Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.C1(S([C:24]2[N:33]=[C:32]3[C:27]([C:28](=[O:47])[C:29]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][N:31]3[C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])=[CH:26][C:25]=2[F:48])=O)C=CC=CC=1.C(OCC)C>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:24]2[N:33]=[C:32]3[C:27]([C:28](=[O:47])[C:29]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][N:31]3[C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])=[CH:26][C:25]=2[F:48])[CH2:5]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)c3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 83.8 %

Procedure:
In 3 ml of ethanol was suspended 120 mg of 3-aminopyrrolidine dihydrochloride, and 250 mg of triethylamine was added thereto, after which 300 mg of ethyl 7-benzenesulfinyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added thereto. The resulting mixture was subjected to reaction at room temperature for 3 hours, and to the reaction mixture was added 10 ml of diethyl ether, after which crystals were collected by filtration, and washed with 12 ml of water to obtain 230 mg (yield 83.8%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 64.
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[CH3:41])[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[CH3:41])[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:30])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3C)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1C)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C
Yield: 88.8 %

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chloro-2-methylphenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoate (60 mg, 0.10 mmol, 1 equ.) was dissolved in methanol/tetrahydrofuran (2/1) (0.8 ml). A solution of sodium hydroxide (12 mg, 0.30 mmol, 3 eq.) in water (0.3 ml) was added and reaction mixture heated to 40° C. for 2 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4-{[(2S,4R)-4-[acetyl(4-chloro-2-methylphenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid (50 mg, 89%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1)[CH3:7].[OH-].[Na+].CN(C)[CH:21]=[O:22]>>[CH2:6]([C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:21]=[O:22])=[CH:13][NH:14]2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: CN(C)C=O
Reactant: CCc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorus oxychloride (3.82 g) was added to N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 10 minutes. A solution of 6-ethylindole [Journal of the Chemical Society (J. Chem. Soc.), 7165 (1965)] in N,N-dimethylformamide (6 ml) was added to the reaction solution, and the mixture was stirred at room temperature for one hour. Ice (20 g) and then a 5N aqueous solution of sodium hydroxide (34 ml) were added to the reaction solution, and the mixture was heated under reflux for one hour. The reaction solution was ice-cooled, and the precipitated crystals were collected by filtration to give 6-ethylindole-3-carboxaldehyde (2.76 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:10]#[N:11])=[CH:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N+]([CH3:16])([O-])=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:10]#[N:11])[CH2:16][CH:5]1[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:12]
Reactant: COC(=O)C(C#N)=CCC(C)C
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)C1(C#N)CC1CC(C)C
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-cyano-5 methyl-hex-2-enoic acid methyl ester (20.2 g, 121 mmol) in dry acetonitrile (110 mL) was added nitromethane (9.8 mL, 181 mmol) and a portionwise addition of alumina-supported potassium flouride (40% wt, 39.3 g). The reaction mixture was stirred under reflux for 2 hours and cooled to room temperature. The solid was removed by filtration through a short pad of celite and washed with acetonitrile. Excess of solvent was removed in vacuo and the residue was re-dissolved in ether. The ether layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes/EtOAc (8:2) as an eluent to give 15 g (69%) of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid methyl ester as colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=2.9 Hz, 3H), 1.00 (d, J=3.0 Hz, 3H), 1.35-1.42 (m, 2H), 1.65 (m, 1H), 1.79-1.94 (m, 3H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 19.3, 22.3, 22.4, 25.5, 27.9, 30.1, 39.0, 53.4, 117.3, 168.5.
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])[CH:8]=[C:7]2[C:15]([F:18])([F:17])[F:16])([O-:3])=[O:2].[OH-].[K+].[CH3:21]I>>[CH3:21][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[C:7]([C:15]([F:18])([F:16])[F:17])=[CH:8][C:9]1=[O:14]
Reactant: O=c1cc(C(F)(F)F)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: Cn1c(=O)cc(C(F)(F)F)c2cc([N+](=O)[O-])ccc21
Yield: 57.6 %

