Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([S:3][CH2:2][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[CH:5][CH:6]=1
Reactant: Clc1ccc(SCBr)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(OCSc2ccc(Cl)cc2)c1
Yield: 71 %

Procedure:
The synthesis was effected by reaction of 1-bromomethylthio-4-chlorobenzene and 3-trifluoromethylphenol in the same manner as described in preparation 3(b); yield 71%, b.p. 118°-122° C./0,01 mmHg. 1H NMR (CDCl3); δ 5.13 (CH2), 7.1-7.5 (2 x Ph), MS [70 eV 70, m/z (% rel. int)]: 318. (2,M), 159 (37), 157 (100), 145 (21) 121 (7), 108 (8), 75 (14)
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:28]=[C:29](O)[CH:30]=[CH:31][CH:32]=1>>[F:24][C:25]([F:34])([F:35])[O:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][CH:28]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Yield: 101 %

Procedure:
The title compound (D126) (110 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 3-(trifluoromethoxy)phenol (0.043 ml, 0.338 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]1[C:23]2[C:24]([OH:28])=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][O:20]1)[CH3:18]>CN(C)C=O>[CH2:17]([CH:19]1[C:23]2[C:24]([O:28][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][O:20]1)[CH3:18]
Reactant: CCC1OCc2cccc(O)c21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1OCc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Temperature: 110 °C
Yield: 112.6 %

Procedure:
In a 0.5-2.0 ml micro-wave vial 3-ethyl-1,3-dihydro-2-benzofuran-4-ol (Intermediate 106, 49.7 mg) was dissolved in N,N-dimethylformamide (1.5 ml) to give a pale yellow solution. 2-chloro-5-nitropyridine (48.0 mg, 0.303 mmol) and potassium carbonate (125 mg, 0.908 mmol) were added. The reaction vessel was sealed and heated in micro-wave Biotage Initiator at 110° C. for 1 hour. After cooling, the reaction completed. The reaction mixture was then quenched with 5 ml of water and diluted with 25 ml of Et2O. The aqueous phase was extracted with 3×10 ml of Et2O. The collected organic phases were passed through a phase separator cartridge and evaporated under vacuum to give the title compound as a pale yellow oil (97.6 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:4][C:3]1=[O:18].S(Cl)([Cl:22])(=O)=O.N>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:22])=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:4][C:3]1=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1c(=O)nc(-c2ccccc2Cl)c2ccsc21
Agent: N
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)nc(-c2ccccc2Cl)c2cc(Cl)sc21
Temperature: 50 °C
Reaction time: 7 h

