Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1cc(Cl)ccc1C(=O)O
Reaction time: 2 h
Yield: 78 %

Procedure:
2-Amino-4-chloro-benzoic acid (515 mg, 3.0 mmol) was suspended in dry THF (5 ml) and phenylisocyanate (429 mg, 3.6 mmol) was added. Triethylamine (303 mg, 3.0 mmol) was added and the mixture was stirred for 2 hours. The mixture was diluted with 75 ml ethyl acetate and extracted into 150 ml 1 M aqueous NaOH, and washed once with 50 ml ethyl acetate. The aqueous phase was then acidified with 4 M aqueous HCl and the product extracted with 2×100 ml ethyl acetate. The organic solvent was dried (Na2SO4) and reduced under vacuum, and the product recrystallised from acetone/water to yield 680 mg (78%) of off-white crystals (m.p. 186-188° C.).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([O:16]CC)=O)[CH:8]=2)[NH:3]1.O.[NH2:20][NH2:21]>C(O)C>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([NH:20][NH2:21])=[O:16])[CH:8]=2)[NH:3]1
Reactant: CCOC(=O)COc1ccc2c(c1)CCC(=O)N2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetate (0.4 g, 1.7 mmol) in ethanol (10 mL), hydrazine hydrate (0.9 g, 17 mmol) was added and the reaction was heated at 80° C. for two hours. The solid which formed was filtered and dried. 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetohydrazide was obtained as a white solid (0.25 g, 66%) and was used in the next step without further purification. 1H NMR: 400 MHZ, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.83 (t, J=8.40 Hz, 2H), 4.31 (d, J=4.00 Hz, 2H), 4.41 (s, 1H), 6.76 (d, J=2.00 Hz, 2H), 6.82 (s, 1H), 9.26 (s, 1H), 9.91 (s, 1H). LCMS: RT 0.607 min. LCMS (ES-API), m/z 236.2 (M+H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 20 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 71 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 87%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 55 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:30])[CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (104 mg, 0.27 mmol) in THF (2.7 mL) was cooled to 0° C. and treated with methyl iodide (0.084 mL, 1.35 mmol) and NaHMDS (0.41 mL, 1 M solution in THF, 0.41 mmol). After stirring for 16 h at room temperature, additional methyl iodide (0.042 mL, 0.77 mmol) was added and the mixture was warmed to 35° C. for 6 hours. The reaction was quenched with saturated NH4Cl solution (2 mL), diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, sat'd aq sodium chloride, dried over MgSO4 and concentrated. Purification by column chromatography (5-40% ethyl acetate in heptane) gave ethyl 2-(tert-butoxycarbonyl(methyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (59 mg, 55%). Rf 0.34 (20% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 4.72-4.68, 4.43-4.38 (m, 1H, rotamers), 4.15 (q, J=7.3 Hz, 2H), 2.81, 2.77 (s, 3H, rotamers), 1.87-1.61 (m, 2H), 1.53-1.23 (m, 28H), 0.78 (t, J=7.3 Hz, 2H). ESI MS found for C20H38B1N1O6 m/z [400.5 (M+1)].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:32])[CH2:20][NH:21][C:22]([CH3:31])([CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[CH3:23])=[CH:15][C:10]=1[NH:11]C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O>[NH2:11][C:10]1[CH:15]=[C:16]([CH:19]([OH:32])[CH2:20][NH:21][C:22]([CH3:23])([CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[CH3:31])[CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(C(O)CNC(C)(C)CCn2ccnc2)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CCn1ccnc1)NCC(O)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
A mixture of 15 gm of 2'-benzyloxy-5'-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-acetanilide (m.p. of the dioxalate 160°-163° C.), 18.5 gm of KOH, 80 ml of alcohol and 15 ml of water was refluxed for 24 hours, and the resulting 1-(3-amino-4-benzyloxy-phenyl)-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethanol was isolated as the trioxalate (m.p. 95°-100° C.). Aqueous ammonia was used to liberate the base which was reacted with potassium cyanate to form 1-{2'-benzyloxy-5'-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-phenyl}-urea (m.p. 142°-143° C.). Catalytic hydrogenation of 5.1 gm of this compound in 100 ml of methanol with palladium charcoal as the catalyst yielded 3.5 gm of 1-{2'-hydroxy-5'-[1-hydroxy-2-]-4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-phenyl]-phenyl}-urea, whose sulfate of the formula ##STR76## had a melting point of 243°-244° C. The yield was 70% of theory.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24]C(=O)C)[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[O:28]C(=O)C(C)(C)C)[CH2:6]1)(=O)C.[OH-].[K+].C(O)(=O)C>C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[OH:28])[CH2:6]1
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@]12O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@]1(O)CC[C@@H]2O
Temperature: 70 °C

