Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:66]=[CH:65][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:66]=[CH:65][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.9 %

Procedure:
To a solution of 100 mg (0.47 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 7 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 141 mg (0.47 mmol) (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 112 mg off-white foam (47%). MS (EI) 496.1 (M)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.[OH-:25].[Na+]>O>[CH2:13]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH2:20][CH:22]2[O:24][CH2:23]2)=[CH:3][C:4]=1[O:25][C:4]1[CH:3]=[C:2]([CH2:20][CH:22]2[O:24][CH2:23]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: Oc1ccc(OCc2ccccc2)c2ccccc12
Reactant: ClCC1CO1
Agent: [Na+]
Solvent: O
Product: c1ccc(COc2c(Oc3cc(CC4CO4)c4ccccc4c3OCc3ccccc3)cc(CC3CO3)c3ccccc23)cc1

Procedure:
To a solution of 4.3 g. (0.017 mole) 1-hydroxy-4-benzyloxynaphthalene in 15 ml. (0.19 mole) epichlorohydrin, which is heated to its boiling point while stirring, is carefully added dropwise 3.7 ml. 5M aqueous sodium hydroxide solution (0.0187 mole). The apparatus used for carrying out the reaction is equipped with a water separator so that the water distils off azeotropically from the reaction mixture with epichlorohydrin. After distilling off the theoretical amount of water, the reaction mixture is further heated under reflux for 1 hour while stirring, thereafter mixed with 50 ml. toluene, filtered off from inorganic components and the solution evaporated on a rotary evaporator. The product obtained is used for the next reaction step without further purification. Yield 6.1 g.
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:1]1([CH:11]=[C:12]2[CH2:16][C:17](=[O:18])[O:19][C:13]2=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Temperature: 60 °C
Yield: 118.8 %

Procedure:
A mixture of 38 g of (1-naphthalenylmethylene)butanedioic acid and 270 ml of acetic anhydride was heated at 60° C. for one hour. The mixture was evaporated under reduced pressure to give 41.96 g of an oil. The oil was crystallized from 220 ml of toluene-hexane (1:1) to give 24.94 g of crystals, mp 162°-164° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[CH:14]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O[N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[NH3:1].[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([NH:34][C:17](=[O:19])[CH2:16][CH2:15][CH:14]2[C:8]3[C:9](=[CH:10][N:11]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[CH:7]=3)[NH:12][CH2:13]2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)CCC1CNc2cnc(-n3cncn3)cc21
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N
Product: O=C(CCC1CNc2cnc(-n3cncn3)cc21)NN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 139.9 %

Procedure:
To a suspension of 3-(5-(1,2,4-triazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)propionic acid (0.108 g) in dry DMF (3 mL) was added 1-benzylpiperazine (0.11 mL, 0.63 mmol), 1-hydroxybenzotriazole (71 mg, 0.52 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (0.1 g, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) and this mixture was stirred at ambient temperature under nitrogen for 64 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organics were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica eluting with a gradient of 2 to 5% MeOH in DCM, followed by 95:5:1, DCM:MeOH:NH3 to give the title compound (0.126 g, 72%) as a pale yellow foam. 1H NMR (360 MHz, CDCl3) δ 1.88-1.96 (1H, m), 2.07-2.15 (1H, m), 2.30-2.40 (6H, m), 3.28-3.60 (8H, m), 3.72-3.83 (2H, m), 7.19-7.27 (5H, m), 7.57 (1H, s), 7.66 (1H, s), 7.95 (1H, s) and 8.91 (1H, s).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18]C(=O)OC(C)(C)C)[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C@@H:3]([C@H:4]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[CH3:7])[CH2:2][OH:1]
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CO
Reaction time: 1 h

Procedure:
tert-Butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (0.10 g, 0.28 mmol) was taken up in 3 mL of DCM. 1 mL of TFA was added. The mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was taken up in 5 mL of DCM and 5 mL of 5% aq NaOH. The mixture was partitioned, and the aqueous portion was extracted three times with 5 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded (2S,3S,E)-2-amino-3-(4-(trifluoromethyl)phenyl)hex-4-en-1-ol, which was used without further purification.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:56][NH2:57]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:57][N:56]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=1
Reactant: CC(C)Oc1ccc(C(CCCCCl)C(=O)O)cc1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(C)C)cc3)n2)ccc1-n1cnc(Cl)c1
Yield: 43 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (1.50 g, 3.53 mmol, from preparation A) and 6-chloro-2-(4-isopropoxyphenyl)hexanoic acid (1.26 g, 4.42 mmol, from preparation AV) were coupled [N-methylmorpholine (2.00 mL, 17.7 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.556 mL, 17.7 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (50% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(4-isopropoxyphenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (805 mg, 1.52 mmol, 43% yield) as an off-white solid. LC-MS (M+H)+ 529.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Br[CH:10]([CH3:17])[C:11](=O)[C:12]([O:14][CH3:15])=[O:13].[CH2:18](N(C(C)C)C(C)C)C>C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:10]([CH3:17])=[C:11]([C:12]([O:14][CH2:15][CH3:18])=[O:13])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C(=O)C(C)Br
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(Cl)nn2c1C

