Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:31]2)[CH2:26][O:25]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 4 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
To a 200-L glass-lined reactor was charged with 46.3 kg of dichloromethane (DCM). To the reactor was added additional 112.0 kg of dichloromethane followed by 11.9 kg (36.8 mol) of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylpentanoic acid and 8.0 kg (40.6 mol) of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine. With agitation, to the mixture was added 0.44 kg of 1-hydroxybenzotriazole. After cooling to 4° C., 14.0 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added in 4 portions (5.0 kg+3.1 kg+3.8 kg+2.1 kg) over 3 h while maintaining the batch temperature at 4-10° C. The mixture was agitated at 4-12° C. for additional 5 h. HPLC analysis at 2.5 h indicated the completion of the reaction. The mixture was transferred into a 500 L glass-line reactor. After adjusting the batch temperature to below 10° C., the reaction was quenched by adding 119.0 kg of water. The aqueous phase was separated and the organic solvent was removed by distillation in vacuo to a final volume of ca. 30 L. To the residue was added 106.0 kg of ethyl acetate. The mixture was stirred for 30 min, cooled to 0-10° C., and washed with 5 wt % citric acid solution, 10 wt % sodium carbonate solution and 2.5 wt % sodium chloride solution. The solvent was removed by distillation in vacuo at 18-30° C. to a final volume of ca. 30 L. To the residue solution was added 64.7 kg of n-heptane over 2.5 h. After adjusting the batch temperature to 0-5° C. the mixture was agitated for 4.5 h. The solids were collected in a Nutsche filter, rinsed with 16.2 kg of n-heptane, dried with nitrogen flow at 40-45° C. for 20 h to afford 17.2 kg (88.1% yield) of ((S)-2-[4-(2-Chlorophenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide. 1H NMR (300 MHz, DMSO-d6, ethanol removed) δ ppm 0.90 (d, J=6.4 Hz, 3 H), 0.94 (d, J=6.4 Hz, 3 H), 1.05 (br. s., 3 H), 1.06 (br. s., 3 H), 1.36-1.64 (m, 2 H), 1.68-1.84 (m, 1 H), 3.89 (s, 2 H), 4.20 (d, J=18.4 Hz, 1 H), 4.62 (d, J=18.4 Hz, 1 H), 4.68 (s, 1 H), 4.78 (s, 1 H), 4.90 (dd, J=10.7, 4.7 Hz, 1 H), 6.44 (d, J=2.1 Hz, 1 H), 7.37 (td, J=7.8, 1.8 Hz, 1 H), 7.46 (td, J=7.8, 1.2 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.66 (dd, J=7.8, 1.2 Hz, 1 H), 10.81 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.Br[C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].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>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.[Pd].[Pd].O1CCOCC1>[Cl:9][C:4]1[CH:3]=[C:2]([NH:1][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: Brc1cncnc1
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
Product: Clc1cc(Nc2cncnc2)cc(Cl)n1
Temperature: 100 °C
Yield: 61.8 %

Procedure:
4-Amino-2,6-dichloropyridine (1.23 g, 7.55 mmol, 1.20 eq), 5-bromopyrimidine (1.0 g, 6.3 mmol, 1.0 eq), Cs2CO3 (2.87 g, 8.81 mmol, 1.40 eq), Pd2(dba)3 (289 mg, 0.503 mmol, 0.0800 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (437 mg, 0.755 mmol, 0.120 eq) and dioxane (16 mL) were added to a microwave vial. The vial was purged with argon, capped and heated at 100° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 938 mg (62%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 8.95 (s, 1H), 8.76 (s, 2H), 6.95 (s, 2H); [M+1]+: 241.1.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C@@H:10]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]#[CH:29])[CH3:25].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.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.[Pd].[Pd]>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C@@H:10]([CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:11][NH2:12])[C:2]([C:29]#[C:28][CH:27]([O:30][CH2:31][CH3:32])[O:26][CH2:24][CH3:25])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: CC(C)C[C@@H](CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1cnc(Cl)nc1N[C@H](CN)CC(C)C)OCC
Temperature: 25 °C

