Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:18][C:19]1([CH3:27])[CH2:25][C:24](=[O:26])[NH:23][C:21](=[O:22])[CH2:20]1.Br[CH2:29][C:30](OCC)=[O:31]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH2:1][CH:30]([OH:31])[CH2:29][N:23]3[C:24](=[O:26])[CH2:25][C:19]([CH3:27])([CH3:18])[CH2:20][C:21]3=[O:22])(=[O:4])=[O:3])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC(=O)NC(=O)C1
Product: CC1(C)CC(=O)N(CC(O)CS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)C(=O)C1

Procedure:
Reaction of 4-(4′-fluorophenyl)-phenyl methyl sulfone with ethyl 3,3-dimethylglutarimideacetate (prepared from 3,3-Dimethylglutarimide and ethyl bromoacetate (as in Example 120A) following the procedures of Example 126A, followed by reduction as described in Example 126B afforded the two title products which were chromatographically separated to give the desired products.
Reaction SMILES: C([O:4][CH:5]=[CH:6][C@@H:7]([CH3:14])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=O)C.P(=O)(O)(O)O.O>C1(C)C=CC=CC=1>[CH3:13][C:11]1([CH3:12])[CH2:10][CH2:9][CH2:8][C@H:7]([CH3:14])[C@H:6]1[CH:5]=[O:4]
Reactant: CC(=O)OC=C[C@@H](C)CCC=C(C)C
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CCCC(C)(C)[C@@H]1C=O
Temperature: 100 °C

Procedure:
A solution of crude product of Example 3a (6.36 g, 32.4 mmol) in toluene (11 mL) (15.7 g) was added 85% phosphoric acid (12 mL). The mixture was heated to 100° C. for 4 hours. The reaction mixture was cooled to room temperature and toluene (12 mL) along with water (24 mL) was added and the layers were separated. The aqueous layer was extracted with toluene (12 mL×2). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 mL×2) and brine (50 mL×2). Concentration and distillation under reduced pressure (b.p. 65-70° C.) afforded the title compound as a 9:1 mixture of epimers as a colorless oil (2.51 g, Yield: 50%). 1H NMR (400 MHz, CDCl3) (Major) δ 9.63 (d, J=5.2 Hz, 1H), 2.03-1.91 (m, 1H), 1.83-1.75 (m, 1H), 1.64-1.60 (m, 1H), 1.54-1.48 (m, 1H), 1.40-1.35 (m, 1H), 1.24-1.14 (m, 1H), 1.02 (s, 3H), 0.97 (s, 3H), 0.95-0.84 (m, 2H), 0.81 (d, J=6.4 Hz, 3H) ppm. [α]D24=+5.20° (c=1.00, dichloromethane).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:5][CH:4]=1.[I-].C[S+](C)(C)=O.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.[C:31](=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[N:26]1([CH2:31][C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=2)([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: c1c[nH]cn1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)Cn1cncn1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: OC(Cc1ccc(C(F)(F)F)cc1)(Cn1ccnc1)Cn1cncn1