Procedure:
5.83 g of 3-amino-6-chloropyridazine was suspended in 70 ml of ethanol; 9.75 g of methyl 3-bromo-2-oxobutyrate and 8.6 ml of N-ethyldiisopropylamine were added, followed by thermal refluxing for 5 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was ajusted to pH 7 by the addition of an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl acetate and dried to yield 3.9 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C@H:4]([C@H:9]([OH:11])[CH3:10])[C:5]([O:7]C)=[O:6].O.O.[OH-].[Li+].CO>C1COCC1>[CH3:1][CH:2]([CH3:12])[CH2:3][C@H:4]([C@H:9]([OH:11])[CH3:10])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)[C@H](CC(C)C)[C@@H](C)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.6 %

Procedure:
Methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoate (7.99 g, 46 mmol) in 50 mL of THF is treated with 50 mL of water containing 3.9 g (92 mmol) of lithium hydroxide monohydrate. The reaction flask is treated with 5.0 mL of MeOH and allowed to stir for 17 h at 25° C. The mixture is partitioned between water and ether followed by separation of the aqueous layer. The aqueous solution is brought to pH 3 with 6 N aqueous hydrochloric acid and the mixture is extracted with ether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to afford 6.6 g (90%) of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxybutanoic acid.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12]([OH:15])(=O)[CH3:13].[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C>[C:12]([NH:4][C:3]1[C:5]([N+:16]([O-:18])=[O:17])=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])(=[O:15])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccccc1N
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1NC(C)=O
Temperature: 12.5 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
A solution of methyl anthranilate (21.0 mL, 162 mmol) in acetic anhydride (170 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise a mixture of acetic anhydride (35 mL), acetic acid (30 mL) and 60% nitric acid (50 ml, 162 mmol) at 10-15° C. over 2 hr. The reaction mixture was stirred at 10-15° C. for 2.5 hr, and poured into ice-cold water. The resulting solid was collected by filtration, washed with water, and after recrystallization (chloroform/methanol), the crystals were collected by filtration. The filtrate was extracted with methylene chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ether to give the title compound (20.0 g, yield 52%).
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[N:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[OH:14])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.O1CCCC1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CCOCC>[CH3:27][N:28]([CH3:32])[C:29]([O:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:7]=[CH:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:30]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(C=Nc1ccncc1O)CC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C=Nc1ccncc1OC(=O)N(C)C)CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
To a solution prepared from 4-[[(diethylamino)methylene]amino]-3-pyridinol (3.12 g), triethylamine (3.34 g) and tetrahydrofuran (50 mL) was added N,N-dimethylcarbamyl chloride (2.28 g) under nitrogen. The resulting mixture was stirred at ambient temperature for 6 hours, diluted with ether (50 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue chromatographed on silica gel (elution with 10% methanol in dichloromethane) to give 3.00 g of solid. Recrystallization from ether/hexanes afforded 1.57 g of crystalline solid, m.p. 73°-74° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:5][C@@H:4]([NH:29][S:30](N2CCOC2=O)(=[O:32])=[O:31])[CH2:3]1.Cl.CN.C(N[C@@H]1C[C@H](C(O)=O)[C@H](C)C1)(=O)C.[F:55][C:56]([F:63])([F:62])[C@H:57]1[CH2:61][CH2:60][CH2:59][NH:58]1>CC#N>[CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:20])=[O:21])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:5][C@@H:4]([NH:29][S:30]([N:58]2[CH2:59][CH2:60][CH2:61][C@@H:57]2[C:56]([F:63])([F:62])[F:55])(=[O:32])=[O:31])[CH2:3]1
Reactant: FC(F)(F)[C@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4C[C@@H](NS(=O)(=O)N5CCOC5=O)C[C@H]4C)n23)cc1
Agent: CC(=O)N[C@H]1C[C@@H](C)[C@@H](C(=O)O)C1
Agent: CN
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4C[C@@H](NS(=O)(=O)N5CCC[C@@H]5C(F)(F)F)C[C@H]4C)n23)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.200 g, 0.261 mmol, prepared from 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and (1S,2R,4S)-4-acetamido-2-methylcyclopentanecarboxylic acid [prepared from ethyl 4-amino-2-methyl-cyclopentanecarboxylate (WO2009152133) using G, AA, and Z] using H, OO, BB, and ZZ) and (R)-2-trifluoromethylpyrrolidine (0.055 g, 0.392 mmol) in MeCN (1.4 mL) was added TEA (0.073 mL, 0.523 mmol). The reaction was irradiated in a CEM microwave at about 120° C. for about 0.5 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure to afford a residue. The crude material was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM to afford (R)-N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide (0.12 g, 75%, 72% purity) as an off-white solid: LC/MS (Table 1, Method a) Rt=2.79 min; MS m/z: 611 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16](Cl)=[N:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>CC(N(C)C)=O.C(#N)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:16]2[N:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:13]([C:11](=[O:12])[NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:25])([F:24])[F:1])=[CH:5][CH:6]=3)=[CH:18][N:17]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)n2)CC1

