Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@:6]1([O:19][CH3:20])[C@@H:10](O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+]=[N-].C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:20][O:19][C@:6]12[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C@H:10]1[NH:1][CH2:4][CH2:5]2
Reactant: CO[C@]1(CCN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C[C@@H]1O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CO[C@@]12CCN[C@@H]1CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of tert-butyl (3R,4S)-3-(2-azidoethyl)-4-hydroxy-3-methoxypyrrolidine-1-carboxylate (85 mg) in CHCl3 (5 mL) was added triethylamine (140 mg) and MsCl (50 mg) at room temperature. And the mixture was stirred at room temperature for 1 hour. After the period, the mixture was poured into saturated aqueous solution of NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and concentrated. The residue was dissolved in THF (5 mL). To the solution was added 10% palladium on activated carbon (20 mg). The resulting solution was placed under a H2 atmosphere (balloon pressure) and stirred at room temperature for 15 hours. The solution obtained by filtration through Celite and washing the filter cake with MeOH was concentrated in vacuo. The residue was dissolved in CHCl3 (3 mL) and refluxed for 1 day and then cooled to room temperature. The resulting mixture was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give tert-butyl (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[CH:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:48]([O:50][C:51](=[O:65])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([SH:60])=[CH:56][C:55]=1[C:61]([F:64])([F:63])[F:62])[CH3:49]>C1COCC1>[CH2:48]([O:50][C:51](=[O:65])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([S:60][CH2:9][CH:8]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[CH:56][C:55]=1[C:61]([F:62])([F:63])[F:64])[CH3:49]
Reactant: Cc1ccsc1C(=CCO)c1sccc1C
Reactant: CCOC(=O)COc1ccc(S)cc1C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCC=C(c2sccc2C)c2sccc2C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 100 h

Procedure:
To a solution of 3,3-bis-(3-methyl-thiophen-2-yl)-prop-2-en-1-ol (110 mg, 0.44 mmol) and triphenylphosphine (220 mg, 0.88 mmol) in THF was added, at room temperature and under nitrogen atmosphere, DEAD (153 mg, 0.88 mmol). The reaction mixture was stirred for 5 min after which (2-trifluoromethyl-4-mercapto-phenoxy)-acetic acid ethyl ester (70 mg, 0.25 mmol) was added over 15 min. The reaction mixture was stirred at room temperature for 100 hours. The reaction mixture was evaporated and the crude residue was purified on a Horizon using a methylene chloride:heptanes gradient as eluent. The desired {4-[3,3-bis-(3-methyl-thiophen-2-yl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester was isolated in 75 mg (59%) yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](O)[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.P(Br)(Br)[Br:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([Br:19])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: BrP(Br)Br
Reactant: OC1Cc2ccccc2Sc2cc(Br)ccc21
Product: Brc1ccc2c(c1)Sc1ccccc1CC2Br

Procedure:
10.5 G. 3-bromo-10,11-dihydro-11-hydroxydibenzo[b,f]thiepin and 25 cc. phosphorous tribromide are stirred for 2 hours, poured onto ice and extracted with ether. The ether is dried and evaporated to yield 10.65 g. of a brown oil which solifies on standing. The material is used as such for the next step.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([Cl:19])[CH:13]=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:19])[C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1c(Cl)cccc1CBr

