Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[C:5](O)=[N:6][C:7]=1[CH3:8].C1(P(Cl)([Cl:21])=O)C=CC=CC=1>O>[Cl:21][C:5]1[C:4]([C:10]([OH:12])=[O:11])=[CH:3][C:2]([Cl:1])=[C:7]([CH3:8])[N:6]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Cc1nc(O)c(C(=O)O)cc1Cl
Solvent: O
Product: Cc1nc(Cl)c(C(=O)O)cc1Cl
Temperature: 135 °C
Reaction time: 1 h

Procedure:
To 5 g (0.027 mole) of 5-chloro-2-hydroxy-6-methyl-3-pyridinecarboxylic acid was added 35 g of phenylphosphonic dichloride. The mixture was heated to 135° C. for 1.5 hr. After cooling, the reaction solution was poured carefully into 250 ml of water and stirred for 1 hr. The water was extracted with 3×100 ml of methylene chloride. The combined organic extracts were washed with 2×100 ml of water, dried over sodium sulfate, filtered, concentrated by rotary evaporation, taken up in toluene, charcoaled, and concentrated by rotary evaporation. The crude residue was crystallized from hexane to give 1.7 g (31%) of beige analytically pure crystals, m.p. 123°-38° C. with decomposition.
Reaction SMILES: [F-].[K+].C[Si](C)(C)[C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[C:17](I)=[CH:16][CH:15]=[C:14]([Cl:19])[N:13]=1.N>CN(C)C=O.[Cu]I.O1CCCC1>[Cl:11][C:12]1[C:17]([C:5]([F:8])([F:7])[F:6])=[CH:16][CH:15]=[C:14]([Cl:19])[N:13]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Clc1ccc(I)c(Cl)n1
Agent: [Cu]I
Agent: N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Potassium fluoride (2.24 g, 38.5 mmol) and copper (I) iodide (7.33 g, 38.5 mmol) were weighed in a flask, and the mixture was heated with a gas burner while gently shaking under high vacuum until the content becomes a pale-yellow green. After cooling to room temperature, anhydrous N,N-dimethylformamide (50 ml), anhydrous tetrahydrofuran (10 ml) and trimethyl(trifluoromethyl)silane (5.5 ml, 35 mmol) were added. The mixture was heated to 50° C., and stirred for 21 hrs. A mixed solution of 2,6-dichloro-3-iodopyridine (9.59 g, 35.0 mmol) in anhydrous N,N-dimethylformamide (10 ml)—anhydrous tetrahydrofuran (20 ml) was added dropwise to the above-mentioned reaction mixture at 50° C. After stirring at 50° C. for 21 hrs, trimethyl(trifluoromethyl)silane (0.55 ml, 3.5 mmol) was added, and the mixture was stirred for 24 hrs. The reaction mixture was cooled to room temperature, poured into 12% aqueous ammonia, and the mixture was extracted 3 times with diethyl ether. The combined organic layer was washed successively with 12% aqueous ammonia, 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:hexane=1:4) to give 2,6-dichloro-3-(trifluoromethyl)pyridine (7.32 g, yield 97.3%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:27]([C@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[CH2:37][C:38]([F:41])([F:40])[F:39])[CH:28]([CH3:30])[CH3:29]>>[NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:35]3[CH2:34][CH2:33][N:32]([CH2:37][C:38]([F:40])([F:41])[F:39])[C@@H:31]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:36]3)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Oc2cccc3[nH]c(=O)c(N)nc23)n1
Reactant: CC(C)C[C@H]1CNCCN1CC(F)(F)F
Product: COC[C@H](C)Nc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(N2CCN(CC(F)(F)F)[C@@H](CC(C)C)C2)n1

Procedure:
The reaction of (S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (74 mg, 0.2 mmol, Example 122(b)) with (S)-2-isobutyl-1-(2,2,2-trifluoroethyl)piperazine (89 mg, 0.4 mmol) under the conditions of Example 34 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 565 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH:22]([CH3:26])[NH:21]1>>[CH3:19][CH:20]1[NH:21][CH:22]([CH3:26])[CH2:23][N:24]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:25]1
Reactant: CC1CNCC(C)N1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: CC1CN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC(C)N1

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with 2,6-dimethylpiperazine as described in Step 2 of Example 29 to afford 2-(3,5-dimethylpiperazin-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde as a solid. The solid is dissolved in methanol, treated with 1M ethereal hydrochloric acid and concentrated. The residue triturated with ether to give 2-(3,5-dimethylpiperazin-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde hydrochloride (74% yield) as a purple solid. ESI/MS 334 (M+H); RT=2.52 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:12]2[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(C(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 86.3 %

