Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.C([O:34]B(OC(C)C)OC(C)C)(C)C.[OH-].[Na+].OO>CO.C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([OH:34])[CH:13]=[N:12][C:11]=1[NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: OO
Agent: [Li]C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(O)cc2OCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 1.00 g, 2.66 mmol) was added to THF (30 mL) and cooled to −78° C. MeLi (2.07 mL, 3.32 mmol) was slowly added, and the reaction mixture was stirred for 10 minutes. Butyllithium (1.33 mL, 3.32 mmol) was added, and the reaction mixture was stirred for 15 minutes. Triisopropylborate (0.613 mL, 2.66 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to 0° C., and methanol (5 mL), 10% aqueous NaOH (5.1 mL, 12.8 mmol), and 30% aqueous H2O2 (1.27 mL, 13.3 mmol) were added. The reaction mixture was stirred at 0° C. for 1 hour, then purified by silica gel (10-20% EtOAc in hexanes) to give 5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ol (0.198 g, 23.8% yield). 1H NMR (d6-DMSO) δ 7.59 (m, 3H), 7.40 (m, 3H), 7.17 (d, 1H), 6.84 (s, 1H), 5.31 (s, 2H), 2.33 (s, 3H). Mass spectrum (apci) m/z=314.1 (M+H).
Reaction SMILES: [Br-].Br[S+:3]([CH3:5])[CH3:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:4][S:3][CH2:5][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH2:6]
Reactant: C[S+](C)Br
Agent: [Br-]
Solvent: Nc1ccccc1
Product: CSCc1ccccc1N
Yield: 69 %