Procedure:
To a solution of 450 mg of 1-methyl-4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 11 ml of chloroform is added dropwise 0.66 g of sulfuryl chloride. After stirring the reaction mixture for 7 hours at 50°C, the reaction mixture is neutralized with aqueous ammonia, then extracted with chloroform. The chloroform extracts are washed with water, dried and evaporated under reduced pressure to a residue to give crystals, which are recrystallized from ethanol-ether to give 1-methyl-4-(o-chlorophenyl)-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 164° - 166°C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)([CH3:15])[CH2:13][O:12]S1(=O)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:25]([O:27][C:28](=[O:36])[C@:29](O)([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:36])[C@:29]([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=1)([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH3:15])([CH3:34])[C:30]([F:32])([F:33])[F:31])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)n2)COS1(=O)=O
Reactant: CCOC(=O)[C@@](C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@](C)(OCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., NaH (0.508 g of a 60% dispersion in mineral oil, 12.69 mmol) was added to a solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (3.84 g, 9.76 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (2.54 g, 13.67 mmol) in DMF (10 ml, soln. predried over 4 Å mol. sieves). The reaction mixture was allowed to stir at rt for 30 min, then at 60° C. for 17 h. The reaction mixture was quenched with H2O and diluted with 1N aq. HCl and EtOAc. The phases were separated and the aq. phase was twice reextracted with EtOAc. The combined org. phases were washed with brines, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (cyclohexane: EtOAc, gradient 0-5 min 100:0, 5-30 min 90:10, 30-40 min 90:10, 40-50 min 80:20, 50-55 min 80:20) yielded the title compound (diastereomer mixture) as a clear oil. HPLC RtH4=1.39 min; ESIMS: 499, 501 [(M+H)+].
Reaction SMILES: C[O-].[Na+].[N+:4]([CH3:7])([O-:6])=[O:5].[C:8]1([CH2:14][CH:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[N+:4]([CH2:7][CH:15]([OH:16])[CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:6])=[O:5]
Reactant: C[N+](=O)[O-]
Reactant: O=CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])CC(O)Cc1ccccc1
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
Sodium methoxide (1.1 g) was added to a stirred solution of nitromethane (Aldrich, 12.2 g) in methanol (100 ml) at 0° C. and the mixture stirred for 10 minutes. A solution of phenylacetaldehyde (Aldrich, 24.0 g) in methanol (50 ml) was added dropwise over 15 minutes and the mixture stirred for 45 minutes at 0° C., then brought to room temperature over 1 hour and stirred overnight. The mixture was evaporated in vacuo and the residue taken up in water and extracted with ether. The combined extracts were washed with water and brine and evaporated in vacuo to give the desired product as a yellow oil (29.0 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][NH:29][CH2:28]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][O:33][C:31]([C:27]1([F:26])[CH2:30][N:29]([C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]2[CH:16]=[N:17][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:4]=3)=[N:14]2)[CH2:28]1)=[O:32]
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: COC(=O)C1(F)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 24 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.20 g, 1.0 eq.) was dissolved in DCM (4 mL). The reaction mixture was cooled to −60° C., at which temperature methyl 3-fluoroazetidine-3-carboxylate hydrochloride (0.09 g, 1.2 eq.) and T3P (50% in EtOAc) (0.427 g, 1.2 eq.) were added, followed by DIPEA (0.146 g, 2 eq.). The clear reaction mixture was stirred at −60° C. for 45 min and concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (20-30% ethyl acetate in hexane) to give (Z)-methyl-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylate. (40 mg; 24% yield). 1H NMR (400 MHz, CDCL3) δ 9.51 (S, 1H), 8.62 (s, 2H), 7.96 (s, 1H), 7.20-7.18 (d, J=10.8, 1H), 5.70-5.68 (d, J=10.8 Hz, 1H), 4.15-3.82 (m, 4H), 3.82 (s, 3H).
Reaction SMILES: Br.[Al].ClC(Cl)=[CH:5][C@@H:6]1[C@H:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12].Cl.[CH2:16]([Br:18])[Br:17]>>[Br:17][C:16]([Br:18])=[CH:5][CH:6]1[CH:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12]
Reactant: BrCBr
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Agent: Br
Agent: Cl
Agent: [Al]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)O
Reaction time: 0.33 h