Procedure:
A mixed solution of tert-butyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (6.52 g, 12 mmol), phenylboronic acid (1.76 g, 14.4 mmol) and sodium carbonate (3.18 g, 30 mmol) in toluene (50 mL), ethanol (10 mL) and water (10 mL) was stirred under an argon atmosphere at room temperature for 10 min. To the obtained mixture was added tetrakis(triphenylphosphine)-palladium (0.69 g, 0.6 mmol) and the mixture was refluxed under heating under an argon atmosphere for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate (5.01 g, 86.4%) as crystals.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][NH:18][N:19]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:26][C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[C:20]([N:6]1[C:5]2[CH:24]=[CH:25][C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][NH:18][N:19]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(Br)ccc21
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 110 °C
Yield: 8.1 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (190 mg, 0.478 mmol) in DMF (5 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (126 mg, 0.57 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.048 mmol) and 2M aq. Na2CO3 (1 mL, 2 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-20% 7M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (16 mg, 8%) as a light yellow solid. LCMS (ESMS): m/z 412.67 (M++1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@:8]1([CH2:15][N+:16]([O-])=O)[CH2:14][C@H:13]2[C@@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@:8]1([CH2:15][NH2:16])[CH2:14][C@H:13]2[C@@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC=C[C@@H]21
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@]1(CN)C[C@@H]2CC=C[C@@H]21
Reaction time: 5.5 h
Yield: 28.7 %

Procedure:
Tert-butyl[(1S,5R,6R)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (peak 1, 21.6 g, 80.8 mmol) was dissolved in ethanol (200 mL) and water (100 mL). To the solution, iron powder (45.1 g, 80.8 mmol) and ammonium chloride (2.59 g, 48.5 mmol) were added, and the mixture was stirred for 5.5 hours under heating to reflux. To the reaction solution, iron powder (9.0 g, 161 mmol) was then further added, and the mixture was further stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with a saturated aqueous solution of sodium bicarbonate and ethyl acetate, and filtered to remove insoluble matter. From the filtrate, the organic solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate from the aqueous layer. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by amino column chromatography to obtain the compound of interest as a pale yellow oil (5.5 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][C:14]#[N:15])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9][C@H:8]1[CH2:13][C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-cyanomethyl-4-hydroxypyrrolidine (2.95 g) in dichloromethane (30 ml) were added triethylamine (1.85 g) and a solution of methanesulfonyl chloride (1.76 g) in dichloromethane (2 ml) at ice-cooling. After stirring at 5°-10° C. for 1 hour, the solution was poured into an ice water. The separated organic layer was washed with water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated to give (2R,4R)-1-allyloxycarbonyl-2-cyanomethyl-4-methanesulfonyloxypyrrolidine (4.44 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N:11]1([C:14]2[CH:19]=[C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[CH:26]2[CH2:27][C:28]([CH3:35])([CH3:34])[CH2:29][C:30]([CH3:32])([CH3:33])[CH2:31]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A mixture of 4-[5-morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (103 mg, 0.212 mmol) produced in Example (81d), trifluoroacetic acid (1 mL, 13.0 mmol) and dichloromethane (2 mL) was stirred for 1 hour at room temperature. Ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 42 mg of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CO>N1C=CC=CC=1>[S:23]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)([CH3:22])(=[O:25])=[O:24]
Reactant: O=C(c1ccc(CN2CCC(O)CC2)o1)N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)OC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 91.8 %

Procedure:
In 70 ml of pyridine was dissolved 3.47 g (11.88 mmol) of Compound t and with ice-cooling, 1.9 ml (23.77 mmol) of methanesulfonyl chloride was added dropwise. The mixture was stirred at 0° C. for 4.5 hours and, after addition of 5 ml of methanol, stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was dissolved in 100 ml of methylene chloride. This solution was washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.04 g (91.8%) of 1-[5-(4-mesyloxypiperidinomethyl)-2-furancarbonyl]piperidine (Compound u) as red-brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN5CCCC5)CC4)c3c2)cc(Cl)c1O
Yield: 60.8 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.068 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (30 mg, 0.106 mmol) to afford the desired product (21.5 mg, 61%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.29 (s, 1H), 8.07-7.99 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 3.99 (s, 3H), 3.54 (d, J=12.4 Hz, 2H), 3.22 (t, J=11.7 Hz, 2H), 2.82 (s, 4H), 2.71 (d, J=6.5 Hz, 2H), 2.60-2.51 (m, 1H), 2.06-1.81 (m, 7H), 1.71-1.59 (m, 2H), 1.36-1.27 (m, 2H), 1.27-1.19 (m, 2H); ESI MS m/z 520 [C30H34ClN3O3+H]+; HPLC 98.6% (AUC), tR=10.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[C:15]([CH3:21])[N:14]=3)[N:12]=2)=[C:4]([F:22])[CH:3]=1.C1(=O)O[CH2:26][CH2:25][O:24]1.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][CH2:25][OH:24])[CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:19])[CH3:20])[N:16]=[C:15]([CH3:21])[N:14]=3)[N:12]=2)=[C:4]([F:22])[CH:3]=1
Reactant: O=C1OCCO1
Reactant: Cc1nc(-c2c[nH]c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2cn(CCO)c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Yield: 71 %

