Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[C:8]([CH:11]([OH:14])[CH2:12][CH3:13])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:15][C:2]1([CH3:1])[C:6]2[CH:7]=[C:8]([C:11](=[O:14])[CH2:12][CH3:13])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCC(O)c1ccc2c(c1)C(C)(C)CO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To a solution of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-propan-1-ol (2.6 g, 12.60 mmol) in dry dichloromethane (40 mL) was added at room temperature pyridinium chlorochromate (3 g, 13.86 mmol). The reaction mixture was stirred for 1 hour at room temperature then filtered over celite. Water was added and the layers separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (5% ethyl acetate in hexane) to give 530 mg of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-propan-1-one (58%). 1H NMR (300 MHz; CDCl3): δ 1.21 (t, J=7.2 Hz, 3H), 1.37 (s, 6H), 2.94 (q, J=7.2 Hz, 2H), 4.32 (s, 2H), 6.80 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.81 (d, J=8.4 Hz, 1H).
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:48][CH2:47][C@H:46]([OH:49])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:50])=[CH:30][C:29]=1[NH:51][C:52]([C:54]1([C:57](O)=[O:58])[CH2:56][CH2:55]1)=[O:53].[F:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:48][CH2:47][C@H:46]([OH:49])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:50])=[CH:30][C:29]=1[NH:51][C:52]([C:54]1([C:57]([NH:65][C:64]2[CH:66]=[CH:67][C:61]([F:60])=[CH:62][CH:63]=2)=[O:58])[CH2:56][CH2:55]1)=[O:53]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Reactant: Nc1ccc(F)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (365 mg) was added to a mixture of 1-[({2,5-difluoro-4-[(2-{[((S)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylic acid triethylamine salt (175 mg), 4-fluoroaniline (0.0587 ml) and tetrahydrofuran (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 68 hours and 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the mixture and stirred, and the mixture was partitioned after the addition of ethyl acetate and tetrahydrofuran (1:1) (40 ml) and water (30 ml). The organic layer was washed with brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (128.5 mg, 75%) as a white solid.
Reaction SMILES: O=[C:2]1[N:6](CC2C=CC=CC=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C(#N)C>[CH:29]1([NH:32][C:14]([CH:4]2[CH2:3][CH2:2][NH:6][CH2:5]2)=[O:16])[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(NC1CC1)C1CCNC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 16.4 g (75 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1 N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94°-96° C.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:35])([F:34])[F:36])[CH:27]=3)=[O:24])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2cccc(OC(F)(F)F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(Br)cc1
Product: Brc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.774 g (4.5 mmol) 4-bromoaniline is heated under nitrogen atmosphere for 1.5 h at 90° C. The process is then carried out as in Example 21. Title compound is obtained after recrystallization from acetate/hexane and drying under HV (8 h at 100° C.); m.p. 201-202° C.; ESI-MS: (M+H)+=391 und 393.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[CH:12][N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][NH:9]3)[CH2:3][CH2:2]1.[F:14][C@@H:15]1[C@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][C@H:16]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[OH-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.C1(NC2N=C3C(NC=N3)=CN=2)CC1.[NH4+].[OH-]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH:1]1([NH:4][C:5]2[N:13]=[CH:12][N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:16]2[O:17][C@H:18]([CH2:21][OH:22])[C@@H:19]([OH:20])[C@H:15]2[F:14])[CH2:3][CH2:2]1
Reactant: c1nc(NC2CC2)c2nc[nH]c2n1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CC4)ncnc32)[C@H](F)[C@@H]1O
Temperature: 37 °C

Procedure:
6-(Cyclopropylamino)-9H-purine (0.2 g, 1.1 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g, 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. The pH of the suspension was adjusted to 7.0 with KOH. Thymidine phosphorylase (2,000 I.U.) and purine nucleoside phosphorylase (5,540 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 5, 0.2 g of 6-(cyclopropylamino)purine and 2,000 I.U. of thymidine phosphorylase and 5,540 I.U. of purine nucleoside phosphorylase were added. On day 9, 0.2 g of 6 (cyclopropylamino) purine was added and the pH of the reaction was adjusted to 7.0 with KOH. Thymidine phosphorylase (2,000 I.U.) and purine nucleoside phosphorylase (5,540 I.U.) were added. On day 20, the pH of the reaction was adjusted to 9.4 with NH4OH and the reaction was applied to a 2.5×8.5 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing with water, the product was eluted with water/methanol (7/3). Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound that analyzed as a 0.4 hydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:48])[NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][N:53]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:48])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:52]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-(−)-3-dimethylaminopyrrolidine (44 mg), followed by stirring at room temperature for 3.5 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br-].[CH3:10][C:11]1([CH:16]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:17])[O:15][CH2:14][CH2:13][O:12]1.[N+:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)([O-:39])=[O:38].[NH4+].[Cl-]>C1COCC1.CS(C)=O>[N+:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[CH:17][CH2:16][C:11]2([CH3:10])[O:12][CH2:13][CH2:14][O:15]2)=[CH:42][CH:41]=1)([O-:39])=[O:38]
Reactant: CC(C1(C)OCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(CC=Cc2ccc([N+](=O)[O-])cc2)OCCO1
Reaction time: 1 h
Yield: 48 %

