Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([Cl:27])[CH:18]=4)[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN1CCCC1=O>CO>[Cl:27][C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH:5]=[CH:4][N:3]=[C:2]4[NH:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:16]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(NCCC(=O)OC(C)(C)C)nccc34)no2)cc1Cl
Temperature: 180 °C
Yield: 14.9 %

Procedure:
1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 200 mg, 0.5 mmol), di-isopropylethylamine (0.873 ml, 1.0 mmol) and 1,1-dimethylethyl β-alaninate (726 mg, 5 mmol; available e.g. from Novabiochem) were placed into a 20 ml microwave vial, and N-methyl-2-pyrrolidinone (NMP, 8 ml) was added. The mixture was heated under microwave irradiation at 180° C. for one hour, diluted with methanol and chromatographed over an SCX cation exchange column (Biotage), which was washed with methanol and dichloromethane and eluted with methanolic ammonia. Washings and eluate from the SCX column were re-combined and evaporated in vacuo until only NMP remained. Water (20 ml) was added to the reaction mixture and a solid precipitate formed. The precipitate was collected by filtration and azeotroped twice with toluene. The solid was dissolved in dichloromethane (5 ml) and chromatographed on a silica column, eluting with dichloromethane to yield the title compound (38 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH2:18])[N:6]=1)[CH:2]=[CH2:3].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C.O>C(#N)C>[C:19]([NH:18][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCNc1nc(N)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCNc1nc(NC(C)=O)nc2ccc([N+](=O)[O-])cc12
Yield: 80.7 %

Procedure:
After 100 mg (0.41 mmol) of 4-allylamino-2-amino-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, 84 mg (0.82 mmol) of acetic anhydride and 0.06 ml (0.45 mmol) of triethylamine were added thereto, and then the reaction mixture was subjected to heating under reflux overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing successively with a saturated aqueous sodium hydrogen carbonate solution and brine and drying over anhydrous sodium sulfate. The solvent was distilled off, followed by recrystallization from ethyl acetate-hexane to give 95 mg (80.7%) of the title compound.
Reaction SMILES: [N+](=[CH:3]P(=O)(OC)OC)=[N-].CC(C)([O-])C.[K+].[CH:16]1([O:21][C:22]2[CH:23]=[C:24]([C:30]3([CH:40]=O)[CH2:35][CH2:34][C:33]4([O:39][CH2:38][CH2:37][O:36]4)[CH2:32][CH2:31]3)[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[CH:16]1([O:21][C:22]2[CH:23]=[C:24]([C:30]3([C:40]#[CH:3])[CH2:31][CH2:32][C:33]4([O:36][CH2:37][CH2:38][O:39]4)[CH2:34][CH2:35]3)[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(C2(C=O)CCC3(CC2)OCCO3)cc1OC1CCCC1
Reactant: COP(=O)(C=[N+]=[N-])OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl (diazomethyl)phosphonate (0.516 g, 3.44 mmole, prepared as in Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem 1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (10 mL) was added via cannulation to a solution of potassium t-butoxide (0.386 g, 3.4 mmol) dissolved in dry tetrahydrofuran (10 mL) at -78° C. under an argon atmosphere. To this was added rapidly a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-formylcyclohexane (0.62 g, 1.72 mmol) in dry tetrahydrofuran (10 mL). After 2 h, the reaction was warmed to room temperature, water was added and the mixture was extracted three times with ethyl acetate. The combined organic extract was washed with brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate provided a white solid. mp 53.5°-55° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][C:56]1[C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=[CH:58][N:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:55][C:56]1[C:61]([C:62]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:63])=[CH:60][CH:59]=[CH:58][N:57]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 2-methyl-3-pyridinecarboxylic acid (46.6 mg, 0.340 mmol) and DIPEA (0.178 ml, 1.019 mmol). The reaction mixture was stirred for 2 hours at room temperature.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17][C:18]([F:27])([F:26])C1C=CC(N)=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:18]([F:27])([F:26])[F:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1O

Procedure:
The title compound was prepared following the procedure described in Step 1 for the synthesis of 2a using 4-trifluoromethylaniline instead of aniline. 1H NMR (DMSO-d6) δ (ppm): 1.26 (3H, t, J=7.14 Hz), 4.22 (2H, q, J=7.14 Hz), 7.80 (1H, d, J=9.34 Hz), 8.00 (m), 8.39 (1H, s), 8.64 (1H, s). m/z 286.5 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH:10]([C:12]#[N:13])[CH2:11][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:15][OH:16]>N1C=CC=CC=1.ClCCl.O>[OH:16][N:15]=[CH:2][CH2:1][C:4]1[C:9]2[CH:10]([C:12]#[N:13])[CH2:11][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: CC(=O)c1cccc2c1C(C#N)C2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC1Cc2cccc(CC=NO)c21

