Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1Cl
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2[nH]c(C(O)C(F)(F)F)nc2cc1Cl
Temperature: 108 °C

Procedure:
4-Chloro-5-methyl-benzene-1,2-diamine (5.06 g; 32.3 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (7.11 g; 49.4 mmoles) were suspended in 6N HCl (12 mL; 72 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (9.12 g; 109 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a purple/brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](O)([C:18]([F:21])([F:20])[F:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N1C=CC=CC=1>C(OCC)C>[CH2:1]([O:8][C:9]([N:11]=[C:12]([C:18]([F:19])([F:21])[F:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)(NC(=O)OCc1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)C(=NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-hydroxypropanoate (49.0 g, 153 mmol) in diethyl ether (350 mL) was added dropwise TFAA (35.3 g, 168 mmol) at 0° C. followed by addition of pyridine dropwise (26.5 g, 336 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 6 h. The mixture was filtered and the filtrate was concentrated to afford ethyl 2-(benzyloxycarbonylimino)-3,3,3-trifluoropropanoate (45.0 g, 97% yield), which was used directly without further purification.
Reaction SMILES: [H-].[Na+].[N:3]([C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:7]1)=[N+:4]=[N-:5].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>C1COCC1.C(OCC)(=O)C>[N:3]([C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH:16]=2)[CH2:7]1)=[N+:4]=[N-:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c([C@@H]3C[C@@H](N=[N+]=[N-])c4ccccc43)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c([C@@H]3C[C@@H](N=[N+]=[N-])c4ccccc43)cn(S(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
1 g Sodium hydride (60% in mineral oil) was added to 2 g 3-((1R,3R)-3-azido-indan-1-yl)-6-methoxy-1H-indole in 50 mL dry THF at 5° C. and the reaction mixture was stirred 1 hour at 5° C. 2 g p-toluene sulfonic acid chloride was added in portions at 5° C. and stirring was continued for another 4 hours. Ice was added and after 1 hour water and ethyl acetate was added. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate, silica gel), 2.5 g 3-((1R,3R)-3-azido-indan-1-yl)-6-methoxy-1-(toluene-4-sulfonyl)-1H-indole was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(C=O)ccc1OS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 3-ethoxy-4-hydroxybenzaldehyde (3.0 g, 18.1 mmol, 1.0 equiv) and N,N-dimethylaminopyridine (2.87 g, 23.5 mmol, 1.3 equiv) in dichloromethane (10 mL) under Ar at 0° C. was added methanesulfonyl chloride (1.68 mL, 2.48 g, 21.7 mmol, 1.2 equiv). After the reaction mixture was stirred for 1 h, water (100 mL) was added, the solution extracted with dichloro-methane (3×50 mL) and the combined organic phases dried over MgSO4. Removal of the solvent by evaporation under reduced pressure provided the title compound in quantitative yield (4.8 g). 1H NMR (300 MHz, CDCl3): δ 1.42 (t, J=7.0 Hz, 3H), 3.19 (s, 3H), 4.14 (q, J=7.0 Hz, 2H), 7.41 (s, 2H), 7.45 (s, 1H), 9.89 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.53, 38.94, 64.99, 112.20, 124.38, 125.17, 136.01, 142.92, 151.63, 190.65. MS (ISP): 245.2 [M+H]+.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH3:24])[CH3:14]>>[CH2:16]([N:15]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:23][CH3:24]
Reactant: CCNCCCCCCNCC
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CN(CC)CCCCCCN(CC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-diethylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-ethyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = CH3CH2, X = (CH2)6, Z = H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH:37]=O)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([O:7]C)=[O:6].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH2:37][NH:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52])[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([OH:7])=[O:6]
Reactant: NCCCN1CCCC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield following steps 5 and 6 described above, using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 1-(3-aminopropyl)pyrrolidin-2-one as the reactant amine MS: m/e 687.5 (MH+), 1.71 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.91 (s, 3H) 0.96 (s, 3H) 1.05 (s, 3H) 1.08 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 0.85-1.91 (m, 20H) 1.96-2.20 (m, 6H) 2.44 (t, J=8.03 Hz, 2H) 2.47-2.56 (m, 1H) 2.83 (d, J=13.05 Hz, 1H) 3.07 (t, J=7.03 Hz, 2H) 3.21 (d, J=13.05 Hz, 1H) 3.43 (t, J=6.40 Hz, 2H) 3.52 (t, J=7.15 Hz, 2H) 4.62-4.66 (m, 1H) 4.75 (d, J=1.51 Hz, 1H) 5.35 (dd, J=6.02, 1.51 Hz, 1H) 7.22 (t, J=7.65 Hz, 1H) 7.64 (dd, J=9.79, 1.51 Hz, 1H) 7.75 (dd, J=7.91, 1.63 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −114.92 (s, 1 F).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1>CO>[CH3:1][O:14][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([OH:5])[CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(O)c1
Yield: 99 %

