Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:16](Cl)([Cl:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([Cl:18])=[O:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Nc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(N(C(=O)Cl)c2ccccc2)c1
Yield: 99 %

Procedure:
A solution of 5.5 g (27.9 mmole) of N-(3,5-dimethylphenyl)aniline, 27.9 mL of 1.93M phosgene in toluene and 15 mL of toluene was heated at 90° C. under nitrogen for 2 hours with stirring. The solution was cooled, flushed with nitrogen for 2 hours to remove excess phosgene and concentrated in vacuo to give 7.15 g (99%) of a red oil.
Reaction SMILES: C([O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1)(C)C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:20][C:18]([F:19])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([OH:22])=[O:4])=[N:13][CH:14]=1
Reactant: CC(C)OC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(5-Trifluoromethyl-pyridin-2-yl)-benzoic acid isopropyl ester was dissolved in 10 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (161 mg, 3.84 mmol) was added. After stirring for 3 h at room temperature, the volatiles were removed under vacuum and 5 ml of water were added to the mixture, which was brought to pH 6 with 1N HCl. The resulting slurry was extracted with ethyl acetate, the combined organic layers were dried (magnesium sulfate), filtered and concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].[N+](C1C=CC([O:19][C:20]([C:22]2[C:30]3[S:29][C:28]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:27][C:26]=3[C:25]([O:37][CH3:38])=[CH:24][CH:23]=2)=O)=CC=1)([O-])=O>CN(C)C=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1CCCC1>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:20]([C:22]1[C:30]2[S:29][C:28]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[N:27][C:26]=2[C:25]([O:37][CH3:38])=[CH:24][CH:23]=1)=[O:19])#[N:9]
Reactant: Cn1ncc(C#N)c1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(N3CCCCC3)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCCCC3)nc12
Yield: 75.5 %

Procedure:
Starting from 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (125 mg) in dimethyl formamide (10 ml), sodium hexamethyldisilazide in tetrahydrofuran (1.1 ml, 1.0 M), and 4-methoxy-2-(piperidin-1-yl)benzothiazole-7-carboxylic acid 4-nitrophenyl ester (210 mg). Purification by flash chromatography (eluent 5% methanol in dichloromethane) followed by trituration with ethyl acetate yielded the title compound as an off-white solid (152 mg). TLC Rf 0.48 (ethyl acetate); Mpt 290-291° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:16])([CH3:15])[CH:9]=[C:8]2[CH3:17])=[O:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:18](=[O:20])[CH3:19])[C:10]([CH3:16])([CH3:15])[CH:9]=[C:8]2[CH3:17])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc2c(c1)C(C)=CC(C)(C)N2
Product: COC(=O)c1ccc2c(c1)C(C)=CC(C)(C)N2C(C)=O

Procedure:
A mixture of 1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester (2.3 g) and a catalytic amount of N,N-dimethylaminopyridine in acetic anhydride (60 ml) was stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/11/9 (v/v) as eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.CC(=O)OCC>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(O)Cn1cc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnn(CC(=O)O)c2)CC1
