Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:7])=[N:5][N:6]=1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>CN1CCCC1=O>[CH3:1][C:2]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:4]([CH3:7])=[N:5][N:6]=1
Reactant: Cc1nnc(C)o1
Reactant: NCCCCO
Solvent: CN1CCCC1=O
Product: Cc1nnc(C)n1CCCCO
Yield: 77.8 %

Procedure:
2,5-Dimethyl-1,3,4-oxadiazole (3.8 g), 4-aminobutanol (3.5 g) and N-methylpyrrolidone (10 ml) were heated at 150° for 18 hours. The mixture was evaporated under high vacuum and the residue chromatographed on silica eluting with a mixture of ethyl acetate and methanol. The fractions containing the product were evaporated under vacuum to leave the title compound, (5.1 g), which was used directly.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=O>C(OC(=O)C)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=[CH:1][C:2]1[N:3]=[N:4][C:5]([CH:8]=[CH:13][C:12]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:10]([Cl:9])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Cc1ccc(C)nn1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])c(Cl)c3)nn2)cc1Cl
Yield: 18.3 %

Procedure:
First, 28 g of 3,6-dimethylpyridazine and 98 g of 3-chloro-4-nitrobenzaldehyde were dissolved in 1.5 liters of acetic anhydride to produce 21 g of 3,6-di(3-chloro-4-nitrostyryl)-pyridazine.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:19][C:20]([F:24])([F:23])[CH2:21][SH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:19][C:20]([F:24])([F:23])[CH2:21][S:22][C:2]1[CH:9]=[C:8]([C:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: FC(F)(F)CS
Reactant: N#Cc1ccc(-c2n[nH]cc2C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2n[nH]cc2C(F)(F)F)cc1SCC(F)(F)F
Yield: 56.9 %

Procedure:
0.65 g (2.4 mmol) of 2-chloro-4-(4-trifluoromethylpyrazolyl)benzonitrile, 0.33 g (2.9 mmol) of 2,2,2-trifluoroethanthiol and 0.40 g (2.9 mmol) of potassium carbonate were stirred in 5 ml of N,N-dimethylformamide at room temperature overnight. The resulting reaction mixture was poured into 50 ml of water, and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.48 g of 2-(2,2,2-trifluoroethylthio)-4-(4-trifluoromethylpyrazolyl)benzonitrile (yield 57.1%) as a milk-white powder (m.p. 90-91° C.).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:64][C@@H:65]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:70]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:71]
Reactant: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.7 %

Procedure:
To a solution of ethyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (18, 200 mg, 0.48 mmol), DCC (120 mg, 0.58 mmol) and DMAP (6 mg, 0.048 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (161 mg, 0.48 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (6 mL) and cooled to 0° C. Dimethylamine (6 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 140 mg (55%) of the title compound as a colorless semi solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:32]([C:35]1[CH:36]=[C:37](B(O)O)[C:38]([O:41][CH3:42])=[N:39][CH:40]=1)([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>C(OCC)(=O)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:37]4[C:38]([O:41][CH3:42])=[N:39][CH:40]=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:36]=4)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: COc1ncc(C(C)C)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Product: COc1ncc(C(C)C)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 50 °C

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 8, 2.0 g, 3.77 mmol), 5-isopropyl-2-methoxypyridin-3-ylboronic acid (1.25 g, 4.53 mmol) and K2CO3 (1.56 g, 11.31 mmol) were added to a round bottom flask, which was then evacuated and charged with nitrogen 3 times. THF (15 mL) and water (3 mL) were then added. After evacuating and charging again with nitrogen, 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.369 g, 0.566 mmol) was added and the reaction heated for 60 minutes at 50° C., at which time LCMS showed complete conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL saturated NH4Cl solution. The ethyl acetate layer was washed with brine (100 mL), then filtered through a 20 g plug of sodium sulfate, eluting with 50 mL ethyl acetate. The filtrate was concentrated prior to flash purification. The crude was purified by silica gel chromatography, eluting with a 0-20% ethyl acetate/hexanes gradient followed by isocratic elution at 20% ethyl acetate/hexanes. Pure fractions were concentrated to give product as colorless foam. LCMS (M+H)+: 601.4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=O)[O:28]CC)[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:28])[N:34]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH3:33])[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC1CCCC1
Reactant: CCOC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1)C1CCCC1
Temperature: 130 °C