Procedure:
To 62.8 mmol of LDA in 226.4 ml of THF, is added dropwise at 0° C. a solution of 28.8 g (62.2 mmol) of (2-methyl-dioxolane-2-yl-2-ethyl)triphenylphosphonium bromide in 60 ml of DMSO. After 1 h at 0° C., 7.8 g (51.6 mmol) of p-nitrobenzaldehyde dissolved in 40 ml of THF are added. The reaction medium is hydrolyzed with a NH4Cl saturated solution and is extracted with ethyl ether. The organic phase is dried over Na2SO4 and concentrated. After purification by flash chromatography (silica, eluent: heptane: 70; ethyl acetate: 30), the product is obtained with a 48% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[C:13]([NH:15][N:16]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]1[C:22]([O:24]C)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][CH:30]=1>>[Br:21][C:18]1[CH:19]=[CH:20][N:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])[C:17]=1[C:22](=[O:24])[NH:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:36])([F:27])[F:37])[N:34]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)n1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cccc(C(F)(F)F)n1
Yield: 50.7 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(benzyloxycarbonylamino)propanamido)-3-bromo-1H-pyrrole-2-carboxylate (2.00 g, 4.7 mmol) and 6-(trifluoromethyl)pyridin-2-amine (3.00 g, 18.5 mmol) following the experimental procedure described in Preparation 44a. 1.32 g (51% yield) of the desired compound were obtained.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.O>CC#N>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:15][CH2:14]2)[N:18]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncnc(Cl)n2)CC1

Procedure:
A solution of 4-N-Boc-aminomethylpiperidine (25 g, 120 mmol), 2,4-Dichloro-1,3,5-Triazine (20 g, 140 mmol) and DIPEA (77.4 g, 600 mmol) in CH3CN (300 ml) was stirred at room temperature for 2 hours. Water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue that was purified using normal phase chromatography, eluting with petroleum ether containing 30% ethyl acetate to give tert-butyl (1-(4-chloro-1,3,5-triazin-2-yl)piperidin-4-yl)methylcarbamate as an off white solid (30.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:13][CH2:12]1.[F:14][C:15]([F:22])([F:21])[C@@H:16]([OH:20])[CH2:17][CH2:18][OH:19].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH:11]1([C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=2[O:20][C@H:16]([C:15]([F:22])([F:21])[F:14])[CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1
Reactant: OCC[C@H](O)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2CC2)c(O[C@@H](CCO)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 48 h
Yield: 8.4 %

Procedure:
6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 180 mg, 901 μmol), (S)-4,4,4-trifluorobutane-1,3-diol (394 mg, 2.73 mmol) and potassium tert-butoxide (307 mg, 2.73 mmol) were combined with DMF (3 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 48 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (23 mg, 8.3%) and its regioisomer; MS (EI) 304.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][C:3]1=2>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:11]1([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([OH:1])[CH:10]=[CH:9][CH:8]=3)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCCc2[nH]c(-c3ccccc3)cc21
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1cccc2[nH]c(-c3ccccc3)cc12

Procedure:
The 2-phenyl-4-hydroxy-indole was synthesised from 4-oxo-2-phenyl-4,5,6,7-tetrahydroindole by aromatisation with palladium-on-charcoal in diphenyl ether and has a melting point of 120°-123° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11][CH:10]([CH2:12][SH:13])[CH2:9][S:8]1)[CH3:2].[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Br)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][S:13][CH2:12][CH:10]2[CH2:9][S:8][C:7]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[S:11]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared by the procedure of Example 2 using the mercaptan produced in Example 31 (2.0 g, 0.0056 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (prepared as described in U.S. Pat. No. 4,565,882, Example 14) (2.0 g, 0.006 mol) and anhydrous potassium carbonate (3.5 g) in methyl ethyl ketone (25 ml) at reflux overnight. The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.1 g (70%) of the product as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:16])[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1B(O)O>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>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc(Br)cc1=O
Reactant: OB(O)c1cc(Cl)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Cn1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
3.8 g (12 mmol) of tert-butyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate and 3.4 g (14.4 mmol) of 2-bromo-5-chlorophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 3.9 g (purity 94%, 76% of theory)
Reaction SMILES: Br[CH:2]([CH3:11])[CH2:3][CH2:4][C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[CH3:11][CH:2]([CH2:3][CH2:4][C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[C:12]#[N:13]
Reactant: [C-]#N
Reactant: Cc1ccc(CCC(C)Br)o1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(CCC(C)C#N)o1
Reaction time: 16 h

