Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH2:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:12]#[CH:13].CCN(CC)CC>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.[Cu]I.CC#N>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:12][CH2:11][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CCNS(C)(=O)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol), Et3N (1.7 mL, 12.1 mmol), and CH3CN (30 mL) was added Pd(PPh3)4 (462 mg, 0.4 mmol) followed by CuI (76 mg, 0.4 mmol). The reaction was heated at reflux for 24 h and was cooled to room temperature. The volatiles were removed in vacuo and the residue was purified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc in hexanes) to yield 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a pale yellow solid (1.1 g). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H), 3.10 (s, 3H); MS 274 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][N:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][N:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1ccnc(CO)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccnc(COC2CCCCO2)c1
Reaction time: 8 h

Procedure:
To a solution of 1.64 g of ethyl 2-(hydroxymethyl)isonicotinate in 32.8 ml of dichloromethane were added 1.24 ml of dihydropyrane and 2.32 g of pyridinium p-toluenesulfonate, followed by stirring overnight. Ethyl acetate was added thereto, followed by washing with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.4 g of ethyl 2-[(tetrahydro-2H-pyran-2-yloxy)methyl]isonicotinate.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)([CH:9]=[C:10]=[CH2:11])[CH3:8].Cl.C[OH:21]>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][C:10](=[O:21])[CH3:11])[CH3:8]
Reactant: C=C=CC(C)(O)c1ccccc1-c1ccccc1
Reactant: CO
Agent: Cl
Product: CC(=O)C=C(C)c1ccccc1-c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 10 g. of 2-(p-biphenylyl)-3,4-pentadien-2-ol in 200 ml. of anhydrous methanol is added 3 ml. of concentrated hydrochloric acid (12 N). The resulting mixture is stirred at room temperaure for 3 hours and then in an ice bath for 2 hours. Solids formed are filtered off and recrystallized from pentane to obtain 2-(p-biphenylyl)-2-penten-4-one, m.p. 130°-133° C. 2-(p-(biphenylyl)-4-chloro-2,4-pentadiene, byproduct, remains in the mother liquor.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: Cc1cccc2c(Oc3ccc(C#N)cn3)cccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Oc2cccc3c(CBr)cccc23)nc1
Temperature: 70 °C

Procedure:
To a solution of 6-(5-methylnaphthalen-1-yloxy)nicotinonitrile (Preparation 22) (530 mg, 2.04 mmol) in carbon tetrachloride (30 mL) under argon was added N-bromosuccinimide (435 mg, 2.44 mmol) followed by benzoyl peroxide (25 mg, 0.1 mmol). The mixture was heated to 70° C. for 16 h. The reaction mixture was cooled, filtered through celite, and washed with DCM (70 mL). The organic phase was washed with NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=3.93 min; m/z (ES+)=341.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:40])[C:32]#[C:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:40])[CH:32]=[C:33]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH3:8])[N:10]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:29]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Product: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCCc3cccc(N(C)C(=O)OC(C)(C)C)n3)ccc21
Yield: 81 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and the commercially available phenyl propynoic acid ethyl ester using the procedure described in Example 16, step (d1), in 81% yield as an E/Z isomeric mixture. H1 NMR (Cl3CD), δ: 7.57–7.53 (m, 1H), 7.52–7.46 (m, 1.5H), 7.44 (m, 1H), 7.41–7.34 (m, 2.5H), 7.29 (m, 1H), 7.12 (d, 0.5H, J=2.1 Hz), 7.07 (m, 1.5H), 6.97 (m, 1.5H), 6.76 (m, 1H), 6.70 (m, 0.5H), 6.59 (d, 0.5H, J=3.2 Hz), 6.51 (d, 0.5H, J=3.5 Hz), 6.22 (s, 0.5H), 6.15 (s, 0.5H), 4.38 (m, 2H), 4.09 (c, 1.5H, J=7.0 Hz), 4.01 (c, 1.5H, J=7.2 Hz), 3.39 (m, 3H), 3.21 (m, 2H), 1.52 (s, 9H), 1.16 (t, 1.5H, J=7.2 Hz), 1.03 (t, 1.5H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1Cl)[CH:8]=[CH2:9].[OH-].[K+]>CS(C)=O>[CH2:7]([O:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:5]1[CH:6]=[C:2]([Cl:1])[N:3]=[CH:4]1)[CH:8]=[CH2:9]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Temperature: 90 °C
Yield: 40.4 %