Procedure:
A suspension of 5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-3-methyl-1H-[1,2,4]triazole (2.9 g, 7.96 mmol) in toluene (50 mL) was treated with ethylene carbonate (25 mL) and heated at reflux for 5 h. The cooled reaction mixture was diluted with DCM and passed through a pad of silica eluting with DCM then 20% methanol in DCM. Methanolic fractions were combined and concentrated in vacuo to give a pale tan solid. The solid was triturated in diethyl ether to give 2-[2-(4-Bromo-2-fluoro-phenyl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol as a white solid (2.3 g, 71%). LCMS: RT=2.85 min, [M+H]+ =408/410. 1H NMR 400 MHz (CDCl3) δ: 8.16 (1H, s), 7.67-7.20 (3H, m), 5.83 (1H, m), 4.05 (2H, t, J=5.10 Hz), 3.92 (2H, t, J=5.10 Hz), 2.44 (3H, s), 1.50 (6H, d, J=6.65 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[N:15]=[C:16]([OH:25])[C:17]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:18]=2[N:24]=1.C(N(CC)CC)C>[Pd].CN(C)C=O>[OH:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([N:21]2[CH2:22][CH2:23][C:17]3[C:16]([OH:25])=[N:15][C:14]([CH3:13])=[N:24][C:18]=3[CH2:19][CH2:20]2)[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: Cc1nc(O)c2c(n1)CCNCC2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(O)c2c(n1)CCN(c1nc(C)nc(O)c1[N+](=O)[O-])CC2

Procedure:
In analogy to the procedure described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example. 1a) was treated with the 2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (prepared from the corresponding N-benzyl derivative [Bull. Chem. Soc. Jap. (1971), 44(1), 153-8] by catalytic hydrogenation with palladium on charcoal) in N,N-dimethylformamide in the presence of triethylamine at room temperature to yield the title compound as yellow solid; m.p.>200° C.; MS: [M+H]+=333.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][CH:22]([CH2:36][CH3:37])[C@@H:23]([C:25]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[OH:24]>>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:21][C@H:22]([C:23]([C:25]2[N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][N:26]=2)=[O:24])[CH2:36][CH3:37])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
Similarly prepared according to the general procedure given for Example 43 but using (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid, prepared as described in reference 21, and (S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol, prepared as in reference 26; MS: 519 (M+Na), LC-MS retention time 4.5 min; 1H NMR (CDCl3) 8.19 (d, J=7 Hz, 2H), 7.65–7.51 (m. 3H), 6.64 (d, J=7 Hz, 1H), 5.44–5.38 (m, 1H), 3.69–3.38 (m, 8H), 3.05–2.98 (m, 1H), 2.76 (dd, J=16 Hz & 10 Hz, 1H), 2.26 (dd, J=16 Hz & 3 Hz, 1H), 2.10 (m, 1H), 1.80 (m, 1H), 1.75–1.59 (m, 6H), 1.28–1.13 (m, 5H), 1.03–0.98 (t, J=7 Hz, 3H), 0.92–0.81 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][Zn+])#[N:32]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=5[C:31]#[N:32])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1ccccc1C[Zn+]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3C#N)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.23 min; Mass spectrum (ESI+): m/z=508 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][NH:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:33][CH2:34][N:35]1[C:43]2[C:38](=[CH:39][C:40](B(O)O)=[CH:41][CH:42]=2)[C:37]([CH3:47])=[N:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][NH:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:36]=[C:37]3[CH3:47])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(COCc2ccccc2)c2ccc(B(O)O)cc12
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1cncc(Cl)n1)Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(COCc2ccccc2)c2ccc(-c3cncc(NCC(Cc4ccccc4)NC(=O)OC(C)(C)C)n3)cc12
Temperature: 75 °C
Yield: 160.9 %

Procedure:
A mixture of the compound from step C (0.42 g, 1.17 mmol), the boronic acid 5 from step B (0.47 g, 0.58 mmol), and potassium carbonate (0.16 g, 1.17 mmol) in DMF/water (5 mL/2 mL) was degassed, placed under nitrogen and was added to PdCl2(dppf) (29 mg, 0.035 mmol). The mixture was heated at 75° C. for 11 h under nitrogen, and then cooled and extracted with ethyl acetate (50 mL×2). Chromatography on silica eluting with a 20% to 70% gradient of ethyl acetate/hexane gave the title compound (0.54 g, 81%). LCMS (+APCI) m/z 579 (M+H).