Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)/[CH3:24]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=[C:26]2[CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)CCCOc1cccc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(CCCOc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.36 g, 1.83 mmol) in DCM (20 mL) was added trimethylaluminium (2.7 mL, 5.40 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(4-(3-fluorophenoxy)butanamido)but-2-enoate (0.80 g, 2.71 mmol) in DCM (4 mL) was added slowly and the resulting mixture was stirred at rt for 24 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow solid (0.40 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([P:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([SH:17])=[S:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([P:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([S:17][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: BrCc1ccccc1
Product: S=P(SCc1ccccc1)(C1CCCCC1)C1CCCCC1

Procedure:
Benzyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain benzyl dicyclohexylphosphinodithioate, m.p. 107°14 108° C, which on testing lasted 350 hours longer than the control. The total number of hours required to reach failure was 1.9 times that of the control.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:46]1([CH2:52][CH2:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][NH:55]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O>[N:46]1([CH2:52][CH2:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][N:55]2[CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[N:13]=[C:12]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C1CCN(CCC2CCCCN2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCN4CCCCC4CCN4CCCCC4)cccc32)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and 2-[2-(piperidin-1-yl)ethyl]piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([C:45](Cl)=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:45]([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)=[O:46])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3cccc4ccccc34)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 1-naphthalenecarbonyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Product: CC(=O)c1cc2c(cc1OCC(C)C)C(C)(C)CCC2(C)C
Yield: 105.4 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl)-ethanone (0.250 g, 1.01 mmol) was alkylated with isobutylbromide (0.195 g, 1.42 mmol, 0.154 mL) as described in Example 21. Aqueous workup gave 1-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-ethanone 0.322 g (crude) as an orange oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, Ar—H), 6.81 (s, 1H, Ar—H), 4.13 (d, J=6.2 Hz, 2H, OCH2), 2.62 (s, 3H, CH3), 2.16 (m, 1H, CH), 1.68 (app br d, 4H, 2CH2), 1.30 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3), 1.08 (d, J=6.7 Hz, 6H, 2CH3).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[N+:12]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[Cl:21])([O-:14])=[O:13].Cl>C(#N)C.O>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[S:22]([C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)(=[O:23])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CCCCNCCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCCN(CCCC)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To 565 g of dibutylamine were added 2.5 liters of water and 230 g of sodium hydroxide and the mixture was cooled to 0° C. To the mixture was added dropwise 1400 ml of an acetonitrile solution containing 1120 g of 3-nitro-4-chlorobenzenesulfonyl chloride while maintaining at 10° C. or lower. After the completion of the reaction, 100 ml of concentrated hydrochloric acid was added thereto. The crystals thus deposited were collected by filtration, washed with water and dried. Yield: 1208 g (79.2%). Melting point: 67° to 68° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1

Procedure:
2,4-Difluoronitrobenzene (10.0 g, 62.9 mmol), t-butyl piperazine-1-carboxylate (11.7 g, 62.9 mmol) and N,N-diisopropylethylamine (8.10 g, 62.9 mmol) were stirred at room temperature in dry acetonitrile (100 mL) for 16 h. The solvent was removed by rotary evaporation and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was removed by rotary evaporation to collect the title compound (19.0 g, 93%). 1H NMR (400 MHz, CDCl3): δ 7.91 (dd, 1H), 6.75 (m, 2H), 3.60 (m, 4H), 3.03 (m, 4H), 1.48 (s, 9H); MS (ESI) m/z: Calculated for C15H20FN3O4Na: 348.13; Observed: 348.1 (M++Na).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>[Ti](Cl)(Cl)(Cl)Cl.CCOCC>[Cl:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[C@@H:6]([OH:7])[CH3:1]
Reactant: [Li]C
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: C[C@H](O)c1cccc([N+](=O)[O-])c1Cl
Temperature: -40 °C
Yield: 84 %

