Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)(C)=O.CC(C)([O-])C.[K+].[CH2:13]([O:20][C:21]([NH:23][C@@H:24]([CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40]([Cl:45])[CH:39]=1)[C:25]([O:27][C:28]1C=CC([N+]([O-])=O)=CC=1)=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:44][C:42]1[CH:43]=[C:38]([CH2:37][C@H:24]([NH:23][C:21](=[O:22])[O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:25]2[CH2:28][O:27]2)[CH:39]=[C:40]([Cl:45])[CH:41]=1
Reactant: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)[C@H]1CO1)OCc1ccccc1
Reaction time: 16 h
Yield: 116.5 %

Procedure:
Step BF (4): To a mixture of trimethylsulfoxonium iodide (20.72 g, 94.2 mmol) in THF (175 mL) was added solid potassium t-butoxide (8.792 g, 78.7 mmol) and the mixture was refluxed for 3 h. The mixture was cooled to 0° C., to which a solution of (S)-4-nitrophenyl 2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)propanoate (15.35 g, 31.40 mmol) in THF (70 mL) was added. The mixture was brought to rt, and stirred for 16 h. Solvents were removed in vacuo. Water and EtOAc were then added, and the solid material filtered (Buchner funnel). The yellowish solid was washed with water and hexane until a white solid remained. The solid was dried in a vacuum oven. All liquid layers were combined and extracted 3 times to EtOAc. The combined organic layers were back-extracted with dilute NaOH, washed with brine, dried over MgSO4, and concentrated in vacuo. The combined material was the desired compound (13.40 g, 97% yield). 1H NMR (500 MHz, CDCl3) δ 6.99-7.39 (m, 8H) 5.80 (d, J=7.93 Hz, 1H) 5.01-5.15 (m, 2H) 4.25-4.37 (m, 2H) 3.31 (s, 3H) 3.26 (s, 3H) 2.96 (d, J=6.41 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:11]=[N:10]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ncnn1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ncnn1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A mixture of methyl 1-(4-nitrobenzyl)-1H-1,2,4-triazole-5-carboxylate (1.3 g), 10% palladium carbon (130 mg) and ethanol (200 ml) was stirred under a hydrogen atmosphere at room temperature for 2 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give methyl 1-(4-aminobenzyl)-1H-1,2,4-triazole-5-carboxylate (0.88 g, 76%) as crystals from a fraction eluted with hexane-ethyl acetate (1:2, v/v). Recrystallization thereof from ethyl acetate-isopropyl ether gave colorless prism crystals. melting point: 101-103° C.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][C:4](OCC)=[O:5].[CH3:15][NH:16][NH2:17]>CCO>[CH3:15][N:16]1[C:4]([OH:5])=[CH:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:17]1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccccn1
Solvent: CCO
Product: Cn1nc(-c2ccccn2)cc1O
Temperature: 85 °C
Yield: 78.8 %