Procedure:
A mixture of 4-chloro-1H-imidazole (3.31 g, 32.0 mmol), 2-(allyloxy)-1-chloro-4-nitrobenzene (6.50 g, 30.8 mmol), and potassium hydroxide flakes (1.90 g, 33.9 mmol) in anhydrous DMSO (50 mL) was heated at 90° C. for 20 h under nitrogen. The reaction mixture was allowed to cool to rt and ice-cold water was added. The resulting precipitate was collected by vacuum filtration. The product was dried, and purified by column chromatography (5% EtOAc/Hexane) to afford the yellow solid 1-(2-(allyloxy)-4-nitrophenyl)-4-chloro-1H-imidazole (3.48 g, 40% yield). LC-MS (M+H)+280.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.97-7.93 (2H, m), 7.77 (1H, s), 7.44 (1H, d, J=8.8 Hz), 6.05-5.98 (1H, m), 5.45-5.37 (2H, m), 4.70-4.65 (2H, m).
Reaction SMILES: [C:1]([O:5]OC(C)(C)C)(C)(C)C.[C:11]([C:15](=[C:17]([F:19])[F:18])[Br:16])([F:14])([F:13])[F:12]>CO>[C:11]([CH:15]([C:17]([CH2:1][OH:5])([F:19])[F:18])[Br:16])([F:14])([F:13])[F:12]
Reactant: FC(F)=C(Br)C(F)(F)F
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: CO
Product: OCC(F)(F)C(Br)C(F)(F)F
Yield: 26 %

Procedure:
In a quartz photochemical reaction vessel equipped with a dry ice condenser, a stirred mixture of methanol (20 g), ditert-butyl peroxide (0.79) and CF3C(Br)═CF2 (10 g, 0.05 mol), was irradiated at 254 nm for ˜6 hr at ambient temperature for under nitrogen. (Note: CF3CBr═CF2 was added as a liquid (BP, 24-25° C.) in one lot before the reaction). Then the reaction mixture was concentrated to remove excess methanol. The concentrated material was taken in ˜40 mL ether, washed with 20 ml 20% aqueous sodium bisulphite followed by brine (10 mL) and distilled to afford the CF3CHBrCF2CH2OH (2.0 g) as a colorless liquid. Yield=26% based on CF3CBr═CF2. Boiling point, 30-31° C./ 8-10 mm Hg. GC-MS: m/e at (C4H4BrF5O) for M+; NMR spectra are consistent with the structure.
Reaction SMILES: [CH2:1]([S:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH3:2].C(N=C=NC(C)C)(C)C.[C:22]([O:26][C:27]([NH:29][C@H:30]([C:35](=[O:46])[O:36][C:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:39])[CH3:38])[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH2:31][C:32]([O:12][C:6]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=1[S:4][S:3][CH2:1][CH3:2])=[O:33])[C:35]([O:36][C:37]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:39])[CH3:38])=[O:46])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCSSc1cccc(C)c1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSSc1cccc(C)c1OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
2-(Ethyldisulfanyl)-6-methylphenol (Compound 105) (423 mg, 2.11 mmol), N,N′-diisopropylcarbodiimide (0.329 ml, 2.11 mmol) and N,N-dimethylpyridin-4-amine (34.4 mg, 0.282 mmol) were added to a solution of (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4-((2-phenylpropan-2-yl)oxy)butanoic acid (Compound 109) (495 mg, 1.41 mmol) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford 4-(2-(ethyldisulfanyl)-6-methylphenyl) 1-(2-phenylpropan-2-yl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 110) (249 mg, 33%).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5](O)=[O:6])[CH2:3]1.C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C=O)C>[CH3:1][N:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([Cl:14])=[O:6])[CH2:3]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCCC(C(=O)Cl)C1

Procedure:
The hydrochloride salt of (±)-N-methylnipecotic acid (1.0 g) was suspended in dichloromethane (25 ml) and stirred at room temperature for 2 h with oxalyl chloride (0.58 ml) and DMF (1 drop). The solvent was then evaporated to yield the hydrochloride salt of N-methylnipecotyl chloride as a pale yellow solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].C(OC(=O)[C:10]([C:24]#[N:25])=[C:11]1[CH2:23][CH2:22][C:14]2([O:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][O:15]2)[CH2:13][CH2:12]1)C.[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH2:16]([O:15][C:14](=[O:19])[CH2:13][CH:10]([C:11]1([CH2:1][CH:2]=[CH2:3])[CH2:12][CH2:13][C:14]2([O:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][O:15]2)[CH2:22][CH2:23]1)[C:24]#[N:25])[CH3:17]
Reactant: C=CC[Mg]Cl
Reactant: CCOC(=O)C(C#N)=C1CCC2(CC1)OCC(C)(C)CO2
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC1(C(C#N)CC(=O)OCC)CCC2(CC1)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Allylmagnesium chloride (2 mol/L in tetrahydrofuran, 56 ml) is added to a solution of cyano-(3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-ylidene)-acetic acid ethyl ester (13.7 g) and CuI (2.7 g) in tetrahydrofuran (100 mL) under argon atmosphere and chilled in an ice bath. The mixture is warmed in the cooling bath to room temperature and stirred overnight. Aqueous NH4Cl solution is then added and the resulting mixture is extracted with tert-butyl methyl ether. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:02:3) to give the title compound. Yield: 5.0 g (31% of theory); Mass spectrum (ESI+): m/z=336 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][NH:14][N:13]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C1N2CCN(CC2)C1.[F:29][C:30]1([F:39])[CH2:33][N:32]([C:34](=[O:38])/[CH:35]=[CH:36]\I)[CH2:31]1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:36]=[CH:35]\[C:34]([N:32]3[CH2:33][C:30]([F:39])([F:29])[CH2:31]3)=[O:38])[N:13]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1Cl
Reactant: O=C(/C=C\I)N1CC(F)(F)C1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 2.7 %

