Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:25][N:26]=O)CCC>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[C:13](=[N:26][OH:25])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCON=O
Reactant: COc1cc2c(cc1OCc1ccccc1)CCC2=O
Product: COc1cc2c(cc1OCc1ccccc1)CC(=NO)C2=O

Procedure:
Similar procedure as described in example 2a was used, starting from 5-Benzyloxy-6-methoxy-indan-1-one and n-butylnitrite to give 5-Benzyloxy-6-methoxy-indan-1,2-dione 2-oxime. LC-MS: m/e 298 (MH+).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14]>COCCOC.O>[Si:17]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: OCc1ccccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CO
Reaction time: 1 h

Procedure:
To a solution of 14.074 g (101.86 mM) of 1,2-benzenedimethanol in 100 ml of 1,2-dimethoxyethane was added 4.07 g (102 mM) of a liquid paraffin suspension of 60% sodium hydride at room temperature and the mixture was stirred at the prevailing temperature for one hour. To this reaction mixture was added a solution of 15.4 g (102 mM) of tert-butylchlorodimethylsilane in 50 ml of 1,2-dimethoxyethane dropwise, and the mixture was stirred at room temperature overnight. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 3/1) to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:41])[O:36][CH2:37][CH2:38][O:39][CH3:40]>ClCCl>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:35](=[O:41])[NH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C:22]4=[O:27])=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Reactant: COCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (150 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and 2-methoxyethyl carbonochloridate (68 mg, 0.544 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 183 to afford the title compound as a solid
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](OS(C)(=O)=O)[CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[C:14]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]2=3)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[N:32]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1)[CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]1=2)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(C(N)=O)nc2)CCN(C)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
Methanesulfonic acid-1-(6-carbamoyl-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl ester (300 mg, 0.678 mmol) was dissolved in 5 mL DMF, and sodium azide (88 mg, 1.357 mmol) was added, and the mixture heated at 100° C. for 1 h. The reaction mixture was monitored by LCMS. After completion of reaction, the reaction mixture was cooled to RT and diluted with water (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (4×40 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase chromatography to yield 5-[1-azido-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylic acid amide (135 mg). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (dd, 1H), 8.1 (t, 1H), 7.9 (t, 1H), 7.33 (dd, 1H), 7.26 (s, 1H), 7.06 (t, 1H), 5.3 (t, 1H), 4.7 (dd, 1H), 4.42 (dd, 1H), 4.4 (dd, 2H), 4.3 (m, 1H), 3.8 (m, 1H),3.6 (m, 1H), 3.34 (dd, 1H), 3.1 (d, 3H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers V-22a-b.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40].C(OC([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)=O)(C)(C)C.Cl>C1COCC1>[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[O:40][CH:51]1[CH2:52][CH2:53][NH:48][CH2:49][CH2:50]1
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC2CCNCC2)c(Cl)c1
Reaction time: 16 h
Yield: 85.9 %

