Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][CH2:49][C:50]1[C:51](=[O:76])[N:52]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[C:68]([C:73]([OH:75])=[O:74])=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:63][CH:62]=2)[C:53]([CH2:56][CH2:57][CH2:58][CH3:59])=[CH:54][CH:55]=1>CN(C=O)C>[CH2:56]([C:53]1[N:52]([CH2:60][C:61]2[CH:62]=[CH:63][C:64]([C:67]3[C:68]([C:73]([OH:75])=[O:74])=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:65][CH:66]=2)[C:51](=[O:76])[C:50]([CH2:49][NH:48][C:7](=[O:8])[CH:6]([CH2:5][SH:4])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:55][CH:54]=1)[CH2:57][CH2:58][CH3:59]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: CCCCc1ccc(CN)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ccc(CNC(=O)C(CS)CC(C)C)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 140 %

Procedure:
2-Acetylsulfanylmethyl-4-methyl-pentanoic acid (24 mg, 1.1 eq) and HATU (44 mg, 1.1 eq) were dissolved in DMF (2 mL). DIPEA (740 μL, 4 eq) was added, and the mixture was stirred at room temperature for 15 minutes. 4′-(3-Aminomethyl-6-butyl-2-oxo-2H-pyridin-1-ylmethyl)biphenyl-2-carboxylic acid HCl (45 mg, 0.1 mmol) was added, and the solution was stirred at room temperature for 4 hours. The reaction was quenched with water (8 mL) and concentrated HCl (3 drops), and the mixture extracted with EtOAc (10 mL). The organic layer was dried over Na2SO4, and evaporated. The residue was dissolved in MeOH (1 mL) and 1M NaOH (3 mL). The solution was stirred under nitrogen for 20 minutes, and the reaction was then quenched with acetic acid (2 mL). The MeOH was evaporated, and the aqueous component extracted with EtOAc (10 mL). The solvent was evaporated and the residue purified by reverse phase chromatography to afford the title compound (7.5 mg, 140 μmol). MS m/z: [M+H+] calcd for C31H39N2O4S, 535.7. found 535.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Si:10]([O:27][CH2:28][C@H:29]1[CH2:34][O:33][CH2:32][C:31](=[O:35])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[Si:10]([O:27][CH2:28][C@H:29]([NH:30][C:36](=[O:37])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:34][O:33][CH2:32][C:31]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:35])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1ccc(Cl)cc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -40 °C
Reaction time: 1 h

Procedure:
4-Chlorophenylmagnesium bromide (1 M solution in diethyl ether, 3.44 mL) was added dropwise to a solution of tert-butyl (R)-3-(tert-butyldiphenylsilanyloxymethyl)-5-oxomorpholine-4-carboxylate (1.47 g) in THF (35 mL) at −50° C. over five minutes, and the reaction solution was stirred at −40° C. for one hour. A saturated ammonium chloride solution was added to the solution in small portions at −40° C., and the reaction solution was returned to room temperature. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.48 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].C(OC(Cl)=O)C(C)C.C(NCC)C>C1COCC1>[CH2:12]([N:14]([CH2:15][CH3:16])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1)[CH3:13]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Yield: 48.3 %

