Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=1>C(O)CCC.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:24])[F:25])=[CH:17][N:16]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(S(C)(=O)=O)ccc1N
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(Nc2ccc(S(C)(=O)=O)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
To a mixture of 2-methoxy-4-(methylsulfonyl)aniline (0.095 g, 0.47 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in 1-butanol (1.5 mL) was added TFA (0.036 mL, 0.047 mmol). The reaction was stirred in a sealed tube at 100° C. for 1.5 h. The reaction was concentrated and the product was isolated by reverse-phase HPLC to give N2-(2-methoxy-4-(methylsulfonyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.18 g, 20%). 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=12.9, 1H), 8.24 (d, J=5.0, 2H), 7.53 (d, J=10.1, 1H), 7.48 (s, 1H), 7.38-7.29 (m, 1H), 3.99 (s, 3H), 3.20 (s, 3H), 2.94 (d, J=4.3, 3H); LRRK2 Ki=0.002.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH2:11][OH:12])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15]>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH:11]=[O:12])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15]
Reactant: CCOc1cc(CO)cc(OCC)c1Cl
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(OCC)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a solution of (4-chloro-3,5-diethoxy-phenyl)-methanol (4.0 g, 17.34 mmol, 1.0 equiv) in THF (40 mL) was added activated MnO2 (15.08 g, 173.4 mmol, 10.0 equiv) and the reaction mixture stirred for 18 h at rt. Filtration through Hyflo Super Cel and purification of the crude material by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate provided 3.7 g (92%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 6H), 4.19 (q, J=7.0 Hz, 4H), 7.07 (s, 2H), 9.89 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.61, 65.22, 106.26, 118.64, 135.08, 156.22, 191.01. MS (EI): 229.4 [M]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([Li])=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1.[Cl:15]N1C(=O)CCC1=O.S(=O)(=O)(O)O>>[Cl:15][C:9]1[CH:8]=[CH:7][C:5]2[CH2:6][C:2]([CH3:14])([CH3:1])[O:3][C:4]=2[C:10]=1[O:11][CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: [Li]c1ccc2c(c1OC)OC(C)(C)C2
Agent: O=S(=O)(O)O
Product: COc1c(Cl)ccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension containing 2,3-dihydro-2,2-dimethyl-6-lithio-7-methoxybenzofuran is prepared as described in Example 1. The suspension is cooled in an ice-water bath and 13.3 g of N-chlorosuccinimide is added. The suspension is stirred at room temperature for eight hours and then acidified with cold aqueous sulfuric acid. The organic phase is separated, washed with water saturated with sodium chloride, then dried over sodium sulfate. The solvent is evaporated to give crude 6-chloro-2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran.
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]\[C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[S:16][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]([OH:40])=O)[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1>>[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[S:16][CH:17]=[C:13](/[CH:12]=[CH:11]\[C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[N:14]=3)[CH2:19][CH2:20]2)=[O:40])[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(/C=C\c3cccc4ccccc34)cs2)CC1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(/C=C\c3cccc4ccccc34)cs2)CC1

Procedure:
tert-Butyl 4-{4-[(Z)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-3, 171 mg) is deprotected analogously to Example II-2 and then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (100 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[(E)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (200 mg).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=2)[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=1)(O)=[O:2].[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1>>[CH3:31][N:28]1[CH:29]=[CH:30][C:26]([NH:25][C:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:13]3[C:7]4[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=4[CH:5]=[C:4]([C:1](=[O:2])[NH:25][C:26]4[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=4)[CH:14]=3)=[CH:21][N:20]=2)=[O:24])=[N:27]1
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)Cc2c(Oc3ccc(C(=O)O)nc3)cc(C(=O)O)cc2O1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)Nc4ccn(C)n4)nc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 149, from 5-(6-carboxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid (163b) (111 mg, 0.288 mmol) and 3-amino-1-methyl-pyrazole (56 mg, 0.576 mmol) to give a white solid (112 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1 H) 8.98 (s, 1 H) 8.30 (d, J=2.53 Hz, 1 H) 8.22 (d, J=8.59 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.24-7.28 (m, 1 H) 7.07 (d, J=3.03 Hz, 2 H) 6.79 (d, J=2.02 Hz, 1 H) 6.83 (d, J=2.27 Hz, 1 H) 3.84 (s, 3 H) 3.74 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H); LCMS for C25H25N7O4 m/z 488.20 (M+H+); Anal. Calcd. for C25H25N7O4.0.1 CHCl3: C, 59.50; H, 5.15; N, 19.35; Found: C, 59.77; H, 5.17; N, 18.96.
