Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1C=CC(/C(=C\C(O)=O)/C(O)=S)=CC=1.C(O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[S:25][C:24]([C:29]([O-:31])=[O:30])=[CH:23][C:22]2=[O:32])C.[Na+].S(=O)(=O)(O)O>>[CH3:1][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[S:25][C:24]([C:29]([OH:31])=[O:30])=[CH:23][C:22]2=[O:32]
Reactant: Cc1ccc(/C(=C\C(=O)O)C(O)=S)cc1
Reactant: CCOc1ccc2sc(C(=O)[O-])cc(=O)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc2sc(C(=O)O)cc(=O)c2c1
Reaction time: 0.5 h

Procedure:
4.7 parts of 4-methylphenylthio fumaric acid, made in analogous manner to part (a) of Example 1, was added in small lots to 20 parts of stirred concentrated sulphuric acid. The solution was allowed to stand for 30 minutes and then it was cautiously poured on to ice. The resulting precipitate was filtered off, washed with water and crystallised from an ethanol/dioxan mixture to give 2.3 parts of 6-methyl-1-thiachromone-2-carboxylic acid, melting point 236°-7°C.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[CH:7][CH2:6]1)[CH3:3].N1CC[CH2:34][CH2:33][CH2:32]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[NH:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[O:16])=[CH:9][CH2:10]2)[CH2:1][CH2:34][CH2:33][CH2:32][CH2:3]1
Reactant: C1CCNCC1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2cccs2)=CC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=CCC(=NN2CCCCC2)C=C1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.24 mmol) from Example 19, a pre-mixed piperidine (0.12 mL, 1.21 mmol) and HOAc (0.11 mL, 1.92 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (21 mg). MS 496.1 and 498.1 (M+H, Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>CC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][S:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)(=[O:26])=[O:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(O)cc2s1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3cccs3)cc2s1
Yield: 76.1 %

Procedure:
A solution of (6-hydroxybenzothiazol-2-yl)carbamic acid tert-butyl ester (intermediate 14) (527 mg, 1.979 mmol), 2-thiophenesulfonyl chloride (433 mg, 2.37 mmol) and triethylamine (677 μl, 4.75 mmol) in 10 ml of acetone is stirred overnight at room temperature. The reaction medium is concentrated to dryness. The residue obtained is washed with water, with acetone and then with ethyl ether to give 621 mg of thiophene-2-sulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (light gray powder) in a yield of 76%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(Cl)c4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 399 [MH+].
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:29])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:28][CH2:27][C@@H:16]3[N:17]4[C:26]5[C:25]([C@@H:15]3[CH2:14]2)=[CH:24][CH:23]=[CH:22][C:21]=5[NH:20][CH2:19][CH2:18]4)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:29])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:28][CH2:27][C@@H:16]3[N:17]4[C:26]5[C:25]([C@@H:15]3[CH2:14]2)=[CH:24][CH:23]=[CH:22][C:21]=5[NH:20][CH2:19][CH2:18]4)=[CH:5][CH:4]=1
Reactant: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3)c1ccc(F)cc1
Yield: 94.8 %

Procedure:
1-(4-Fluoro-phenyl)-4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one HCl salt (500 mg, 1.20 mmol) is suspended in 20 mL of methanol. NaBH4 (136 mg, 3.60 mmol) is added slowly into the suspension at room temperature. The suspension changed into a clear solution during the addition of NaBH4. After an hour, additional 90 mg of NaBH4 is added into the mixture to push the reaction to completion. The reaction mixture is quenched by adding 10 mL of water. After solvent is removed by rotary evaporation, the residue is treated with 10 mL of 1N NaOH aqueous solution, and then extracted with methylene chloride three times. The combined organic phase is washed with water, dried with anhydrous sodium sulfate, and then evaporated to dryness under vacuum to give 434 mg off-white foamy solids with 98% purity and 95% yield. MS (ESI) m/z 382.2 [M+1-1]+
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:37])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[C:16]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:17]=4[N:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[C:16]4[CH2:22][CH2:21][NH:20][CH2:19][C:17]=4[N:18]=3)=[CH:11][CH:12]=2)=[O:37])[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(4-(3-cyclopropylureido)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (3.27 g, 6.43 mmol) in DCM (40 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and the resulting residue was dissolved in the minimum MeOH and precipitated from Et2O to give a pale yellow solid (498 mg, 0.95 mmol, 15% yield).
Reaction SMILES: COC1C=CC(C2CCN(C3C=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][CH2:56][CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cccc(N2CCC(c3ccc(OC)cc3NCc3ccc(OCCN4CCCCCC4)cc3)C2)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1cccc(N2CCC(c3ccc(OC)cc3N)C2)c1
Agent: Cl
Product: COc1cccc(N2CCC(c3ccc(OC)cc3NCCCc3ccc(OCCN4CCCCCC4)cc3)C2)c1