Procedure:
To a solution of ethyl 3-oxo-3-(pyridin-2-yl)propanoate (25.00 g, 129 mmol, Matrix Scientific) in EtOH (60 mL) was added methylhydrazine (6.81 mL, 129 mmol). The mixture was heated at about 85° C. for about 3 h then cooled to rt and concentrated at rt under reduced pressure. The material was triturated with Et2O (40 mL). The solids were collected by filtration then washed with Et2O to give 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-ol (17.80 g, 79%). The filtrate was concentrated under reduced pressure then the material was triturated with 1:1 DCM/Et2O. The solids were collected by filtration and washed with Et2O to give a second crop of 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-ol (1.20 g, 5%): LC-MS (Table 1, Method g) Rt=1.05 min, m/z 176 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 11.05 (s, 1H), 8.50-8.47 (m, 1H), 7.83-7.80 (m, 1H), 7.78-7.69 (m, 1H), 7.24-7.19 (m, 1H), 5.90 (s, 1H), 3.57 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:19])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].CO.O>C(O)(C)(C)C>[O:12]([CH2:11][CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][OH:2])=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CCOc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(CCOc1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A mixture of N-(3-phenoxy)propionyl-proline methyl ester (2.8 g) and sodium borohydride (950 mg) was suspended in tertiary butyl alcohol (40 ml). To the stirred suspension, dry methanol (8 ml) was added dropwise under reflux. Thereafter, the mixture was stirred under reflux for 1 hour. The heated mixture was cooled to room temperature and water (10 ml) was added under cooling with ice. Methanol and tertiary butyl alcohol were distilled off under vacuum and the residue was subjected to extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under vacuum and the resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: chloroform) to obtain the end compound as an oil (2.3 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:7]=[CH:6]2.C(Cl)[Cl:21].N1C=CC=CC=1.CS(Cl)(=O)=O>>[Cl:21][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)n1ncc2cc(CO)c(F)cc21
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2cc(CCl)c(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
A solution of tert-butyl 5-(hydroxymethyl)-6-fluoro-1H-indazole-1-carboxylate (29F, 3.0 g, 11.27 mmol) in methylene chloride (50.00 mL, 780.0 mmol) at room temperature. was treated with pyridine (4.56 mL, 56.33 mmol) and methanesulfonyl chloride (1.31 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (300 mL) washed with aq HCl (100 mL), brine (100 mL), dried (MgSO4), filtered, concentrated in vacuo, and purified using chromatography (SiO2, EtOAc/Hexanes) to provide tert-butyl 5-(chloromethyl)-6-fluoro-1H-indazole-1-carboxylate (24G, 1.9 g; Yield=59%)
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[CH:9]=1)(=[O:5])=[O:4].[CH3:16][C:17]1([CH3:32])[CH2:22][CH2:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH2:18]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:20]2[CH2:21][CH2:22][C:17]([CH3:32])([CH3:16])[CH2:18][CH:19]=2)[CH:9]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
A solution of 177 mg (0.604) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid methylamide (as prepared in Example 30, step (c)) in toluene (5 mL) and EtOH (2.5 mL) was treated with 157 mg (0.664 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 2.40 mL (4.83 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 70.0 mg (0.0604 mmol) of Pd(PPh3)4, and heated to 80° C. for 17 h. The mixture was diluted with EtOAc (15 mL) and washed with water (1×10 mL). The aqueous layer was extracted with EtOAc (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 65.0 mg (33%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 6.90 (dd, 1H, J=8.0, 2.0 Hz), 6.85 (d, 1H, J=2.0 Hz), 6.63 (d, 1H, J=8.0 Hz), 5.65-5.59 (m, 1H), 5.00-4.91 (m, 1H), 4.06-3.97 (br s, 2H), 3.26-3.18 (m, 2H), 2.93-2.85 (m, 2H), 2.67 (d, 3H, J=5.2 Hz), 2.29-2.21 (m, 2H), 2.18 (s, 2H), 2.02-1.96 (m, 2H), 1.58-1.50 (m, 2H), 1.02 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=1[CH3:39].O>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:30]=2[CH3:39])[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(Cl)[nH]c12
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(Cl)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To the mixture of methyl 2-chloro-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 65 (0.5 g, 1.691 mmol) in N,N-Dimethylformamide (DMF) (10 ml) was added in potassium carbonate (0.467 g, 3.38 mmol) and 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (0.428 g, 1.691 mmol). The reaction mixture was stirred at 80° C. for 1 h. The reaction was cooled down. Water (100 mL) was added in. The solid precipitated. Filtration gave the solid which was purified on a silica column (20-60% EtOAc/Hexane) to give the product as white solid (0.66 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H) 3.07-3.16 (m, 4H) 3.68-3.78 (m, 4H) 3.91 (s, 3H) 5.63 (s, 2H) 6.41 (d, J=7.83 Hz, 1H) 7.28 (t, J=7.83 Hz, 1H) 7.39 (d, J=2.27 Hz, 1H) 7.50 (d, J=2.53 Hz, 1H) 7.63 (d, 1H). MS (ES+) m/e 468.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23](O)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][NH:33][CH2:32][CH2:31]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([F:27])[CH:29]=4)[CH2:34]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4cc(F)ccc4C3)c3ccccc3n2)cc(OC)c1OC
Yield: 63.4 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 94 (63.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.88 and 3.07 (2t, 2H), 3.54 and 4.05 (2t, 2H), 3.76-3.78 (2s, 3H), 3.87 and 3.92 (2s, 6H), 4.50 and 5.00 (2s, 2H), 6.93-7.14 (m, 2H), 7.38-7.91 (m, 4H), 7.99-8.18 (m, 3H); MS (ESI) m/z 474 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C=O.[H-].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Clc1cc(Cl)nc(OCc2ccccc2)n1