Procedure:
10.07 g of the product of Step 1 and 6.13 g of hydroxylamine hydrochloride in 200 ml of pyridine are stirred at ambient temperature for 19 hours. After removal of the pyridine by evaporation, the yellow oil obtained is taken up in dichloromethane and water. The organic phase is removed, dried and concentrated, allowing the expected product to be isolated.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[C:17]1([CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: c1ccc(C2CCCN2)cc1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Product: CCCC[C@@H](C(=O)N1CCCC1c1ccccc1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid A-5 and commercially available 2-phenyl-pyrrolidine B-5 according to General Procedure B.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:30][S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:42][CH:41]=2)=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)cc1
Reaction time: 8 h
Yield: 40.5 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 4-(methylsulfonyl)benzoic acid (16.09 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.016 g, 39%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.59 (t, 1H), 8.11-8.18 (m, 2H), 8.00-8.07 (m, 2H), 7.63 (t, 1H), 7.47-7.53 (m, 1H), 7.41-7.45 (m, 1H), 7.36-7.41 (m, 2H), 4.70 (d, 2H), 3.16 (s, 3H). LCMS m/z 494.9 (M+1).
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19](O)[C:16]=1[CH:17]=[O:18]>CC(C)=O>[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:6][CH3:7])[C:16]=1[CH:17]=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(C)c(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C)cc(C)c1C=O
Reaction time: 48 h
Yield: 88.5 %

Procedure:
Dimethylsulfate (16.4 g; 130 mmole) and potassium carbonate (20.7 g; 150 mmole) were added to a solution of 2,4-dimethyl-6-hydroxybenzaldehyde (20.0 g; 130 mmole) in acetone (200 ml). The mixture was heated under reflux with stirring for 48 hours and then evaporated to dryness. The residue was dissolved in dichloromethane and washed successively with water, aqueous sodium hydroxide (1M) and water, and then was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2,4-dimethyl-6-methoxybenzaldehyde (18.9 g; 89.0%). The product was obtained as a brown oil and was characterized by its proton magnetic resonance spectrum, the details of which are recorded in Table 2 below.
Reaction SMILES: CN([CH2:4][CH:5]([CH:15]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH3:35])[C:16](=[CH2:27])[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:7])C.IC.C(N(C(C)C)CC)(C)C.[OH-].[K+]>C(#N)C>[F:34][C:30]1[C:29]([CH3:35])=[C:28]([CH:15]([C:16](=[CH2:27])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:18])[C:5](=[CH2:4])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[O:7])[CH:33]=[CH:32][CH:31]=1
Reactant: C=C(C(=O)c1cccc(OC)c1)C(c1cccc(F)c1C)C(CN(C)C)C(=O)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: C=C(C(=O)c1cccc(OC)c1)C(C(=C)C(=O)c1ccccc1F)c1cccc(F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of crude 2-((dimethylamino)methyl)-3-(3-fluoro-2-methylphenyl)-1-(2-fluorophenyl)-5-(3-methoxyphenyl)-4-methylenepentane-1,5-dione (7.5 g, 15.7 mmol) in acetonitrile (60 mL) was added iodomethane (11.7 mL, 187 mmol) and diisopropylethylamine (5.4 mL, 31.3 mmol). The mixture was stirred at room temperature for 2 h, during which time a precipitate formed. To this heterogeneous mixture was added 2 M KOH (26 mL, 52 mmol), and the resulting mixture was refluxed for 6 h and then allowed to stand for 48 h. The mixture was partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted twice with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated to dryness. The residue was purified over silica gel using 30% EtOAc/hexanes to give 3-(3-fluoro-2-methylphenyl)-1-(2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dimethylenepentane-1,5-dione (3.2 g, 47% yield), (characterized by LCMS and 1H NMR), LRMS (M+H+) m/z=433.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C@@H:4]([C:5]#[C:6][C:7](C(O)=O)=[O:8])[C@H:3]1[C:12]([O:14][C@H:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13].[C:32]([OH:37])([CH2:35][CH3:36])([CH3:34])[CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[C@@H:4]([C:5]#[C:6][C:7]([O:37][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:8])[C@H:3]1[C:12]([O:14][C@H:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]
Reactant: CCC(C)(C)O
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
82 mg of 4-dimethylamino-pyridine were added with stirring at 5° C. to a mixture of 2.5 g of (S)α-cyano-3-phenoxybenzyl(1R,cis)2,2-dimethyl-3-[2-carboxycarbonylethynyl]-cyclopropane-carboxylate, 12.5 ml of methylene chloride and 2.5 ml of tert.-amyl alcohol followed by the addition of 1.55 g of dicyclohexylcarbodiimide. The mixture was stirred at 20° C. for 41/2 hours and was cooled to 0° C. and filtered. The filtrate was evaporated to dryness under reduced pressure and was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.35 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-tert.-amyloxycarbonyl-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH:12]1[C:17]([C:18]([CH2:20]Br)=[O:19])=[CH:16][CH:15]=[C:14]([Br:22])[CH:13]=1.CCOC(C)=O>C(O)C.O>[Br:22][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:19])[CH2:20][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cccc(SCC(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
10.09 g (70.5 mmol) 3-mercaptoanisole were added to a freshly prepared solution of 4.6 g (70.5 mmol) KOH in 75 ml ethanol and 30 ml water. Over a period of 30 min, 20.0 g (70.5 mmol) 2,4-dibromoacetophenone in 150 EtOAc were added at 0° C. and the solution was stirred at RT over night. The suspension was concentrated and dissolved in EtOAc and water. The inorganic phase was extracted with EtOAC, the combined organic phases were washed with water and brine and dried over Na2SO4. Evaporation yielded 25.1 g (quant) 1-(4-Bromo-phenyl)-2-(3-methoxy-phenylsulfanyl)-ethanone as white crystalline, MS: 336 (M, 1Br). (In analogy to Jones, Charles D.; Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.; Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity. J. Med. Chem. (1984), 27(8), 1057–66.)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:24][OH:25]>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=[N:24][OH:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NO
Reactant: Cc1nonc1C(=O)Nc1cccc(C#N)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1nonc1C(=NO)Nc1cccc(C#N)c1
Yield: 10.8 %