Reaction SMILES: [C:1]([CH2:3][C@H:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[C:5](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:6])#[N:2].[Li+].[BH4-].Cl>C1COCC1.O>[OH:6][CH2:5][C@@H:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[CH2:3][C:1]#[N:2]
Reactant: N#CC[C@@H](C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC[C@@H](CO)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-[(R)-β-Cyano-α-(2-fluorophenyl)-propionyl]-4-(R)-phenyl-2-oxazolidinone (400 g, 1.18 mol) is suspended in THF (4000 mL) and H2O (25 mL). The reaction mixture is cooled in ice bath to 0° C. and a solution of LiBH4 in THF (2M, 887 ml, 1.77 mol, 1.5 eq) is added slowly. The mixture is then stirred at 0° C. for 2 hours, after which 2N HCl (1500 mL) is cautiously added. The resulting solution is then extracted with Et2O (2×1500 mL). The combined organic phases are then washed with saturated NaCl solution (2×1500 mL), dried over MgSO4 and concentrated in vacuo. The solid 4(R)-phenyl-2-oxazolidinone is recovered by filtration and washed with Et2O (2×100 mL). The filtrate is then chromatographed (silica gel, EtOAc/Hexanes, 1:3) to give β(R)-(hydroxymethyl)-β-(2-fluorophenyl)-propionitrile as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=[O:25])=[CH:21][CH:22]=2)[CH:17]=[N:16]1>>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=[O:25])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=1
Reactant: COc1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: COc1ccc(Cn2ncc3cc(C=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1-bromomethyl-4-methoxy-2-trifluoromethyl-benzene and 1H-indazole-5-carbaldehyde following General Procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12].C1C(=O)N([Br:25])C(=O)C1>C1COCC1>[Br:25][C:16]1[CH:17]=[C:13]([C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[O:12])[NH:14][CH:15]=1
Reactant: O=C(c1ccc[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: O=C(c1cc(Br)c[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of (2-chloro-5-nitro-phenyl)-(1H-pyrrol-2-yl)-methanone (600 mg, 2.4 mmol) (from Aldrich, Milwaukee, Wis.) and NBS (504 mg, 2.8 mmol) in THF (60 mL) was stirred at room temperature for overnight. The reaction was concentrated, diluted with ethyl acetate (100 mL), washed wit 1N NaOH, brine and concentrated. The residue was recrystallized to give 310 mg (39%) of (4-bromo-1H-pyrrol-2-yl)-(2-chloro-5-nitro-phenyl)-methanone.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][N:7]([CH:9](C)C#N)[CH3:8]>[Pd]>[CH3:9][N:7]([CH3:6])[CH2:8][CH2:2][CH2:1][NH:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8]
Reactant: CC(C#N)N(C)C
Reactant: CCNCC
Agent: [Pd]
Product: CN(C)CCCNCCCN(C)C
Yield: 58 %

Procedure:
GB-A 1,157,637, GB-A 1,157,638 and GB-A 1,157,639 disclose the reaction of 2-methylglutarodinitrile with diethylamine in the presence of hydrogen and palladium on barium sulfate or preferably palladium on carbon to form 5-diethylamino-2-methylvaleronitrile. Despite the long reaction time and a diethylamine excess of 200 mol % no tetraethyl derivative was found, although the diethylamino group reacts not only with the nitrile groups in position 5 but also with that in position 1 (ratio 4 to 1). DE-A 3,935,641 describes the synthesis of a secondary amine over a palladium catalyst. The reaction of dimethylaminopropionitrile takes place in this case with itself under hydrogenating conditions to form bis(3-dimethylaminopropyl)amine. The formation of a tertiary amine is achieved only when a spinel is used as support material which is considerably expensive to produce, and the yield is not more than 58%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C1N=C[N:15](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (21.6 mmol) in DMF (20 mL) was added N,N-carbonyldiimidazole (54.1 mmol). The reaction mixture was allowed to stir at rt for 30 min and then ammonium carbonate (97.4 mmol) was added in portions over several minutes. The reaction mixture was allowed to stir until for 5 days and then poured into water. A white precipitate formed. The mixture was extracted with EtOAc. The organic solutions were combined, washed sequentially with water, 1N HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4 filtered and concentrated to give 2-bromo-5-methoxybenzamide (18.5 mmol, 