Procedure:
1-(4-trifluoromethylphenyl)-3-(1,2,4,-triazol-1-yl)propan-2-one (1.5 g), trimethylsulphoxonium iodide (1.5 g), imidazole (0.46 g), potassium carbonate (0.75 g) in tert-butyl alcohol (20 ml) was heated at φ° for 3 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was separated, washed with water and then brine, and dried. The dried extract was evaporated to dryness under reduced pressure, and the residue was purified by chromatography on silica, using 5% by volume methanol in chloroform as eluent. After evaporation of the solvent, the residue crystallised from a mixture of ethyl acetate and hexane to give 3-(imidazol-1-yl)1-(1,2,4-triazol-1-yl)-2(4-trifluoromethylbenzyl)-propan-2-ol, m.p. 154-155°C. (Example 30). In a similar manner there were prepared 2-(4-chlorobenzyl)-3-(imidazol-1yl)-1-(1,2,4-triazol-1-yl) propan-2-ol, m.p. 159-161° (Example 31) and 1,3-di(imidazol-1yl)-2-(4-trifluoromethylbenzyl)propan-2-ol, m.p. 177-178° (Example 32). ##STR1##
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)CC.[Sn:13](Cl)([CH3:16])([CH3:15])[CH3:14].N#N>C1COCC1>[CH3:14][Sn:13]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: C[Sn](C)(C)Cl
Agent: CCC[Mg]Cl
Agent: N#N
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccnc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To anhydrous THF (100 ml) containing 3-bromo-pyridine (3.29 g, 20.82 mmol), were added 1.2 eq of /PrMgCl (12.49 ml, 2M in THF) and the resulting mixture was stirred for 2 hours under N2 (10° C.). Subsequently 1.2 eq of (CH3)3SnCl were added and the reaction mixture was stirred for 18 hours at room temperature (under N2). The reaction mixture was quenched with a saturated NH4Cl solution, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-trimethylstannanyl-pyridine (71) (3.32 g, 66%). LCMS (method A): Rt: 2.09 min, ([M+H]+=242). 1H-NMR (400 MHz, CDCl3): δ 8.62 (bs, 1H), 8.52 (dd, J=5 Hz, 2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.25-7.21 (m, 1H), 0.33 (s, 9H), with Sn satellites at 0.41 and 0.27.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](=[N:18][NH2:19])[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClS([N:26]=[C:27]=[O:28])(=O)=O.C(OCC)(=O)C.O>CCCCCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](=[N:18][NH:19][C:27]([NH2:26])=[O:28])[C:7]2[CH:8]=[CH:9][C:10]([CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=NN)c2ccc(Cl)cc2)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)Cc1ccc(C(=NNC(N)=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
4-chloro-4'-methylsulfonylmethylbenzophenone-hydrazone (1.3 g) and chlorosulfonyl isocyanate (0.63 g) were added to ethyl acetate (100 ml), and the mixture was stirred for one hour at room temperature. Then, water (100 ml) was added, and the mixture was further stirred for 16 hours at room temperature. The reaction mixture was subjected to liquid separation, and the ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with a solvent mixture of ethyl acetate:n-hexane=4:1, to obtain the desired product (1.2 g, melting point: 189° to 191° C., yield: 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH:6]=O.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O-:18])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl:51]CCCl>>[ClH:51].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])[CH2:26][CH2:27]2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13]
Reactant: ClCCCl
Reactant: CNC(=O)Oc1ccc(C=O)cc1OC
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNC(=O)Oc1ccc(CN2CCN(c3ccccc3[N+](=O)[O-])CC2)cc1OC
Product: Cl
Yield: 68 %

Procedure:
To a solution of 3-methoxy-4-(methylaminocarbonyloxy)benzaldehyde (0.60 g) in 1,2-dichloroethane (6 ml) was added 1-(2-nitrophenyl)piperazine(0.60 g) in 1,2-dichloroethane (5.5 ml), followed by sodium triacetoxyborohydride (0.92 g), with stirring. The reaction mixture was stirred for 6 hrs at ambient temperature, poured into saturated sodium carbonate solution (75 ml) and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel), eluting with dichloromethane, followed by 0.2, 0.5, 1.0, 2.0% methanol:dichloromethane. The appropriate fractions were collected and concentrated to give 0.78 g (68%) of product, free base. The free base was dissolved in dichloromethane, diluted with diethyl ether and ethereal hydrogen chloride was added. The precipitate was collected and recrystallized from 2-propanol to give product, mp 214-218° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[CH2:34]([OH:36])[CH3:35]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:32])[C:29]([O:36][CH2:34][CH3:35])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: FC(F)(F)Oc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Reactant: CCO
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Yield: 86 %

Procedure:
Ethyl {1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate was prepared from 1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole (2.80 g, 7.62 mmol), oxalyl chloride (2.0 mL, 23 mmol), and ethanol (4.5 mL) according to the procedure described in Step 3 of Example 1. Purification by flash chromatography using 5-10% ethyl acetate in hexane as an eluant then drying at 60° C. furnished the title compound as a yellow gum (3.05 g, 86%). 1HNMR (300 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.45 (s, 1H), 7.8 (d, 2H, J=9.2 Hz), 7.75 (d, 1H, J=9.2 Hz), 7.6 (d, 1H, J=9.2 Hz), 7.45 (d, 2H, J=9.2 Hz), 7.3-7.4 (m, 5H), 5.85 (s, 2H), 4.35 (q, 2H, J=7.5 Hz), and 1.35 ppm (t, 3H, J=7.5 Hz).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C1(B(O)O)C=CC=CC=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>O>[C:17]1([CH:23]2[CH2:5][CH2:4][CH2:3][CH2:2][C:1](=[O:7])[CH2:6]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: O=C1C=CCCC1
Agent: OB(O)c1ccccc1
Solvent: CO
Solvent: O
Product: O=C1CCCCC(c2ccccc2)C1
Temperature: 50 °C
Yield: 83 %