Procedure:
N-Bromosuccinimide (4.67 g, 26.23 mmol) was added to a stirred solution of 6-methyl-2-chloro-1-nitrobenzene (4.5 g, 26.23 mmol) in distilled carbon-tetrachloride. Benzoyl peroxide (0.01 g) was added to the reaction mixture and the mixture was refluxed for 8 h. The solid separated was filtered. The filtrate was concentrated to get the crude product, which was purified by using column chromatography (silica gel, pet.ether 60-80° C.) to obtain the title compound. Yield: 2.69 g, (41%); MS: m/e (CI) 253 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](=[O:32])[NH:19][C:20]3([C:29]([OH:31])=[O:30])[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:33]>O1CCOCC1.O1CCOCC1.O>[ClH:33].[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[C:18]([NH:19][C:20]2([C:29]([OH:31])=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:32])[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)c2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1CNCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 8-(2-carboxy-indan-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (226) (128 mg, 0.29 mmol) in 6 ml dioxane is added dropwise 4N solution of HCl in dioxane/water (0.72 mL) and the resulting solution is stirred at RT for 4 h. The concentration gave an HCl salt of (219) as white solid (246 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH4+].[Cl-]>CCO.O.[Fe]>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[C:3]=1[NH2:9]
Reactant: Nc1cccc(Br)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(Br)c1N
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A mixture of 3-bromo-2-nitroaniline (2 g, 9.2 mmol), Fe powder (1.54 g, 27.6 mmol) and NH4Cl (4.8 g, 52 mmol) in EtOH and H2O was stirred under reflux for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was diluted water extracted with ethyl acetate and the combined organic layers were dried and concentrated in vacuum to give the crude desired product (1.7 g, Yield 85%). This crude was used in the next step without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:57][CH3:58])([O:55][CH3:56])=[O:54])[NH2:52].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:55][CH3:56])([O:57][CH3:58])=[O:54])[NH:52][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])=[CH:34][C:26]=1[Cl:25]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: O=C(NCc1ccc2cc[nH]c2c1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.4 g, 6.4 mmol) was added to a solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (Example 117; 1.9 g, 5.8 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 2.10 g, 10.6 mmol) in N,N-dimethylformamide (20 mL). 1-hydroxybenzotriazole (861 mg, 6.4 mmol) was then added, followed by diisopropylethylamine (2 mL, 11.6 mmol). The solution was stirred overnight at room temperature and then it was concentrated under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between water and ethyl acetate and the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine, then was dried (MgSO4), filtered and evaporated in vacuo. The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane) to give rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (2.1 g, 72% yield) which was used in subsequent reactions without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CCO.[Pd]>[F:24][C:21]([F:22])([F:23])[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: FC(F)(F)Oc1ccccc1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: FC(F)(F)Oc1ccccc1C1CCNCC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-4-(2-trifluoromethoxy-phenyl)-1,2,3,6-tetrahydro-pyridine (described herein below) in EtOH was added (0.2 wt %) 10% Pd/C, followed by (5 eq.) TFA in a sealed tube. The reaction mixture was stirred at 50° C. under 3.0 bar of H2 for 12 h. The reaction mixture was filtered over Celite and the filtrate evaporated down to dryness. Redissolution in EtOAc, washing with 1N NaHCO3 and concentration gave the crude product which was directly used for the next step.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:34]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([O:35][C:32]1[N:31]=[N:30][C:29]([N:14]2[CH2:13][C:12]3[CH2:8][N:9]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=3[CH2:15]2)=[CH:34][CH:33]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Clc1ccc(OCCc2ccccc2)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCCc3ccccc3)nn1)C2

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (example 1b) (500 mg, 1.26 mmol), 3-chloro-6-phenethyloxypyridazine (example 4a) (296 mg, 1.26 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (67.9 mg, 65.6 μmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (81.7 mg, 131 μmol) and cesium carbonate (1.645 g, 5.048 mmol) were stirred in 5 ml of dioxane under an argon atmosphere at 80° C. for 4 h. The reaction mixture was concentrated and admixed with ethyl acetate and water, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 104 mg (14%), M+H+: 481.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2,6-dimethyl-4-nitro-4′-(trifluoromethyl)biphenyl (600 mg, 2.03 mmol) in ethanol (20 mL) was added 10 wt % palladium on carbon (18 mg). The reaction was pressurized to 50 psi hydrogen and stirred at room temperature overnight. The reaction was filtered onto Celite and concentrated. Purification by column chromatography gave 2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-amine (480 mg, 89%) as a light yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.65 (d, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 6.48 (s, 2H), 3.80 (s, 2H), 1.94 (s, 6H). MS (M+1): 266.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CN(C=O)C>[CH3:20][C:18]1[O:19][C:15]2[CH:14]=[C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH:26]=[CH:25][C:16]=2[C:17]=1[C:21]([NH:23][CH3:24])=[O:22]
Reactant: COC(=O)CCCBr
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCCC(=O)O)ccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 119-A (200mg, 0.57 mmol), methyl 4-bromobutanoate (155mg, 0.85 mmol), and Cs2CO3 (433 mg, 1.14 mmol) in a mixed solvent of CH3CN (4 mL)/DMF(1 mL) was heated to 65° C. overnight. The reaction mixture was extracted with EtOAc, concentrated and dissolved in 5 mL of MeOH. To the solution was added 1 N NaOH (1 mL). The solution was stirred at room temperature for 2 hours and then heated to 60° C. for 2 hours. The solution was acidified with AcOH to a pH of about 6 and extracted with EtOAc. The concentrated residue was purified by HPLC using 20-60% CH3CN/H2O over 30 min. to give 4-{[4-({2-methyl-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}oxy)quinolin-7-yl]oxy}butanoic acid 119.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O.O>[CH2:15]([O:3][CH2:4][CH2:5][C:6]1([CH2:12][CH2:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCC1(CCO)CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCC1(CCOCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (881 mg) in N,N-dimethylformamide (20 mL) was added 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (2.92 g) under ice cooling. To the solution was further added benzyl bromide (2.83 mL) under ice cooling, and it was stirred at room temperature for 63 hours. Water and 3N hydrochloric acid were added to the solution, and it was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=6:4) to give the title compound (2.93 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:6]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:7]=1.[CH3:32][CH:33]1[NH:37][C:36](=[O:38])[CH2:35][CH2:34]1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:5]3[CH:4]=[CH:3][C:2]([N:37]4[C:36](=[O:38])[CH2:35][CH2:34][CH:33]4[CH3:32])=[CH:7][C:6]=3[N:8]3[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]3=[O:15])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Yield: 11.9 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidine-2,4-dione (155 mg) described in Preparation Example 256 and 5-methylpyrrolidin-2-one (52 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (21 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([O:43]C)=[O:42])[CH:8]=[CH:9][CH:10]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(O)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([OH:43])=[O:42])[CH:8]=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)OC)c1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 26.2 %