Procedure:
To a solution of 0.16 g of ethyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-carbamate obtained in stage a) below in 2 mL of tetrahydrofuran are added successively 0.368 mL of N-methylcyclopentylamine and 0.512 mL of triethylamine. The reaction mixture is heated by microwave at 130° C. for 3 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 0.048 g of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-1-cyclopentyl-1-methylurea, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][CH:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]([NH2:16])=[O:15].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:12][CH:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]([NH2:16])=[O:15])[CH:9]=1
Reactant: NC(=O)C(N)CC(F)(F)F
Reactant: N#Cc1cc(F)c(F)cc1Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)cc1Br
Yield: 45.1 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (123 mg, 0.564 mmol), 2-amino-4,4,4-trifluorobutanamide (88 mg, 0.564 mmol) and DIEA (0.250 mL, 1.43 mmol) in DMSO (4 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, which was eluted with 0-70% EtOAc in hexane to give 2-(5-bromo-4-cyano-2-fluorophenylamino)-4,4,4-trifluorobutanamide (90 mg).
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH:3]=1.C(OC(=O)C)(=[O:20])C>>[O:20]=[C:3]1[C:4]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:6]=[CH:7][NH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2ccc[n+]([O-])c2)cc1
Product: COC(=O)c1ccc(-c2ccc[nH]c2=O)cc1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (20 mL) was added to methyl 4-(1-oxidopyridin-3-yl)benzoate (704 mg), followed by stirring at 130° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, followed by two times azeotropy with toluene. The resulting residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 10%) to obtain methyl 4-(2-oxo-1,2-dihydropyridin-3-yl)benzoate (651 mg) as a pale brown solid.
Reaction SMILES: [C:1]1([C:6]2[C:18]([CH:19]([OH:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[C:17]([CH:31]([CH3:33])[CH3:32])[CH:16]=[C:15]3[C:7]=2[C:8](=[O:34])[CH2:9][C:10]2([O:14]3)[CH2:13][CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Rh]>[CH:1]1([C:6]2[C:18]([CH:19]([OH:30])[C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=3)=[C:17]([CH:31]([CH3:32])[CH3:33])[CH:16]=[C:15]3[C:7]=2[C:8](=[O:34])[CH2:9][C:10]2([O:14]3)[CH2:11][CH2:12][CH2:13]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc2c(c(C3=CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: [Rh]
Solvent: CCO
Product: CC(C)c1cc2c(c(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2

Procedure:
63 mg (0.031 mmol) of rhodium-on-carbon (5%) are added to a solution of 289 mg (0.61 mmol) of rac-5-cyclopent-1-en-1-yl-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 62A) in 10 ml of ethanol, and the mixture is hydrogenated under a hydrogen pressure of 60 bar at room temperature for 18 h. For work-up, the suspension is filtered through kieselguhr, the filter cake is washed with ethyl acetate and the filtrate is concentrated under reduced pressure. The residue is taken up in 10 ml of ethanol, the same amount of rhodium-on-carbon is added again and the mixture is hydrogenated under a hydrogen pressure of 60 bar at room temperature for a further 18 h. The suspension is again filtered through kieselguhr, the filter cake is washed with ethyl acetate and the filtrate is concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 15:1).
Reaction SMILES: [Br-].[CH2:2]([P+:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+].COC1C=C(C2(C=CCCCC)CCCC2)C=C(OC)C=1>C1COCC1>[CH2:3]([CH:2]=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCC=CC1(c2cc(OC)cc(OC)c2)CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a suspension of pentyltriphenylphosphonium bromide (5 equiv.) in dry THF (0.1 8M) at 0° C., under an argon atmosphere was added potassium bis(trimethylsilyl) amide (4.9 equiv.). The mixture was warmed to 10° C. and stirred for an additional 30 min to ensure complete formation of the orange ylide. The resulting slurry was used in the preparation of 1-(3,5-dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:31][O:32][C:33](=[O:42])[CH2:34][C:35]1([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:41][CH2:40][CH2:39][CH2:38][C:35]2([CH2:34][C:33]([O:32][CH3:31])=[O:42])[CH2:36][CH2:37]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC1(CCCN)CC1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1(CCCNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Temperature: 0 °C

Procedure:
A solution of 591 mg (1.51 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxa-diazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2), 376 mg (1.81 mmol) of methyl[1-(3-amino-propyl)cyclopropyl]acetate hydrochloride, 859 mg (2.26 mmol) of HATU and 1 ml of N,N-diiso-propylethylamine in 10 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was poured into ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and, after filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative RP-HPLC. This gave 233 mg (0.43 mmol, 28.5% of theory) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[C:6]2=[O:14].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>[C:16]1([C:2]2[C:13]3[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([CH3:15])[C:6]3=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1Cc2c(cc3c(c2Br)CCC3)C1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: CC1Cc2c(cc3c(c2-c2ccccc2)CCC3)C1=O
Temperature: 80 °C
Yield: 97.1 %