Procedure:
Anhydrous hydrogen bromide gas was introduced through a pipet (below the liquid level in the flask) to a stirred suspension of a small portion of aluminum shot in methylene bromide (250 ml) at 60°. The temperature was maintained at 60°-65° by heating or cooling as required during the portionwise addition of the aluminum shot (9.67 g, 0.358 mole total). The flow of HBr was maintained until all the aluminum had reacted to produce a cloudy brown mixture. The temperature of the reaction mixture was then reduced to 0°-5°, and a solution of cis-3-(2,2-dichlorovinyl)2,2-dimethylcyclopropanecarboxylic acid (50.0 g, 0.24 mole) in methylene bromide was added dropwise over a period of an hour to the vigorously stirred mixture under a nitrogen atmosphere. The reaction mixture was allowed to stir for 1 hour 20 minutes at 0.5°; then a flow of nitrogen was passed through the reaction mixture at reduced pressure (20 mm) for 11/2 hours. The entire reaction mixture was then poured slowly into a mixture of ice and 1 N hydrochloric acid and extracted twice with diethyl ether. The combined ethereal solution was dried over anhydrous magnesium sulfate, and the ether was removed under reduced pressure, affording a gray-brown solid, which was dried in a vacuum oven, affording 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (70.7 g). The crude product was recrystallized from hexane and sublimed. The cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid thus obtained was 93% pure by glc analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[CH3:16][N:17]([CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[Na+]>[Cl-].[Na+]>[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[NH2:24][C:20]1=[CH:19][C:18](=[N+:17]([CH3:25])[CH3:16])[CH:23]=[CH:22]/[C:21]/1=[N:1]\[C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: CN(C)c1cccc(N)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Cc1c(/N=C2\C=CC(=[N+](C)C)C=C2N)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
60 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one and 60 mmol of N,N-dimethylbenzene-1,3-diamine was dissolved in 300 ml of ice-water. This solution was admixed with 60 mmol of ferric chloride and 300 ml of saturated aqueous sodium chloride. Sodium perchlorate was added to saturation, and the mixture was left to stand for 30 minutes at zero degrees.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+]>CO>[F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[NH2:36])=[CH:19][CH:20]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a dry flask was added a solution of 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanone (CB55) (0.98 g, 2.4 mmol) in dry methanol (30 mL). The flask was evacuated/backfilled with nitrogen and ammonium acetate (2.6 g, 34 mmol) was added, followed by sodium cyanoborohydride (0.18 g, 2.9 mmol). The reaction was stirred at room temperature overnight. The solution was quenched with water and extracted with ethyl acetate. The organics were dried, filtered, and concentrated to provide the title compound as a white solid (0.42 g, 34%): 1H NMR indicated the presence of 2 isomers, which were not separated. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (two s, 1H), 8.14-8.03 (m, 4H), 7.66-7.60 (m, 2H), 7.53-7.40 (m, 2H), 3.47-3.16 (br s, 2H), 3.29 (td, J=11.0, 3.8 Hz, 1H), 2.59 (td, J=11.6, 11.1, 3.7 Hz, 1H), 2.17-2.04 (m, 1H), 1.86-1.68 (m, 3H), 1.68-1.30 (m, 4H); ESIMS m/z 402 ([M]+).
Reaction SMILES: P(Br)(Br)([Br:3])=O.O=[C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]=2[CH:10]=[CH:9][NH:8]1>ClCCCl>[Br:3][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]=2[CH:10]=[CH:9][N:8]=1
Reactant: N#Cc1cccc2c(=O)[nH]ccc12
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Product: N#Cc1cccc2c(Br)nccc12

Procedure:
Phosphorus oxybromide (6.7 g) was added to a suspension of 1-oxo-1,2-dihydro-5-isoquinolinecarbonitrile (2 g) in 1,2-dichloroethane (100 ml). The resulting suspension was heated under reflux overnight. The solvent was removed in vacuo and the residue was washed with aq NaHCO3 (2N, 2×15 ml) to afford, after drying, the title compound (2.27 g). δH (DMSO-d6, 400 MHz): 7.99 (2H, m), 8.54 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:15])=[O:14])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Ni]>[C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:14])=[O:15])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1)C(N)=O
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1)C(N)=O

Procedure:
A solution of (S)-3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-succinamic acid tert-butyl ester (1.30 g, 2.70 mmol) in THF (75 mL) was shaken with Raney Nickel (0.50 g) under H2 (33 psi) for 18 h using a Parr apparatus. The reaction mixture was filtered through celite and concentrated. (S)-3-(4-Amino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester was obtained (1.20 g, 98%) as an off white solid. MS (APCI) m/z 448.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: Fc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 43.2 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (92 mg, 43%). MS (ISP) 427.0 [(M+H)+]; mp 262° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12]O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: OCCCc1ccc2c(c1)OCO2
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: BrCCCc1ccc2c(c1)OCO2

Procedure:
Compound 21-1 (9.72 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (5.27 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 6.5 hr. To the reaction mixture was slowly added water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.05 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]Cl.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: COc1cc(CN2CCNCC2)cc(OC)c1OC

