Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[Cl:17][S:18]([C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1S(=O)(=O)Cl

Procedure:
(The used starting compound is prepared by reacting 4'-cyano-4-methoxy-biphenyl with chloro sulfonic acid)
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[CH:14]=[C:13]([F:20])[C:12]=1[CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(COC)OC.FC(F)(F)S(O)(=O)=O>[F:7][C:24]1[CH2:25][CH2:26][CH:21]([C:12]2[C:11]([F:10])=[CH:16][C:15]([CH2:17][CH2:18][CH3:19])=[CH:14][C:13]=2[F:20])[CH2:22][CH:23]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCc1cc(F)c(C2CCC(=O)CC2)c(F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COCCOC
Product: CCCc1cc(F)c(C2CC=C(F)CC2)c(F)c1

Procedure:
535 ml of diethylaminosulphur trifluoride (DAST) were added dropwise in 3 portions over 60 hours to a solution of 0.63 g of 4-(2,6-difluoro-4-propylphenyl)cyclohexanone in 15 ml of dimethoxyethane and 50 ml of trifluoromethanesulphonic acid. The reaction solution was subsequently partitioned between sodium carbonate solution and ether. The organic phase was washed twice with water and the aqueous phases were individually extracted twice with ether. The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was evaporated completely. The resulting crude product (0.8 g) was purified by chromatography and gave 0.36 g of 1-fluoro-4-(2,6-difluoro-4-propylphenyl)cyclohex-1-ene, m.p. (C/I) 62.5° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:30][O:31][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>C(Cl)Cl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@@H:9]([C:11]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])=[O:39])=[O:13])[CH3:10]
Reactant: COC(=O)CCCCCN
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CCCCCNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 25 h

Procedure:
Boc-(D)-alanine (5.1 g, 26.9 mmol) in 100 ml of methylene chloride (CH2Cl2) was cooled to 0° C. and 5.9 ml (53.8 mmol) of N-methylmorpholine (NMM) were added. After cooling this vigorously stirred solution to -78° C., 3.5 ml (26.9 mmol) of isobutylchloroformate (IBCF) were added to this reaction which was run entirely under an Ar atmosphere. The mixture was allowed to warm slowly to 20° before it was again cooled to -78° C. and 4.9 g (26.9 mmol) of 6-aminohexanoic acid methylester hydrochloride were added in a single portion. Following warming this mixture to room temperature, it was allowed to stir 25 hour (h). Precipitated N-methylmorpholine hydrochloride was filtered off and the filtrate, after diluting with CH2Cl2 (200 ml), was washed 3×100 ml of 0.5N potassium bisulfate (KHSO4). The combined aqueous washes were extracted with a 100 ml portion of CH2Cl2 and the combined organics were washed 1×75 ml of brine, dried over Na2SO4 (anhy.), and stripped of all solvent under reduced pressure. By thin layer chromatography (10% ethanol (EtOH)/chloroform (CHCl3)) the yellow liquid title product was essentially one spot and used in subsequent reactions without further purification. Optical rotation [α]D +21.5° and +93.7° (365 nm) CHCl3. NMR shift of the (D)Ala methyl=1.34δ (CDCl3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1)(=[O:26])[CH3:25]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: CC(=O)Cl
Product: CC(=O)n1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was acylated with acetyl chloride using the method of Example 18. The product was chromatographed on silica gel eluting with ethyl acetate to give a pale yellow oil, which crystallised from ether to afford the title compound (E30) as a white solid mp 127°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:24][C:23]2[CH:26]=[C:27]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COc1ccc(-c2ccsc2)cc1C=O
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Product: COC(=O)C1CCC(NCc2cc(-c3ccsc3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 2-methoxy-5-(thiophen-3-yl)benzaldehyde (P. J. Ward, D. R. Armour, D. E. Bays, B. Evans, G. M. P. Giblin, N. Hernon, T. Hubbard, K. Liang, D. Middlemiss, J. Mordaunt, A. Naylor, N. A. Pegg, M. V. Vinder, S. P. Watson, C. Bountra, and D. C. Evans, J. Med. Chem. 1995, 38, 4985-92).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:17]([C@@H:18]([NH2:20])[CH3:19])=[CH:16][C:15]3[C:10](=[C:11]([Cl:21])[CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[C:30](Cl)([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:17]([C@@H:18]([NH:20][C:30](=[O:31])[O:32][CH2:33][CH:34]3[C:46]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:40]4[C:35]3=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH3:19])=[CH:16][C:15]3[C:10](=[C:11]([Cl:21])[CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(Cn2c([C@H](C)N)cc3cccc(Cl)c3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2c([C@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc3cccc(Cl)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(4-methoxybenzyl)-3-(1-aminoethyl)-8-chloroisoquinolin-1(2H)-one (343) (20 g, 58.3 mmol, 1.0 eq) and NaHCO3 (12.7 g, 291.51 mmol, 5.0 eq) in DCM (120 mL) and water (60 mL) at RT, Fmoc-Cl (15.7 g, 61.22 mmol, 1.05 eq) was slowly added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (200 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford (S)-(9H-fluoren-9-yl)methyl 1-(2-(4-methoxybenzyl)-8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (344).
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)—N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in an ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (3 L). The filtrate was concentrated and the residue was purified over silica gel (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)—N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH:13]=C.[O:15]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:15]
Reactant: O=[O+][O-]
Reactant: C=CCc1c(Br)ccc2c1COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1OCc2c1ccc(Br)c2CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4-prop-2-en-1-yl-2-benzofuran-1(3H)-one (1.27 g, 5.02 mmol) in MeOH (50 mL) and DCM (50 mL) was bubbled O3 at −78° C. until the solution turned blue; excess ozone was removed on high vacuum. After the solution's color changed to colorless, NaBH4 (0.8 g, 20 mmol) was added to the reaction mixture and it was subsequently stirred at room temperature for 30 min. LC and TLC indicated that reaction had gone to completion. The solvent was removed on high vacuum; the residue was then re-dissolved in EtOAc and washed with water, dried over Na2SO4, filtered and concentrated to dryness. The organic residue was absorbed onto silica gel and was separated on silica gel column to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][C:13]([OH:15])=O.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:12]/[C:13]([N:22]2[CH2:23][CH2:24][NH:19][C:20](=[O:25])[CH2:21]2)=[O:15])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CNCCN1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Reaction time: 16 h
Yield: 71.6 %

