Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([O:12][C:13](=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[NH:17][C:16]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1.C(=O)=O.N1C2C(=CC=CC=2)C=CC=1>C(N(CC)CC)C.N1C=CC=CC=1>[C:1]([O:4][CH:5]([O:12][C:13](=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)[C:16]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)OC(OC(C)=O)c3ccccc3)c2c1
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc2c(c1)c(CC(=O)OC(OC(C)=O)c1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
Another method of preparing the compound I according to the invention is the acylation of (5-methoxy-2-methyl-3-indoleacetoxy)-benzyl acetate and subsequently splitting off the benzyl group. The mixed anhydride of p-chlorobenzoic acid with a monoalkyl ester of carbon dioxide is preferably used as acylation agent for this purpose. The reaction takes place by simply mixing the reactants and slowly heating them to 200°C until the evolution of carbon dioxide, starting at about 80°C, has ended. It is advantageous to use an excess of anhydride, preferably in the ratio of 1:2 to 1:3. The reaction takes place in the presence of a catalytic quantity of an organic base. As the organic base it is possible, inter alia, to use quinoline and pyridine and, more particularly triethylamine. The subsequent hydrogenation of the [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate which is formed takes place as described under A.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].Cl.[NH2:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(#N)C>[CH:32]([NH:31][C:29]([C@H:26]1[CH2:25][CH2:24][C@@H:23]([NH:22][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH:5]=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])[CH2:28][CH2:27]1)=[O:30])([CH3:34])[CH3:33]
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)cc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-4-(4-methoxybenzyloxy)-1-nitrobenzene (507 mg, 1.82 mmol), cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (404 mg, 1.82 mmol), DIPEA (0.70 mL, 4.02 mmol) and ACN (3.6 mL) were placed in a sealed tube, and the tube was heated at 80° C. for 6 hours. The mixture was allowed to cool and evaporated. The residue was diluted with DCM (15 mL), washed with water (×2), and then washed with brine. The organic layer was dried over Na2SO4. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% MeOH in DCM. The title compound was collected as a yellow solid (476 mg, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[C:4]([F:25])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23]([CH3:24])=[O:34])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[C:4]([F:25])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3F)c[nH]c12
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.16 mmol) of the compound from Example 6 were introduced into 2 ml of dichloromethane at 0° C., 40.7 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 29 mg (46% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][CH2:60][CH2:61][N:62]1[CH2:66][CH2:65][CH2:64][C:63]1=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:60][CH2:61][N:62]([CH2:66][CH3:65])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCN1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-(3-aminopropyl)pyrrolidin-2-one. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (t, J=7.07 Hz, 3H) 1.17 (m, 2H) 1.35-1.80 (m, 12H) 2.32 (q, J=7.07 Hz, 2H) 2.87 (br. d., 2H) 3.33 (s, 3H) 3.76 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.64 Hz, 2H) 4.46 (m, 1H) 7.47 (d, J=8.59 Hz, 1H) 7.50 (s, 1H) 8.14 (d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calculated for C29H39F2N7O3, 572. found 572.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[C:12]([I:20])=[CH:13][C:14]([S:16](F)(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Cl)=[CH:26][CH:25]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:16]([C:14]2[CH:13]=[C:12]([I:20])[C:9]3[CH2:10][CH2:11][NH:5][CH2:6][CH2:7][C:8]=3[CH:15]=2)(=[O:17])=[O:18])=[CH:26][CH:25]=1
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: O=C(N1CCc2cc(S(=O)(=O)F)cc(I)c2CC1)C(F)(F)F
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)c1cc(I)c2c(c1)CCNCC2