Procedure:
6-Nitro-4-trifluoromethyl-1H-quinolin-2-one (2.50 g, 9.7 mmol) was methylated with KOH (5.46 g, 97.3 mmol) & MeI (6.1 mL, 97.3 mmol), as to give 1-methyl-6-nitro-4-trifluoromethyl-1H-quinolin-2-one (1.52 g, 57%): δH (CDCl3)=3.80 (s, 3H), 7.20 (s, 1H), 7.55 (d, 1H), 8.50 (dd, 1H), 8.75 (d, 1H). An EtOAc (50 mL) solution of this compound (1.26 g, 4.6 mmol) was treated with a slurry of Pd (10% on C, 95 mg, 0.09 mmol) in i-PrOH (2 mL). The mixture was stirred under a H2 atmosphere for 80 min, then more Pd (10% on C, 24 mg, 0.02 mmol) was added. After 20 min under H2, the mixture was filtered through Celite & the solvent removed to yield the title compound (1.06 g, 95%): δH (CDCl3)=3.70 (s, 3H), 3.75–3.85 (br s, 2H), 7.00–7.10 (m, 3H), 7.20 (d, 1H).
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]>C(O)C>[OH:1][C@H:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: CC(C)C(=O)NCCN
Solvent: CCO
Product: CC(C)C(=O)NCCNC[C@H](O)COc1ccccc1
Yield: 46 %

Procedure:
A mixture of (S)-1,2-epoxy-3-phenoxypropane (0.495 g.) and N-(2-aminoethyl)isobutyramide (0.429 g) in ethanol (25 ml) was heated under reflux for 48 hours. The reaction mixture was cooled and solvent removed by rotary evaporation in vacuo. The residual solid was purified by column chromatography on silica (Merck, Art. 7736) using 5% v/v methanol in dichloromethane as eluant. The solid thereby obtained was purified by recrystallisation from ethyl acetate to give (S)-N-(2-[2-hydroxy-3-phenoxypropyl]aminoethyl)isobutyramide (0.425 g), m.p. 88°-89° C., 24 [α]D -5.8° [c, 1.04; methanol], mixed m.p. with material from Example 1, 88°-89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH:21]1([C:19]2[N:12]3[C:13]([CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:11]3)=[C:16]([CH3:17])[N:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCCCC3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(C4CCCCC4)n3n2)cc1
Yield: 33.2 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclohexane-carboxamide (Intermediate 63) (90 mg, 0.25 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.25 mL, 2.68 mmol), to afford 7-cyclohexyl-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (28 mg) as a yellow solid. 1H NMR (DMSO): δ9.46 (s, 1H), 9.06 (s, 1H), 7.71 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 3.75 (s, 3H), 3.14 (m, 1H), 2.43 (s; 3H), 1.95 (m, 2H), 1.84 (m, 2H), 1.80-1.60 (m, 3H), 1.51-1.36 (m, 2H), 1.36-1.25 (m,1H).
Reaction SMILES: BrC1C=C(C)C=CN=1.[Li]CCCC.C[Si](C)(C)C#CC(=O)C.[CH3:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:38])([C:32]#[C:33][Si](C)(C)C)[CH3:31])[CH:25]=1.O.O.[F-].[K+]>O1CCCC1.CO>[CH3:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:38])([C:32]#[CH:33])[CH3:31])[CH:25]=1
Reactant: Cc1ccnc(C(C)(O)C#C[Si](C)(C)C)c1
Agent: CC(=O)C#C[Si](C)(C)C
Agent: Cc1ccnc(Br)c1
Agent: [F-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(C)ccn1
Temperature: -78 °C