Procedure:
A mixture of 30 mg of 3β ,19-diacetoxy-14β-hydroxy-17β-pivaloxy-5α-androstane and 3.0 ml of 0.2 N methanolic potassium hydroxide was heated at 70° C. for 16 hours under nitrogen whereupon the mixture was neutralized with 0.2 N glacial acetic acid in ethyl acetate and evaporated to dryness at reduced pressure. The residue obtained was treated with ethyl acetate and filtered through diatomaceous earth. Evaporation of the filtrate yielded 3β ,14β ,17β ,19-tetrahydroxy-5α-androstane as indicated by tlc analysis.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11]=O.[C:13](#[N:17])[CH2:14][C:15]#[N:16].[OH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[NH2:16][C:15]1[O:18][CH:19]2[C:20]3[C:24](=[CH:25][CH:26]=[C:27]2[CH:11]([C:2]2[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=2)[C:14]=1[C:13]#[N:17])[N:23]=[CH:22][CH:21]=3
Reactant: N#CCC#N
Reactant: O=Cc1cnc2ccccc2n1
Reactant: Oc1cccc2[nH]ccc12
Product: N#CC1=C(N)OC2C3=CC=NC3=CC=C2C1c1cnc2ccccc2n1
Yield: 79 %

Procedure:
The title compound was prepared from quinoxaline-2-carbaldehyde, malononitrile and 4-hydroxyindole by a procedure similar to Example 57 in 79% yield. 1H-NMR (Acetone-d6): 10.54 (brs, 1H), 8.86 (s, 1H), 8.07 (m, 2H), 7.86 (m, 3H), 7.39 (t, J=2.74, 5.49 Hz, 1H), 7.17 (dd, J=8.51, 0.82 Hz, 1H), 6.81 (dd, J=8.51 Hz, 1H), 6.61 (m, 1H), 6.51 (s, 2H), 5.25 (s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH:28]=O)[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].C([O:33]C1C=CC=CC=1NCCN)(C)C>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:33])[CH:19]=[CH:20][CH:21]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccccc1CCCNCc1cccc(C2CCCCN2C=O)c1
Reactant: CC(C)Oc1ccccc1NCCN
Product: CC(C)Oc1ccccc1CCCNCc1cccc(C(=O)N2CCCCC2)c1

Procedure:
(3-{[3-(2-Isopropoxy-phenyl)-propylamino]-methyl}-phenyl)-piperidin methanone. The title compound was prepared as in Example 1, steps D and E, substituting 3-(2-isopropoxy-phenyl)-propylamine for N1-(2-isopropoxy-phenyl) -ethane-1,2-diamine in step E. MS (ESI): mass calculated for C25H34N2O2, 394.26; m/z found, 395.3 [M+H]+, 417.3 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.38-7.32 (m, 3H), 7.27-7.24 (m, 1H), 7.15-7.10 (m, 2H), 6.86-6.82 (m, 2H), 4.53 (hept, J=6.1 Hz, 1H), 3.81 (s, 2H), 3.70 (br s, 2H), 3.32 (br s, 2H), 2.68-2.62 (m, 4H), 1.85-1.77 (m, 2H), 1.67 (br s, 4H), 1.50 (br s, 2H), 1.32 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[OH:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>C1COCC1>[CH3:18][C:17]1[C:10]2[O:9][CH2:2][CH:12]([OH:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(C=O)c1O
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1OCC2O