Procedure:
Synthesized from 5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (202 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl {5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (188 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (153 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>O.C(O)(C)C>[NH:1]([C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:24])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
First, 27.3 g (364 mmol) of glycine and 29.1 g (727 mmol) of sodium hydroxide were dissolved in a mixed solvent of 450 g composed of i-propanol and 200 g of water under stirring at room temperature, then cooled to 10° C. Next, 100 g (364 mmol) of palmitic acid chloride was added dropwise thereto over a period of 1 hour. The reaction product was returned to room temperature, then stirred for about 15 hours. Next, 400 g of water was added thereto, following which 73.8 g (727 mmol) of 35% hydrochloric acid was added dropwise. The solid that deposited out was recovered, slurry washed, and purified by re-crystallization from methanol, giving 36.4 g (yield, 32%) of N-palmitoyl-Gly as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[OH:46][C:45]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:11][C:42](=[O:43])[C:41]=1[S:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH:31]([CH3:33])[CH3:32]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methoxyacetophenone (2.26 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 221°-223° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.40 (m, 1H), 3.85 (s, 3H), 6.78 (s, 1H), 6.92 (m, 1H), 7.10 (m, 4H), 7.27 (m, 1H), 7.81 (d, 2H), 12.38 (brs, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[O:14][C:15]([C:18]3[N:19](C(OC(C)(C)C)=O)[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+]>CO.CC(C)=O.CCCCCC>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:18]1[C:15]1[O:14][C:13]([NH:12][C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=[CH:10][CH:9]=2)=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(C)(=O)=O)c3)o2)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Yield: 63.3 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-(methylsulfonamido) phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 24 (0.221 g, 0.472 mmol) in methanol (30 mL) was added potassium carbonate (0.652 g, 4.71 mmol) at room temperature. Reaction mixture was refluxed for 2 hours. After completion of the reaction (as judged by TLC) it was concentrated using rotavapor and the crude product was purified by MPLC column chromatography (Biotage; Acetone/hexane as an eluent) to provide N-(3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenyl)methanesulfonamide 25 (0.11 g, 63% yield) as a solid. MS (ES) m/z 369 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:10]2[C:11]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=3)[CH2:7][CH2:8][C:9]2=[O:14])=[CH:19][CH:18]=1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CCc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol), 4-methoxybenzyl chloride (388 μL, 2.86 mmol) and potassium carbonate (1.08 g, 7.80 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow solid which was subjected to flash chromatography on silica gel using 1% MeOH/CH2Cl2 to give an off-white solid (605 mg, 74.5%). 1H-NMR (DMSO-d6) δ: 8.15 (d, J=2.7 Hz, 1H), 8.02 (dd, J=2.7, 9.0 Hz, 1H), 7.15 (dd, J=3.0, 9.0 Hz, 1H), 6.88-6.85 (m, 4H), 5.14 (s, 2H), 3.70 (s, 3H), 3.11-3.06 (m, 2H), 2.80-2.75 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Si:15](Cl)([CH3:18])([CH3:17])[CH3:16].CCN(CC)CC>CN(C=O)C>[CH3:16][Si:15]([CH3:18])([CH3:17])[O:1][C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 1.0 L flask was added tert-butyl 4-oxopiperidine-1-carboxylate (150.0 g, 752.8 mmol), which was dissolved in DMF (400 mL). To this solution was added TMS-Cl (114.7 mL, 903.4 mmol), followed by NEt3 (251.8 mL, 1807 mmol). The resulting heterogeneous mixture was warmed to 70° C. and stirred overnight under a N2 atmosphere. The mixture was cooled to ambient temperature, diluted with hexanes (250 mL) and filtered. The solids were washed with hexanes (4×250 mL). The combined organic phases were washed with a saturated aqueous NaHCO3 (3×250 mL) and brine (3×250 mL), dried over Na2SO4, and concentrated. The crude product was carried on directly to the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]=1[N:34]1[CH:38]=[N:37][CH:36]=[N:35]1)[CH:29]=O)[CH3:24].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:29][C:28]3[CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]([N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=3)[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)([CH3:5])[CH3:21]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cncn1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C(=O)OC)cc3)CC2)cc(OCC)c1-n1cncn1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[4-(piperidin-4-ylcarbamoyl)-phenyl]-propionic acid methyl ester (example 60e) was reacted with 3,5-diethoxy-4-[1,2,4]triazol-1-yl-benzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless oil. MS: 550.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[C:1]([O:5][C:6](=[O:36])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:43]([C:42]2[S:41][C:40]3[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=3[C:38]=2[Cl:37])=[O:44])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[CH:28][CH:29]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)CC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(N(Cc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)C(=O)c2sc3ccccc3c2Cl)CC1