Reaction time: 18 h
Yield: 48.4 %

Procedure:
To a solution of 3-trifluoroacetyl-9-iodo-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonyl fluoride (5.29, 11.5 mmol) in tetrahydrofuran (50 ml) was added 4-fluorophenylmagnesium chloride (50 ml, 1M in tetrahydrofuran, 50 mmol). The resulting solution was stirred for 18 h without cooling then poured into saturated aqueous sodium potassium tartrate (150 ml), and extracted with diethyl ether (100 ml), The resulting organic layer washed with brine (100 ml), dried (MgSO4), and evaporated. Isolation using an SCX column and crystallisation from diethyl ether gave the subtitle compound as a white solid (2.4 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].C[O-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:25])[C:21](OC)=[O:22])=[CH:16][CH:15]=1>O1CCCC1>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:21](=[O:22])[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH3:25]
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Reactant: Cc1nsc(N)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(=O)Nc2snc(C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
5-Amino-4-chloro-3-methylisothiazole (7.4 g, 0.050 mol) was added to a suspension of sodium methoxide (6.1 g, 0.112 mol) in tetrahydrofuran (160 ml) and the mixture was stirred at room temperature for 20 minutes. A solution of methyl 2-(4-methoxyphenyl)propionate (8.8 g, 0.045 mol) in tetrahydrofuran (40 ml) was added dropwise and the mixture was stirred for 3 hours at room temperature. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 2.5:97.5, to give N-(4-chloro-3-methylisothiazol-5-yl)-2-(4-methoxyphenyl)propionamide (12.5 g) as a colourless solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])=[O:15].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:24])([F:25])[F:26])=[O:15]
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccccc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-(2-trifluoromethyl-phenyl)-urea (1 g) was dissolved in dry dichloromethane (20 ml) and cooled in an ice-bath. A 1M solution of BBr3 in dichloromethane (4 ml) was added drop-wise, and the solution stirred at room temperature for 30 minutes. Water was added, and after vigorous stirring, the mixture was extracted with dichloromethane. Drying (MgSO4), filtration, concentration in vacuo and flash chromatography provided a product which was slurried with petrol, filtered, washed with petrol and dried to afford 1-(2-Hydroxy-5-trifluoromethyl-phenyl)-3-(2-trifluoromethyl-phenyl)-urea (340 mg). Mp.=158-159° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[C:10]([CH:18]=[CH:19][C:20](O)=[O:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([NH:29][N:30]([C:20](=[O:21])/[CH:19]=[CH:18]/[C:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[CH:31]([CH3:33])[CH3:32])=[O:28]
Reactant: Cc1ccc2c(C=CC(=O)O)cn(C(=O)OC(C)(C)C)c2c1
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(/C=C/C(=O)N(NC(=O)c3cccc(F)c3)C(C)C)cn(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing 3-(1-(tert-butoxycarbonyl)-6-methyl-1H-indol-3-yl)acrylic acid (200.0 mg, 0.66 mmol), 3-fluoro-N′-isopropylbenzohydrazide (195.4 mg, 1.00 mmol) and HATU (378.6 mg, 1.00 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.16 ml, 1.00 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (50% EtOAc) for refinement and dried so that white (E)-tert-butyl 3-(3-(2-(3-fluorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-6-methyl-1H-indole-1-carboxylate was obtained (161.0 mg, 50.9%).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[NH:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])N>C(O)C>[C:13]1([C:4]2[CH:3]=[N:2][N:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CNN
Reactant: CN(C)C=C(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