Procedure:
Under a nitrogen atmosphere 0.945 g (7.35 mmol) trimethylsulphoxonium chloride were placed in 20 mL THF, and 0.300 g (7.50 mmol) sodium hydride (55%, suspension in mineral oil) were added batchwise. The reaction mixture was refluxed for 2 h. Then 1.00 g (7.35 mmol) 2-hydroxy-3-methylbenzaldehyde in 20 mL THF were added dropwise to the reaction mixture and it was refluxed overnight. Then PE was added and the suspension obtained was filtered. The filtrate was evaporated down i. vac. and purified by flash chromatography. The fractions containing the product were combined and evaporated down.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([Cl:11])=[N:8]2)=[C:4]([Cl:12])[N:3]=1.[CH3:13][C:14]1([CH3:24])[O:21][C:20](=[O:22])[C:17]2([CH2:19][CH2:18]2)[C:16](=[O:23])[O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Cl:11])[N:8]2[CH2:19][CH2:18][CH:17]2[C:16](=[O:23])[O:15][C:14]([CH3:24])([CH3:13])[O:21][C:20]2=[O:22])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]c(Cl)nc2n1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(CCn2c(Cl)nc3c(Cl)nc(N)nc32)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
A mixture of 2-amino-6,8-dichloropurine (2.04 g), 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (1.73 g) and anhydrous potassium carbonate (2.12 g) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 18 hours under dry nitrogen. The solvent was evaporated and the residue dissolved in water (60 ml) and acidified from pH 10 to pH 4 with dilute hydrochloric acid. The yellow precipitate was filtered off, washed with water and dried to give 2-amino-6,8-dichloro-9-[1-(2,2-dimethyl-1,3-dioxane4,6-dione-5-yl)eth-2-yl]purine (2.2 g, 50%). T.1.c. r.f. 0.65 (25% methanol-dichloromethane).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][C@@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH2:8][NH:9][CH3:10].C[CH2:39][N:40](C(C)C)[CH:41](C)C.CNC>C(Cl)Cl.C1COCC1>[CH3:10][N:9]([CH2:8][C@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH3:6])[C:3](=[O:4])[CH2:2][N:40]([CH3:41])[CH3:39]
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)CCl
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN(C)C(=O)CN(C)C)c34)cc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Chloroacetyl chloride (33 μl, 0.42 mmol) was added drop wise to a solution of 5-[(1R)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (172 mg, 0.40 mmol, obtained as described in Example 103, preparation of starting materials)) and DIPEA (139 μl, 0.8 mmol) in DCM (2 ml). The mixture was stirred at room temperature for 1 hour. THF (5 ml) was added to the solution and dimethylamine was bubbled in the reaction mixture. After 30 minutes, the solvents were evaporated under vacuum. The mixture was diluted with DCM, washed with water and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 4% 7N ammonia-methanol in DCM) to give the title compound (85 mg, 41%) as a pale solid; NMR spectrum (CDCl3) 1.53 (d, 3H), 2.28 (s, 6H), 2.30 (s, 3H), 2.53 (s, 3H), 3.15-3.05 (m, 5H), 3.54 (dd, 1H), 3.95 (dd, 1H), 5.10 (m, 1H), 6.91 (d, 1H), 7.12 (m, 3H), 7.46 (d, 1H), 7.55 (d, 1H), 7.64 (m, 1H), 7.72 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H); Mass spectrum: MH+ 515.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][C:27]2[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[CH3:32][C:30]1[CH:31]=[C:27]([CH2:26][O:25][CH:23]2[CH2:22][NH:21][CH2:24]2)[S:28][CH:29]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1csc(COC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Solvent: ClCCl
Solvent: CCO
Product: Cc1csc(COC2CNC2)c1
Product: Cl
Reaction time: 3 h