Procedure:
The title compound was prepared from amine (264) (220 mg, 0.43 mmol) and 3-chlorobenzo[b]thiophene-2-carbonyl chloride (110 mg, 0.48 mmol) following Method D.
Reaction SMILES: [CH3:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C([Li])CCC.[CH3:15][Si:16]([CH3:26])([CH3:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>C1COCC1>[CH3:15][Si:16]([CH3:25])([CH3:26])[C:17]1[CH:18]=[C:19]([CH2:20][CH2:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])[CH:22]=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CCc1cccc([Si](C)(C)C)c1)OCC
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 52.6 %

Procedure:
To a solution of diethyl methylphosphonate (2.28 g, 15 mmol) in THF (20 ml) was added n-butyllithium (17 mmol, 1.6 M solution in hexane) at −78° C. After 45 min, the white suspension was added to a solution of the bromide 37 (3.65 g, 15 mmol) in THF (20 ml) and the mixture was stirred for 1.5 h. The temperature was then increased to −10° C. and after 1 h the deeply red colored solution was quenched by addition of saturated NH4Cl (aq). Volatiles were removed under reduced pressure and the residue was purified by flash chromatography (silica, EtOAc) to give 2.48 g (53%) of 38 as a colorless liquid. IR (film): 3473, 2955, 1248, 1058 and 1031; 1H NMR (200 MHz, CDCl3): δ0.30 (9H, s), 1.31 (6H, t, J=7 Hz), 2.10 (2H, m), 2.92 (2H, m), 4.11 (4H, m) and 7.29 (4H, m); 13C NMR (50 MHz, CDCl3): δ−1.2, 16.4, 26.3, 28.6, 29.0, 61.5, 127.9, 128.4, 131.2, 132.9, 139.9, 140.2 and 140.7; HR-MS (EI): e/m 314.1453 (M+C15H27O3PSi requires 314.1467).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl.O>CCO.CC(O)=O.[Fe]>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([F:10])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(F)cc1C=O
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of 4-chloro-5-fluoro-2-nitrobenzaldehyde (1.50 g, 7.37 mmol), concentrated hydrochloric acid (0.30 ml, 3.68 mmol), and iron (1.32 g, 23.6 mmol) in EtOH (18 mL), AcOH (18 mL), and water (9 mL) was heated to reflux for 30 minutes, then cooled to RT. The resulting suspension was filtered through CELITE™ and the filtrate was then partitioned between EtOAc and water. The layers were separated, the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2-amino-4-chloro-5-fluorobenzaldehyde as a yellow solid (1.15 g, 90% yield). m/z=174 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CN(C)C=O.[C:9](=[S:11])=[S:10].[CH2:12](Br)[C:13]#[CH:14]>O>[CH2:14]([S:10][C:9](=[S:11])[N:2]([CH3:3])[CH3:1])[C:13]#[CH:12]
Reactant: CNC
Reactant: S=C=S
Reactant: C#CCBr
Solvent: CN(C)C=O
Solvent: O
Product: C#CCSC(=S)N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.3 Grams of a 40% dimethylamine aqueous solution was added to 40 ml of dimethylformamide, and while maintaining the mixture at a temperature of 5°-10° C., 4.8 gr of carbon disulfide was added dropwise under agitation over the period of 30 minutes. Thereafter, the temperature of the mixture was maintained at a room temperature and 7.1 gr of propargyl bromide was added dropwise thereto over the period of 30 minutes. The reaction mixture was agitated at the same temperature for one hour and at 40°-50° C. for additional two hours to complete the reaction. The reaction mixture was poured into water and the separated organic substance was extracted twice with 50 ml of benzene, washed with diluted hydrochloric acid and further washed with water, and after removal of benzene by distillation, 9.2 gr of the desired product was obtained. M.p.: 57°-59° C. The results of elemental analysis were shown as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
4-Methyl-3-nitroanisole (2.7 mL; manufactured by Sigma-Aldrich Co.) was dissolved in carbon tetrachloride (20 mL; manufactured by Wako Pure Chemical Industries, Ltd.), and NBS (4.0520 g; manufactured by Tokyo Chemical Industry Co., Ltd.) and hydrated benzoyl peroxide (348 mg; manufactured by Sigma-Aldrich Co.) were added to the solution. The mixture was purged with nitrogen, and was stirred for 3 hours at reflux. The reaction solution was filtered, and then the filtrate was washed with an aqueous solution of NaHSO3 and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=94:6→73:27). Thus, the title compound (3.2549 g) was obtained.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[N:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[N:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cn1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)nc2)C(=O)CCC1
Temperature: 25 °C

Procedure:
Trimethyloxonium tetrafluoroborate (121 mg, 0.82 mmol) is added to a solution of N,N-diisopropylethylamine (276 μL, 1.58 mmol) and 1-((6-cyanopyridin-3-yl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 30, 346 mg, 0.804 mmol) in dichloromethane (10 mL). The mixture is stirred at room temperature over night, and another portion of trimethyloxonium tetrafluoroborate (121 mg, 0.82 mmol) is added. After 1 h the mixture is diluted with dichloromethane, and washed with water and saturated aqueous sodium chloride solution. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 300 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.09 min (V011_S01).