Procedure:
4, 6-Dichloro-2-(methysulfonyl)pyrimidine (Compound III-5) (21.3 g, 93.8 mmol) and benzyl alcohol (Compound II-64) (10.1 g, 93.8×1.0 mmol) were introduced into a 500 ml eggplant type flask, to which dimethylformamide (150 ml) was added to form a solution. While stirring in ice bath, 60% sodium hydride (3.94 g, 93.8×1.05 mmol) which had been washed with hexane was added. After bubbling was ceased, ice bath was removed and the reaction solution was stirred for 2 hours at room temperature. The reaction mixture was poured onto ice and the separated organic matter was extracted with ethyl acetate. The organic phase was washed successively with diluted hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and thereafter, the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, ethyl acetate/hexane=1/50(v/v)) to obtain the compound (I-173) as an oily product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])(=O)=O.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)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].COCCOC>[N:23]1([C:7]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCC2)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
In a nitrogen atmosphere, a mixture of dimethyl 5-trifluoromethanesulfonyloxyisophthalate (1.37 g, 4.00 mmol), pyrrolidine (0.50 mL, 6.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.040 mmol), 2-(di-tert-butylphosphino)biphenyl (24 mg, 0.080 mmol), potassium phosphate (1.19 g, 5.60 mmol) and 1,2-dimethoxyethane (12 mL) was stirred at 80° C. for 12 hours. After left cooled, the reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[O:8])=[CH:4][N:3]=1
Reactant: NCC1CCOCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCOCC1)c1ccc(Cl)nc1
Temperature: 45 °C
Reaction time: 5 h
Yield: 30.5 %

Procedure:
Combined 6-chloronicotinic acid (2.0 g, 12.69 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (2.193 g, 19.04 mmol) and EDC (4.87 g, 25.4 mmol) in CH2Cl2 (100 mL) then added Hunig's base (6.65 mL, 38.1 mmol) and the mixture stirred at 20° C. for 24 h. More (tetrahydro-2H-pyran-4-yl)methanamine (1 g, 0.7 equiv), Hunig's base (2.2 mL, 1 equiv.) and DMAP (ca. 10 mg) were added and the reaction was heated at 45° C. for 18 h. More Hunig's base (3 mL) and DMAP (80 mg) was added and heating continued at 50° C. for 5 h. The reaction was then concentrated in vacuo to give a residue which was taken up in EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (100 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 0 to 100% EtOAc in hexanes, then filtered and dried in the lyophilizer to give the title compound (0.985 g, 30.5% yield) as a white solid. MS m/z 255, 257 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 2 H) 1.60 (dd, J=12.9, 1.8 Hz, 2 H) 1.78 (td, J=7.4, 3.7 Hz, 1 H) 3.13-3.20 (m, 2 H) 3.26 (td, J=11.7, 2.1 Hz, 2 H) 3.84 (dd, J=11.4, 2.5 Hz, 2 H) 7.64 (dd, J=8.3, 0.5 Hz, 1 H) 8.23 (dd, J=8.3, 2.5 Hz, 1 H) 8.74 (t, J=5.6 Hz, 1 H) 8.82 (dd, J=2.5, 0.8 Hz, 1 H).
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Cl.[Cl-].[K+]>O1CCCC1.ClCCl>[CH2:9]1[O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:15][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:14][CH2:13][CH2:12][O:11][CH2:10]1
Reactant: ClCCOCCCl
Reactant: OCCOCCOCCOCCO
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C1COCCOCCOCCOCCOCCO1
Reaction time: 18 h
Yield: 119.9 %

Procedure:
A 3 l three-necked round-bottomed flask, fitted with a mechanical stirrer, a reflux condenser and a 250-ml dropping funnel was charged with potassium hydroxide pellets (416 g. containing 6.3 mol KOH), tetraethylene glycol (1.25 mol) and tetrahydrofuran (1000 ml). The reaction vessel was placed in a heating mantle and gently heated. After 15 minutes a solution of bis(2-chloroethyl) ether (3.125 mol) in tetrahydrofuran (150 ml) was added in one stream from the dropping funnel to the vigorously stirred reactants. The reaction mixture was then heated under reflux, with stirring for 18 hours. Subsequently, the reaction mixture was cooled and boiled down under a pressure of 1.9 kPa to give a brown slurry to which dichloromethane (750 ml) was added. The resulting suspension of potassium chloride was filtered and the potassium chloride filtered off was washed with dichloromethane (100 ml). The combined filtrate and washings were dried over anhydrous magnesium sulphate and the solvent was evaporated at a pressure of 1.9 kPa to give a residue of crude 18 -crown-6 (396 g) containing 0.531 mol of 18-crown-6 (yield 42.5%, calculated on starting tetraethylene glycol), potassium chloride and at least eight other compounds among which 1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxacyclohexatriacontane, hexaethylene glycol and unreacted tetraethylene glycol. The crude 18-crown-6 was used as described hereinafter.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:10](=O)[CH2:11][CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH2:10][CH2:11][CH3:12]
Reactant: Cc1c(N)cccc1Br
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNc1cccc(Br)c1C
Yield: 97.9 %