Procedure:
4-Formylbenzoic acid (11.2 g, 74.6 mmol) and triethylamine (10.4 mL, 75 mmol) was dissolved in THF (100 mL) and cooled to −10° C. i-Butylchloroformate (10.3 mL, 78 mmol) was added and stirring was continued for 10 minutes at −10° C. before diethylamine (9.7 mL, 94 mmol) was added and solution was allowed to reach 25° C. After concentration, aqueous workup and chromatography on silica (0-100% EtOAc in heptane), a total of 7.4 g (50%) compound I was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
A mixture of methyl 6-chloronicotinate (1.02 g, 5.93 mmol), morpholine (0.57 ml, 6.52 mmol), potassium carbonate (1.06 g, 7.71 mmol) and DMF (20 ml) was stirred at 100° C. for 6 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropy ether to give the title compound (0.93 g, 71%) as a colorless powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12](C(OCC)=O)[N:11]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CCO.O>[N+:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[O:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)([O-:21])=[O:20]
Reactant: CCOC(=O)n1nc(OCCN2CCOCC2)c2cc([N+](=O)[O-])ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(OCCN3CCOCC3)c2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of the morpholinoethoxy indazole described above (combined with a previous batch made in an identical manner) (309 mg, 0.848 mmol) in EtOH (2.0 mL) was added a solution of KOH (48 mg, 0.848 mmol) in water (1.0 mL) and the reaction mixture maintained at RT for 16 hr. The reaction mixture was then purified directly, without work-up, by SCX capture and release to afford 4-(2-((5-nitro-1H-indazol-3-yl)oxy)ethyl)morpholine as a bright yellow solid (221 mg, 86%); Rt 0.94 min (Method 2, acidic); m/z 293 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[N:3]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:22])=[O:12])=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc2c(c1)c(C=O)c(Cl)n2-c1ccccc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C(=O)O)c(Cl)n2-c1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 125.5 %

Procedure:
The compound of step 3 (456 mg, 1.59 mmol) was dissolved in tert-butanol (15 ml) and 2-methyl-2-butene (3 ml), and a solution of sodium chlorite (1.32 g, 14.6 mmol) and sodium dihydrogenphosphate (1.32 g, 11.0 mmol) in water (6 ml) was added. The reaction mixture was stirred at room temperature for 48 h and afterwards at 80° C. for 2.5 h. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 602 mg of the crude title compound.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][CH2:5][C@H:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11].C(Cl)Cl.[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[CH3:12][C@@H:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([O:1][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: C[C@H](CCCC=O)CCCC(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CCCC=O)CCCC(C)(C)O[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
3.10 g of (S)-9-hydroxy-5,9-dimethyl-decanal was dissolved in 60 ml of abs. CH2Cl2 and treated successively at 0° with 57 mg of DMAP, 7.0 ml of NEt3 and 3.1 ml of TMS-Cl. The reaction mixture was kept for 30 minutes at RT and then poured onto crushed ice, extracted twice with ether, washed twice with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=95/5) yielded 3.90 g of (S)-5,9-dimethyl-9-trimethylsilanyloxy-decanal as colorless oil, 98.6% pure according to GC.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([NH:11][C:8]([C:7]2[C:2]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)c1cccnc1Nc1ccccc1
Temperature: 190 °C
Yield: 26.3 %

Procedure:
To a suspension of 31.5 g (0.2 mole) of 2-chloro-3-pyridinecarboxylic acid in 75 mL of xylene was added 18.6 g (0.2 mole) of aniline, and the reaction mixture was heated at 190° C. (oil bath) for 45 min; then cooled. The xylene was filtered, and the reaction melt that had formed was crushed and partitioned between 100 mL of aqueous NaHCO3 (pH 8) and CH2Cl2 (150 mL). The solid that remained suspended in the two-phase system was filtered and discarded. The filtrate was concentrated to 200 mL, and the solid that precipitated from the two-phase system was filtered to give 7.6 g (13%) of N-phenyl-2-(phenylamino)-3-pyridinecarboxamide. Acetic acid was added to the filtrate to acidify the aqueous layer to pH 6 and the CH2Cl2 layer was separated. The aqueous solution was extracted with CH2Cl2 and the combined extracts were concentrated to 100 mL; the solid that precipitated was filtered and washed sequentially with water and CH2Cl2 to give 15.6 g of the product. An additional 5.3 g of the product was obtained from the filtrate for a total yield of 20.9 g (49%). The combined product was triturated with CH2Cl2 and then filtered to give 19.6 (46%) of the product as a yellow solid; mp 152°-155° C.; TLC (C6H12 -EtAc; 4:1 and EtAc-MeOH-NH4OH, 16:3:1) showed a single component. MS (EI) m/e (relative intensity): 214 (M+, 100), 213 (94), 195 (70), 169 (45), 168 (70), 167 (22), 77 (37), 51 (26).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)/[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A solution of triphenylphosphine (165 mg, 0.63 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (112 mg, 0.63 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid (123 mg, 0.37 mmol) in methylene chloride (3 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (92.5 mg, 0.93 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide (36 mg, 23%) as an amorphous solid: EI-HRMS m/e calcd for C19H19ClN6OS (M+) 414.1029, found 414.1029.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][CH:42]=[C:34]([Cl:33])[CH:35]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(Cl)c4)c3)csc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (35.4 mg, 0.108 mmol) (from Example 3 supra) in THF (3 mL) were added diisopropylethyl-amine (28 mg, 0.216 mmol) (Aldrich) and then 3-chlorobenzoyl chloride (28 mg, 0.161 mmol) (Aldrich). The reaction was stirred at room temperature for 20 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 75/25 to 50/50) to give 3-[3-(3-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 38.2 mg, 75.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[ClH:32]>CCO.[Pd]>[ClH:32].[C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 99 %