Procedure:
Through this general procedure p-anisidine could be converted into 4-methoxy-2-(methylthiomethyl)aniline in 62 percent yield. The procedure is quite general. For a series of anilines (toluidine, aniline, p-chloroaniline, 4-nitroaniline, and p-ethoxycarbonylaniline) reaction of the aniline with the chlorine:sulfur compound complex chlorodimethylsulfonium chloride through the azasulfonium halide salt gave the corresponding 2-(methylthiomethyl)anilines in 54, 67, 45, 31 and 35% yields, respectively. The reaction is not restricted to chlorodialkylsulfonium chlorides. For example, when bromodimethylsulfonium bromide was used with aniline to form the azasulfonium bromide salt of aniline a 69 percent yield of 2-(methylthiomethyl)aniline was obtained. Treatment of aniline with halotetramethylenesulfonium halide (chloride or bromide) to form the azasulfonium salt followed by base treatment, gave 2-(2-tetrahydrothienyl)aniline in 20 percent yield. The use of β-keto sulfides and β-carboalkoxysulfides in this reaction provided a simple route to indoles and 2-oxindoles. Treatment of p-anisidine with chlorine:sulfur compound complex ##EQU11## to form the azasulfonium halide salt of the anisidine, followed by triethylamine, according to the above general procedure, gave 2-methyl-5-methoxy-3-methylthioindole in 38 percent yield. The reaction is not restricted to p-anisidine. With aniline, p-chloroaniline, and benzocaine, we obtained the corresponding unsubstituted, 5-chloro- and 5-ethoxycarbonyl-2-methyl-3-methylthioindoles in 68, 45 and 33 percent yields, respectively. Raney nickel desulfurization of the 3-methylthio compound gave 5-methoxy-2-methylindole in 72 percent yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Tert butyl-2-oxo-1-pyrrolidinecarboxylate (190 mg, 1.02 mmol), 4-chloroaniline (64 mg, 0.5 mmol) and acetic acid (184 mg) were mixed in dichloroethane (5 mL). Sodium triacetoxyborohydride (326.5 mg) was added and the reaction mixture kept on stirring at room temperature for overnight. After addition of aq. NaHCO3 the reaction mixture was diluted by addition of ethyl acetate. Two layers were separated. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by flash chromatography (0-15% ethyl acetate in petroleum spirit, 40-60) to give the subtitled product (140 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.O.C(#N)C>CN(C=O)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)[C:12](=[O:24])[CH:13]=1
Reactant: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 mg (0.13 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(furan-2-ylmethoxy)-1H-pyridin-2-one in 1.5 mL DMF is added 42 μL (0.52 mmol) pyrrolidine at RT. The reaction mixture is stirred for 2 h at RT and is directly added to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: ClC(Cl)C(O)=O.N[C:8]1[N:9]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=3)[C:31]([CH3:40])=[CH:30][CH:29]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1.N([O-])=O.[Na+].[Br:45]CBr>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:45][C:8]1[N:9]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=3)[C:31]([CH3:40])=[CH:30][CH:29]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1
Reactant: BrCBr
Reactant: COc1ccc2c(C)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Product: COc1ccc2c(C)ccc(-n3c(Br)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
Dichloroacetic acid (0.1 mL, 1.2 mmol) was added to a mixture of compound 10 (304 mg, 0.6 mmol), benzyltriethyl ammonium bromide (492 mg, 1.8 mmol) and sodium nitrite (828 mg, 12 mmol) in dibromomethane (10 mL). The mixture was stirred at room temperature for 18 hours in the dark. The reaction mixture was then concentrated and the resulting residue was purified by column chromatography (95% dichloromethane/5% methanol) to afford 80 mg, 24% yield of 4-(2-(5-bromo-4-(7-methoxy-4-methylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid (11).
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.BrC1C=CC(OCCN(C(C)C)C(C)C)=C(F)C=1.[CH:40]([N:43]([CH:75]([CH3:77])[CH3:76])[CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[C:58]([O:60]C)[CH:57]=[CH:56][C:55]=2[CH:62]2[CH2:71][CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[C:67]([O:72]C)[CH:68]=3)[CH2:63]2)=[CH:49][C:48]=1[F:74])([CH3:42])[CH3:41]>>[CH:75]([N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[C:58]([OH:60])[CH:57]=[CH:56][C:55]=2[CH:62]2[CH2:71][CH2:70][C:69]3[CH:68]=[C:67]([OH:72])[CH:66]=[CH:65][C:64]=3[CH2:63]2)=[CH:49][C:48]=1[F:74])([CH3:76])[CH3:77]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN(C(C)C)C(C)C)c(F)c1)C2
Agent: CC(C)N(CCOc1ccc(Br)cc1F)C(C)C
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Product: CC(C)N(CCOc1ccc(Nc2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1F)C(C)C
Yield: 22.3 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and [2-(4-bromo-2-fluorophenoxy)ethyl]diisopropylamine according to an analogous synthetic method to Example 116, [4-(2-diisopropylaminoethoxy)-3-fluorophenyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (133 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (28 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8](=[O:10])[CH3:9])[CH2:3][C:4]([OH:6])=O.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][CH:2]1[CH:7]=[C:8]([CH3:9])[O:10][C:4](=[O:6])[CH2:3]1
Reactant: CC(=O)CC(C)CC(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1=CC(C)CC(=O)O1
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A solution of 3-methyl-5-oxohexanoic acid (2.1 g) in benzene (26 mL) was treated at rt with thionyl chloride (1.26 mL). The mixture was heated to 85° C. where it stirred for 2 days. At the conclusion of this period, the mixture was cooled to rt and concentrated under vacuum to provide 4,6-dimethyl-3,4-dihydropyran-2-one as a dark brown oil, which was used directly in Step 4 without purification. Mass spectrum m/z 127.37 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=2[F:33])[CH:24]=1>>[CH3:37][C:34]([C:22]1[C:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=2[F:33])=[CH:24][C:19]([CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH:20][CH:21]=1)([CH3:35])[CH3:36]
Reactant: COc1ccc(F)c(-c2cc(CCl)ccc2C(C)(C)C)c1
Reactant: CCC[C@@H](CC(=O)OC)c1ccc(O)cc1
Product: CCC[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Yield: 50.7 %

Procedure:
Compound 7.1 (0.051 g, 0.2 mmol) was alkylated by reaction with compound A (0.08 g, 0.3 mmol) according to the method given in Example 1 to give compound 7.2 as a clear oil (0.05 g, 44% yield). MS ESI (pos.) m/e: 515.2 (M+Na)+, 510.2 (M+H2O)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.ClCCl.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C[C@@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CCN[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 158.2 %

Procedure:
To (±)-(2R,4R)-tert-butyl 2-(4-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (0.10 g, 0.34 mmol) in dichloromethane (10 mL) added trifluoroacetic acid: dichloromethane 1:4 (5 mL) and the mixture was stirred at 25° C. for 30 minutes. The solution was concentrated and dried to give title compound (±)-(2R,4R)-2-(4-fluorophenyl)piperidin-4-ol (105 mg, 99% yield) as the trifluoracetic acid salt. 1H NMR (400 MHz, d6-DMSO): 7.56 (m, 2H), 7.31 (m, 2H), 4.53 (t, 1H), 4.12 (br s, 1H), 3.32 (q, 1H), 3.20 (d, 1H), 2.10 (t, 1H), 1.85 (br d, 2H), 1.79 (dd, 1H). MS (EI) for C11H14FNO: 196 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH:3]=[CH:4][C:5]([OH:7])=O.[CH:9]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:19][C:5](=[O:7])[CH:4]=[CH:3][CH:2]([CH3:1])[CH3:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)C=CC(=O)O
Reactant: NC1CCCc2ccccc21
Product: CC(C)C=CC(=O)NC1CCCc2ccccc21