Procedure:
N-(3-Cyanophenyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (25 mg, 0.11 mmol) was suspended in benzene (2 mL) under an atmosphere of nitrogen. Phosphorus pentachloride (25 mg, 0.12 mmol) was added and the solution was heated at reflux for 2.5 hrs. The reaction was then evaporated to dryness. The crude was dissolved in EtOH (1.6 mL) and hydroxylamine (200 μL, 3 mmol, 50% solution in water) was added to the reaction. The crude was purified by preparative LCMS to afford the desired product (2.9 mg). MF═C11H9N5O2; LCMS calculated for C11H9N5O2 (M+H)+: m/z=244.1.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.[H-].[Na+].[Br:34]Br.Cl>CN(C)C=O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:11]([C:17]([NH:18][CH:19]([CH:21]3[CH2:23][CH2:22]3)[CH3:20])=[O:24])=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=2[Br:34])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reactant: BrBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reaction time: 0.42 h
Yield: 72.4 %

Procedure:
A mixed solution comprising 0.24 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide and 5 ml of dimethylformamide was cooled with ice, 46 mg of 60% sodium hydride was added, and the temperature was returned to room temperature, followed by stirring for 25 minutes. The reaction liquid was cooled with ice again, and a mixed solution comprising 0.15 g of bromine and 1 ml of dimethylformamide was dropwise added over a period of 1 minute, followed by reaction at room temperature for 2 hours and 45 minutes. After completion of the reaction, the reaction liquid was slowly added to 60 ml of diluted hydrochloric acid. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 0/1) to obtain 0.20 g of the desired product (melting point: 244 to 247° C.) in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([F:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CC(O)C>[F:11][C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH2:10][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1F
Solvent: CC(C)O
Product: COc1cc(CCN2CCOCC2)c(F)cc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 64.1 %

Procedure:
To 5-ethenyl-4-fluoro-2-nitrophenyl methyl ether (0.43 g, 2.2 mmol) in 10 mL of iPrOH was added, morpholine (0.56 g, 6.54 mmol). The mixture was heated to 180° C. 1.5 h in the microwave. The solvent was rotovaped down and the residue purified by flash chromatography to give the title compound of step A (0.4 g, 1.41 mmol, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 7.62 (d, J=8.80 Hz, 1H), 6.99 (d, J=6.23 Hz, 1H), 3.94 (s, 3H), 3.70-3.75 (m, 4H), 2.87 (t, J=7.33 Hz, 2H), 2.58-2.66 (m, 2H), 2.49-2.56 (m, 4H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl.O>C(O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: COC(=O)Cc1cccc(NS(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Methyl 3-(methanesulfonylamino)phenylacetate (3.36 g, 13.8 mmol) was dissolved in ethanol (16 mL) and 1N NaOH (30 mL) added. The reaction was stirred for 1 hour, then 1N HCl (50 mL) and water (50 mL) were added. The product was extracted into ethyl acetate (3×50 mL) and the combined extracts were washed with water and brine and dried (MgSO4). Removal of solvent afforded 3-(methanesulfonylamino)phenylacetic acid (2.90 g, 92%). 1H NMR (DMSO-6) δ 12.32 (1H, br), 9.69 (1H, br), 7.26 (1H, dd), 7.10 (2H, m), 7.00 (1H, d), 6.57 (1H, s), 3.54 (2H, s), 2.97 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:34]([N:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:45]([CH:43]2[CH2:44][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]2)=[O:46])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCN(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)-2-oxoethyl]carbamoyl}-azetidine-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one (Step 3) (220 mg, 0.46 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (100 mg, 0.50 mmol) (Peptech), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (275 mg, 0.925 mmol), HOAT (64 mg, 0.470 mmol), and DMF (7 mL). The compound was isolated (294 mg). MS (ESI, pos. ion) m/z: 674 (M+H), (ESI, neg. ion) m/z: 672 (M−H). Calc'd for C33H44ClN5O6S: 674.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([Cl:33])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[C:25]([Cl:33])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: FC(F)(F)c1ccc(Br)cc1Cl
Product: O=C1N(c2ccc(C(F)(F)F)c(Cl)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 4-bromo-2-chloro-1-trifluoromethyl-benzene. Off-white solid. MS (ESI): 507.1 (MH+).