Procedure:
Methyl (1RS,2SR,3RS)-3-[2-(3-Carbomethoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.08 g, crude) was dissolved in propan-2-ol (1 ml) and aqueous sodium hydroxide (1M, 1 ml, 1 mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3M-aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extract was purified by column chromatography on silical-gel (eluant: 30% EtOAc/hexane/5%AcOH) to give the title compound as a colorless solid (20 mg)
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([OH:36])=O)[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH3:37]>C1COCC1>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([NH2:37])=[O:36])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14])[CH2:7]2
Reactant: N
Reactant: C[C@@H]1CN2c3c(cc4c(-n5cc(C(=O)O)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: C1CCOC1
Product: C[C@@H]1CN2c3c(cc4c(-n5cc(C(N)=O)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: 1-[(2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-1H-pyrazole-4-carboxylic acid (Example 186) and saturated NH3 in THF (2 mL). Purification by reverse phase HPLC.
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl.[Pd]>CC(C)=O.C1COCC1>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: Brc1c[nH]nc1-c1ccccc1
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.1 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aqueous HCl to a pH of 7.0 to 7.5. The crude product, whose palladium level was 270 ppm, was dissolved in acetone (16 mL/g of bromophenyl pyrazole starting material) and THF (2.65 mL/g) at 50° C. TMT (0.23 equiv.) was added, and the mixture was stirred at 50° C. for 15 min, cooled to room temperature, and filtered three times through a Darco zeta pad. A sample of filtrate was evaporated to dryness, affording a solid containing 92 ppm of palladium. The remaining filtrate was concentrated and recrystallized by adding water, affording 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 51 ppm of palladium.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].Cl.[NH2:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(#N)C>[CH:32]([NH:31][C:29]([C@H:26]1[CH2:25][CH2:24][C@@H:23]([NH:22][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH:5]=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])[CH2:28][CH2:27]1)=[O:30])([CH3:34])[CH3:33]
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)cc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-4-(4-methoxybenzyloxy)-1-nitrobenzene (507 mg, 1.82 mmol), cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (404 mg, 1.82 mmol), DIPEA (0.70 mL, 4.02 mmol) and ACN (3.6 mL) were placed in a sealed tube, and the tube was heated at 80° C. for 6 hours. The mixture was allowed to cool and evaporated. The residue was diluted with DCM (15 mL), washed with water (×2), and then washed with brine. The organic layer was dried over Na2SO4. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% MeOH in DCM. The title compound was collected as a yellow solid (476 mg, 59% yield).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16]>CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1ccccn1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C=Cc2ccccn2)cc1
Yield: 45.6 %

Procedure:
A mixture of 20.4 g (0.2 mol) acetic acid anhydride, 18.6 g (0.2 mol) 2-methylpyridine and 26.2 g (0.2 mol) 4-cyanobenzaldehyde is heated to reflux for 24 h. One allows to cool, mixes with excess ether and filters. One isolates 18.8 g of title compound (46% of theory) of the m.p. 98°-98° C.
Reaction SMILES: [C:1]([N:4]1[C:9]2[N:10]=[C:11]([C@H:24]([NH2:26])[CH3:25])[N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[C:13](=[O:14])[C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:28][C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:4]1[C:9]2[N:10]=[C:11]([C@H:24]([NH:26][CH2:28][C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)[CH3:25])[N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[C:13](=[O:14])[C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(CBr)n(C)n1
Reactant: CCOc1ccc(-n2c([C@@H](C)N)nc3c(c2=O)CCCN3C(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c([C@@H](C)NCc3cc(C)nn3C)nc3c(c2=O)CCCN3C(C)=O)cc1
Yield: 59.2 %

Procedure:
D4 (70 mg, 0.20 mmol), C3 (37 mg, 0.20 mmol), and potassium carbonate (30 mg, 0.22 mmol) were stirred in dimethylformamide at room temperature overnight. The reaction mixture was partitioned between 4:1 ether:dichloromethane and water. The organic layer was washed with water and brine. It was dried over magnesium sulfate, filtered, then concentrated in vacuo. Purified by chromatography (2% to 5% methanol with 0.1% ammonium hydroxide in dichloromethane), yielding 55 mg of D5.