Procedure:
To ether cooled to −78° C. was added titanium (IV) chloride (0.85 mL, 7.8 mmol) and a 1.6M solution of methyl lithium in ether (4.9 ml, 7.8 mmol). After warming the mixture to −40° C., it was transferred via double-tipped needle to a −78° C. ether solution of 2-chloro-3-nitrobenzaldehyde (1.0 g, 5.6 mmol), which can be synthesized according to the procedure in J. Med. Chem. 1088, 31, 936-944. The reaction was allowed to slowly warm to rt and was quenched with the addition of MeOH and water. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated to an oil. The crude material was purified by flash column chromatography (10% EtOAc:hexanes) to give 0.98 g of the racemic compound (84%). The enantiomers were separated using packed column supercritical fluid chromatography (SFC) on a 3×25 cm Dalcel® AD-H column with a 90 g/min total flow (81 q/min CO2-90%) (9 g/min MeOH-10%) to give the title compound as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.86 (m, 1H), 7.58 (m, 1H), 5.62 (d, J=4.4 Hz, 1H), 5.06 (m, 1H), 1.30 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18](O)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:30]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[C:19](=[O:30])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(CNc2nc(Cl)cc3nccnc23)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (3.35 g, 8.5 mmol) in dichloromethane (50 mL) was added Dess-Martin periodinane (4.33 g, 10.2 mmol) at room temperature. The reaction mixture was stirred at that temperature overnight. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was used directly in the next step. MS (m/z): 392 (M+H)+.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[NH:12]CC(O)COC1C=CC=C2C=1C=C(CC)N2>C(O)C>[NH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CCc1cc2c(OCC(O)CNC3CCc4ccccc4C3)cccc2[nH]1
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from 2-ethyl-4-(2,3-epoxypropoxy)indole (10 g), obtained from 2-ethyl-4-hydroxyindole and epichlorohydrin according to the method described in Swiss Patent 527,188, and 2-aminotetralin (7.95 g) in ethanol (90 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-ethylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 17 wherein Z is ethyl, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1.[CH3:20][Si:21]([CH3:26])([CH3:25])[C:22]#[C:23][CH3:24]>>[CH2:8]([N:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=[C:3]1[CH2:2][CH2:24][C:23]#[C:22][Si:21]([CH3:26])([CH3:25])[CH3:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC#C[Si](C)(C)C
Reactant: ClCc1nc2ccccc2n1CCc1ccccc1
Product: C[Si](C)(C)C#CCCc1nc2ccccc2n1CCc1ccccc1
Yield: 102.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-1-phenethyl-1H-benzo[d]imidazole (500 mg, 1.8 mmol) and trimethyl(prop-1-ynyl)silane (249 mg, 2.22 mmol). 1-phenethyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (639 mg, Yield: 100%) was obtained as a brown oil which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([C:11](=[O:13])[CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[Br:14]Br>C(Cl)Cl>[Br:14][CH2:12][C:11]([C:2]1([CH3:1])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:13]
Reactant: CC(=O)C1(C)Cc2ccccc2C1
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C(=O)CBr)Cc2ccccc2C1

Procedure:
1-(2,3-Dihydro-2-methyl-1H-inden-2-yl)ethanone (3.69 g) in methylene chloride (40 ml) is stirred and cooled at 10° C. during the dropwise addition of bromine (2.82 g)/methylene chloride (10 ml). Work-up of the resultant solution gives 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]([CH3:29])[CH3:28].C(N(CC)CC)C>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), N-amino-2-(dimethylamino)acetamide (147.5 mg, 0.95 mmol), and molecular sieves in ethanol was added triethylamine (0.25 mL, 1.86 mmol). The reaction was allowed to stir under a nitrogen atmosphere at 75° C. overnight. The reaction was filtered using a fritted funnel and the filtrate was concentrated. This was purified by semi-preprative HPLC. The material was taken up in ethyl acetate and washed with aqueous sodium bicarbonate. This organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (192 mg, 23% yield). 1H NMR (CD3OD) δ 8.7 (s, 1H), 8.0-8.1 (m, 3H), 7.7 (d, 1H), 7.25 (t, 2H), 4.5 (s, 2H), 3.0 (s, 6H), ES-MS (m/z) 337 [M+1]+.
Reaction SMILES: Br[C:2]1[N:23]=[C:5]2[N:6]=[C:7]([CH3:22])[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:4]2[N:3]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>O1CCOCC1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:9]1[N:4]2[N:3]=[C:2]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)[N:23]=[C:5]2[N:6]=[C:7]([CH3:22])[C:8]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: C1CSCCN1
Reactant: COC(=O)c1c(C)nc2nc(Br)nn2c1-c1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(C)nc2nc(N3CCSCC3)nn2c1-c1ccc(Cl)cc1Cl
Temperature: 75 °C
Yield: 91.3 %

Procedure:
To a stirred solution of methyl 2-bromo-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (30 mg, 0.07 mmol) in dioxane (2 mL) was added thiomorpholine (15 μL, 0.14 mmol). After heating to 75° C. for 16 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded methyl 7-(2,4-dichlorophenyl)-5-methyl-2-thiomorpholino-[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (28 mg, 90%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:12][CH2:13][O:14]C)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.C(=O)=O>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[C:6]2[O:12][C:13](=[O:14])[CH2:11][C:7]=2[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1c(C)cccc1C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc2c1OC(=O)C2
Temperature: -30 °C
Yield: 37.2 %