Procedure:
To a solution of tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate 5.0 g (12.3 mmole) in toluene (36 mL) and triethyl amine (7.2 mL) was added under nitrogen, 3,3-diethoxyprop-1-yne 2.8 mL (19.7 mmole), Pd2(dba)3 1.1 g (1.23 mmole), and triphenylarsine 3.8 g (12.3 mmole). The contents were heated to 70 degrees for 24 hrs. After cooling to room temperature, the reaction mixture was filtered through CELITE™ and then concentrated under vacuum. The crude product was columned over silica gel using hexane/ethyl acetate (0-30%) to afford (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. LCMS (ESI) 455 (M+H).
Reaction SMILES: Cl.CN.[OH-].[K+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH:15]([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:21]([BH3-])#[N:22].[Na+].Cl>CO>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:22][CH3:21])[CH:15]([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [BH3-]C#N
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1C
Reaction time: 0.33 h

Procedure:
A mixture of methylamine hydrochloride (1.40 g) in methanol (30 ml) at 0° under nitrogen is treated with potassium hydroxide pellets (331 mg) followed by the racemic 1-benzyl-3-methyl-4-piperidone (3.00 g) and is stirred at 0° for 20 min. Then sodium cyanoborohydride (371 mg) is added, and the reaction mixture is warmed to 20°-25° and stirred at 20°-25° for 18 hrs. The mixture is then adjusted to pH 2.5 with 3M aqueous hydrochloric acid, concentrated under reduced pressure, diluted with water (40 ml), adjusted to pH 12 with potassium hydroxide pellets, saturated with sodium chloride, and extracted with methylene chloride (3×40 ml). The combined organic phase is dried over sodium sulfate and concentrated under reduced pressure to give the 1-benzyl-3-methyl-4-(methylamino)piperidine intermediate as a diastereomeric mixture.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].[I-].[K+]>C(C(C)=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:19]([O:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH:18]=[CH2:17]
Reactant: O=Cc1ccc(O)cc1O
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Product: C=CCOc1cc(O)ccc1C=O

Procedure:
15.23 g of 2,4-dihydroxybenzaldehyde was dissolved in 200 ml of methyl ethyl ketone. Then, 15.54 g of potassium carbonate, 9.73 ml of allyl bromide, 18.67 g of potassium iodide, and 3.55 g of tetrabutylammonium bromide were successively added to the reaction solution. This reaction solution was heated to reflux under nitrogen atmosphere for 1.5 hours. The precipitate was removed by filtration, and the filtrate was concentrated under a reduced pressure. Ethyl acetate and water were added to the residue, so as to separate an organic layer. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 13.72 g of the subject compound.
Reaction SMILES: OC[CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1.[I-:15]>>[I:15][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: COC(=O)c1ccc(CCCCO)s1
Product: COC(=O)c1ccc(CCCI)s1

Procedure:
Methyl 5-(4-hydroxybutyl)thiophene-2-carboxylate 112 (1.07 g, 4.99 mmol) was converted to 1.61 g (99%) iodide 113 according to the procedures described in Example 5.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][C:32]1[CH2:33][NH:34][CH2:35][CH2:36][CH:37]=1>C(OCC)C.C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][C:32]1[CH2:33][N:34]([CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH2:35][CH2:36][CH:37]=1
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: COc1ccc2[nH]cc(CC3=CCCNC3)c2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CC3=CCCN(CCC(=O)c4ccc(F)cc4)C3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.9 ml; 0.0063 mol) was added to a solution of 3-chloro-4'-fluoropropiophenone (1.2 g; 0.0063 mol) in diethyl ether (10 ml). The resulting mixture was stirred for 3 hours at room temperature. Then the mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up with a mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (0.79 g; 0.0028 mol), triethylamine (0.8 ml; 0.0057 mol) in methylene chloride (20 ml). The reaction mixture was refluxed for 4 hours. Then the reaction was concentrated under vacuum and the residue was triturated with 1N hydrochloric acid. The aqueous phase was decanted, and the guming solid was twice washed with water and triturated with diethyl ether. The title compound hydrochloride was collected by filtration, washed with diethyl ether and recrystallized with a mixture (1/2) of ethyl acetate/acetone. 0.86 g of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([CH2:17][CH2:18][C:19](OC)=O)(=[O:16])=[O:15])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[ClH:33].[NH2:34][CH2:35][CH2:36][C:37]1[C:45]2[S:44][C:43](=[O:46])[NH:42][C:41]=2[C:40]([OH:47])=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>>[ClH:33].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([CH2:17][CH2:18][CH2:19][NH:34][CH2:35][CH2:36][C:37]2[C:45]3[S:44][C:43](=[O:46])[NH:42][C:41]=3[C:40]([OH:47])=[CH:39][CH:38]=2)(=[O:15])=[O:16])=[CH:6][CH:7]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [BH3-]C#N
Product: O=c1[nH]c2c(O)ccc(CCNCCCS(=O)(=O)NCCOCCc3ccc(F)cc3)c2s1
Yield: 5.7 %