Procedure:
DEAD (0.90 ml) was added to a solution of triphenylphosphine (1.44 g), 2-chloro-4-fluorophenol (0.806 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.0 g) in THF at RT. The reaction was stirred for 16 hrs, HCl (2 ml, 4M in dioxan) added and the mixture stirred at RT for 16 hrs. The mixture was then evaporated to dryness, triethylamine (5 ml) added, re-evaporated, dissolved in methanol (10 ml) and placed on to a SCX cartridge (Varian, 10 g), eluted first with methanol then with 10% NH3 in methanol. The basic fractions were combined and evaporated to give the sub-title compound as an oil (0.98 g)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:12]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:17]1[C:24]1[CH:29]=[C:28]([N+:30]([O-])=O)[C:27]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=O)=[CH:26][C:25]=1F)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:17]1[C:24]1[C:25]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:26][C:27]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[NH:30][C:28]=2[CH:29]=1)(=[O:14])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(=O)OC1CCN(C(C)=O)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Product: CC(=O)OC1CCN(C(C)=O)C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained as a white solid in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using 4-(methanesulfonyl)phenol and (1-acetyl-2-(2-fluoro-5-nitro-4-((pyridin-2-ylcarbonyl)amino)phenyl)pyrrolidin-3-yl acetate diastereomer A.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([N:15]=[C:16]=[S:17])[C:12]([F:18])=[CH:11][C:10]=2[Cl:19])[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C(O)C>[CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]3)=[S:17])[C:12]([F:18])=[CH:11][C:10]=2[Cl:19])[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(Sc2cc(N=C=S)c(F)cc2Cl)CC1
Reactant: C1CCNNC1
Solvent: CCO
Product: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CC1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
While stirring at room temperature, a solution of 6.3 g of 1-(2-chloro-4-fluoro-5-isothiocyanato-phenylthio)-cyclopropanecarboxylic acid methyl ester in 30 ml of ethanol is added dropwise to a solution of 2.2 g of hexahydropyridazine in 30 ml of ethanol. After stirring for 30 minutes at room temperature, the reaction mixture is concentrated by evaporation in vacuo, yielding 7.9 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclopropanecarboxylic acid methyl ester having a melting point of from +156° to +157° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[F:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccncc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccncc4F)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine following a procedure analogous to that described in Example 28. LC (method 10): tR=1.71 min; Mass spectrum (ESI+): m/z=400 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19]([NH2:22])(=[O:21])=[O:20])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C.[C:52](O)(=[O:54])[CH3:53]>ClCCl.C(OCC)(=O)C>[C:52]([NH:22][S:19]([CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[CH2:16][CH2:15]1)(=[O:21])=[O:20])(=[O:54])[CH3:53]
Reactant: CC(=O)O
Reactant: NS(=O)(=O)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NS(=O)(=O)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 18 h
Yield: 61.8 %

Procedure:
To a stirred solution of the product of Example 105 (141 mg, 0.28 mmol) in dichloromethane (10 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol), dimethylaminopyridine (66 mg, 0.57 mmol) and acetic acid (0.035 mL, 0.58 mmol). The mixture was stirred for 18 hours, diluted with ethyl acetate (20 mL), washed with 2N aqueous hydrochloric acid (20 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica eluting with ethyl acetate: dichloromethane:iso-hexane 2:1:1, to afford the desired product (90 mg).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1>C(Cl)(Cl)Cl>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[CH:15]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: c1ccc2c(c1)CCCN2
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CCCN2CCc1c[nH]c2ccccc12

Procedure:
1,2,3,4-Tetrahydroquinoline (5.94 g, 5.6 ml, 44.6 mmol) was added to a solution of 3-(2-bromoethyl)-indole (5.00 g, 22.3 mmol) in dry chloroform (25 ml) at room temperature and the mixture was then stirred under reflux for 5 h. The reaction mixture cooled overnight. The organic phase was extracted with dil. sulfuric acid (2×50 ml). The aqueous phase was rendered basic with 5N NaOH, while cooling with ice, and extracted with ether (3×50 ml). The organic phase was dried over Na2SO4 and concentrated i. vac. Yield: 5.35 g (Ind-62, 88%)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)C>[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NC(=O)C1(c2ccccc2)CCNCC1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (19 mg, 0.051 mmol, 1 eq.) in 2 mL of ethanol was added N-tert-butyl-4-phenylpiperidine-4-carboxamide (13.2 mg, 0.051 mmol, 1 eq.) and triethylamine (0.02 mL, 0.15 mmol, 3 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 22 mg (72%) of N-tert-butyl-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidine-4-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.32 (m, 9 H) 2.17 (s, 2 H) 2.39-2.58 (m, 2 H) 4.07 (s, 2 H) 5.01 (s, 2 H) 7.10-7.44 (m, 12 H) 7.51 (d, J=6.59 Hz, 1 H) 8.37 (s, 1 H), [M+H]+ 599.7.
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>>[F:1]/[C:2](=[CH:8]\[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)/[CH2:3][OH:4]
Reactant: CCOC(=O)/C(F)=C/c1ccc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OC/C(F)=C/c1ccc2ccccc2c1
Yield: 88.7 %

Procedure:
The reaction of ethyl (Z)-2-fluoro-3-(2-naphthyl)acrylate (3.77 g) with diisobutylaluminum hydride was carried out in a similar manner as described in Reference example 3 to give the titled compound (2.77 g) as a colorless solid.
Reaction SMILES: ClCl.[OH-:3].[Na+:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16](=[O:18])C)[CH:10]=[CH:9]2.[Cl:19][O-].[Na+]>>[Cl:19][O-:3].[Na+:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:3])[CH:10]=[CH:9]2
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 0 °C