Procedure:
Next, the scope of boronic acids that can be utilized was briefly examined. More specifically, the general experimental procedure for the 1,4-addition of arylboronic acids to enones will be described using 2-cyclohexen-1-one and phenylboronic acid. A mixture of 2-cyclohexen-1-one (96 mg, 1 mmol) and phenylboronic acid (158 mg, 1.3 mmol) was taken in a round bottom flask. A toluene solution (3 ml) containing Rh(acac)(CO)2 (5 mg, 0.02 mmol) and JanaPhos (70 mg, 0.03 mmol, Rh/P=1/3) was added to it in an inert atmosphere. A solution of methanol and water (1:1, 0.5 ml) was added to it via syringe. The reaction mixture was heated at 50° C. for 15 hours until the starting material was consumed as indicated by TLC. Then 25 ml methanol was added to it mixture and the catalyst was precipitated out as a white solid. It was filtered out by a Schlenk filter and underwent for the consecutive runs. The filtrate was evaporated under reduced pressure to obtain the crude product which was further purified by column chromatography (10% ethyl acetate in hexane) to obtain the pure product (144 mg, 83% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[Br:14]NC(=O)CCC(N)=O.C(O)(=O)C.O>C(Cl)Cl>[Br:14][C:8]1[C:7](=[O:9])[N:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: O=c1cc(CCl)nc2ccccn12
Reactant: NC(=O)CCC(=O)NBr
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1c(Br)c(CCl)nc2ccccn12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3.564 g, 1.0 equiv.), N-bromosuccinamide (1.0 equiv.) and acetic acid (48.2 mL) was stirred at rt for 4.5 h, at this point LCMS showed reaction was complete. The mixture was poured into water (200 mL) and the resulting precipitate was collected by filtration, washed with water (200 mL) and dried to give an orange solid. The solid was dissolved in DCM (100 mL), dried over Na2SO4, filtered and cond under reduced pressure to give desired 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as an orange solid which was carried forward without any further purification: 1HNMR (400 MHz, DMSO-d6): δ 8.94-8.97 (dd,1H), 8.03-8.08 (m,1H), 7.76-7.80 (dd, 1H), 7.43-7.48 (m,1H), 4.7 (s,2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.Br[C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[C:53]([N+:65]([O-])=O)[CH:52]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:65][C:53]3[CH:52]=[C:51]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:56]=[CH:55][C:54]=3[NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:19])=[CH:21][CH:22]=2)[CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
The acid 325 (3.23 g, 7.03 mmol) and BOP (4.66 g, 10.55 mmol) were added to a solution of 322 (1.2 g, 7.03 mmol) (Compound 322 was synthesized following general procedures B and C starting from compound 2 and phenylboronic acid) in pyridine (40 mL). The reaction mixture was stirred at room temperature for 24 h, concentrated under reduced pressure, diluted with DCM, washed with water, NaHCO3 and brine. The residue was purified by flash chromatography (2-4% MeOH in DCM) to give the title compound 326 (1.74 g, 43%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=1)[CH2:7]2
Reactant: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(CCCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Yield: 108.4 %

Procedure:
A mixture of 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.056 g, 0.11 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-Methyl-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.056 g, 100%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.23-2.66 (m, 18H), 4.18 (s, 2H), 4.72 (s, 2H), 6.88-7.38 (m, 11H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25](C(F)(F)F)[CH:24]=1)[N:19]([CH3:33])[C:18]2=[O:34]>N1C=CC=CC=1>[CH3:33][N:19]1[C:18](=[O:34])[C:17]2[C:22](=[C:13]([NH:12][S:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)(=[O:10])=[O:9])[CH:14]=[CH:15][CH:16]=2)[N:21]=[C:20]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc2c1=O
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(-c2ccccc2)nc2c(NS(=O)(=O)c3cccnc3)cccc2c1=O
Temperature: 80 °C
Yield: 62.7 %