Procedure:
Nα-BOC-NF-CBZ-L-lysine tert-butyl ester (2) (34.51 g, 79.15 mmol) was dissolved in a mixture of 300 ml absolute EtOH and 1 N HCl (88 ml). Prior to the introduction of H2 gas, 10% Pd—C (2.95 g) was added. After 7 hours, additional catalyst (1.0 g) was added. After 5 hours, the black suspension was filtered through a bed of Celite and washed with EtOH. The filtrate was concentrated and the residue dried under high vacuum to give the Nα-BOC-L-lysine tert-butyl ester as its hydrochloride salt (3) (26.59 g, 99%). 1H NMR (CD3OD) δ 3.95 (dd, 1H, J=8.8, 5.0), 2.93 (t, 2H, J=7.7), 1.84-1.60 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CD3OD) δ 173.5, 158.2, 82.7, 80.5, 79.5, 55.5, 40.6, 32.1, 28.7, 28.3, 23.9. HRMS m/z calcd. for C15H31N2O4 303.2284, found 303.2272. [α]26D−10.1° (c=1.00, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]#[CH:35]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:35]#[C:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#Cc1ccccc1F
Product: O=C(N1CCc2ccc(Cl)c(C#Cc3ccccc3F)c2CC1)C(F)(F)F
Yield: 66.2 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with (2-fluorophenyl)-ethyne (241 mg, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 7-chloro-6-(2-fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (262 mg, 68%). MS (ES+) m/z: 396 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([C:15]3[N:16]=[CH:17][N:18]([C:20](C4C=CC=CC=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:39]([O:41]C)=O.CO.[CH3:45][NH2:46]>C1COCC1>[CH3:45][N:46]1[CH2:2][C:3]2[C:12]3[CH:11]=[CH:10][C:9]([C:13]([C:15]4[N:16]=[CH:17][N:18]([C:20]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:3]5[CH:12]=[CH:7][CH:6]=[CH:5][CH:4]=5)[CH:19]=4)=[O:14])=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:39]1=[O:41]
Reactant: CN
Reactant: COC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1CBr
Solvent: CO
Solvent: C1CCOC1
Product: CN1Cc2c(ccc3cc(C(=O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc23)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl 1-bromomethyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthoate (14.0 g) was dissolved in THF (120 mL), and 40% methylamine methanol solution (60 mL) was added. The reaction mixture was stirred at room temperature for 20 hrs. and the solvent was evaporated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: dichloromethane-methanol=40:1) and crystallized from ethyl acetate-diethyl ether to give the title compound (5.5 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[O:17]([CH2:16][CH2:15][CH2:14][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCCOc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCOc2ccccc2)cc1

