Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>C1COCC1.O>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:32])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in THF (Volume: 1.5 mL) at 0° C. The reaction was stirred for 10 minutes before iodomethane (0.200 mL, 3.20 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 50%-100% ethyl acetate in hexanes. (Yield: 41.5 mg, white solid) To obtain white solid as a product. 1H-NMR (400 MHz, DMSO-d6) 7.63-7.57, 7.53-7.47, 7.43-7.16, 7.13-7.05, 6.63, 4.67, 4.58-4.00, 3.78-3.71, 3.21-2.91, 2.79, 1.87-1.52
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[CH2:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:17][CH3:18])[CH2:20][CH2:21]1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: CCN1CCC(N)CC1
Reactant: Clc1ccc2c(Cl)c3c(nc2c1)CCCC3
Product: CCN1CCC(Nc2c3c(nc4cc(Cl)ccc24)CCCC3)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-1,2,3,4-tetrahydroacridine and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=344).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[N:10]([C:18]([NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][CH2:29][N:30]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:24][N:25]=3)=[O:19])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].O.NN>C(O)C>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[N:10]([C:18]([NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:24][N:25]=3)=[O:19])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN3C(=O)c4ccccc4C3=O)s1)c1ccc(Cl)cc12
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 76.5 %

Procedure:
1′-Acetyl-5-chloro-N-(5-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)thiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (0.93 g, 1.57 mmol) was dissolved in ethanol (30 mL). Thereafter, a hydrazine hydrate (0.12 g, 2.36 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 90° C. for 3.5 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (chloroform:methanol=4:1) to obtain the captioned compound (0.56 g, 77%) in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:7][CH:6]=1
Reactant: BrCCCCCCOc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (6-bromohexyloxy)benzene (1.5 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 5:1) and crystallized from diethyl ether-hexane to provide 0.95 g of alpha-oxo-4-[[(6-phenoxy)hexyl]oxy]benzeneacetic acid methyl ester, mp 50°-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:31])[CH2:17][CH2:16][N:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:15]1[CH2:14][CH2:13][C:12]([F:31])([F:11])[CH2:17][CH2:16]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:29])[F:30])=[N:23][CH:22]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]5[CH:63]=[N:64][CH:65]=[CH:66][CH:67]=5)[C:59](=[O:68])[CH2:58][O:57][C:56]=4[N:69]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]5[CH:63]=[N:64][CH:65]=[CH:66][CH:67]=5)[C:59](=[O:68])[CH2:58][O:57][C:56]=4[N:69]=3)=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3cccnc3)C(=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3cccnc3)C(=O)CO4)cc2)CCC1
Yield: 145.9 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(2-oxo-7-phenyl-1-(pyridin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (23 mg, 0.04 mmol) was reacted to afford the title compound (27 mg, quantitative). LCMS (Method A): RT=3.48 min, M+1=464. 1H NMR (500 MHz, MeOD): 8.75 (1H, br s), 8.60 (1H, br s), 8.12 (1H, d), 7.67 (1H, s), 7.49 (1H, s), 7.40-7.36 (4H, m), 7.28-7.24 (3H, m), 7.09 (2H, d), 5.42 (2H, s), 5.12 (2H, s), 2.77-2.72 (2H, m), 2.59-2.53 (2H, m), 2.25-2.21 (1H, m), 1.98-1.94 (1H, m).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:47])/[C:16](/[N:21]2[CH:24]([S:25]S(C3C=CC(C)=CC=3)(=O)=O)[CH:23]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:22]2=[O:46])=[C:17](\[O:19][CH3:20])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCOC.N12CCCCC1C=NCCC2>C1(C)C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([C@@H:16]2[N:21]3[C:22](=[O:46])[C@@H:23]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@H:24]3[S:25][CH:18]=[C:17]2[O:19][CH3:20])=[O:47])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: COC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 670 mg (1 mmol) of 2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methoxycrotonic acid diphenylmethyl ester, 6.7 ml of 1,2-dimethoxyethane and 0.22 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene is stirred for 25 minutes at room temperature under a nitrogen atmosphere. The reaction mixture is diluted with toluene, washed successively with 2 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue, after preparative thick layer chromatography on silica gel using toluene/ethyl acetate, 1:1, gives 7β-phenylacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid diphenylmethyl ester of melting point 166°-169° C. (from methylene chloride/hexane), UV spectrum (ethanol): λmax =258 mμ (ε=4,500), IR spectrum (methylene chloride): characteristic bands at 2.93, 5.62, 5.73, 5.93 and 6.66μ, Rf value~0.54 (silica gel; system toluene/ethyl acetate, 1:1), and amorphous 7β -phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, UV spectrum (ethanol): λmax =258 mμ (ε=6.350), 264 mμ (ε=6,350), 282 mμ (ε=5,600) (shoulder), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 and 6.66μ, Rf value~0.37 (silica gel; system toluene/ethyl acetate, 1:1), in the ratio of 8:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13])[CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1cccc(Cl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=O.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1Br
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2Br)CC1