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.8 g, 2.07 mmol, 1.0 equiv; commercially available from Maybridge, UK), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.62 g, 3.11 mmol, 1.5 equiv; commercially available) and triethylamine (0.43 mL, 0.32 g, 3.11 mmol, 1.5 equiv) in anhydrous DMAc (2 mL) and acetonitrile (9 mL) was heated by microwave irradiation to 120° C. for 20 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.92 g (81%) of the title compound. MS (ISP): 550.2 [M+H]+.
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Li].O>CCOCC>[C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH3:26])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (0.59 g, 1.79 mmol) in Et2O (25 mL) under Ar at −70° C., was added methyl lithium (1.4 M in Et2O; 1.88 mL, 2.63 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 min and then allowed to warm to RT over 15 min and stirred at this temperature for 1 h. The mixture was cooled to 0° C. to which was slowly added H2O (25 mL) and the solution was extracted between Et2O (100 mL) and H2O (100 mL). The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo to afford the title compounds as a light yellow oil (0.58 g, 94%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.42-0.57 (m, 3H, —NHCH(CH2CH3)CH(CH3)OH), 0.97-1.15 (m, 5H, —NHCH(CH2CH3)CH(CH3)OH+—NHCH(CH2CH3)CH(CH3)OH), 2.01 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 3.26 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.39 (d, 1H, J=4.10 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.13-7.50 (m, 15H, 3×Bz).
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:34])=[N:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:19])[CH3:20])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1C(CC(O)(C=O)C(F)(F)F)C(C)C
Reactant: Cc1ncc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1C(CC(O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)C(C)C

Procedure:
In the same way as in Example 61, 280 mg (0.87 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-5-methyl-2-(trifluoromethyl)hexanal, 175 mg (1.1 mmol) of 5-amino-2-methylquinazoline and 0.45 ml of titanium tetraethoxide are reacted to give 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-5-methyl-2-(trifluoromethyl)hexan-2-ol. 360 mg of resulting crude imine are cyclized in the same way as in Example 61 at −30° C. with 6 ml (6 mmol) of 1 M boron tribromide solution in dichloromethane to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-70%) and subsequent preparative HPLC (SunFire C18, water/methanol) yield 6 mg of product.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>C(O)C>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: OCCCCCCCCCCCBr
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCCCCCCCCCSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
1.45 g of 85% potassium hydroxide was dissolved in 100 ml of ethanol at room temperature. 2.78 g of 4-mercaptophenol was then added to the above-prepared solution, and dissolved therein. To the above prepared reaction mixture, 5.0 g of 11-bromo-1-undecanol was added, and the reaction mixture was allowed to react for 3 hours under the condition that the ethanol was refluxed. The thus obtained reaction mixture was cooled to room temperature, and concentrated by use of a rotary evaporator. The concentrated reaction mixture was poured into 500 ml of water, followed by vigorous stirring. Thus, a white solid separated out. The resultant white solid was recrystallized from a mixed solvent of ethyl acetate and hexane, so that 4.5 g of 4-(11-hydroxyundecylmercapto) phenol was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([N:22]3[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[N:24]=[CH:23]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:40][C:41]([NH:44][S:45]([C:48]1[S:52][C:51](Br)=[CH:50][CH:49]=1)(=[O:47])=[O:46])([CH3:43])[CH3:42].CCCCCCC>C1(C)C=CC=CC=1>[C:41]([NH:44][S:45]([C:48]1[S:52][C:51]([C:25]2[N:24]=[CH:23][N:22]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=3)[CH:26]=2)=[CH:50][CH:49]=1)(=[O:46])=[O:47])([CH3:43])([CH3:40])[CH3:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)c(C)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A stirred mixture of 4-(3-methyl-4-trifluoromethyl-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.7) (0.33 g, 0.5 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.16 g, 0.55 mmol), tetrakis(triphenyl-phosphine)palladium (0.035 g, 0.03 mmol) in toluene (6 mL) was heated under reflux conditions for 15 h, heptane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a light yellow solid.