Procedure:
A solution of oxalyl chloride (4.19 g, 33.0 mmol) in dichloromethane (12.5 ml) was added dropwise at room temperature to a solution of 3-chlorocinnamic acid (5.48 g, 30.0 mmol) and N,N-dimethylformamide (2 drops) in dichloromethane (240 ml). After 2 h the solution was evaporated and the residue redissolved in dichloromethane (160 ml), then a solution of piperazin-2-one (2.70 g, 27 mmol) and triethylamine (6.07 g, 60.0 mmol) in dichloromethane (80 ml) was added dropwise at 0° C. The reaction mixture was allowed to reach room temperature over 16 h, then poured onto 10% aq. potassium hydrogensulfate solution. The organic layer was washed with sat. aq. sodium hydrogencarbonate solution and 10% aq. sodium chloride solution, dried, and evaporated to produce the title compound (5.12 g, 72%). Yellow solid, MS (EI)=264.1 (M)+.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20].Cl>CCOCC.O1CCCC1.CCCCCC>[CH3:10][C:6]1([CH3:11])[C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[S:9][CH2:8][CH2:7]1
Reactant: O=C=O
Reactant: CC1(C)CCSc2cc(Br)ccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CCSc2cc(C(=O)O)ccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
11 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran were dissolved in a mixture of 100 ml of ether and 10 ml of tetrahydrofuran and treated at -78° C. with 33 ml of a 1.6 molar solution of n-butyllithium in hexane. The reaction solution was held at -50° C. for 15 minutes, again cooled to -78° C. and gassed with carbon dioxide for 2 hours. Thereafter, the mixture was poured on to ice, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic phases were washed with water, dried and evaporated. After recrystallization of the crude product from ethyl acetate/hexane, there were obtained 4.6 g of 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxylic acid, melting point 202°-204° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=O)C1C=CC=CC=1.[H-].[Na+].[H][H].Br[CH2:23][C:24]([C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:25]>O.CN(C)C=O>[O:25]=[C:24]([C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)[CH2:23][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:17]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: [H][H]
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CNCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
To a round bottomed flask were added 4-benzyloxycarbonylpiperazin-2-one (234.26 mg, 1.0 mmol) along with N,N-dimethylforamide(5.0 ml), and sodium hydride (73.0 mg (60%), 1.0 mmol). After the evolution of hydrogen had ceased the reaction was allowed to stir for an additional 30 minutes. To this was added 1 adamantyl bromomethyl ketone(257.18 mg, 1.0 mmol). The reaction stirred at Rt. for 18 hrs. The reaction was poured into water(25ml) and extracted with ethylacetate(2×25 ml). The ethylacetate layer was washed with brine and dried (MgSO4). Solvent removal yielded 4-benzyloxycarbonyl-[1-(2-oxo-2-(adamant-1-yl)ethyl]piperazin-2-one. 400 Mhz H1 NMR (CDCl3): 1.68-1.91(m,12H), 2.06 (br s,3H), 3.32(t,2H), 3.77(t,2H), 4.20(s,2H), 4.34(s,2H), 5.16(s,2H), 7.36(m,5H). The material was used with out further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]1=[O:21].[F:22][C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:24]=1F.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:22][C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:24]=1[NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)[C:3]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 130 °C
Yield: 72.3 %