Procedure:
Prepared in a similar manner as described in example 4 from 4-methyl-pent-2-enoic acid and 1,2,3,4-tetrahydro-naphthalen-1-ylamine. MS (M+H, 244.2).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1>[Cl:3][C:4]1[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
According to Scheme A, a mixture of NaH (60% dispersion in oil, 0.40 g, 9.8 mmol) and THF (10 mL) was cooled to 0° C., then solid 2-chlorobenzoimidazole (1.0 g, 6.5 mmol) was added portion wise over 10 min. The resulting mixture was stirred at 0° C. for 1 h, then 2-(trimethylsilyl)-ethoxymethyl chloride (1.5 mL, 8.5 mmol) was added. The reaction mixture was allowed to warm to 23° C. and was stirred 16 h. The mixture was carefully poured over ice (200 g) and then was extracted with Et2O (3×100 mL). The combined organic extracts were dried, filtered, and concentrated. The residue was purified (FCC) (1:99 to 15:85 EtOAc/hexanes) to yield the titled compound, which has been previously described (WO 2005/012296, Janssen Pharmaceutica N.V., Example 7).
Reaction SMILES: C[N+]1([O-])CCOCC1.[OH:9][C@@H:10]([CH2:40][C@H:41]([CH2:45][OH:46])[CH:42]([CH3:44])[CH3:43])[C@@H:11]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:12][C@H:13]([CH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2[CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:20][CH:19]=1)[CH:14]([CH3:16])[CH3:15]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:42]([C@H:41]1[C:45](=[O:46])[O:9][C@H:10]([C@@H:11]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:12][C@H:13]([CH2:17][C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][N:24]3[CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:20][CH:19]=2)[CH:14]([CH3:15])[CH3:16])[CH2:40]1)([CH3:44])[CH3:43]
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](CO)C(C)C)C(C)C)cc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]3C[C@@H](C(C)C)C(=O)O3)C(C)C)cc21
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a stirred solution of N-methylmorpholine-N-oxide (270 mg, 2 mmol) in dry CH2Cl2 (10 mL) was added activated 4 Å molecular sieves (500 mg) at rt under N2. After stirring for 2 h this mixture was added to a mixture of tetrapropylammonium perruthenate (22 mg, 0.062 mmol) and tert-butyl (3S,5S,6S,8S)-6-hydroxy-8-(hydroxymethyl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (0.33 g, 0.62 mmol) in dry CH2Cl2 (20 mL). The mixture was stirred overnight and filtered through a pad of silica gel. The filtrate was washed with water and brine, evaporated, and purified by flash chromatography on silica gel to afford tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methylpentylcarbamate (120 mg, 37%). 1H NMR (400 MHz, CDCl3): δ7.93 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 6.98 (d, J=8.0 Hz, 1H), 4.46-4.38 (m, 4H), 3.89 (m, 1H), 3.29 (s, 6H), 2.86 (m, 1H), 2.58-2.52 (m, 2H), 2.18-2.2.08 (m, 5H), 1.70 (m, 2H), 1.47 (s, 9H), 1.04 (d, J=6.4 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H); MS: 530 (M++1)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][CH3:20])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]([CH3:20])[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CNCCc1ccc(F)cc1
Product: CN(CCc1ccc(F)cc1)C(=O)c1ccc(Br)s1

Procedure:
From 5-bromo-thiophene-2-carboxylic acid (1.0 g) and [2-(4-fluorophenyl)-ethyl]-methyl-amine (the compound of Preparation Example 14) (740 mg), a colorless solid (1.39 g) was obtained, in the same way as Preparation Example 118-b).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[C:11]([NH2:14])(=[O:13])[CH3:12]>>[NH:8]1[C:7]2=[C:2]([NH:14][C:11](=[O:13])[CH3:12])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: CC(N)=O
Reactant: Clc1nccc2cc[nH]c12
Product: CC(=O)Nc1nccc2cc[nH]c12
Yield: 8.69 %

Procedure:
N-(1H-Pyrrolo[2,3-c]pyridin-7-yl)acetamide (Intermediate 6, yield: 8.69%) was synthesized from 7-chloro-1H-pyrrolo[2,3-c]pyridine using acetamide.
Reaction SMILES: Cl.[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>O1CCOCC1>[C:2]1([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH3:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(c1ccccc1)N1CCC[C@H](C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(c1ccccc1)N1CCC[C@H](C(=O)O)C1
Reaction time: 0.5 h