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-bromo-1H-pyrazol-1-yl)acetic acid (867 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.2 g) and Pd(PPh3)4 (232 mg) in dioxane (15 mL) and sat. K2CO3 (7.5 mL) was heated at 100° C. overnight. After cooling down, EA was added and the mixture was washed with water and brine. The combined aq. layers were acidified to pH=2 with NaHSO4 and extracted with EA. The org. layers from the second extraction were dried (MgSO4), filtered off and evaporated in vacuo to afford 1.05 g of brown resin that was used without purification. LC-MS (B): tR=0.72 min; [M+H]+: 308.26.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3,5-dichlorophenyl boronic acid according to Procedure A. A white solid: mp 245-246° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.77 (m, 2H), 7.67-7.64 (m, 2H), 7.56 (bs, 1H), 6.96 (d, 1H, J=7.98 Hz), 1.7 (s, 6H); MS (EI) m/z 321 ([M+H]+, 40%); Anal. Calc. For C16H13Cl2NO2: C, 59.32, H, 4.11, N, 4.32. Found: C, 59.13, H, 4.29, N, 4.17.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:14][NH2:15])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: NN
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: COc1cc(NN)ccc1[N+](=O)[O-]
Yield: 74.8 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (2.5 g, 14.60 mmol) in ethanol (25 mL) was added hydrazine hydrate (2.1 g, 43.8 mmol). The reaction mixture was refluxed for 3-4 h. The reaction mixture was concentrated to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 4.46 (s, 2H), 6.31 (d, J=9.3 Hz, 1H), 6.50 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 8.25 (s, 1H); MS (m/z): (184.01 M)+.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH2:6]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([O:22][C@H:8]1[CH2:7][CH2:6][C@H:5]2[C@H:4]3[C@H:13]([CH2:12][CH2:11][C@:9]12[CH3:10])[C@@H:14]1[C:19](=[CH:18][C:17](=[O:21])[CH2:16][CH2:15]1)[CH2:20][C@H:3]3[CH2:1][CH3:2])(=[O:25])[CH3:24]
Reactant: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
i)—A solution of (7α,17β)-7-ethyl-17-hydroxyestr-4-en-3-one (Example 1, 2.0 g) in dry pyridine (15 ml) was treated with acetic anhydride (1.86 ml) and the reaction mixture was stirred at room temperature for 6.5 h; additional acetic anhydride (1.86 ml) was added after 3 h. The mixture was cooled to 0° C.; water was added and stirring was continued for 30 min. The product was extracted into ethyl acetate; the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure, to give (7α,17β)-17-(acetyloxy)-7-ethylestr-4-en-3-one (2.15 g). The product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH:14](C(OC)=O)[C:15]([O:17]C)=O)=[O:4].CCCCCC.C(O)(=O)C>Cl>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:14][C:15](=[O:17])[NH:11]2)([OH:2])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C1Cc2c(cccc2C(=O)O)N1
Yield: 38.1 %

Procedure:
Dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate (3.0 g) was refluxed in 50 mL of 6 N hydrochloric acid overnight. The mixture was concentrated to dryness and refluxed for 2 hours with 1.1 g of tin (11) chloride in 20 mL of ethanol. The mixture was filtered through Celite, concentrated and chromatographed on silica gel in ethyl acetate:hexane:acetic acid to give 0.65 g (37% yield) of 4-carboxy-2-oxindole as a while solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=2[N:9]=[C:8]2[C:17](=NCCCC)[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:7]=12)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:32]>C(OCC)(=O)C.CCOCC>[CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=2[N:9]=[C:8]2[C:17](=[O:32])[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:7]=12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C1c2ccccc2CCc2c1nc1c(cnn1CC)c2NCCCC
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCNc1c2c(nc3c1cnn3CC)C(=O)c1ccccc1CC2

Procedure:
7.2 g. of N-butyl-11-(butylimino)-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]-pyridin-4-amine (0.018 mol.) and 100 ml. of aqueous sulfuric acid (30%) are reacted according to the procedure of Example 6, yield: 4.7 g. (75%); m.p. 181°-183° (ethyl acetate/ether).