Procedure:
(S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.0 g, 13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 4.2 g, 20 mmol) and Na2CO3 (2.9 g, 27 mmol) were dissolved in DMF (30 mL) and heated at 130° C. overnight. The reaction was concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol, 70% yield) as yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[OH:23][C:5]1[C:6]([CH2:20][CH2:21][CH3:22])=[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:12]([C:13]3[NH:26][N:25]=[N:24][N:14]=3)[CH:11]=2)[CH:18]=[CH:19][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(C#N)c2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(-c3nnn[nH]3)c2)ccc(C(C)=O)c1O
Yield: 82.8 %

Procedure:
A mixture of 8.25 g 3-[(4-acetyl-3-hydroxy-2-propyl phenoxy)methyl]benzonitrile, 5.20 g sodium azide and 4.30 g ammonium chloride in 125 mL anhydrous dimethylformamide was stirred and heated at 120° for 6 hr. The solvent was removed in vacuo and the residue was treated with 250 mL water and acidified with 10 mL 6N hydrochloric acid. The resulting solid was recrystallized from ethanol-water to give 7.78 g, mp 194°-195° of 1-[2-hydroxy-3-propyl-4-[[3-(1H-tetrazol-5-yl)phenyl]methoxy]phenyl]ethanone.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:14][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCCc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClC1CCCc2ccccc21
Reaction time: 2 h

Procedure:
One hundred grams of 1,2,3,4-tetrahydro-1-naphthol were dissolved in 1 liter of chloroform and 53.9 ml of pyridine. The mixture was cooled with an external ice bath and 98.6 ml of thionyl chloride were added over a 1 hour period. The reaction mixture was stirred an additional 2 hours with cooling, concentrated in vacuo, and the residue taken up in 1 liter of methylene chloride. The methylene chloride solution was washed with water, a 5% sodium bicarbonate solution, water again, dried over sodium sulfate, and evaporated to dryness to provide the desired intermediate 1,2,3,4-tetrahydro-1-chloronaphthalene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C[O-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 51.8 %

Procedure:
(S)-1-(tert-Butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (10.0 g) was added to a mixed solution of p-methoxyphenol (11.64 g) and a solution of sodium methoxide in methanol (1M, 47 ml), and the mixture was stirred at 75° C. for 14 hours under heating. The reaction mixture was poured into water and extracted with toluene. The extract was washed with 10% sodium hydroxide and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (8.20 g).
Reaction SMILES: C1N2CCN(CC2)C1.[Li]CCCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>C(OCC)C.O>[F:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccnc1
Reactant: CN(C)C=O
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1ncccc1F
Temperature: -17.5 °C
Reaction time: 0.75 h
Yield: 55 %

Procedure:
To a solution of DABCO (8.8 g, 78.2 mmol) in anhydrous diethyl ether (250 mL) at −25° C. was added n-BuLi (1.6 M in hexanes, 49 mL, 78.2 mmol). The mixture was stirred between −25 to −10° C. for 45 min and then cooled to −70° C. To the above solution was added 3-fluoropyridine (5.9 mL, 71 mmol) dropwise. The reaction was stirred between −70 to −60° C. for 1.5 h before DMF (11.0 mL, 2.0 eq.) was added. After 1.0 h stirring at −70° C., water (150 mL) was added and warmed up to rt. The layers were separated and the aqueous layer was extracted with methylene chloride (5×100 mL). The combined organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the crude was purified by silica gel column chromatography using gradient EtOAc in hexanes to give 5.4 g (55-60% yield) of 65A. 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.57 (m, 2H) 8.61 (d, J=2.20 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [Cl:1]C1CC(=O)NC1=O.[F:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:13]=[CH:12][CH:11]=1.O.C(Cl)Cl>C(#N)C>[Cl:1][C:11]1[CH:12]=[CH:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:15][C:10]=1[F:9]
Reactant: Fc1cccc(N2CCOCC2)n1
Reactant: O=C1CC(Cl)C(=O)N1
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Fc1nc(N2CCOCC2)ccc1Cl
Temperature: 70 °C
Yield: 22.4 %