Procedure:
A solution of [2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetic acid (500 mg, 1.77 mmol), Boc-piperazine (329 mg, 1.77 mmol), EDC (418 mg, 2.12 mmol), HOBt (286 mg, 2.12 mmol) and TEA (530 mg, 5.31 mmol) in 20 mL of DCM was stirred at room temperature overnight. The solvent was removed under reduce pressure and the crude was purified via prep-TLC to afford tert-butyl 4-{[2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate.
Reaction SMILES: NO.C(=O)/C=C/CC.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.C([Zn]CC)C.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>CCCCCC.C1(C)C=CC=CC=1>[C:24]([O:27][CH:16](/[CH:17]=[CH:18]/[CH2:13][CH3:9])[CH2:15][CH3:14])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccccc1
Agent: CC/C=C/C=O
Agent: CC[Zn]CC
Agent: NO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC/C=C/C(CC)OC(C)=O
Reaction time: 48 h

Procedure:
A vial was charged with aminoalcohol 1 (0.0032 g, 0.011 mmol) prepared as in Example 1. To the vial was added 1.62 mL of a stock solution containing trans-2-pentenal (0.34 g), t-butylbenzene internal standard (0.25 g), 1 M diethylzinc in hexane (8.0 mL), and toluene (4.0 mL). After 48 h, acetic anhydride (0.200 mL) was added. After an additional 72 h, a sample of the solution was analyzed by gas chromatography at 80° C. on a Cyclodex B stationary phase. The product trans4-hepten-3-yl acetate was formed 85% enantiomeric excess.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:13]([C:14]#[C:15][Si](C)(C)C)[CH2:12][CH2:11][C@H:6]1[C:7]([O:9]C)=[O:8])=[O:4].O[Li].O>CO.O>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:13]([C:14]#[CH:15])[CH2:12][CH2:11][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)CCl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl (5R)-1-(chloroacetyl)-5-((trimethylsilyl)ethynyl)-L-prolinate (3.69 g, 12.2 mmol) in MeOH (24 mL) and H2O (24 mL) at room temperature was added LiOH.H2O (0.8 g, 18 mmol). The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was taken up in water and extracted with diethyl ether (2×). The aqueous layer was acidified to pH˜3 by adding 4% KHSO4 dropwise. The solution was extracted with ethyl acetate (3×). Combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 216 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2][C:3]([O-])(C)[CH3:4].[K+].O.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:11]1[C:10]2[C:1](=[CH:2][CH:3]=[CH:4][CH:9]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCC
Reactant: CCC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the suspension of ethyl triphenyl phosphonium bromide (5.69 g, 15.3 mmol) in anhydrous THF (30 ml), a solution is added by drops of potassium tert-amylate (8.7 ml, 14.7 mmol, 1.7 M solution in toluene) using a syringe at room temperature. After 1 hour, the reaction mixture is cooled to a temperature of 0° C., the solution of crude aldehyde previously obtained is added (3.32 g, 11.79 mmol) in THF (10 ml), and mixing is continued for hours at room temperature. Then, water (1 ml) is added, and dilution takes place with n-hexane (30 ml). The sediment created is filtered, and the residue is chromatographed on silica gel (cyclohexane), obtaining naphthalene derivative with formula 25 in the form of a yellow oil (3.12 g, 90%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][O:27]CC1C=CC=CC=1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][OH:27])[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(CCOCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(CCO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 4.5 h
Yield: 112.9 %

Procedure:
tert-Butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-benzyloxyvalerate (500 g), ethyl acetate (750 mL) and tetrahydrofuran (1510 mL) were mixed. To the mixture was added 20 w/w % palladium hydroxide (50 g). The mixture was stirred for 4.5 hr under hydrogen atmosphere (1 atm). The palladium hydroxide was filtered off and the filtrate was concentrated in vacuo to give the title compound (455.76 g) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].[CH2:36](C1CCNCC1)C1C=CC=CC=1.C(OC1C=CC=CC=1CN(CC1C=CC=CN=1)CCCCl)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:14][CH2:15]1)[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:36]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Agent: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(Cc2ccccc2)CC1)Cc1ccccn1
Yield: 64 %