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure C. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-4-methylpyridine (8.5 g, 49.41 mmol, 1.00 equiv) in tetrahydrofuran (110 mL). This was followed by the addition of n-BuLi (22 mL, 1.20 equiv) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. To this was added 4-(trimethylsilyl)but-3-yn-2-one (7.6 g, 54.19 mmol, 1.10 equiv) dropwise with stirring at −78° C. The resulting solution was warmed slowly to 0° C. and stirred for 10 min at this temperature. The reaction was then quenched by the addition of 10 mL of sat. aq. ammonium chloride. The resulting solution was extracted with 2×40 mL of ethyl acetate and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether:ethyl acetate (5:1). This resulted in 6.5 g (56%) of 2-(4-methylpyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol as colourless oil. Into a 250-mL round-bottom flask, was placed a suspension of 2-(4-methylpyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol (6.5 g, 27.85 mmol, 1.00 equiv) and potassium fluoride dihydrate (6.6 g, 2.50 equiv) in methanol (50 mL). The resulting solution was stirred for 4 h at 50° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 2×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 3.5 g (78%) of 2-(4-methylpyridin-2-yl)but-3-yn-2-ol as a pink solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:41](OC(N1CCC(C2NC(C3C=C(C=CC=3C)C(O)=O)=C(C)N=2)(C)CC1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=C(C=CC=3C)C(O)=O)=C(C)N=2)CC1)=O)(C)(C)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[NH:22][C:23]([C:27]5([CH3:41])[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]5)=[N:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Agent: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 182.3, except 3-(2-(1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 185.2) was used in place of 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C[N-]C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CCl
Reactant: N#Cc1cccc(O)c1
Agent: C[N-]C
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(C#N)c1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
430 mg (2 mmol) of 1-t-butoxycarbonyl-(2R)-2-chloromethyl pyrrolidine was dissolved in 5 ml of dimethylamide, and 238 mg (2 mmol) of 3-hydroxy benzonitrile, 500 mg (3 mmol) of potassium iodide, and 414 mg (3 mmol) of potassium carbonate were added thereto and stirred at 90° C. for 3 days. The reaction mixture was treated in an ordinary manner with ethyl acetate as the extractant, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:23]O>>[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CO
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
Thionyl chloride (1 mL) was added to a stirred mixture of 3-cyclohexyl-1H-indole-6-carboxylic acid (30.4 g, 0.125 mol) in methanol (300 mL). The mixture was stirred at reflux for 18 hours, treated with decolorizing carbon, and filtered. The filtrate was concentrated to about 150 mL at which point crystallization occurred. The filtrate was cooled to room temperature and filtered. The solid was washed with cold methanol followed by diethyl ether to provide the desired product as a pale purple solid (22.2 g, 69% yield). ESI-MS m/z 258 (MH+); 1H NMR (300 MHz, CDC3) δ 1.35 (m, 4H), 1.63 (s, 1H), 1.78 (m, 3H), 2.06 (d, J=8.05 Hz, 2H, 3.90 (m, 1H), 7.08 (d, J=1.83 Hz, 1H), 7.62 (s, 1H), 7.65 (s, 1H), 7.74 (d, J=1.46 Hz, 1H), 7.77 (d, J=1.46 Hz, 1H), 8.08 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8].CO.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: CCC(CC)COc1ccc(Cl)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)COc1ccc(Cl)cc1CO
Temperature: 25 °C