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13].[CH3:14][Mg]Cl.C1COCC1>C1(C)C=CC=CC=1>[CH3:8][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]
Reactant: C[Mg]Cl
Reactant: c1cc[cH-]c1
Agent: Cl[Ti]Cl
Agent: [Ti+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[c-]1cccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a well stirred slurry of titanocene dichloride (Cp2TiCl2) (249 g, 1.00 mol) in toluene (2.75 L) chilled to −5° C. (internal temp) was added methyl magnesium chloride (CH3MgCl) (750 mL, 3.0M in THF, 2.25 mol) over 1 h, maintaining the temperature below 8° C. The resulting orange slurry is aged at 0-5° C. for 1 h, or until the insoluble purple Cp2TiCl2 has dissolved. A NMR was taken to confirm reaction completion (see below), then the reaction was quenched into a solution of 6% aqueous ammonium chloride (700 mL), maintained at 0-5° C. The layers were separated and the organic phase was washed with cold water (3×575 mL) and brine (575 mL), then was dried with Na2SO4 (220 g). The filtered organic layer was evaporated to 1.5 Kg (maintaining an internal temperature of 25° or less). Weight % assay by 1H NMR showed the solution to contain 187 g product (90%, 12.5 wt % solution in toluene/THF). Typically, the material was greater than 95% pure, with only traces of the starting material and monomethyl intermediate. The solution may be further concentrated to 1.0 Kg, giving a 18 wt % solution in toluene, allowing for an easier assay. However, the presence of a small amount of THF increases the stability of the compound. The material was stored under nitrogen in a sealed carboy at 0° C. 1H NMR Cp2Ti(CH3)2: δ6.05 (s, 10H), −0.05 (s, 6H). Cp2TiCl(CH3): δ6.22 (s, 10H), 0.80 (s, 3H). Cp2TiCl2: δ6.56 (s, 10H). 13C NMR Cp2Ti(CH3)2: δ113.20 (Cp2), 45.77 ((CH3)2). Cp2TiClCH3: δ115.86 (Cp2), 50.37 (CH3). Cp2TiCl2: δ120.18.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:8]([CH:9]=1)[O:10][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Temperature: 70 °C

Procedure:
A flask was charged with 5-nitro-2-pentafluoroethyl-phenol (3.67 g, 14.2 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (9.71 g, 57.1 mmol), K2CO3 (7.9 g, 57.1 mmol), and acetone (20 mL). The reaction was heated at 70° C. for 3 days. The acetone evaporated from the reaction. No reaction was observed, so the organic material was recovered by extraction of water with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. This crude mixture was dissolved in DMF (20 mL), combined with K2CO3 (5.9 g, 42.1 mmol) and heated to 70° C. for 24 h. The reaction mixture was cooled to RT, taken up in EtOAc and washed with 2 N NaOH, and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The aqueous layer was acidified, extracted with EtOAc and dried with MgSO4, filtered, concentrated in vacuo and combined with the other portion. The title compound was purified by column chromatography using 0-10% MeOH in CH2Cl2.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:2]1([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([Cl:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 263, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 7.80 (d, 2H), 7.40-7.20 (m, 6H), 6.90-6.80 (m, 6H), 5.30 (dd, 2H), 4.90 (d, 1H), 3.75 (m, 1H), 3.20 (m, 1H), 3.00-2.80 (m, 5H). MS (EI) for C28H25ClFN5O3 found 534 (MH+).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:23]2[C:28]([C:29]=1[CH:14]=[O:15])=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
A mixture of POCl3 (0.79 ml) and N-methylformanilide (1.07 ml) was stirred at 22° C. for 10 min. To the solid formed was added a solution of 5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (2.00 g from Example 15) in 1,2-dichloroethane (25 ml) and the solution was stirred at reflux temperature for 5 h. The solution was poured into a solution of ice-cold water (40 ml) containing sodium acetate (4.6 g) and stirring was continued at 22° for 2 h. The layers were separated, the aqueous layer extracted with dichloromethane, the combined extracts were dried, evaporated and the residue was chromatographed on silica using n-heptane/AcOEt (10:1) to give 5-fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid. MS: 376.4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(Cc1cncc(Br)c1)S(=O)(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-((5-bromopyridin-3-yl)methyl)ethanesulfonamide (1.8 g, 5.55 mmol) and triethylamine (1.683 g, 16.64 mmol) in DCM (20 mL) at 0° C. is added ethanesulfonyl chloride (1.426 g, 11.09 mmol), and the mixture is stirred at 0° C. for 1 h. Silica gel (10 g) is added and the mixture is concentrated in vacuo. The residue is purified by silica chromatography eluting with 0 to 2% MeOH-DCM to give N-((5-bromopyridin-3-yl)methyl)-N-(ethylsulfonyl)ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.3 Hz, 6H), 3.48 (q, J=7.3 Hz, 4H), 4.92 (s, 2H), 8.0 (t, J=2.1 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[CH:14]2.Cl>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([CH3:20])=[CH:14]3)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc2cc(N)ccc2[nH]1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2cc(Nc3nc(Cl)ncc3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (1 mmol) and 5-amino-2-methylindole (1.5 mmol) were dissolved in 3 ml CH3OH and 9 ml H2O. After the reaction mixture was stirred at room temperature for 1 h, it was diluted with H2O, acidified with 2N HCl, and sonicated. The reaction mixture was then filtered, washed with H2O and dried to give N-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1H-indol-5-amine in a yield of 78%.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:15][NH2:16]>ClCCl>[OH:14][C:8]1[CH:7]=[CH:6][C:5]([S:2](=[O:4])(=[O:3])[NH:16][CH3:15])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 63 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 120 ml dichloromethane at RT was added dropwise 317 mmol methylamine (8 M solution in ethanol) and the mixture was allowed to stir at RT for 1 h. The mixture was then concentrated in vacuo. The residue was suspended in 1 M aq NaOH solution and extracted twice with ether. The aqueous phase was acidified with 5 M aq HCl, saturated with NaCl, and extracted 3 times with THF. The combined THF extracts were washed twice with saturated aqueous NaCl solution and dried with Na2SO4. Evaporation in vacuo yielded the title compound. MS (m/e): 249.0 (M+NH4+, 100%), 231.9 (M+H+, 63%)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:8][CH:14]=1
Reactant: Cc1ccc(C(N)=O)s1
Reactant: O=C(CCl)CCl
Product: Cc1ccc(-c2nc(CCl)co2)s1
Yield: 46 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-methyl-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole. The yield was 46%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: [C:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:19]1CCC[CH2:20]1.C([Li])CCC.CN(C)C=O>C(Cl)Cl>[F:18][C:13]1[C:12]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:20]=[O:19]
Reactant: CCCCCCCCCC#Cc1ccccc1F
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
To a solution of 2-(1-undecynyl)fluorobenzene (7.00 g) and tetrahydrofuran (70 ml) was added slowly n-butyllithium (1.6M, 17.8 ml) at -78° C. The reaction mixture was stirred at -78° C. for 1.5 hrs. Dimethylformamide (2.28 ml) was added slowly, and the solution was allowed to warm to room temperature over 1 hr, with stirring. Methylene chloride (300 ml) was added, and the solution was washed with 50% hydrochloric acid. The aqueous phase was extracted with methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica (250 g), eluting with hexane followed by ethyl acetate/hexane (1:4). The appropriate fractions were collected and evaporated to provide 3.53 g (45.2%) of product as an oil.
Reaction SMILES: [C:1]([CH:5]1CC2O[CH:6]1C=C2)(OC)=[O:2].[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(Cl)Cl.Cl>O>[CH2:12]([NH:30][C:1](=[O:2])[CH:5]=[CH2:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)C1CC2C=CC1O2
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution and 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added to 134.8 parts stearylamine. The reaction medium is heated to 60° C. and stirred for 15 hours at this temperature. 300 parts of chloroform are next added and the mixture neutralised with 4 parts concentrated hydrochloric acid. 100 parts of water are added, the organic phase is separated off, and the aqueous phase extracted with 50 parts chloroform. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. under a vacuum of 20 Torr. The residue is heated in a vacuum to 110° to 120° C. (bath temperature 140° C.). At the conclusion of the furane separation, the sedimentation temperature increases to 140° C. The mixture is cooled down, the product is dissolved in hot acetone, filtered, and allowed to recrystallise. 117 parts N-stearylacrylamide having a melting point of 75° to 77° C. are obtained.