Procedure:
10 g (37.7 mmol) of 4-Bromo-2-methyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (1b), 5.5 g (45.3 mmol) of phenylboronic acid, 8.8 g (80 mmol) of sodium carbonate, 80 ml of ethylene glycol and 12 ml of water were placed under a protective argon atmosphere and heated to 80° C. While stirring vigorously freshly prepared catalyst solution of 20 mg of palladium (II) acetate, 260 mg of 3,3′,3″-phoshinidynetris(benzenesulfonic acid)trisodium salt (TPPTS) in 4 ml of water were added to the reaction and the reaction mixture was refluxed for 3 hrs. After cooling to room temperature, 40 ml of water was added and the ethylene glycol phase was extracted three times with a total of 240 ml of toluene. The combined organic phases were washed twice with a total of 250 ml of aqueous sodium chloride and dried over 150 g of sodium sulfate. Removal of solvents gave 9.6 g of brawn oil, which was gradually crystallized (97%, GC-MS).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:18])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:19]1([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15](=[O:16])[N:14]3[C:9]=2[C:10]([CH3:18])=[C:11]([C:26]2[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH:12]=[CH:13]3)[CH2:21][CH2:20]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 62.3 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-methyl-phenyl boronic acid (65 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (90 mg, 62%). ESI-MS m/z: 362 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6](=[NH:10])OCC.[NH3:14]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6](=[NH:10])[NH2:14]
Reactant: CCOC(=N)c1cccc(Cl)c1
Reactant: N
Agent: Cl
Solvent: CO
Product: N=C(N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
A 1-L round bottom flask was charged with ethyl 3-chlorobenzimidate hydrochloride (26.9 g, mmol, 122 mmol, 1 eq.) and NH3 (7N in methanol, 360 mL, 2.52 mol, 20 eq.) in methanol (270 mL). The resulting mixture was stirred at room temperature for 3 days. The volatile material was removed under reduced pressure and the resultant off-white solid was used in the next step without further purification (23.9 g, 89% yield). 1H NMR (DMSO-d6, 500 MHz) δ 9.48 (br s, 4H), 7.97-7.94 (m, 1H), 7.84-7.79 (m, 2H), 7.65 (t, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[I:14]I.OS([O-])=O.[Na+]>C(Cl)Cl.O>[I:14][C:4]1[CH:3]=[C:2]([CH3:1])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Cc1ccc(N)cc1
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of 4-methylaniline (53.5 g, 500 mmol) in DCM (200 mL) was added a solution of NaHCO3 (50.4 g) in water (500 mL), and then I2(127 g) was added. The mixture was stirred at rt overnight. The mixture was treated with aqueous NaHSO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated in vacuo to afford the product as brown oil (110 g, yield 95%). 1H NMR (300 MHz, CDCl3): δ 7.48 (dd, J=1.8 & 0.6 Hz, 1H), 6.96 (dd, J=8.1 & 1.8 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 3.98 (bs, 2H), 2.22 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 57, step C) (5.0 g, 11.6 mmol), methane sulfonyl chloride (1.4 mL, 17.5 mmol) and DCM (200 mL) was added TEA (80.1 mL, 58.2 mmol). The reaction was stirred at rt and monitored by TLC. After complete consumption of the starting material the clear yellow solution was concentrated onto silica gel and purified by chromatography to afford the title compound of step A as a yellow solid (3.54 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.5 Hz, 1H), 6.57 (dd, J=9.2, 2.6 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.09-4.00 (m, 2H), 3.89 (s, 3H), 3.10-3.03 (m, 4H), 2.99-2.90 (m, 2H), 2.84 (s, 3H), 2.61-2.52 (m, 5H), 1.85-1.77 (m, 2H), 1.50-1.37 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 71.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 3-methoxyphenylboronic acid (available from Combi-Blocks Inc.; 61 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-3′-methoxy-biphenyl-2-carboxylic acid (65 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.15 (br s, 1H), 8.46 (s, 1H), 8.28-8.39 (m, 2H), 8.20 (d, J=7.8 Hz, 1H), 8.09 (dd, J=8.5, 1.8 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 6.86-7.06 (m, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[C:20](Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:23]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: FC(F)(F)Oc1cc(Br)cc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Br)cc(OC(F)(F)F)c3)cc21

Procedure:
Prepared from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-trifluoromethoxybenzene according to Procedure B. White solid: mp 214-216° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97 (d, 1H, J=8.0 Hz), 1.68 (s, 6H); MS (ESI) m/z 414 ([M−H]−, 100%); Anal. Calc. For C17H13BrF3NO3: C, 49.06, H, 3.15, N, 3.37. Found: C, 49.16, H, 3.05, N, 3.30.