Procedure:
3-(4-Chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (0.1 g, 1.0 eq.) was dissolved in DMF (5 mL). DABCO (0.071 g, 2 eq.) was added and stirred for 30 min. (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.095 g, 1.1 eq.) was then added. The reaction mixture was stirred at room temperature for 5 h and then poured into iced water (50 mL). Product was extracted with EtOAc (3×15 mL). The combined organic layers was washed with brine, (20 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.150 g of crude product, which was purified by chromatography to obtain (Z)-3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)prop-2-en-1-one (0.004 g, 3% yield). 1H NMR (400 MHz, DMSO) δ=9.32 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.47-7.49 (d, J=10.4 Hz, 1H), 6.00-5.04 (d, J=10.4 Hz, 1H), 4.55-4.58 (m, 2H), 4.33-4.36 (m, 2H) LCMS calcd for C16H10ClF8N4O [M+H]+: 461.7. Found: 461.14, at 2.99 min retention time.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH:20][C:27](=[O:30])[CH2:28][CH3:29])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) (150 mg, 0.56 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL), cooled at 0° C., propionyl chloride (57 mg, 0.62 mmol) was added dropwise. Upon complete addition, the ice bath was removed and the reaction continued at room temperature overnight. Then CH2Cl2 (10 mL) and aqueous NaOH 10% (10 mL) were added, the organic layer was separated, and washed with H2O and saturated NaCl. The combined organic layers were dried over Na2SO4, filtered and concentrated in vaccuo. The crude product was purified by column chromatography on silica gel, eluting with an EtOAc/hexane gradient (80-100%), yielding the target product (100 mg, 55%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH3:7])[CH3:2].C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C.CN(C=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C(=O)OC
Reactant: CCOC(OCC)N(C)C
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(C=CN(C)C)C(=O)OC
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of 2-ethoxycarbonyl-3-methoxycarbonyl-but-2-enoic acid ethyl ester (15 g, 61.5 mmol), dimethylformamide diethyl acetal (11.1 mL, 64.5 mmol) and DMF (15 mL) was heated at 80° C. for 5 h. After the mixture was cooled, 200 mL of benzene was added, and the resulting mixture was washed several times with 1 M HCl and water. The organic layer was dried over MgSO4 and concentrated to give an orange solid, which was recrystallized from hexanes/CCl4 to give 8.1 g of the title compound as a bright yellow solid. 1H NMR (CDCl3, 200 MHz): δ=6.70 (d, 1H, J=13.2 Hz), 5.66 (d, 1H, J=13.4 Hz), 4.10-4.40 (m, 4H), 3.88 (s, 3H), 2.96 (br s, 6H), 1.20-1.40 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([O:36]C)[CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[C:17]([F:27])[C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([OH:36])[CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[C:17]([F:27])[C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)([OH:14])[C:10]([F:13])([F:11])[F:12]
Reactant: COc1cc(-c2ccc(C(C)C(O)(c3cc(F)c4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F
Agent: BrB(Br)Br
Product: CC(c1ccc(-c2ccc(F)c(O)c2)cc1Cl)C(O)(c1cc(F)c2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 1, step 4, 6-[2-(3-chloro-4′-fluoro-3′-methoxy-biphenyl-4-yl)-1-hydroxy-1-trifluoromethyl-propyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with BBr3 to give the title compound as a light yellow oil. MS (m/e, ISP neg. ion)=526.2 [M−H+].
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:13]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cc2ccccc2c(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc(Br)cc3ccccc23)CC1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
A mixture of dibromoisoquinoline (150 mg, 0.52 mmol), tert-Butyl 1,4-diazepane-1-carboxylate (104 mg, 0.52 mmol) and potassium carbonate (144 mg, 1.04 mmol) in DMF (5 ml) was heated to 90° C. for 18 hours. The reaction mixture was allowed to cool down to room temperature and was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a colourless oil (160 mg, 76% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][N:27]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:19](=[O:20])[C:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:24])[C:9]([CH3:25])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:23])[CH3:22]
Reactant: CNC1CCCCC1
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)N(C)C3CCCCC3)ccc2n1C