Procedure:
1-Chloroethyl chloroformate (50.0 μL, 0.4 mmol) was added to a solution of 1-benzhydryl-3-(4-methylthiophen-2-ylmethoxy)-azetidine (150.0 mg, 0.4 mmol) in dichloromethane (4.5 mL) at 0° C. The reaction mixture was stirred 3 hours, then 30 minutes at room temperature. Ethanol (6 mL) was added and the reaction mixture was stirred at 35° C. for an additional 4 hours. After concentration to dryness, the crude was triturated in pentane (2×10 mL) to give a yellow solid (94.0 mg, quantitative) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[SH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12](O)=[O:13].[CH2:19]=O.O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[C:12](=[O:13])[CH:11]([CH2:15][C:16]([OH:18])=[O:17])[S:10][CH2:19]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C=O
Reactant: O=C(O)CC(S)C(=O)O
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)CC1SCN(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
3,4-Dichloroaniline (16.2 g, 0.1 mol) and mercaptosuccinic acid (15 g) were dissolved in xylene (200 ml). While stirring, 37% formalin (8.5 ml) was added followed by heating to reflux. The water formed (9 ml) during this reaction was removed azeotropically. The reaction mixture was filtered hot, befored removing the solvent, to leave an oil, 3-(3,4-dichlorophenyl)-4-oxo-5-thiazolidineacetic acid, which solidified. This crude product was esterified in isopropyl alcohol (500 ml) and concentrated sulfuric acid (3 ml). Removal of the solvent left a crude product which was taken up in methylene chloride, washed with water, dried and evaporated. Recrystallization of the product from toluene/ligroin gave 1-methylethyl 3-(3,4-dichlorophenyl)-4-oxo-5-thiazolidineacetate which had a melting point of 54°-56° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>CN(C)C=O>[ClH:21].[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][CH2:22][N:9]1[N:10]=[C:11]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[C:12]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:13]1
Reactant: CN(C)CCCCl
Reactant: CCCCOC(=O)c1nnn(-c2ccc(Br)cc2)c1N
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nn(CCCN(C)C)nc1Nc1ccc(Br)cc1
Product: Cl

Procedure:
A mixture consisting of 8.5 gm (0.025 mol) of n-butyl 1-(4-bromophenyl)-5-amino-1H-1,2,3-triazole-4-carboxylate, 100 ml of absolute dimethylformamide and 9.1 gm (0.075 mol) of 1-chloro-3-(N,N-dimethylamino)-propane was reacted and worked up as in Example 1. 1.5. gm of the desired compound were obtained, corresponding to 13% of theory, with a melting point of 158° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1C=C(OC)[C:8]([CH3:13])=[CH:7][C:6]=1[NH:14][CH3:15])=[O:4].[C:16]([O:19][C:20](=O)[CH3:21])(=O)C.[CH:23](O)=[O:24].[OH-].[Na+]>O>[Cl:1][CH2:2][C:3]([C:5]1[CH:21]=[C:20]([O:19][CH3:16])[C:8]([CH3:13])=[CH:7][C:6]=1[N:14]([CH3:15])[CH:23]=[O:24])=[O:4]
Reactant: CNc1cc(C)c(OC)cc1C(=O)CCl
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)CCl)c(N(C)C=O)cc1C
Reaction time: 1 h