Procedure:
To methanol (300 mL) was added acetyl chloride (8.9 mL) dropwise in 10 minutes with stirring. 3-Hydroxyphenylacetic acid (25 g, 164 mmol) was added to the mixture at one time. The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated and the residue was concentrated in vacuo to afford 3-hydroxyphenyl acetic acid methyl ester (27.3 g, 99% yield) as a red oil.
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-chloroaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 72%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].O[C@@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[N:9]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O[C@H]1CC[C@H](CC2C=NC(C(F)(F)F)=CC=2)N1C(OC(C)(C)C)=O>CO.O>[F:22][C:20]([F:23])([F:21])[C:17]1[N:16]=[CH:15][C:14]([CH2:13][C@H:10]([NH:9][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][CH2:12][C:8]#[CH:1])=[CH:19][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)nc2)CC[C@H]1O
Agent: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)nc2)CC[C@@H]1O
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CCC[C@H](Cc1ccc(C(F)(F)F)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethyl 1-diazo-2-oxopropyl phosphonate (505 mg, 2627 μmol) (commercially available from TCI America Organic Chemicals Product List (Order Number D3546)), followed by K2CO3 (545 mg, 3941 μmol) was added to a diastereomeric mixture of (2R,5R)-tert-butyl 2-hydroxy-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-1-carboxylate and (2S,5R)-tert-butyl 2-hydroxy-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-1-carboxylate (455 mg, 1314 μmol) in MeOH (1.3 mL) at room temperature. The mixture was stirred at room temperature for 4 hours, diluted with H2O (15 mL), and extracted with DCM (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 10% to 30% EtOAc/hexanes) to deliver (R)-tert-butyl 1-(6-(trifluoromethyl)pyridin-3-yl)hex-5-yn-2-ylcarbamate (284 mg, 63%) as an off-white solid. LCMS (API-ES) m/z: 343.1 (M+H+).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]([CH3:36])([CH3:35])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32][OH:33])[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH:13]=1.Cl[C:38]1[CH:39]=[N:40][CH:41]=[N:42][CH:43]=1.C(O[K])(C)(C)C>CS(C)=O>[CH3:36][C:9]([CH3:35])([CH3:8])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[C@@H:30]([CH3:34])[CH2:31][CH2:32][O:33][C:38]2[CH:39]=[N:40][CH:41]=[N:42][CH:43]=2)[CH:13]=1
Reactant: C[C@@H](CCO)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Reactant: Clc1cncnc1