Procedure:
A solution of 43 (3.0 g, 14.4 mmol) and TMEDA (2.6 ml, 17.3 mmol) in THF (40 ml) was cooled to −50° C., and dropwise and slowly added with sec-BuLi (1.3 M in cyclohexane, 13.3 ml, 17.3 mmol). The reaction mixture was warmed to −30° C., and then cooled again to −60° C., and dry ice was added to the mixture. The reaction mixture was warmed to room temperature over 1 hour, added with waster (50 ml) and ethyl acetate (50 ml). The aqueous layer was separated, acidified with 2N HCl to pH 3-4, and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), and dried. The solvent was removed in vacuo. The residue was dissolved in toluene (50 ml), added with p-TsOH.H2O (250 mg), and heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and poured into an aqueous diluted sodium bicarbonate solution (60 ml). The organic layer was separated and washed with saturated brine (60 ml). After drying, the solvent was removed in vacuo, and the residue was purified by column chromatography to yield 1.02 g (37%) of 44. 1H NMR (CDCl3) δ: 1.40 (9H, s, tBu), 3.71 (2H, s, CH2), 7.02-7.27 (3H, m, 3×Ar—H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(OC(C)(C)C)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Br:22][C:10]1[C:11]2[C:16](=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH2:20][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:12]=2)[NH:8][C:9]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Product: O=[N+]([O-])c1cc(CN2CCOCC2)cc2c(Br)c(-c3ccccc3)[nH]c12

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole prepared in Step B of Preparation 47 and morpholine were reacted according to the same procedures as Steps C and D of Preparation 47 to give the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]([C:9]1[CH:27]=[CH:26][C:12]2[CH2:13][C@@H:14]3[C@H:19]([CH3:20])[C@:18]([CH3:21])([C:11]=2[CH:10]=1)[CH2:17][CH2:16][N:15]3[CH2:22][CH2:23][O:24][CH3:25])=[O:8]>FC(F)(F)C(O)=O>[CH3:25][O:24][CH2:23][CH2:22][N:15]1[CH2:16][CH2:17][C@:18]2([CH3:21])[C@@H:19]([CH3:20])[C@H:14]1[CH2:13][C:12]1[CH:26]=[CH:27][C:9]([C:7]([NH2:6])=[O:8])=[CH:10][C:11]=12
Reactant: COCCN1CC[C@@]2(C)c3cc(C(=O)NCc4ccc(OC)cc4OC)ccc3C[C@@H]1[C@@H]2C
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CC[C@@]2(C)c3cc(C(N)=O)ccc3C[C@@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of (2R,6R,11R)-N-(2,4-dimethoxybenzyl)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (360 mg, 0.80 mmol) in trifluoroacetic acid (5 mL) was stirred at ambient temperature for 2 hours. The mixture was concentrated under reduced pressure before quenching with ice/ammonium hydroxide (28%) (25 mL). The crude product was extracted twice to using dichloromethane (100 mL) and the combined organic layers dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the crude product that was purified by prep-HPLC giving (2R,6R,11R)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (130 mg, 54% yield); LC/MS (M+H)+=303.2.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[C:14]([O:18][C:19]([N:21]([CH3:33])[C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]([CH3:33])[C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
2-Bromoacetonitrile (0.200 ml, 2.87 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.183 ml, 1.05 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2K-B) (309 mg, 0.955 mmol) in N,N-dimethylformamide (2.5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30) to afford (R)-cyanomethyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-B) (272 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:9][C:8]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]C(=O)C)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:9][C:8]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(OCCCCCOC(C)=O)c(CCC(=O)OCC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(OCCCCCO)c(CCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 66.4 %

Procedure:
A solution of 1.0 g (2.2 mmol) of 2-[[5-(acetyloxy)pentyl]oxy]-5-(4-ethoxy-4-oxobutoxy)benzenepropanoic acid ethyl ester from the preceding example, and 0.018 g of p-toluenesulfonic acid monohydrate in 10 mL of ethanol was stirred and refluxed for 30 hr and stirred at room temperature for 21 hr. Most of the ethanol was removed in vacuo and the residue was diluted with water and worked-up with ether in the usual manner (the combined ether extracts were additionally washed with saturated aqueous sodium bicarbonate). The product was purified by flash chromatography on silica gel, eluting with 1:1 hexane-ethyl acetate. There was obtained 0.6 g (66.5%) of 2-[(5-hydroxypentyl)oxy]-5-(4-ethoxy-4-oxobutoxy)benzenepropanoic acid ethyl ester as a viscous oil.