Procedure:
2-Chloro-5'-methoxy-4'-methyl-2'-(methylamino)acetophenone (10 g) is added at ambient temperature to a stirred mixture of acetic anhydride (23 ml) and formic acid (16 ml), previously stirred at 55° for a 1hour, and the resultant mixture is stirred for 2 hours at 20°. Water (80 ml) followed by aqueous sodium hydroxide (specific gravity 1.5, 60 ml) are added, whilst maintaining the temperature below 10°. The mixture is then extracted with dichloromethane to give a solution of 2'-(2-chloroacetyl)-4'-methoxy-5'-methyl-N-methylformanilide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])(O)[C:6](F)([F:17])[C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.C1CCN2C(=NCCC2)CC1>CCOC(C)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[C:6]([F:17])[C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2]
Reactant: CCN1N=C(Oc2ccc(C(F)(F)F)cc2)C(F)(F)C1(O)c1cccc(C#N)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)c(F)c1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-{1-ethyl-4,4-difluoro-5-hydroxy-3-[4-(trifluoromethyl)phenoxy]-4,5-dihydro-1H-pyrazol-5-yl}benzonitrile (crude, 2.1 g, 5.11 mmol), DCM (25.5 mL) and triethylsilane (2.45 mL, 15.3 mmol) was cooled to −78° C. and treated with BF3 etherate (1.94 mL, 15.3 mmol) in a single portion. The reaction was allowed to warm to rt overnight and checked via LCMS at 16 h. The reaction was treated with DBU (3.85 mL, 25.6 mmol) dropwise and checked via LCMS after 30 minutes, requisite product dominates. The reaction was diluted with EtOAc and washed with sat aq. NaHCO3 2×, brine, dried (MgSO4) and concentrated to afford an opaque brown residue purified via MPLC, 100 g silica, 5-35% EtOAc in heptanes to afford 3-{1-ethyl-4-fluoro-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}benzonitrile as a clear, colorless oil. MS: cal'd 376 (MH+), exp 376 (MH+).
Reaction SMILES: [Cl:1]C1C=CC=C(CC=CCCl)C=1.Cl[CH:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH:15]=[CH2:16].[CH2:25]([N:27]([CH2:35][CH3:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:26]>O>[Cl-:1].[Cl:24][C:20]1[CH:19]=[C:18]([CH2:17][CH:14]=[CH:15][CH2:16][N+:27]([CH2:25][CH3:26])([CH2:35][CH3:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[CH:22][CH:21]=1
Reactant: C=CC(Cl)Cc1cccc(Cl)c1
Reactant: ClCC=CCc1cccc(Cl)c1
Reactant: CCCCCCCN(CC)CC
Solvent: O
Product: CCCCCCC[N+](CC)(CC)CC=CCc1cccc(Cl)c1
Product: [Cl-]

Procedure:
Heat a mixture of 6.0 g (0.03 mole) of 1-chloro-3-(4-chloro-2-butenyl)benzene and 3-chloro-4-(3-chlorophenyl)-1-butene (in a ratio of 4:3) and 5.1 g (0.03 mole) N,N-diethylheptanamine at 100° C. for about 20 hours. Dissolve in 100 ml water and wash with 3×75 ml hexane and then extract with methylene chloride. Dry methylene chloride extract over magnesium sulfate, filter and evaporate the solvent in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30]N=[CH:28][CH:27]=1.[CH2:34](N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:34]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccncc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CN)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CNC(=O)c2ccccc2)cc1

Procedure:
The title compound is prepared by the procedure of Example 116 using 3.0 g of product from Example 99, 2.01 g of isonicotinoyl chloride hydrochloride, 3.8 of triethylamine and 100 ml of methylene chloride. The product is purified by chromatography (silica gel: 3.5% methyl alcohol/chloroform) followed by recrystallization from heptane/methanol to give 3.06 g of the desired product as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][CH:10]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:21]1([S:27]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]([Br:8])=[CH:10]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
Add triethyl amine (Et3N) (6.7 mL, 48 mmol, 4 eq) and DMAP (240 mg, 2.0 mmol, 0.1 eq) to a slurry of 3-bromo-6-nitro indole, 2 (4.82 g, 20 mmol) in 100 mL of CH2Cl2. Let the solution stir until the 3-bromo-6-nitro indole dissolves and then add benzenesulfonyl chloride (3.1 mL, 24 mmol, 1.2 eq). Let the solution stir overnight. Filter off the precipitate, which forms, wash the precipitate with CH2Cl2, and collect the filtrates to give 6.83 g of the title compound. Sequentially wash the combined filtrates with 1 M HCl, saturated sodium bicarbonate, and brine. Dry the organic layer over Na2SO4, filter, and then concentrate the filtrate. Boil the resulting solid in ˜30 mL of CH2Cl2 and a little MeOH, add 30 mL hexanes, let cool, and then filter off the precipitate to give another 1.3 g of the title compound. 1H NMR (DMSO-d6) δ 8.74 (d, 1H, J=2.2 Hz), 8.58 (s, 1H), 8.19 (dd, 1H, J=2.2, 8.8 Hz), 8.08-8.05 (m, 2H), 7.75-7.68 (m, 2H), 7.63-7.59 (m, 2H)—.