Procedure:
A solution of 5-Chloro-2-(2-ethyl-butoxy)-benzaldehyde, 10, (2.83 g 11.8 mmol), MeOH (50 mL) was cooled to +5° C. under N2 atmosphere and NaBH4 (0.54 g, 14.2 mmol) was added. The mixture was allowed to warm to RT over 2 hours and the volatiles were removed in vacuo. The reaction mixture was partitioned between water and CH2Cl2. The organic layer was washed with sat. brine, dried (Na2SO4) and evaporated to dryness to give 2.61 g of 5-chloro-2-(2-ethyl-butoxy)-phenyl]-methanol, 11 as a pale yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To 551 mg methyl 6-[(tert-butoxycarbonyl)amino]-1H-indole-2-carboxylate dissolved in 15 mL dichloromethane was added 5 mL trifluoroacetic anhydride, and the mixture stirred at room temperature for 1.5 h. P The mixture was partitioned between dichloromethane and 1 N sodium hydroxide until neutral, dried over magnesium sulfate and concentrated. Obtained 360 mg of the crude methyl 6-amino-1H-indole-2-carboxylate. To 200 mg (1.05 mmol) of crude product dissolved in 5 mL dichloromethane and 340 □L pyridine at 0° C. was added 81 □L methanesulfonyl chloride. The mixture was stirred at 0° C. for 1 h, was partitioned between dichloromethane and 1 N hydrochloric acid until neutral, was dried over magnesium sulfate and concentrated to obtain 333 mg of methyl 6-[(methylsulfonyl)amino]-1H-indole-2-carboxylate as crude product.
Reaction SMILES: BrCBr.O1CCC[CH2:5]1.[Si:9]([O:16][C@H:17]1[CH2:21][C:20](=O)[C:19]([CH2:23][C:24]#[CH:25])=[C:18]1[CH3:26])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>ClCCl.[Zn].[Ti](Cl)(Cl)(Cl)Cl.O.CCCCCC>[CH3:26][C:18]1[C@@H:17]([O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:21][C:20](=[CH2:5])[C:19]=1[CH2:23][C:24]#[CH:25]
Reactant: C1CCOC1
Reactant: C#CCC1=C(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Solvent: ClCCl
Solvent: CCCCCC
Product: C#CCC1=C(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC1=C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
1H-NMR (solvent: CDCl3, internal standard: TMS) δ value (ppm): 4.69(brd, 1H), 3.11(ABq, 2H), 2.74(dd, 1H), 2.28(dd, 1H), 2.16(s, 3H), 1.96(t, 1H), 0.92(s, 9H), 0.15(s, 3H), 0.12(s, 3H). 2 Dibromomethane (13.04 g) and zinc dust (14.71 g) were added to tetrahydrofuran (120ml), and the resulting mixture was cooled to 0°~5° C. A dichloromethane solution (50 ml) of 1M titanium tetrachloride was added to the tetrahydrofuran solution over about 10 min, and the resulting mixture was allowed to react for 3 days at 0°~5° C. Then a solution of (S)-4-tert-butyldimethylsilyloxy-3-methyl-2-(2-propynyl)cyclopent-2-ene-1-one (13.22 g) in dichloromethane (50 ml) was added at 0°~5° C. over about 10 min. After the reaction was continued for 2 hours at the same temperature, hexane (200 ml) and then a slurry consisting of sodium bicarbonate (75 g) and water (40 ml) were added After stirring for 2 hours at 0°~5° C., the organic layer was separated by decantation. The obtained residue was extracted three times with n-hexane (200 ml). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resultant residue was subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate=50:1) to afford the desired product, (S)-2-methyl-4-methylidene-3-(2-propynyl)-1-tert-butyldimethylsilyloxycyclopent-2-ene (9.02 g, yield 68.7%) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[O:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Reactant: c1ccc(-c2coc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccc3)co2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-Phenyl-1,3-oxazol-2-yl)piperazine (391 mg, 0.807 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (370 mg, 1.61 mmol), diisopropylethylamine (0.141 ml, 0.807 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 2 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 44.0 mg (14.1%) of the desired product. mp 171-172° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH2:12])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH:12][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1cc(CN)c(Br)cc1C(=O)NC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
After dissolving the N1-methyl-4-(aminomethyl)-5-bromo-2-ethoxybenzamide (6.77 g) in pyridine (50 ml), 4-nitrobenzenesulfonyl chloride (5.3 g) was added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were then added for separation. The organic layer was washed with 1 N hydrochloric acid and brine and the precipitated crystals were filtered out (5.57 g). The organic layer of the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was washed with ethyl acetate and filtered. A total of 8.31 g of the title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10](N)=[O:11].[OH-].[K+].C([OH:28])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([C:10]([OH:28])=[O:11])[NH:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1
Reactant: NC(=O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl

Procedure:
A mixture of 12.7 parts of 2-(2,6-dichlorophenyl)-2-(2-naphthylamino) acetamide and 250 parts of potassium hydroxide/ethanol 1 N is stirred and refluxed for 48 hours. The reaction mixture is evaporated. The oily residue is dissolved in 400 parts of water and the solution is acidified with concentrated hydrochloric acid solution. The sticky product is extracted with 1,1'-oxybisethane. The extract is washed twice with water, dried and evaporated. The oily residue is triturated three times in petroleumether. The solid product is filtered off and recrystallized from 50 parts of glacial acetic acid. The product is washed with petroleumether, dried and dissolved in 80 parts of 1,1'-oxybisethane. The solution is stirred with activated charcoal, filtered and the filtrate is evaporated. The oily residue solidifies on triturating in 2-propanol and petroleumether. The solid is filtered off and dried, yielding 1.6 parts of 2-(2,6-dichlorophenyl)-N-(2-naphthyl)glycine; mp. 171.7° C.