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride 7 (280 mg, 1.3 mmol) was added to a solution of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 5 (100 mg, 0.313 mmol) in pyridine (5 mL). The reaction mixture was heated at 80° C. for 12 h. The pyridine was removed in vacuo. The residue was taken up in CH2Cl2, washed with sat. aq NaHCO3, dried (MgSO4) and concentrated. The crude residue was purified by MPLC eluting with CH2Cl2/MeOH (0-10%) followed by recrystallization from CH3CN to give Compound 361 (77 mg, 53% yield). MS (ESI) calcd for C21H15F3N4O3S: 460.08. found: 461 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][CH:28]([C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38])[OH:29]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:26]([CH2:27][CH:28]([OH:29])[C:30]4[C:31]([F:38])=[CH:32][C:33]([F:37])=[CH:34][C:35]=4[F:36])[CH3:25])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1c(F)cc(F)cc1F
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1c(F)cc(F)cc1F

Procedure:
Analogous to the procedures described in Example 38, N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2) is treated with rac-2-(methylamino)-1-(2,4,6-trifluorophenyl)ethanol (Preparation 44) to afford the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: C1=CCCCC1
Product: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
31.6 g (0.072 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-(1-benzyl-piperidin-4-yl)-amide are dissolved in 180 ml ethanol and 180 ml methanol, mixed with 84 ml (0.83 mol) of cyclohexene and 6.53 g of palladium hydroxide (20% on charcoal) and refluxed for four hours. The hot reaction mixture is filtered through kieselguhr and the reaction mixture is concentrated by rotary evaporation.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][O:26][C:20]=2[CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O.C(OCC)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][O:26][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1cccc2c1C(=O)c1sccc1CO2
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(O)(C(=O)Nc1cccc2c1C(=O)c1sccc1CO2)C(F)(F)F
Reaction time: 1 h
Yield: 89 %

Procedure:
In dimethylacetamide (3 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.32 g, 2.03 mmol), and thionyl chloride (148 μl, 2.03 mmol) was added thereto at -15° C., followed by stirring at -15° to -5° C. for one hour. To this reaction mixture was added 9-amino-4,10-dihydrothieno[3,2-c][1]benzoxepin-10-one obtained in Reference Example 11 (0.23 g, 1.02 mmol), and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, the obtained oily residue was dissolved in ethyl acetate (20 ml). The organic layer was washed successively with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give Compound 7 (0.34 g, 89%).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]1[C:37]2[O:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27].O>CN(C)C=O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[C:37]3[O:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:34]([CH3:44])[C:33](=[O:45])[C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:11][CH2:10]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCN3CCN(c4ccccc4Cl)CC3)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride and 4.2 g of anhydrous potassium carbonate in 25 ml of dimethylformamide was stirred at ambient temperature for 15 minutes. 4.81 g of Intermediate I was added, and stirring was continued for 2 days. The reaction mixture was then poured into 200 ml of cold water, and extracted with diethyl ether and ethyl acetate. The organic extracts were washed in turn with aqueous sodium chloride solution, 0.1N aqueous acetic acid solution, aqueous sodium chloride solution, aqueous 4% sodium carbonate solution and water, and were then dried on anhydrous sodium sulfate. After evaporation to dryness in vacuo, the residue was dissolved in 160 ml of acetonitrile and excess hydrogen chloride in diethyl ether was added. The insoluble title compound was recrystallized from acetonitrile. Yield 3.6 g, m.p. 138°-143° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19]([C:26]([NH2:28])=[O:27])=[N:20][C:21](Cl)=[C:22]([NH2:24])[N:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:17][C:18]1[C:19]([C:26]([NH2:28])=[O:27])=[N:20][C:21]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[C:22]([NH2:24])[N:23]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: NC(=O)c1nc(Cl)c(N)nc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c(N)nc1N
Temperature: 25 °C
Yield: 27.4 %

Procedure:
To a mixture of 4-phenoxyphenylboronic acid (0.22 g, 1.02 mmol), 3,5-diamino-6-chloropyrazine-2-carboxamide (0.176 g, 0.919 mmol), sodium carbonate (0.33 g, 2.06 mmol) in toluene (14 mL), ethanol (3.5 mL), and water (3.5 mL) was added tetrakis(triphenylphosphine)palladium (60 mg). The mixture was refluxed overnight. The reaction was allowed to cool to room temperature, then partitioned between water and ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product as a solid. Flash chromatography (Silica gel; 6:4 ethyl acetate/dichloromethane to 7:3 ethyl acetate/dichloromethane) and subsequent recrystalization from chloroform afforded 81 mg (27%) of the desired product as white solid. 1H NMR (CDCl3): δ 7.58 (d, J=9.0 Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 7.38 (bs, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.10-7.05 (m, 4H), 5.26 (bs, 1H), 4.97 (s, 4H).