When only the 4,5-diphenyl isomer is desired the following procedure is preferred. A mixture of 778 g (3.96 mol) deoxybenzoin, 580 mL (4.38 mol) of N,N-dimethylformamide dimethyl acetal, and 775 mL of methyl tert-butyl ether was refluxed for 3 hours. The reaction mixture was cooled on ice to 0°-5° C. The precipitated solid was collected by filtration, the filter cake washed with 250 mL of cold methyl tert-butyl ether twice and dried in vacuum chamber at 65° C. to afford 913 g (92%) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one, mp 128°-133° C. A slurry of 913 g (3.64 mol) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one in 3.4 L of absolute ethanol was treated with 618 g (4 mol) of ethyl hydrazinoacetate hydrochloride in one portion. The mixture was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the filtrate treated with 7 L of 50% aqueous ethanol with stirring. Cooling of the resultant solution to 0°-5° C. provided a white solid which was collected by filtration, washed with 250 mL of cold 50% ethanol twice and dried in vacuum at 40° C. to provide 970 g (87%) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate, mp 76°-80° C., containing none of the 3,4-diphenyl isomer detectable by GLC.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C([NH:16][CH2:17][C:18]([OH:20])=[O:19])(OC(C)(C)C)=O.[CH2:21](O)[C:22]#[C:23][CH3:24].Cl[Si](C)(C)C>C1COCC1.C(OCC)(=O)C.Cl.CO>[NH2:16][CH:17]([C:23]([CH3:24])=[C:22]=[CH2:21])[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC#CCO
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C=C(C)C(N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an LDA solution (75.6 mmole prepared from diisopropylamine and 1.55M n-butyl lithium at -78° C.) in 100 ml of dry THF was added dropwise 36 mmole of N-BOC-glycine butynal ester (prepared from N-BOC-glycine and 2-butyn-1-ol according to the method of R. Olsen, et al, JOC, 47, 1962, 1982), in 20 ml of THF. After 1 hour, 9.6 ml of chlorotrimethylsilane was added and the reaction mixture was slowly brought to room temperature and then heated to reflux for 1 hour. On cooling to room temperature, 20 ml of methanol was added and after another hour the reaction mixture was concentrated. The resulting residue was taken in ethyl acetate and extracted repeatedly with 5% NaHCO3. The aqueous portion was acidified in a two phase system containing CH2Cl2 with 20% HCl to pH 3.0. The CH2Cl2 portion was separated and the aqueous phase repeatedly extracted with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, brine and dried over anhydrous MgSO4. On concentration 1.3 gm of a residue showing an allene band at 1960 cm-1 was obtained. This was taken in 50 ml of a saturated HCl ethyl acetate solution at room temperature upon which a yellow precipitate formed. After 1 hour, the reaction mixture was concentrated and the resulting residue taken in water and washed with CH2Cl2. The aqueous portion was then applied on an ion-exchange column (H+) eluting with 20% pyridine-water. The eluant was concentrated, partially purified by reverse phase chromatography and upon crystallization from acetone-water, the desired product was obtained: mp. 195°-200° C. (dec), IR (KBr): 1960 cm-1 (C=C=C), 'H NMR (δD2O): 1.82 (t, 3H, J=3.2 Hz, CH3), 4.2 (t, 1H, J=1.7 Hz, CHN), 5.0 ppm (m, 2H, H2C=C).
Reaction SMILES: ClC[C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].C([O-])(=O)C.[Na+]>ClCCCl.O.C(OCC)(=O)C>[O:4]=[C:3]1[C:13]2[CH:12]=[CH:11][C:10]([NH:14][C:15](=[O:17])[CH3:16])=[CH:9][C:8]=2[O:7][CH2:6]1
Reactant: COc1cccc(NC(C)=O)c1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32.6 g (0.181 mol) of chloroacetyl chloride are added, followed within 15 minutes by 20 g (0.121 mol) of N-(3-methoxyphenyl)acetamide, to a solution of 64.6 g (0.484 mol) of aluminum chloride in 100 ml of 1,2-dichloroethane at 0° C. under argon. The temperature rises to 10° C. during this. The mixture is then slowly warmed to room temperature and stirred overnight. The brown mixture is added to ice-water, and ethyl acetate is added. After vigorous stirring, N-(3-methoxy-4-chloroacetylphenyl)acetamide precipitates and is filtered off with suction and dried under higher vacuum. The resulting solid is introduced into 140 ml of ethanol and, after addition of 13.2 g (0.154 mol) of sodium acetate, heated under reflux overnight. Cooling is followed by addition of water, and the ethanol is stripped off in a rotary evaporator. The precipitated solid is filtered off with suction on a frit and dried. 9.35 g (40% of theory) of the product result as a solid with a pale reddish color.