Procedure:
To a solution of 3-bromo-2-methylphenylamine (1.5 g, 8.06 mmol) in dry CH2Cl2 with 3A molecular sieves was added propionaldehyde (580 μL, 8.06 mmol) and the resultant mixture stirred at room temperature for 20 min under nitrogen. Acetic acid (561 μL, 8.06 mmol) and sodium triacetoxyborohydride (4.78 g, 22.56 mmol) were added and the resultant mixture stirred under nitrogen at room temperature for 16 h. Saturated sodium bicarbonate (60 mL) was added portionwise and the resultant mixture stirred for 0.5 h and extracted with CH2Cl2 (2×100 mL). The organic solution was dried (Na2SO4) and the solvents removed in vacuo to afford the title compound as a yellow oil (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.[CH3:8][O:9][C:10]1[C:18]([S:19][CH3:20])=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[CH3:8][O:9][C:10]1[C:18]([S:19][CH3:20])=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:11]=1[C:12]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1)=[O:13]
Reactant: Cn1nnnc1N
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1SC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1c(C(=O)Nc2nnnn2C)ccc(C(F)(F)F)c1SC
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.6 %

Procedure:
1.45 g (98% by weight; 14.3 mmol) of 5-amino-1-methyl-1H-tetrazole were added to 3.00 g (11.3 mmol) of 2-methoxy-3-(methylsulfanyl)-4-(trifluoromethyl)benzoic acid in 30 ml of dry pyridine. 2.00 g (15.8 mmol) of oxalyl chloride were then added, and the mixture was subsequently stirred at room temperature (RT) for three days. Another 500 mg (3.94 mmol) of oxalyl chloride were then added, and the mixture was subsequently stirred at RT for 16 h. For work-up, the contents were substantially freed from the solvent on a rotary evaporator. The residue was stirred with dichloromethane and a saturated solution of sodium bicarbonate. The organic phases were then separated and the organic phase was freed from the solvent on a rotary evaporator. The residue was purified chromatographically, which gave 1.83 g of clean product.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([F:16])([F:15])[F:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:17][C:18]([F:23])([F:22])[C:19]([NH2:21])=[NH:20]>CCO>[CH2:9]([O:8][C:6]([C:5]1[C:11]([C:13]([F:14])([F:15])[F:16])=[N:20][C:19]([C:18]([F:23])([F:22])[F:17])=[N:21][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: N=C(N)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1C(F)(F)F
Yield: 38.9 %

Procedure:
A solution of ethyl ethoxymethylene-4,4,4-trifluoroacetoacetate (15 g, 62.5 mmol) and trifluoroacetamidine (12.6 g, 112.5 mmol) in EtOH (50 mL) was heated at reflux for 24 h under N2. The reaction mixture was cooled and concentrated. Chromatography (SiO2, 20% EtOAc/hexane) afforded ethyl-2,4-bis (trifluoromethyl)pyrimidine-5-carboxylate as an oil (7.0 g, 39%), 1HNMR (CDCl3) δ 9.37 (s, 1H), 3.70 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:53][C@H:54]1[O:59][C@@H:58]([CH3:60])[CH2:57][N:56]([C:61]2[CH:66]=[CH:65][C:64]([N:67]3[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)=[CH:63][CH:62]=2)[CH2:55]1.[CH3:73][O:74][C:75]([C:77]1[CH:82]=[CH:81][C:80]([C:83]2[CH:88]=[CH:87][C:86](OS(C(F)(F)F)(=O)=O)=[CH:85][CH:84]=2)=[CH:79][CH:78]=1)=[O:76]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:73][O:74][C:75]([C:77]1[CH:82]=[CH:81][C:80]([C:83]2[CH:88]=[CH:87][C:86]([N:70]3[CH2:69][CH2:68][N:67]([C:64]4[CH:63]=[CH:62][C:61]([N:56]5[CH2:55][C@H:54]([CH3:53])[O:59][C@H:58]([CH3:60])[CH2:57]5)=[CH:66][CH:65]=4)[CH2:72][CH2:71]3)=[CH:85][CH:84]=2)=[CH:79][CH:78]=1)=[O:76]
Reactant: COC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reactant: C[C@@H]1CN(c2ccc(N3CCNCC3)cc2)C[C@H](C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(N3CCN(c4ccc(N5C[C@@H](C)O[C@@H](C)C5)cc4)CC3)cc2)cc1
Temperature: 80 °C
Reaction time: 28 h
Yield: 55.2 %

Procedure:
To a mixture of cesium carbonate (6.33 q), palladium(II) acetate (156 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (648 mg) in dioxane (28 ml) was successively added cis-2,6-dimethyl-4-(4-piperazinylphenyl)morpholine (4.59 g) and 4′-trifluoromethanesulfonyloxy-1,1′-biphenyl-4-carboxylic acid methyl ester (5 g) in a stream of nitrogen. The mixture was stirred at ambient temperature for 30 minutes and at 80° C. for a further 28 hours. After cooling to room temperature, water was added to the reaction mixture. The resulting precipitates were filtered, washed with water and dried to give 4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylic acid methyl ester (3.72 g).