Procedure:
The title compound can be prepared by two procedures designated as procedure A and procedure B below. The starting material of formula II used in each of these procedures is prepared as follows: A sodium hypochlorite solution was prepared by introducing chlorine gas (11.2 g) into a solution of NaOH (15.3 g) in 200 ml of ice water. Solid (6-bromo-2-naphthalenyl)ethanone [9.5 g, 38.1 mmoles, prepared according to the procedure of R. B. Girdler et al., J. Chem. Soc. (C), 518 (1966)] was added to the stirred sodium hypochlorite solution at 0° C. and then the mixture was heated on a steam bath for 1 hr. The precipitate was removed by filtration. Sodium metabisulfite (5 g) was added to the cooled (0° C.) filtrate. The mixture was adjusted to pH 5 with concentrated HCl. The precipitate was collected and dried. The collected precipitate was crystallized from boiling ethanol by the addition of water to afford 5.5 g (two crops) of 6-bromo-2-naphthalenecarboxylic acid; mp 288°-290° C.; NMR (CDCl3) δ 7.68 (2d, J=8 Hz, J2 =2 Hz, 1H), 7.97 (m, 2H), 8.05 (d, J=8 Hz, 1H), 8.25 (d, H), 8.58 (d, 1H), IR (CHCl3), 2800, 1680, 1625, 1567 cm-1 ; UVλmax (EtOH) 333 nm (ε1080), 323 (880), 317 (1020), 286 (9040), 237 (54,350).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:30]=[O:31])=[CH:3][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: CN(C)C=O
Reactant: COCCCCc1cc(Br)ccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCCc1cc(C=O)ccc1OC
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-1-methoxy-2-(4-methoxy-butyl)-benzene (8.10 g, 29.7 mmol; described in EP0678 503 B1) in absolute THF (170 mL), cooled to −78° C., is added dropwise over 30 min and under an argon atmosphere a 1.6M solution of n-butyllithium in hexane (20.4 mL, 32.6 mmol). After stirring for 5 min, a mixture of DMF (5.03 mL, 65.2 mmol) in THF (20 mL) is added over 30 min at −78° C. Stirring is continued over 15 min at −78° C., and the reaction mixture is gradually warmed and stirred for an additional hour at room temperature before quenching with 1N HCl. The aqueous layer is extracted with diethyl ether (3×200 mL), the combined organics are dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 4:1) gives the title compound as yellowish oil. TLC, Rf (hexane/AcOEt 4:1)=0.27. MS: 223.2 [M+H]+. 1H-NMR (CDCl3): δ 1.6-1.74 (m, 4H) 2.70 (t, 2H), 3.37 (s, 3H), 3.43 (t, 2H), 3.96 (s, 3H), 6.99 (dd, 1H), 7.73 (d, 1H), 7.76 (dd, 1H), 9.70 (s, 1H) ppm.
Reaction SMILES: C(OC(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:19])=[O:18])=[CH:9][CH:8]=1)=O)C.N.C(NS(C1C2C(=CC=CC=2)C(O)=CC=1)(=O)=[O:56])CCCCCCCCCCCCCCC>ClCCl>[CH2:21]([NH:20][S:17]([C:10]1([OH:56])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH2:9]1)(=[O:19])=[O:18])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(OC(=O)OCC)c2ccccc12
Reactant: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(O)c2ccccc12
Agent: N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)C1(O)CC=Cc2ccccc21
Reaction time: 1 h