Procedure:
The title compound (0.092 g) was prepared according to the method of Example 3e) using methyl 3-[2-[2-(4-fluorophenyl)ethoxy]ethylaminosulphonyl]propanoate (1.0 g), diisobutylaluminiumhydride (1.5 M in toluene, 4 ml), 7-(2-aminoethyl)4-hydroxy-1,3-benzothiazol-2-(3H)-one hydrochloride (0.875 g) and sodium cyanoborohydride (0.354 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][CH:37]=1.[NH2:46][C:47]1[NH:51][N:50]=[C:49]([CH3:52])[CH:48]=1.C(N(C(C)C)CC)(C)C.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>CC(N(C)C)=O>[CH3:52][C:49]1[CH:48]=[C:47]([NH:46][C:43](=[O:44])[CH2:42][C:39]2[CH:38]=[CH:37][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)=[CH:41][CH:40]=2)[NH:51][N:50]=1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: Cc1cc(N)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4cc(C)n[nH]4)cc3)c2cc1OC
Yield: 51.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.113 g) and 2-hydroxypyridine N-oxide (0.065 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid (0.1 g), 5-amino-3-methylpyrazole (0.058 g), diisopropylethylamine (0.051 ml) and DMA (1 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The resultant reaction mixture was transferred onto a Waters ‘β Basic Hypersil’ reversed-phase preparative HPLC column (5 microns silica, 30 mm diameter, 250 mm length) that was eluted with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.064 g); 1H NMR: (DMSOd6) 2.18 (s, 3H), 3.64 (s, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.25 (s, 1H), 7.24 (d, 2H), 7.38 (s, 1H), 7.41 (d, 2H), 7.55 (s, 1H), 8.53 (s, 1H), 10.53 (br s, 1H), 11.99 (br s, 1H); Mass Spectrum: M+H+ 420.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C@H:27]2[CH2:32][C@H:31]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH:42][C:43]4[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=4[CH3:50])=[O:41])[CH2:35][CH2:34]3)[CH2:30][CH2:29][NH:28]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:28]1[CH2:29][CH2:30][C@@H:31]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH:42][C:43]3[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=3[CH3:50])=[O:41])[CH2:37][CH2:38]2)[CH2:32][C@@H:27]1[CH2:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
3,5 di(trifluormethyl)benzoyl chloride (0.0011 mol) was added to a mixture of (±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.001 mol) in DCM (20ml). The mixture was stirred for 5 minutes. Triethylamine (2ml) was added. The mixture was stirred at RT for 3 hours, washed with a diluted NaOH solution and with water, and then dried. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.32 g (44%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 139).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4]Br.[C-:12]#[N:13].[Na+]>C1(C)C=CC=CC=1.O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][C:12]#[N:13]
Reactant: COc1cccc(Cl)c1CBr
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(Cl)c1CC#N
Yield: 87.3 %