Procedure:
The same procedure as described for compound 20 was applied to 4-benzyl piperidin (0.30 g, 1.73 mmol), compound 19 (0.4 g, 1.15 mmol), KI (0.57 g, 3.45 mmol) and K2CO3 (0.79 g, 5.75 mmol). The residue was redissolved in CH2Cl2 and chromatographed on a silica-gel column with the following eluents: 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as yellow oil (64% yield). 1H NMR (CDCl3) δ 8.453 (dd, 1H, Ar), 7.576 (ddd, 1H, Ar), 7.516 (m, 2H, Ar), 7.224 (m, 2H, Ar), 7.135 (m, 1H, Ar), 7.075 (m, 4H, Ar), 6.982 (m, 2H, Ar), 3.730 (s, 2H, —CH2—), 3.655 (s, 2H, —CH2—), 2.864 (d, 2H, —CH2—), 2.482 (t, 4H, —CH2—CH2—), 2.324 (t, 2H, —CH2—), 1.888 (t, 2H, —CH2—), 1.728 (p, 2H, —CH2—), 1.586 (d, 2H, —CH2—), 1.502 (m, 1H, —CH—), 1.324 (s, 9H, —C(CH3)3), 1.288 (overlapped m, 2H, —CH2—). Mass Spec.=486.35 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[F:12][C:13]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:14]=1[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:42](=O)[CH3:43].O>O1CCOCC1>[F:12][C:13]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:14]=1[CH:15]=[CH:42][CH3:43]
Reactant: O=[N+]([O-])c1ccc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC=Cc1cc([N+](=O)[O-])ccc1F
Reaction time: 1 h

Procedure:
At 10° C., 5.99 g (32.7 mmol) sodium bis(trimethylsilyl)amide are added dropwise to a solution of 13.5 g (27.3 mmol) of the compound from Example 47A in 145 ml of dioxane. The mixture is stirred at this temperature for 1 h. A solution of 2.40 g (54.5 mmol) of acetaldehyde in 5 ml of dioxane is then added, and the reaction is stirred at RT for 1 h. 400 ml of water are then added, the mixture is extracted three times with dichloromethane and the combined organic phases are washed twice with saturated aqueous sodium chloride solution. After drying over sodium sulphate and subsequent filtration, the solvent is removed under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=40:1). This gives 5.2 g (100% of theory) of the desired product as an E/Z isomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11e, and 4-chlorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 1H), 7.81 (d, 2H), 7.77 (d, 2H), 7.48 (d, 2H), 7.32 (d, 1H), 7.12 (m, 3H), 7.04 (d, 1H), 6.88 (d, 1H), 6.80 (s, 1H), 4.33 (s, 2H), 4.30 (s, 2H), 3.64 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H),
Reaction SMILES: [N+](C1C=CC(C(OO)=O)=CC=1)([O-])=O.[C:14]([OH:18])([CH3:17])([CH3:16])C.[OH:19][C:20]1[CH:38]=[CH:37][C:36]2[C@@H:35]3[C@H:25]([C@H:26]4[C@@:30]([CH2:33][CH2:34]3)(CC)[CH:29]=[CH:28]C4)[CH2:24][CH2:23][C:22]=2[CH:21]=1>C(Cl)CCl>[O:18]1[C@H:16]2[C@:30]3([CH2:33][CH2:34][C@H:35]4[C@@H:25]([CH2:24][CH2:23][C:22]5[CH:21]=[C:20]([OH:19])[CH:38]=[CH:37][C:36]=54)[C@@H:26]3[CH2:17][C@@H:14]12)[CH2:29][CH3:28]
Reactant: CC(C)(C)O
Reactant: CC[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2
Agent: O=C(OO)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: CC[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@H]1O[C@H]12
Reaction time: 18 h

Procedure:
At room temperature, a solution of 360 mg. of p-nitroperbenzoic acid in 2.5 ml. of tert.-butanol and 0.5 ml. of ethylene chloride is gradually added to 450 mg. of 3-hydroxy-18-methyl-1,3,5(10),16-estratetraene in 15 ml. of ethylene chloride. After 18 hours, the crude product is worked up as described in (A) and purified by preparative layer chromatography (eluent: hexane/ethyl acetate = 7 : 3). In this way, 310 mg. of 16α,17α-epoxy-3-hydroxy-18-methyl-1,3,5(10)-estratriene is isolated as an oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:63][O:64][C:65](=[O:83])[C@@H:66]([NH2:82])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=2[CH3:81])=[CH:70][CH:69]=1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:82][C@H:66]([C:65]([O:64][CH3:63])=[O:83])[CH2:67][C:68]2[CH:69]=[CH:70][C:71]([C:74]3[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=3[CH3:81])=[CH:72][CH:73]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCCC2)cc1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (72 mg), EDCl (33 mg), HOBt (24 mg), and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (59 mg) were suspended in 3 mL DCM and NMM (0.067 mL) added. The mixture was stirred at room temperature for 3 hours and the mixture was directly purified over silica (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH) to give (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (86 mg). LCMS: (m/z) 791.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1CN(C)C(Cl)=O.[C:15]([Cl:18])(=[O:17])[NH2:16]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:16]([CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])[C:15]([Cl:18])=[O:17]
Reactant: NC(=O)Cl
Reactant: Cc1cccc(C)c1CN(C)C(=O)Cl
Product: CCCCCN(C(=O)Cl)c1c(C)cccc1C

Procedure:
When 2,6-dimethylphenyl-N-methyl-N-methylcarbamoyl chloride in Example 7D is replaced with the above carbamoyl chloride then the products prepared are