Procedure:
4-Ethoxycarbonyloxy-N-hexadecylnaphthalene-1-sulphonamide (21.5 g, 41.4 mmole) was added to liquid ammonia (250 ml), in portions with stirring, at -78° C. (acetone-drycold bath). The mixture was stirred for 1 h, and the excess ammonia allowed to evaporate. The residue was dissolved in ethyl acetate, washed with water and dried (MgSO4). Removal of the solvent gave a pale brown oil which was dissolved in hot dichloromethane (100ml) and then cooled in an ice-bath. The off-white precipitate was collected and dried in air to yield pure N-hexadecyl-4-hydroxynaphthalene-4-sulphonamide, 7.7 g, 42%. TLC analysis (1:3 EtOAc : 40°-60° petrol) showed one spot (Rf =0.4) and spectroscopic data was consistent with the product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44][CH2:43]2)=[CH:38][C:32]=1[C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[CH3:36][N:35]([CH3:37])[C:33]([C:32]1[CH:38]=[C:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]2)[CH:40]=[CH:41][C:31]=1[NH:30][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1)=[O:34]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN(C)C(=O)c1cc(C2CCC(O)CC2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)cc3C(=O)N(C)C)n2)c(OC)c1)OCC

Procedure:
The title compounds were prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.20 g, 0.45 mmol) and 2-amino-5-(4-hydroxycyclohexyl)-N,N-dimethylbenzamide (Compound 173A, 0.130 g, 0.496 mmol). The reaction mixture was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash unit eluting with 0 to 5% MeOH in DCM to afford the individual trans and cis isomers. Cis: 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 7.86 (d, J=8.34 Hz, 1H), 7.60 (d, J=7.83 Hz, 1H), 7.26 (dd, J=1.77, 8.59 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.96 (t, J=1.89 Hz, 1H), 6.73 (d, J=7.83 Hz, 1H), 3.92-4.01 (m, 4H), 3.89 (br. s., 1H), 3.77 (s, 3H), 3.13-3.23 (m, 2H), 2.91 (d, J=15.16 Hz, 6H), 2.56 (t, J=11.87 Hz, 1H), 1.79-1.92 (m, 2H), 1.70-1.78 (m, 2H), 1.49-1.61 (m, 4H), 1.18 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 681.2723 [MH+]. HPLC: tR=1.45 min (UPLC TOF MS: polar—3 min). Trans: 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 7.85 (d, J=8.84 Hz, 1H), 7.58 (d, J=8.08 Hz, 1H), 7.26 (dd, J=2.02, 8.34 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.96 (s, 1H), 6.73 (d, J=7.83 Hz, 1H), 4.57 (d, J=4.55 Hz, 1H), 3.91-4.01 (m, 4H), 3.76 (s, 3H), 3.40-3.54 (m, 1H), 3.14-3.23 (m, 2H), 2.91 (d, J=18.95 Hz, 6H), 1.93 (d, J=9.35 Hz, 2H), 1.79 (d, J=12.38 Hz, 2H), 1.45-1.58 (m, 2H), 1.22-1.35 (m, 2H), 1.19 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 680.2332 [MH+]. HPLC: tR=1.40 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1B1OC(C)(C)C(C)(C)O1)[C:18]([O:20]C)=[O:19]>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:24]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[CH3:14])[N:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ncc2c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: Cc1cc(C(=O)O)ccc1-c1ncc2cc(O)ccc2n1

Procedure:
Prepared according to Scheme 6, B conditions, starting from Intermediate 8 and methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. 1H NMR (DMSO-d6 400 MHz): δ 9.54 (s, 1H), 8.00-7.86 (m, 4H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 2.59 (s, 3H). MS (ESI): m/z 280.9[M+H]+.
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18]C2C=CC(CBr)=CC=2)=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18][C:9]2[CH:10]=[CH:2][C:3]([CH2:4][NH2:5])=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
To a stirred mixture of potassium phthalimide (3.60 g, 19.4 mM) and dry N,N-dimethylformamide (200 ml) was added dropwise a solution of 4-(4-methylthiophenoxy)benzylbromide (5.00 g, 16.2 mM) in dry N,N-dimethylformamide at room temperature, the mixture was stirred for 5 h at the same temperature. The mixture was poured into water, and the mixture was extracted with toluene. The extract was washed with 5N NaOH, water and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was diluted with methanol (200 ml), and to the mixture was added dropwise hydrazine monohydrate (1.10 g, 21.1 mM). The mixture was stirred for 6 h under reflux, and this was cooled to the room temperature and concentrated in vacuo. The residue was diluted with chloroform and the mixture was filtered through celite. The filtrate was washed with 5N NaOH(x3) and brine(x2), dried with potassium carbonate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzylamine (3.02 g, 76%) as colorless crystals, m.p. 61.8° C.