85%), which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:31][CH:32]=[CH2:33])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH:20]([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>C1COCC1>[C:50]([O:49][C:47](=[O:48])[CH2:46][C@@:20]1([CH3:21])[C:14]2=[N:13][CH:12]=[C:11]([N:10]([CH2:31][CH:32]=[CH2:33])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:34])[C:16](=[O:17])[N:15]2[C@@H:18]([C:22](=[O:30])[NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:19]1)([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)CC2C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)Nc1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To Intermediate 18c (495.7 mg, 1.08 mmol) in THF at −78° C. was added LiHMDS (2.268 mL, 2.268 mmol) dropwise. After 10 min, tert-butyl bromoacetate was added and the mixture was stirred at −78° C. for 20 min. It was allowed to warm to −40° C. over 20 min, then quenched with NH4Cl. The reaction mixture was diluted with EtOAc, then washed with H2O, brine, dried (Na2SO4) and concentrated. It was purified by SiO2 chromatography (50% EtOAc/hexanes) to afford 367.9 mg (59%) of intermediate 38a.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[N:27]=3)[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8]CC1C=CC(OC)=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:35])([CH3:33])[CH3:34])[N:27]=3)[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(COc2cc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ncc3C)c(=O)c2Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(O)c(Cl)c1=O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To a solution of 3-chloro-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (2.53 g, 5.00 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1.0 mL). The solution was stirred for several hours at room temperature. The solution was concentrated, diluted with water and extracted several times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated to provide 1.7 g of the title compound: MS (M+H) 388.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:9]([CH2:8][C:7]1[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=1[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)Oc1ccccc1CNCc1ccccn1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)Oc1ccccc1CN(CCCCCCBr)Cc1ccccn1

Procedure:
Compound 10 was synthesized with 9 (2 g, 8.84 mmol), using 1,6-dibromohexane (30 g, 130 mmol) and K2CO3 (1.22 g, 8.84 mmol) following a procedure analogous to that described for 2. Purification was carried out on a silica gel TLC plate that was developed in with a 1% methanolic NH3 (7 M NH3 in methanol/99% CH2Cl2. The product was isolated as pale yellow oil (73%).δ 1H NMR (CDCl3) δ 8.491 (dd, 1H, Ar), 7.630 (t, 1H, Ar), 7.565 (t, 2H, Ar), 7.120 (t, 2H, Ar), 7.020 (t, 2H, Ar), 3.740 (s, 2H, —CH2—), 3.660 (s, 2H, —CH2—), 3.334 (t, 2H, —CH2—), 2.452 (s, 2H, —CH2—), 1.787 (p, 2H, —CH2—), 1.516 (m, 2H, —CH2—), 1.354 (s, 9H, —C(CH3)3), 1.269 (m, 4H). Mass Spec.=435.18 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15](=[O:26])[N:16]([CH3:25])[C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([N:16]([CH3:25])[C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[O:26])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)N(C)[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)N(C)[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-1-methyl-1-((R)-1-phenyl-ethyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([C:24]([CH3:44])([CH3:43])[C:25]([NH:27]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[N:12]1([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([NH:27][C:25](=[O:26])[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:44])[CH3:43])=[CH:3][CH:4]=3)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccccc1
Reactant: Brc1ccc2ncc(N3CCOCC3)nc2c1
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: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)Nc1ccc2ncc(N3CCOCC3)nc2c1)c1ccccc1
Temperature: 120 °C
Yield: 168.8 %

Procedure:
A mixture of 7-bromo-2-morpholin-4-yl-quinoxaline [intermediate example 2.1] (50 mg), 2-phenyl-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isobutyramide (87 mg, 0.24 mmol) and Pd(PPh3)4 in 1:1 Toluene/EtOH (2 mL) was treated with 1M aq. sodium carbonate solution and heated at 120° C. under microwave irradiation for 15 minutes. The reaction was partitioned between EtOAc and water, the phases separated and the organic layer concentrated in vacuo. The reaction was repeated and the combined crude products were purified by trituration with DMSO to give the title compound (108 mg). UPLC-MS: RT=1.36 min; m/z (ES+) 453.27 [MH+]; required MW=452.56.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][CH2:41][N:42]1[C:46](=[O:47])[C:45]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:44]2[C:43]1=[O:52]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][CH2:41][N:42]5[C:43](=[O:52])[C:44]6[C:45](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]5=[O:47])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CC[C@@H](Cc2nn(CCN3C(=O)c4ccccc4C3=O)c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.8 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, 0.699 mmol) in N,N-dimethylformamide (3 mL) in a 5 mL microwaveable vial was added potassium carbonate (300 mg, 2.1 mmol, 3 eq) and N-(2-chloroethyl)phthalimide (300 mg, 1.43 mmol, 2 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 90° C. Analysis by LC/MS displayed the reaction had progressed to 20% completion. The reaction was irradiated in the microwave at 185° C. for 60 min. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 30-60% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the intermediate compound (142 mg, 33%). MS(ES)+ m/e 602.0 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])=[CH:4][CH:3]=1.[C:17](O)(=[O:19])[CH3:18].C(OC(=O)C)(=O)C>CCOCC>[C:17]([N:8]([CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: CCCCCCC(C)Nc1ccc(I)cc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCCC(C)N(C(C)=O)c1ccc(I)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 70 %

Procedure:
A flask containing N-(4'-iodophenyl)-2-amino octane (1.50 g, 4.5 mmol) was charged with acetic acid (15 ml) and acetic anhydride (15 ml). The reaction flask was immersed in an oil bath which was warmed to 70° C. over a period of 0.5 hr. After stirring for 19 hrs, the reaction was allowed to cool, diluted with ether (200 ml), washed with water (2×50 ml), saturated aqueous sodium bicarbonate (4×50 ml), water (2×50 ml) and brine (50 ml), dried (Na2SO4), filtered, and evaporated in vacuo. Flash column chromatography (silica, 1:4; EtOAc:hexanes) provided N-acetyl-N-2-octyl-4-iodoaniline (1.48 g, 70%) as a white solid. Mp 60°-62° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:10][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[Pt](=O)=O>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[N:10][C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)c1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nc2cc(N)ccc2[nH]1
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Platinum(IV) oxide (0.020 g, 0.090 mmol) was added to a suspension of 1,1-dimethylethyl 5-nitro-1H-benzimidazole-2-carboxylate (0.472 g, 1.793 mmol) in ethanol (20 mL) in a pressure vessel. The mixture was evacuated and flushed with nitrogen, then evacuated and flushed with hydrogen (50 Psi). After 1 h, the reaction mixture was filtered through Celite. The filtrate was concentrated and the residue was dried under vacuum to give the title compound (0.359 g, 69%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 10.03 (s, 1H), 7.66 (d, 1H), 6.49-6.90 (m, 2H), 3.77 (br. s., 2H), 1.64 (s, 9H). MS: m/z 234 (M+1).
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH2:4][CH2:3]1.[CH2:15]([O:22][C:23]1[C:24](Cl)=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:16]1([CH2:15][O:22][C:23]2[C:24]([N:2]3[CH2:3][CH2:4][CH:5]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][C:10]4=[O:14])[CH2:6][CH2:7]3)=[N:25][C:26]([C:29]([F:31])([F:32])[F:30])=[N:27][CH:28]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCCN1CC1CCNCC1
Reactant: FC(F)(F)c1ncc(OCc2ccccc2)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCN1CC1CCN(c2nc(C(F)(F)F)ncc2OCc2ccccc2)CC1
Yield: 79.8 %

Procedure:
A mixture of 1-[(4-piperidinyl)methyl]-2-pyrrolidinone hydrate (XXV 0.63 g, 3.46 mmol), compound XXIV (1.0 g, 3.46 mmol), and sodium carbonate (0.8 g, 6.92 mmol) in acetonitrile (20 mL) was refluxed for 18 hr. The mixture was cooled, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent to give the desired product (1.2 g, 79.8%, mp: 155°-157°).