Procedure:
In a flask, hydrochloric acid in dioxane (4M, 2 mL) was added to (3S)-tert-butyl 1-(1-phenylethyl)piperidine-3-carboxylate (0.031 g, 0.108 mmol), and the reaction was stirred for 30 minutes. Ethanol (2 mL) was added to the reaction, and the resulting solution was concentrated in vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([N:17]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[S:5][CH:6]=1.[Li]CCCC.CN([CH:40]=[O:41])C>C1COCC1>[Si:10]([O:9][CH2:8][CH:7]([N:17]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:4]1[S:5][CH:6]=[C:2]([CH:40]=[O:41])[CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(C=O)cs1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-[1-(4-bromothiophen-2-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-N-(3-methylbutyl)benzenesulfonamide (227 mg, 0.415 mmol) was dissolved in 4.1 mL THF and cooled to −78° C. n-BuLi (174 μl (2.5M in hexanes), 0.436 mmol) was added dropwise. The mixture was stirred 5 minutes and DMF (322 μL) was added in one portion. The mixture was stirred 20 minutes and then quenched with aqueous ammonium chloride. The quenched mixture was warmed to room temperature, DCM was added and the phases separated with a phase extractor. The solvent was removed under reduced pressure. The title compound was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[N:24]=[CH:23]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C([O-])(C)=O.[NH4+]>C1COCC1>[OH:8][CH2:9][C@H:10]([N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[N:24]=[CH:23]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccccc21)n1cnc(C(N)=O)c1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1cn([C@@H](CO)CCn2ccc3ccccc32)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To an ice cooled solution of 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(1-indolyl)-2-butyl]imidazole-4-carboxamide (176.3 mg, 0.427 mmol) in THF (5 ml) was added dropwise 1.0 M Bu4NF in THF (641 ml). After the addition was completed, the reaction mixture was stirred at ice-bath temperature for 30 minutes. 25% AcONH4 (4 ml) was added, and the resulting mixture was stirred for several minutes and then extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel (6 g) column chromatography eluting with chloroform/methanol. (10:1) to give 1-[(R)-1-hydroxy-4-(1-indolyl)-2-butyl]imidazole-4-carboxamide (81.7 mg, 64.1%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:27])([CH3:26])[O:6][C@H:7]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10][C@@H:9]([C:23](O)=[O:24])[CH2:8]1)([CH3:4])[CH3:3].B.C1COCC1>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:27])([CH3:26])[O:6][C@H:7]1[CH2:8][C@@H:9]([CH2:23][OH:24])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:12]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To cis-(3RS,5RS)-5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinecarboxylic acid (0.80 g; 2.0 mmol) in THF (20 ml) was added 1N BH3.THF in THF (6.0 ml; 6.0 mmol) and the reaction was allowed to stir at room temperature under N2 for 6 h. Excess borane was quenched by the addition of MeOH and the reaction was allowed to stir for 2 hours. The reaction was partitioned between EtOAc (150 ml) and water (25 ml) the layers were separated and the organic layer was washed with brine and dried with Na2SO4. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (550 mg; 73%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:42][C:43]1[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:42][C:43]2[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=2)=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(N)cs1
Reactant: O=C(O)c1cc(F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc(F)ccn2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A solution of 4-fluoropicolinic acid (1.0 g, 6.4 mmol), HATU (2.9 g, 7.6 mmol), and N-methylmorpholine (0.84 mL, 7.6 mmol) in N,N-dimethylformamide (12 mL) was stirred at 0° C. for 30 minutes. Methyl 4-aminothiophene-2-carboxylate (990 mg, 7.0 mmol) was added, the reaction was stirred for 30 minutes at 0° C., then warmed to room temperature, and stirred for an additional 2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile/H2O (1:1) and the solids were isolated by filtration, washed with water, acetonitrile, then dried to afford methyl 4-(4-fluoropicolinamido)thiophene-2-carboxylate as a white powder (1.0 g, 56% yield). M+1=281.1.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:16]C)=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#N.[ClH:18]>>[ClH:18].[ClH:18].[CH3:1][NH:3][C:4]([NH2:16])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15]
Reactant: CNC(=NCCSCc1[nH]cnc1C)NC#N
Agent: Cl
Product: CNC(N)=NCCSCc1[nH]cnc1C

Procedure:
A solution of N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine (2.0 g.) in hydrochloric acid (25 ml.) was heated on the steam bath for 2 hours. Concentration followed by recrystallisation of the product from ethanol-ether afforded N-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine dihydrochloride (1.44 g.) m.p. 204°-206°.