Procedure:
483 g of 2-chloro-6-methoxybenzyl bromide in 410 ml of toluene are reacted with 131 g of sodium cyanide in 132 ml of water and 3.28 g of Aliquat 336. 325 g of colorless oil are obtained (b.p. 103° C./0.08 mbar).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[N:4]=[C:3]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:23]=1[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:20][O:21][C:22]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:23]=1[CH2:32][N:33]1[CH2:34][CH2:35][N:36]([CH2:8][C:5]2[N:4]=[C:3]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])[CH2:37][CH2:38]1
Reactant: Cc1c(C=O)nc(-c2ccc(C(F)(F)F)cc2)n1C
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: COc1ccc(CN2CCN(Cc3nc(-c4ccc(C(F)(F)F)cc4)n(C)c3C)CC2)c(OC)c1OC
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A solution of 1,5-dimethyl-4-formyl-2-(4-trifluoromethylphenyl)imidazole (0.5 g), 1-(2,3,4-trimethoxyphenylmethyl)piperazine (0.54 g), and titanium(IV)isopropoxide (0.73 g) was allowed to stand for 1 hour at room temperature. Ethanol (10 ml) was added, and the resultant solution was stirred for 1 hour. Sodium cyanoborohydride (90 mg) was then added, and the mixture stirred overnight. Sodium hydroxide was then added until the pH was just over 7, the solvent removed under reduced pressure, and the residue partitioned between methylene chloride/water. The mixture was filtered, the organic layer separated, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel, eluting with ethyl acetate/methanol/ammonia (97/3/0.5), to yield 0.45 g of 1-(2,3,4-trimethoxyphenyl)methyl-4-[(2-(4-trifluoromethylphenyl)-1,5-dimethylimidazol-4-yl)methyl]piperazine. Treatment with anhydrous hydrochloric acid in ethanol converted the base to its dihydrochloride salt, m.p. 235° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C([Li])CCC.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1cc(Br)c2c(c1)CCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cc2c1OCC2
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A sample of 19 (6.0 g, 26.5 mmol) in freshly distilled dry THF was degassed at −78° C. and n-butyllithium (25 mL of 1.05 M, 26 mmol) was added dropwise by syringe. Then N,N-dimethylformamide (2.9 mL, 26 mmol) was added dropwise via syringe. The reaction mixture was allowed to come to room temperature overnight. Saturated ammonium chloride (10 mL) was added to and the mixture was stirred for 30 minutes. The solvent was removed and the residue was taken up in dichloromethane (50 mL), and washed with water (3×50 mL) then dried with anhydrous sodium sulfate. Solvent removal yielded yellow crystals (1.6 g) which were washed with ether and recrystallized from a minimum of hot methanol to give white crystals of 20 (1.32 g, 22%) mp=99-100° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[C:21]([O:25][C:26](=[O:43])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([NH2:39])=[CH:34][C:33]=1[C:40](=[O:42])[NH2:41])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>C(O)CCCC.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.[Pd].[Pd]>[C:21]([O:25][C:26](=[O:43])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([NH:39][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:5]([Cl:20])=[CH:4][N:3]=2)=[CH:34][C:33]=1[C:40](=[O:42])[NH2:41])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(OCCCNC(=O)OC(C)(C)C)c(C(N)=O)cc1N
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCO
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2cc(C(N)=O)c(OCCCNC(=O)OC(C)(C)C)cc2C)ncc1Cl
Temperature: 100 °C
Yield: 61.6 %

Procedure:
To a mixture of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)acrylamide (15 mg, 49 umol), tert-butyl(3-(4-amino-2-carbamoyl-5-methylphenoxy)propyl)carbamate (22 mg, 68 umol), and sodium carbonate (25 mg, 23 umol) in 1 mL of amyl alcohol under Ar, was added Pd2(dba)3 (9.6 mg) and DavePhos (15 mg). The resulting mixture was heated at 100° C. for 2 hr. After filtration, the product was purified by prep-HPLC, giving 18 mg of white powder (62%). MS: m/z 596.2 (ES+, M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]>C(O)(=O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[C:11]=1[Br:1])=[O:6]
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
Bromine (1.69 g, 0.54 ml, 10.54 mmol) was added dropwise to a stirred solution of methyl-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 49α, 1.85 g, 7.03 mmol) in acetic acid (20 ml) at 10° C. The resulting reaction mixture was stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. Acetic acid was removed from the reaction mixture under reduced pressure and residue obtained was dissolved in ethyl acetate (150 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (50 ml) followed by washing with brine (50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was washed with a mixture of ethyl acetate in hexanes (10:90) to obtain the title compound (2.1 g, 87.5%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[CH2:31]([O:36][C:37](Cl)=[O:38])[CH2:32][CH2:33][CH2:34][CH3:35]>O1CCOCC1>[CH2:31]([O:36][C:37](=[O:38])[NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:22]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCOC(=O)Cl
Reactant: Cn1cncc1C(=NOCc1nccc(N)n1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)Nc1ccnc(CON=C(c2ccccc2)c2cncn2C)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 9.5 %

Procedure:
To a solution of 2-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.65 mmol) in 1,4-dioxane (10 mL) were sequentially added triethylamine (0.18 mL, 1.30 mmol) and chloroformic acid pentyl ester (0.38 mL, 2.60 mmol). After stirring at room temperature for 19 h, the mixture was concentrated in vacuo, diluted in ethyl acetate (50 mL), washed with water (20 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification on silica gel afforded pentyl{2-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}carbamate [26 mg, yield 9%; HPLC/MS: m/z=423 (M+H); log P(HCOOH)=2.66].