Reaction SMILES: [ClH:1].Cl.C(OC1C=CC(C(N2CC[C@@H](NC)C2)CC2(O)CCCCC2)=CC=1)C1C=CC=CC=1.C(O[C:38](=O)[NH:39][C@@H:40]1[CH2:44][CH2:43][N:42]([C:45](=O)[CH:46]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:56][CH:55]=2)[C:47]2([OH:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:41]1)(C)(C)C>>[ClH:1].[ClH:1].[CH2:61]([O:60][C:57]1[CH:58]=[CH:59][C:54]([CH:46]([C:47]2([OH:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:45][N:42]2[CH2:43][CH2:44][C@@H:40]([NH:39][CH3:38])[CH2:41]2)=[CH:55][CH:56]=1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2ccc(OCc3ccccc3)cc2)C2(O)CCCCC2)C1
Agent: CN[C@@H]1CCN(C(CC2(O)CCCCC2)c2ccc(OCc3ccccc3)cc2)C1
Agent: Cl
Product: CN[C@@H]1CCN(CC(c2ccc(OCc3ccccc3)cc2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 13, step 2,1-{1-[4-(benzyloxy)phenyl-2-[(3R)-3-(methylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl{(3R)-1-[[4-(benzyloxy)phenyl](1-hydroxycyclohexyl)acetyl]pyrrolidin-3-yl}carbamate. MS m/z 409; HRMS: calcd for C26H36N2O2+H+, 409.28495; found (ESI, [M+H]+), 409.2876.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(C)C=CC=CC=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>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]>[N+:14]([C:4]1[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Br)ccc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
4-(4-Bromo-2-nitrophenyl)morpholine (500 mg, 1741 μmol) and morpholine (303 μL, 3483 μmol) were dissolved in toluene (71047 μL, 666992 μmol). To the stirred mixture was added X-Phos (125 mg, 261 μmol), sodium tert-butoxide (335 mg, 3483 μmol) and tris(dibenzylideneacetone)dipalladium (o) (112 mg, 122 μmol) in one portion. The reaction was heated to reflux for 2 h. After this time TLC and LC/MS show desired product. The reaction was cooled to rt and evaporated in vacuo. The residue was taken up in EtOAc (80 mL) and washed with satd aq. sodium bicarbonate solution (40 mL) and brine (40 mL). The separated organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Column chromatography (hexanes:EtOAc, 1:0 to 1:2) gave desired product.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:8]([Cl:26])=[CH:9][C:10]([OH:25])=[C:11]([CH:24]=1)[C:12]([N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:15])=[O:13].Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32].C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:6][C:7]1[C:8]([Cl:26])=[CH:9][C:10]([O:25][CH2:28][CH2:29][CH2:30][C:31]#[N:32])=[C:11]([CH:24]=1)[C:12]([N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:15])=[O:13]
Reactant: N#CCCCBr
Reactant: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1OCCCC#N
Temperature: 50 °C
Yield: 68 %

Procedure:
To a stirring DMF solution (6 mL) containing 5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (300 mg, 0.81 mmol) was added 4-bromo-butyronitrile (0.096 mL, 0.97 mmol) and K2CO3 (223 mg, 1.62 mmol). The mixture was heated at 50° C. for 8 hrs. Additional 0.5 eq. of 4-bromobutyronitrile and 0.5 eq of K2CO3 were added and the mixture was heated for another 8 hrs. The mixture was diluted with dichloromethane, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography to afford 5-bromo-4-chloro-2-(3-cyano-propoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide (241 mg). MS [M+H]+: 439.1; tR=2.62 min (method 1)
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:6][C@H:5]([NH:7][C:8](=[O:20])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)[C@@H:4]([NH:21]S(C(C)(C)C)(=O)=O)[CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[NH2:21][C@H:4]1[CH2:3][C:2]([F:29])([F:1])[CH2:6][C@@H:5]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:16]=[CH:17][CH:18]=[N:19]1
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-[(1S,2S)-4,4-difluoro-2-(2-methylpropane-2-sulfonamido)cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (1.7 g, 3.98 mmol) in DCM (100 ml) at 0° C. was added anisole (CAS number 100-66-3; 7.82 ml, 71.6 mmol) followed by the drop wise addition of trifluoromethanesulfonic acid in DCM (0.2M, 1.55 ml, 17.5 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 18 hours. The reaction mixture was quenched with sodium hydroxide (0.2M) until pH 11 obtained then extracted with DCM. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by SCX chromatography (2M ammonia in methanol) to afford the title compound.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CS(N)(=O)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
A solution of 25.2 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride and 5.8 g. of methanesulfonamide in 250 ml. of pyridine was stirred under reflux for 2 hours and then concentrated in vacuo. The residue was partitioned between water and diethyl ether; the aqueous layer acidified with 1N HCl, and the organic layer separated, dried (MgSO4), and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid followed by CH2Cl2 -hexane afforded the product as a white solid.