Procedure:
Chlorosuccinimide (10.29 g, 77 mmol) was added to a solution of 4-(6-fluoropyridin-2-yl)morpholine (11.7 g, 64.2 mmol) in ACN (15 mL). The reaction mixture was heated to 70° C. for 30 min. Water and DCM were added. The organic phase was separated, washed with aqueous NaHCO3, brine and subsequently dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes) to afford 3.11 g of 4-(5-chloro-6-fluoropyridin-2-yl)morpholine.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15](=[O:18])[S:16][CH:17]=2)=[CH:9][CH:8]=1)(=O)C>CO.O>[O:18]=[C:15]1[S:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][OH:4])=[CH:12][CH:11]=2)=[CH:17][S:16]1
Reactant: CC(=O)OCCc1ccc(-c2csc(=O)s2)cc1
Solvent: O
Solvent: CO
Product: O=c1scc(-c2ccc(CCO)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of compound 7 (40.0 g, 0.143 mol) dissolved in 500 ml methanol and 40 g K2C03 dissolved in 300 ml water was stirred at room temperature for 1 hour. The mixture was extracted with 300 ml chloroform. The chloroform solution was washed with water, concentrated, recrystallized (methanol/ether), and dried to give 23.8 g (70.0%) of compound 8. Analysis of the product gave the following results: mp 92°-94° C.; NIR (KBr) 3258, 3060, 2927, 1697, 1632, 1503, 1055, 1046, 868 cm-1 ; 1H NMR (300 MHz) δ 1.55 (s, 1H), 2.89 (t, 2H, J=6.8 Hz), 3.88 (t, 2H, J=6.8 Hz), 6.79 (s, 1H), 7.26-7.38 (m, 4H); 13C NMR (75 MHz) δ 192.52, 140.08, 134.80, 130.89, 129.79, 126.43, 111.19, 63.27, 38.75. Anal. Calcd. for C 11 H10O2S2 : C, 55.44; H, 4.23; Found: C, 56.32; H, 4.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClCCl.Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])=[CH:17]3)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2ccc3[nH]c(CCCN(C)C(=O)OC(C)(C)C)cc3c2)cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNCCCc1cc2cc(C(=O)Nc3ccc(OC)c(OC)c3)ccc2[nH]1
Reaction time: 2.5 h

Procedure:
A 250 round bottom flask was charged with tert-butyl 3-(5-(3,4-dimethoxyphenylcarbamoyl)-1H-indol-2-yl)propyl(methyl)carbamate (2.75 g, 5.88 mmol), dichloromethane (32 mL), and 1M hydrochloric acid in diethyl ether (32 mL) and the resulting mixture stirred for 2.5 h. The resulting mixture was then concentrated in vacuo, the residue triturated with diethyl ether, and placed under high vacuum to yield 2-(3-methylamino-propyl)-1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl)-amide. MS (ES+) 368 (M+1); HPLC: Kromasil C18 column (50×2 mm; 3.5μ), gradient 10-90% (MeCN+0.16% TFA) in (water+0.2% TFA) over 4 min, tR=2.72 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.CS(Cl)(=O)=O.[NH2:13][C:14]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:24][C:22]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([NH:13][C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH:23]=1
Reactant: CNC(=O)c1ccc(Br)cc1N
Reactant: COCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(Br)cc1NC(=O)CCOC
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a mixture of 3-methoxypropanoic acid (0.25 mL, 2.62 mmol), DMAP (0.64 g, 5.24 mmol) and dry DCM (5 mL) was added methanesulfonyl chloride (0.22 mL, 2.88 mmol) dropwise at 0° C. under nitrogen atmosphere. 2-Amino-4-bromo-N-methylbenzamide (0.3 g, 1.31 mmol) was added after stirring for 1 h, and the temperature was allowed to rise to room temperature slowly. The reaction mixture was quenched with sat. NH4Cl solution after 3 h and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with NaHCO3, dried over Na2SO4, filtered, and evaporated to give 0.39 g of the target compound. MS (ESI): 315, 317 (MH+).