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 21.5 g of 3-bromopropylphenyl ether and 100 ml of hexamethylphosphoramide is heated at 100°-110° C. in an oil bath for 20 hours. The mixture is chilled, diluted with 50 ml of water, chilled and filtered. The solid is washed with ethanol-water (1:1) and with water to give yellow crystals, mp 73°-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[O:6][C@@H:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[O:6][C@@H:7]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:22]=[CH:21][C:19]([NH:20][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1
Reactant: COc1ccc(O[C@H](CCN2CCC(c3ccc(N)cc3)CC2)c2ccccc2)cc1OC
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(O[C@H](CCN2CCC(c3ccc(NC(=O)C(C)C)cc3)CC2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
A mixture of 4-{1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}aniline (5.31 mg, 0.0119 mmol), isobutyryl chloride (2.08 mg, 0.019 mmol), N,N-diisopropylethylamine (8.40 mg, 0.0650 mmol) in methylene chloride (1.0 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and chromatographed using a preparative TLC plate [2.5% of NH3 (2.0 M in methanol) in CHCl3] to give the product (3.5 mg, 56.5%) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H, J=8.6 Hz), 7.30–7.20 (m, 4H), 7.20 (m, 1H), 7.11 (d, 2H, J=8.6 Hz), 7.04 (s, 1H), 6.57 (d, 1H, J=8.3 Hz), 6.44 (d, 1H, J=2.6 Hz), 6.22 (dd, 1H, J=2.6, 8.3 Hz), 5.09 (apparent dd, 1H, J=4.4, 8.1 Hz), 3.72 (s, 3H), 3.70 (s, 3H), 3.08 (m, 2H), 2.57 (m, 2H), 2.43 (apparent sept, partially hidden, 2H, J=6.8 Hz), 2.30–2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 517.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.[CH3:8][O:9][C:10]1[C:18]([S:19][CH3:20])=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[CH3:8][O:9][C:10]1[C:18]([S:19][CH3:20])=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:11]=1[C:12]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1)=[O:13]
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1SC
Reactant: Cn1nnnc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1c(C(=O)Nc2nnnn2C)ccc(C(F)(F)F)c1SC
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.6 %

Procedure:
1.45 g (98% by weight; 14.3 mmol) of 5-amino-1-methyl-1H-tetrazole were added to 3.00 g (11.3 mmol) of 2-methoxy-3-(methylsulfanyl)-4-(trifluoromethyl)benzoic acid in 30 ml of dry pyridine. 2.00 g (15.8 mmol) of oxalyl chloride were then added, and the mixture was subsequently stirred at room temperature (RT) for three days. Another 500 mg (3.94 mmol) of oxalyl chloride were then added, and the mixture was subsequently stirred at RT for 16 h. For work-up, the contents were substantially freed from the solvent on a rotary evaporator. The residue was stirred with dichloromethane and a saturated solution of sodium bicarbonate. The organic phases were then separated and the organic phase was freed from the solvent on a rotary evaporator. The residue was purified chromatographically, which gave 1.83 g of clean product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (5-nitropyridin-2-yl)acetate (2.40 g, 11.4 mmol), Raney-Ni (50 mg) in 100 mL of MeOH was stirred at room temperature overnight. The mixture was filtered and concentrated to give ethyl (5-aminopyridin-2-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.06 (dd, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 3.65 (br, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:6]([S:4][CH2:3][CH2:2][CH3:6])=[CH:5][S:4][CH:3]=1
Reactant: Brc1cscc1Br
Solvent: Cc1ccccc1C
Product: CCCSc1cscc1Br
Reaction time: 31 h
Yield: 43.2 %

Procedure:
A mixture of 50 g of 3,4-dibromothiophene, 30 g of 85% potassium propyl mercaptide and 4.5 g of Carbowax®2000 in 50 ml of xylene was heated at reflux for 18 hours. The reaction was cooled, an additional 9 g of the mercaptide was added, and refluxing was continued for an additional 31 hours. After cooling, the mixture was filtered and the filtrate distilled to provide 10.6 g (21.3%) of 3-bromo-4-(propylthio)thiophene, bp 91°-102° C. (1.4 mm).