Agent: CC(C)(C)O[K]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: C[C@@H](CCOc1cncnc1)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 5-(3,3-dimethyl-but-1-ynyl)-3-[(3-hydroxy-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid TFA salt (100 mg, 0.239 mmol) and 5-chloro-pyrimidine (137 mg, 1.194 mmol) were dissolved in DMSO (2 mL). To this solution tBuOK (107 mg, 0.956 mmol) was added in one portion at rt. The reaction was allowed to stir at rt for 1 h and then heated to 60° C. for 1.5 h. Additional tBuOK (50 mg) and 5-chloro-pyrimidine (69 mg) were added and the reaction was run at 60° C. for another 1 h. The reaction was then heated to 100° C. for another 1 h. Additional tBuOK (50 mg) and 5-chloro-pyrimidine (69 mg) were added and the reaction was run at 100° C. overnight. The reaction was cooled to rt and quenched with a 20% (v/v) solution of acetic acid in water. The reaction was diluted with MeOH and 5-(3,3-dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[1-(S)-methyl-3-(pyrimidin-5-yloxy)-propyl]-amino}-thiophene-2-carboxylic acid (4 mg, 2.7%) was isolated by reverse phase HPLC as the TFA salt.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][O:19]C(=O)C)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].CO.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][OH:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 100 ml round bottomed flask with a magnetic stirring bar was added the compound (1d) (1.27 g, 3.40 mmol) methanol (50 ml), and powdered anhydrous potassium carbonate (14 mg, 1 mmol). The mixture was stirred for 5 hours at room temperature. The reaction mixture was then diluted with ether (200 ml) and was washed with water (2×75 ml) and brine (1×100 ml). Drying (MgSO4), filtration and removal of the solvent in vacuo. Recrystallization of the residue from boiling ethyl acetate-hexanes gave the compound (1e) as white crystals: mp 218°-220° C. 'H NMR (CDCl3) δ2.25 (s, 6H), 3.55 (s, 6H), 4.35 (br d, 1H, J=6 Hz), 4.85 (d, 2H, J=6 Hz), 5.13 (s, 1H), 5.93 (br s, 1H), 7.00-7.40 (m, 4H). Anal. Calcd. for C18H21NO5 : C, 65.24; H, 6.39; N, 4.23. Found: C, 65.44; H, 6.41; N, 4.41.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[C:12]([SH:16])[N:11]=[C:10]([O:17][CH3:18])[C:9]=2[C:19]#[N:20])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:26][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[O:26][CH:27]=[C:23]([CH2:22][S:16][C:12]3[C:13]([C:14]#[N:15])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9]([C:19]#[N:20])=[C:10]([O:17][CH3:18])[N:11]=3)[N:24]=2)=[CH:33][CH:32]=1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(O)cc2)c1C#N
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(O)cc2)c1C#N