Procedure:
Synthesized according to General Procedure A: 3,4,5-trimethoxybenzyl chloride (4{16}, 5 g, 23.1 mmol, 1 equiv.), piperazine (11.9 g, 138.5 mmol, 6 equiv.), THF (50.5 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{16} (5.59 g, 91%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 6.46 (s, 2H), 3.75 (s, 6H), 3.72 (s, 3H), 3.30 (s, 2H), 2.78 (t, 4H, J=5.0 Hz), 2.29 (br s, 4H), 1.55 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 152.7, 136.4, 133.7, 105.4, 63.6, 60.5, 55.7, 54.2, 45.8.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH2:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH2:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:33][CH:34]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)C(=O)COc1ccc(CN)cn1
Product: CC(C)(C)C(=O)COc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1
Yield: 49 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (210 mg, 0.5 mmol) with 3-aminomethyl-6-(3,3-dimethyl-2-oxo-butoxy)-pyridine (220 mg, 1 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 7-chloro-6-{[6-(3,3-dimethyl-2-oxo-butoxy)-pyridin-3-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (122 mg, 50%). MS (ES+) m/z: 498 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].C([OH:19])C.[OH-].[Na+]>O>[NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15](=[O:19])[NH2:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCN(CC)Cc1cc(C#N)cc(Br)c1N
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)Cc1cc(C(N)=O)cc(Br)c1N

Procedure:
11 gm of 2-amino-3-bromo-5-cyano-N,N-diethyl-benzylamine were refluxed with a mixture of 70 ml of ethanol and 100 ml of 5 N sodium hydroxide. After cooling, the reaction solution was diluted with 100 ml of water and extracted with chloroform. The chloroform extract was dried over sodium sulfate and evaporated, and the residue was recrystallized from isopropanol, yielding 2-amino-3-bromo-5-carbamoyl-N,N-diethyl-benzylamine, m.p. 140°-142° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([C:28]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]2)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1
Reactant: O=C(Cl)N1CCOCC1
Product: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
8.3 g (26.5 mmol) of methyl 5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylate and 5.2 g (34.5 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to the General Method 3A. Yield: 11.0 g (100% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O.O>[CH2:28]([O:1][C:2]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])=[O:5])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCBr
Reactant: COc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCOc1cc(OC)ccc1C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A mixture of 3-(2-hydroxy-4-methoxybenzoyl)benzoic acid (1 g) and anhydrous potassium carbonate (1.12 g) is heated under reflux in acetone (30 ml) for 30 minutes. Then, 1-bromobutane (1.1 g) is added and the resulting mixture heated under reflux for 48 hours. The reaction mixture is then cooled to room temperature, diluted with water (100 ml) and extracted with ether (3×30 ml). The ether extracts are dried over magnesium sulfate, filtered and evaporated to dryness. The residue is heated under reflux with 2N sodium hydroxide (2 ml) for 4 hours. The mixture is then acidified with concentrated hydrochloric acid, diluted with water (50 ml) and extracted with ether (3×25 ml). Ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from aqueous ethanol to yield 3-(2-butoxy-4methoxybenzoyl)benzoic acid (0.5 g), m.p. 112°-115° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].Br[C:14]1=[C:15]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:16][CH:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])[CH2:18]/[C:19]/1=[N:20]\OS(C)(=O)=O>CCOCC>[NH2:20][C:19]1[CH:18]=[C:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])[N:16]=[C:15]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:14]=1[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: CCOC(=O)C1=C(Br)/C(=N/OS(C)(=O)=O)CC(c2ccc(Cl)cc2F)N1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2F)cc(N)c1OCC(F)(F)F
Reaction time: 0.5 h

Procedure:
To a mixture of 2,2,2-trifluoroethanol (3.9 mL) and K2CO3 (54 mg, 3.9 mmol) was added (E)-ethyl 3-bromo-6-(4-chloro-2-fluorophenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropicolinate (prepared as in Renga, J. M. et al. U.S. Patent Appl. Publ. 2010/0311594 A1, Dec. 9, 2010; 450 mg, 1 mmol). The mixture was stirred for 30 min, then diluted with Et2O and washed with 1 M HCl. The organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 0-50% EtOAc/hexanes affording an off-white solid: (190 mg, 74%): mp 123-135° C.; 1H NMR (300 MHz, CDCl3) δ 8.00 (t, J=8.5 Hz, 1H), 7.23 (m, 3H), 7.15 (dd, J=11.1, 2.0 Hz, 1H), 4.59 (s, 2H), 4.46 (m, 4H), 1.44 (t, J=7.1 Hz, 3H); ESIMS m/z 393 ([M+H]+), 391 ([M−H]−).