured with oil bath preheated to 190° C.). 1H NMR (D2O): δ 4.29 (t, 2H, J=8.5), 2.98 (dt, 1H, J=9 (t), 11 (d)), 2.23 (dt, 1H, J=8 (t), 11.5 (d)). IR (nujol): 3391, 3335, 3208, 3073, 1683, 1669, 1281, 1211, 1109, 1030, 843, 749, 722, 677 cm-1. Mass Spectrum: CI(isobutane): m/z 144 (M+H, 100%), 99 (56).
Reaction SMILES: C1(C2C3C=CC(C([O-])=O)=CC=3N3C=2C2C=CC=CC=2OCC2(COC(C)(C)OC2)C3)CCCCC1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH:44]1([C:50]2[C:51]3[CH:52]=[CH:53][C:54]([C:72]([O:74][CH3:75])=[O:73])=[CH:55][C:56]=3[N:57]3[C:67]=2[C:66]2[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=2[O:64][CH2:63][C:59]2([CH2:62]O[CH2:60]2)[CH2:58]3)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>CCOC(C)=O>[CH2:36]([N:43]1[CH2:62][C:59]2([CH2:58][N:57]3[C:56]4[CH:55]=[C:54]([C:72]([O:74][CH3:75])=[O:73])[CH:53]=[CH:52][C:51]=4[C:50]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[C:67]3[C:66]3[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=3[O:64][CH2:63]2)[CH2:60]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COC1)COc1ccccc1-3
Reactant: NCc1ccccc1
Agent: CC1(C)OCC2(COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)[O-])cc4n3C2)CO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)CN(Cc2ccccc2)C1
Yield: 65 %

Procedure:
This compound was prepared from 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate (Example 2, Step 3) and benzylamine as described in Example 9. Flash chromatography (PE:EtOAc 2:1) gave a mixture of the title compound and methyl 14-cyclohexylspiro[indolo[1,2-e][1,5]benzoxazocine-7,3′-oxetane]-11-carboxylate in 65% yield. MS (ES+) m/z 521 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32]S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC[C@@H](O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.7 g) was dissolved in 10 mL dry THF and 1320 mg triphenylphosphine and 691 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 minutes, then 992 μL DIAD was added dropwise. The reaction was stirred at room temperature for 3 hours and was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc). The resulting residue was dissolved in 20 mL dry DMF, then 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature. The reaction was stirred for 30 minutes and was partitioned between saturated aqueous NaHCO3 and diethyl ether. The aqueous layer was washed again with diethyl ether and the organic layers were combined. The organic layer was washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column)) to give 1.05 g of the product after drying.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O-:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1.F[C:48]1[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=1[F:58]>C(OCC)(=O)C>[Cl:21][C:20]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:16][C:17](=[O:22])[N:18]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][C:49]=2[F:58])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([O-])ncc2Cl)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3F)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
A two liter round bottom flask was charged with tetrabutylammonium 4-(1-(t-butoxycarbonyl)piperidin-4-yloxy)-5-chloropyridin-2-olate (90 g, 158 mmol), NMP (500 mL), and 1,2-difluoro-4-(methylsulfonyl)benzene (30.3 g, 158 mmol). The mixture was heated to 80° C. under nitrogen for 12 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate (500 mL) and distilled water (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To the residue was added 500 mL of 20% ethyl acetate in diethyl ether and the mixture was stirred for 12 hours at room temperature. The slurry was then cooled to 4° C. and stirring was continued for additional 1 hour. The solid was collected by filtration and dried under vacuum for 4 hours at 45° C. to yield t-butyl 4-(5-chloro-1-(2-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (58 g, 70% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.85-7.89 (m, 1H), 7.61-7.64 (m, 1H), 7.32 (s, 1H), 6.02 (s, 1H), 4.57-4.63 (m, 1H), 3.59-3.69 (m, 2H), 3.44-3.55 (m, 2H), 3.11 (s, 3H), 1.83-2.05 (m, 4H), 1.48 (s, 9H); MS m/e 501.2 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Cu]I.CC(O)C>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[CH:3]=[C:2]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3s2)CC1
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CN1CCC(OC(c2cccc(NCc3ccccc3)c2)c2nc3ccccc3s2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A screw-capped tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 41, 190 mg), copper(I) iodide (4 mg), ethylene glycol (45 μL), potassium carbonate (173 mg), benzylamine (54 μL), and propan-2-ol (1 mL). The tube is evacuated, filled with argon and sealed. After stirring at 80° C. for 15 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5). The base is converted into its dioxalate salt in acetone to give {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine, dioxalate melting at 75° C.