Procedure:
64 mg (0.224 mmol) of 4-(4-hydroxyphenyl)-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 88 mg (0.269 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 57 mg (0.672 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 44 mg (41% of theory) of the target compound.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2O)=[CH:12][CH:11]=1>CC(C)=O>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[O:4][CH3:1])=[CH:12][CH:11]=1
Reactant: Oc1cccc2ccc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
Potassium carbonate (3.3 g, 23.9 mmol) and methyl iodide (1.5 ml, 23.9 mmol) were added to a solution of the product from Step D (2.7 g, 11.9 mmol) in acetone (40 ml) at room temperature and the mixture was stirred at 65° C. for 2 hours. The solids were filtered, rinsed with ethyl acetate and the filtrate was evaporated. The residue was dissolved in ethyl acetate and washed with water twice. The aqueous layers were extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate to give 7-bromo-1-methoxynaphthalene (2.5 g, 88%) after chromatography (19:1 heptane/ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J=2.1 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.7, 2.1 Hz, 1H), 7.39-7.43 (m, 2H), 6.85 (dd, J=5.4, 3.0 Hz, 1H), 3.15 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc12
Reaction time: 16 h
Yield: 55 %

Procedure:
Pd/C (300 mg) was added to a solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinolin-4-yl acetate 38 (2.11 mmol) in ethyl acetate (10 mL). Hydrogen gas was bubbled through the reaction for 10 min, and then the reaction was stirred under 1 atm. hydrogen for 16 h. The catalyst was removed by filtration through 10 g of silica. The solvents were removed in vacuo to give 39 (400 mg, 55% yield for both steps).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:21][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCN
Reactant: O=C(O)c1cccc(CCc2ccccc2)c1
Product: CCCNC(=O)c1cccc(CCc2ccccc2)c1

Procedure:
Using preparation method 1, 75C (226 mg, 1 mmol) was reacted with n-propylamine (90 μL, 65 mg, 1.1 mmol). No purification was necessary. White crystals were obtained (107 mg, 40%). NMR 1H (ppm, CDCl3): 7.96-7.89 (m, 2H), 7.56-7.12 (m, 7H), 6.03 (br. s, 1H), 3.42-3.38 (m, 2H), 3.04-2.87 (m, 4H), 1.63 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:16]C(=O)C)[C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:20])#[N:2].[OH-].[Na+]>C1COCC1.O>[F:20][C:4]1[CH:5]=[C:6]([CH:9]([OH:16])[C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cncn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Reaction time: 1 h

Procedure:
Acetic acid (4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl ester (1.26 g, 4.59 mmol) and NaOH (5.5 mL, 5.5 mmol) were dissolved in THF (15 mL) and H2O (25 mL). After 1 h, the reaction was diluted with satd. NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1.N1C=CC=CC=1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>O>[Cl:29][CH2:30][C:31]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: CS(=O)(=O)Nc1cc(N)ccc1Oc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(NC(=O)CCl)ccc1Oc1ccccc1
Yield: 75.3 %

Procedure:
To 150 ml of a dichloromethane solution containing 15.0 g of N-(5-amino-2-phenoxyphenyl)methanesulfonamide and 4.7 g of pyridine was added 6.7 g of chloroacetyl chloride under ice-cooling, followed by stirring for an hour. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate-n-hexane to give 14.4 g of N-(5-chloroacetylamino-2-phenoxyphenyl)methanesulfonamide as colorless crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:12][C:11](=[O:13])[NH:10][NH:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([O-])=[CH:18][CH:17]=1.[Na+]>CN(C=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([CH3:14])[CH2:12][C:11](=[O:13])[NH:10][NH:9]3)=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: [O-]c1ccc(F)cc1
Reactant: CC1(c2ccc(I)cc2)CC(=O)NN1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 30.2 g of 3-p-iodophenyl-3-methyl-pyrazolidin-5-one (obtainable from p-iodoacetophenone via 3-hydroxy-3-p-iodophenyl-butyric acid ethyl ester and 3-p-iodophenyl-2-butenoic acid ethyl ester) and 13.4 g of sodium p-fluorophenolate in 200 ml of DMF is warmed for 8 hours at 130°. Working up in the usual manner gives 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([O-:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:4][C:2]1[N:14]([C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N+:9]([O-:11])=[O:10])[C:6]([CH3:7])=[CH:5][CH:1]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccccc1[N+](=O)[O-]
Yield: 60.3 %

Procedure:
Acetonylacetone (2.0 g, 17.5 mmol), o-nitroaniline (2.6 g, 18.8 mmol, 1.07 eq), and p-toluenesulfonic acid monohydrate (0.31 g, 1.63 mmol) in toluene (75 mL) were heated at reflux with azeotropic removal of water overnight. The crude product was purified by column chromatography over silica gel to give 2.28 g of 2,5-dimethyl-1-(2-nitrophenyl)-1H-pyrrole, which was reduced as in Example 64 to give 0.46 g of 2-(2,5-dimethyl-1H-pyrrol-1-yl)benzenamine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:25][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OC1CCCCC1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Product: Cc1cc(O)ccc1NC(=O)c1cc(OC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 26, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and cyclohexanol (Fluka), the title compound was obtained as a yellow solid after purification by preparative HPLC.