Procedure:
In accordance with a procedure analogous to that of Example 130, the above compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid and N-methyl-cyclohexylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[C:7]([O:8][C:9]2[CH:46]=[CH:45][C:12]([C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:44])([CH3:43])[C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][C:33]([N+:40]([O-])=O)=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[CH:17]=3)([CH3:15])[CH3:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:40][C:33]1[CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:13]([CH3:14])([CH3:15])[C:12]4[CH:11]=[CH:10][C:9]([O:8][C:7]5[C:47]([C:49]([F:50])([F:51])[F:52])=[CH:48][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:46][CH:45]=4)[CH:17]=3)([CH3:44])[CH3:43])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(c1ccc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3C(F)(F)F)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: CC(C)(c1ccc(Oc2ccc(N)cc2C(F)(F)F)cc1)c1cccc(C(C)(C)c2ccc(Oc3ccc(N)cc3C(F)(F)F)cc2)c1
Yield: 89.1 %

Procedure:
Successively, to a reduction vessel equipped with a thermometer, reflux condenser and stirrer, 90 g (0.124 mol) of 1,3-bis[4-(4-nitro-6-trifluoromethylphenoxy)-α, α-dimethylbenzyl]benzene, 500 ml of methyl cellosolve and 5 g of 5%-Pd/c having a moisture content of 50% were charged and reacted at 70°~80° C. for 4 hours in a hydrogen atmosphere. After finishing the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 73.4 g (89% yield) of 1,3-bis[4-(4-amino-6-trifluoromethylphenoxy)-α, α-dimethylbenzyl]benzene as a light yellow crystal having a melting point of 118.5~119.2.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7]C)=O.Cl.[CH2:11]([O:13][C:14](=[NH:16])[NH2:15])[CH3:12].[OH-].[Na+]>O>[CH2:11]([O:13][C:14]1[N:16]=[C:3]([CH2:2][Cl:1])[CH:4]=[C:5]([OH:7])[N:15]=1)[CH3:12]
Reactant: COC(=O)CC(=O)CCl
Reactant: CCOC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1nc(O)cc(CCl)n1

Procedure:
An emulsion of 20.9 g (0.135 mol) of methyl 4-chloroacetoacetate and 23.5 g (0.189 mol) of O-ethylisourea hydrochloride is treated with a solution of 41.3 g (0.31 mol) of sodium hydroxide in 40 ml of water at -20° C. to -10° C. during 5 minutes while stirring well. After stirring at room temperature for 2 hours the resulting crystalline product is filtered off and dried. The crystals, m.p. 156°-158° C., are washed well with diethyl ether. There is obtained 2-ethoxy-4-chloromethyl-6-hydroxy-pyrimidine, m.p. 161°-163° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([CH3:15])[CH2:4][CH2:3]1.[H-].[Na+].[C:18]([C:20]1[CH:25]=[CH:24][N:23]=[C:22](F)[CH:21]=1)#[N:19]>CS(C)=O>[C:18]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:1][C@H:2]2[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([CH3:15])[CH2:4][CH2:3]2)[CH:21]=1)#[N:19]
Reactant: C[C@@H]1CC[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (4.50 g, 22.9 mmol) in DMSO (42 mL) was treated with NaH (0.60 g, 25.1 mmol) in portions, then allowed to stir for 15 min. Solid 4-cyano-2-fluoropyridine (3.83 g, 31.4 mmol) was then added and the reaction was stirred at RT overnight. The reaction was quenched by addition of saturated, aqueous NaHCO3, then diluted further with water. The mixture was extracted three times with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-25% ethyl acetate in hexanes), providing the titled compound as a colorless oil which quickly solidified to give white crystals. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.2 Hz, 1H), 7.05 (dd, J=5.18, 1.3 Hz, 1H), 6.96 (d, J=1.1 Hz, 1H), 5.16 (s, 1H), 4.51 (s, 1H), 4.34 (d, J=15.0 Hz, 1H), 3.05-3.08 (m, 2H), 2.07-2.20 (m, 1H), 1.89-1.95 (m, 2H), 1.35-1.38 (m, 2H), 1.30 (s, 9H), 1.19 (d, J=7.2 Hz, 3H) ppm. LRMS m/z (M+H) 318.4 found, 318.2 required.