Procedure:
A solution of 2-(3-bromobutyl)-5-methyl-furan (20.5 g) and 13 g KCN in 100 ml of dry dimethyl sulphoxide was heated during stirring for 16 hours at 50°-55° C. The mixture was cooled, diluted with water and extracted using ether. The extracts were washed with water, dried on anhydrous MgSO4 and boiled down under vacuum. The residue was subjected to chromatographic adsorption over silicagel with hexane/ethyl acetate (9:1) and gave 14.6 g dl-2-methyl-4-(5-methyl-2-furyl)-butane nitrile.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])/[CH:12]=[CH:13]/[CH3:14].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[NH2:6][C:5]1[C:4]([F:10])=[CH:3][C:2](/[C:13](/[CH3:14])=[CH:12]/[C:11]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([F:9])[CH:7]=1
Reactant: Nc1cc(F)c(Br)cc1F
Reactant: C/C=C/C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(\C)c1cc(F)c(N)cc1F
Temperature: 110 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
A mixture of 4-bromo-2,5-difluoroaniline (5.0 g), ethyl crotonate (4.98 ml), palladium acetate (54.0 mg), tris(2-methylphenyl)phosphine (442 mg), and triethylamine (33.4 ml) was stirred at 110° C. in a nitrogen atmosphere for 48 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The obtained residue was separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (5% ethyl acetate/n-hexane) to give Compound 10a (1.69 g, 29%) as a brown solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:13]2[C:12](=[O:23])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:6]1=[O:34])[CH2:2]CC.BrC[CH2:37][O:38]C>>[F:32][C:30]([F:33])([F:31])[C:26]1[CH:25]=[C:24]([N:7]2[C:8]3[CH2:9][CH2:10][CH2:11][C:12](=[O:23])[C:13]=3[CH:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:5]([CH2:1][CH2:2][O:38][CH3:37])[C:6]2=[O:34])[CH:29]=[CH:28][CH:27]=1
Reactant: CCCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Reactant: COCCBr
Product: COCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1

Procedure:
The title compound is prepared in analogy to 4-(3-butyl-1-(3-(trifluoromethyl)phenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 21), using 1-bromo-2-methoxyethane as alkylating agent. Yield: 15 mg; ESI mass spectrum [M+H]+=470; Retention time HPLC: 1.33 min (V001—006).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3N=CC=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[C:35]4[N:36]([CH:38]=[CH:39][N:40]=4)[CH:37]=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Brc1ncccn1
Reactant: Cc1cc2cc(-c3ncccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2cc(-c3nccn4ccnc34)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-6-(imidazo[1,2-a]pyrazin-8-yl)-3-methylnaphthalen-2-yl)acetic acid (61) was prepared in a similar fashion to compound 59 with the substitution of 8-chloroimidazo[1,2-a]pyrazine hydrobromide (See Guzi, T. J, Paruch, K., et. al. US 20070105864, p. 121) for 2-bromopyrimidine in step 2. The title compound (0.017 g) was isolated as an amorphous pale yellow powder. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H27ClN3O3: 500.7; found: 500.0. 1H-NMR: 400 MHz, (CD3CN) δ: 9.00 (d, J=1.2 Hz, 1H); 8.39 (d, J=4.4 Hz, 1H); 8.20 (dd, J=8.8, 1.2 Hz, 1H); 8.11 (d, J=4.4 Hz, 1H); 8.06 (d, J=1.2 Hz, 1H); 7.99 (s, 1H); 7.62-7.56 (m, 3H); 7.38 (d, J=8.8 Hz, 1H); 7.36 (br d, J=8.8 Hz, 1H); 5.25 (s, 1H); 2.58 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:4]=2[N:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:39][C:24]([F:23])([F:38])[C:25]1[C:26]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]4[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:4]=4[N:3]=3)[C:33](=[O:37])[CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CN(c2ncccc2C(F)(F)F)CCN1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2cc(C(F)(F)F)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2=O)nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole from step (a) above (716 mg, 2 mmol), 4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-2-one from step (b) above (500 mg, 2 mmol), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (207 mg, 0.2 mmol, Strem Chemicals), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (213 mg, 0.4 mmol, Aldrich) and cesium carbonate (978 mg, 3 mmol, Aldrich) in 1,4-dioxane (2 mL) was subjected to microwave irradiation at 160° C. for 1.5 h. The mixture was cooled to room temperature, filtered, and the filtrate was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as a brown oil. MS (ESI, positive ion) m/z: 560 (M+1).