Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[CH:15]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16]1.C(O)(=O)C>C1COCC1>[CH2:13]([O:12][C:10]([C:9]1[N:7]=[CH:8][S:20][C:19]=1[NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:11])[CH3:14]
Reactant: S=C=NC1CC1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncsc1NC1CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a vigorously stirred solution of 311 mg of potassium tert-butylate (2.77 mmol) in THF (5 ml) were slowly added 5 ml of a THF-solution of 300 mg of ethyl isocyanoacetate (2.52 mmol) and 250 mg of cyclopropyl isothiocyanate (2.52 mmol) at −20° C. The mixture was stirred for 15 min at −20° C. and was then allowed to warm to 0° C. in 1.5 h before 0.3 ml of acetic acid were added. The reaction mixture was concentrated in vacuo to give a residue which was purified by flash column chromatography (heptane/ethyl acetate 95:5 to 75:25) to give 5-cyclopropylamino-thiazole-4-carboxylic acid ethyl ester (198 mg, 37%) as a yellow oil. MS (ISP) 213.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1)[CH3:2].[CH3:10][O:11]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:4][C:5]([CH2:8][CH3:9])=[CH:6][C:7]=1[CH:10]=[O:11])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCc1ccc(CC)s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCc1cc(C=O)c(CC)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
Titanium tetrachloride (8.0 cm3, 70 mmol) was added slowly under nitrogen to a stirred solution of 2,5-diethylthiophene (6.0 g, 43 mmol) in dichloromethane (25 ml) at 0° C. After 10 min, 1,1-dichloromethyl methyl ether (5.0 g, 43 mmol) was added dropwise causing a vigorous reaction and the evolution of hydrogen chloride. The dark mixture was stirred at 0° C. for 30 min followed by 1 h at 20° C. and then poured onto ice water (100 ml). The organic phase was separated, the aqueous solution was extracted with dichloromethane (3×20ml) and the combined organic extracts were wahsed with 10% aqueous sodium hydroxide (2×50 ml) and dried. Removal of the solvent gave a brown oil which was distilled at reduced pressure to yield 2,5-diethyl-3-thiophenecarboxaldehyde (4.1 g, 57%) as a colourless oil which darkened rapidly, b.p. 72° C. at 0.3 mmHg (Found M+ 168.0620. C9H12SO requires M, 168.0609) which showed νmax (film) 1195m, 1387m, 1457m, 1676s, 2875m, 2933m and 2970s cm-1 ; δH (CCl4) 1.28 (3H, t, J 8 Hz) 1.32 (3H, t, J 8 Hz), 2.75 (2H, q, J 8 Hz), 3.13 (2H, q, J 8 Hz), 6.93 (1H, s), 9.85 (1H, s); m/z 168 (M+), 153 (M+ -CH3), 139 (M+ -C2H5).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=O)C.O.[NH2:20]N>CCO>[NH:20]1[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]=2[CH:4]=[N:2]1
Reactant: CN(C)C=C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cn[nH]c2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a stirred mixture of tert-butyl 4-((dimethylamino)methylene)-3-oxopiperidine-1-carboxylate (1.0 g, 4 mmol) in EtOH (10 mL) was added hydrazine hydrate (376 mg, 10 mmol). The mixture was stirred at 80° C. for 16 hours until the reaction was shown to be complete by LCMS. The mixture was then concentrated and the residue was extracted with EA (3×30 mL) from water (30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step (810 mg, 90% yield). LCMS: 224.1 (M+1), 114.1 (M+1−100), 168.1 (M+1−56).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([O:25]CC4C=CC=CC=4)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.C>C(O)C.C(OCC)(=O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(-n2ncc3c(O)cccc32)cc1F
Yield: 81.5 %

Procedure:
A mixture of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indazole (D2) (307 mg) in ethanol/ethyl acetate (˜50 mL, 1:1) was hydrogenated in the presence of 10% Pd on charcoal (150 mg) at atmospheric pressure and room temperature for 3 hrs. The mixture was filtered and concentrated and then chromatographed on silica gel (elution with 0-50% ethyl acetate in hexane) to give an off white solid. This was dissolved in ethyl acetate and stirred with charcoal (Norit SX+, 10 mg) for 30 minutes. The mixture was filtered and concentrated to give the title compound (E1) (144 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCCCCCN
Product: CCCCCCNc1cc(C)cc(C)c1
Yield: 90.1 %

Procedure:
Using the general procedure, 5-bromo-m-xylene (136 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (185 mg, 90% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: FC(F)(F)Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 31 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate, 154 was obtained as white solid (45 mg, 31%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.060-9.062 (d, J=1 Hz, 1H), 8.76 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.60-7.63 (t, J=16 Hz, 1H), 7.26-7.28 (t, J=7.5 Hz, 1H), 6.42-6.43 (d, J=8.5 Hz, 1H), 4.75-4.78 (t, J=16.5 Hz, 2H), 3.86-3.92 (m, 4H), 3.15-3.17 (t, J=10.5 Hz, 2H), 2.90-2.92 (t, J=11.5 Hz, 2H), 2.01-2.03 (t, J=11.5 Hz, 2H); MS (ESI) m/z: 443 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1>C(#N)CC.ClCCl>[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:21]=2)=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: COC(=O)CC(=O)CCl
Solvent: ClCCl
Solvent: CCC#N
Product: COC(=O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Yield: 48.3 %

Procedure:
Methyl 4-chloro-3-oxobutanoate (4.32 ml, 37.44 mmol, 2 eq) is added to a solution of 4-(3-chloropropoxy)benzamide (4 g, 18.72 mmol, 1 eq) in propionitrile (50 ml). The mixture is heated at reflux for 48 h. The mixture is then diluted with dichloromethane and filtered. The solvent is removed under vacuum and the residue is purified on silica gel (eluent: ethyl acetate) to give 2.8 g methyl {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetate ax62 as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br)([O-:15])=[O:14].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 172.4 %

Procedure:
A mixture of 4-fluoroanisole-2-boronic acid (3.3 g, 19.4 mmol), 2-nitrobromobenzene (3.56 g, 17.6 mmol), triphenylphosphine (367 mg, 1.4 mmol), triethylamine (4.6 g, 45.8 mmol), and 40 mL of dimethylformamide was sparged with nitrogen for 5 minutes before adding palladium acetate (160 mg, 0.7 mmol) and heating the mixture to 100° C. for 5 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was shaken with 0.1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 2% ethyl acetate/hexanes followed by 4% ethyl acetate/hexanes to give 7.5 g of the title compound. Yield: 86%. EA. MS(FD).
Reaction SMILES: CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:16]([N:23]([S:31]([CH2:34][CH2:35][CH2:36]Cl)(=[O:33])=[O:32])C(=O)OC(C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:38]1([C:44]2[C:45]3[CH:46]=[CH:47][C:48]([C:68]([O:70][CH3:71])=[O:69])=[CH:49][C:50]=3[N:51]3[C:58]=2[C:57]2[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=2[O:55][CH2:54][C@@H:53]([O:63][CH2:64][CH2:65][NH:66][CH3:67])[CH2:52]3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC#N>[CH2:16]([NH:23][S:31]([CH2:34][CH2:35][CH2:36][N:66]([CH3:67])[CH2:65][CH2:64][O:63][C@H:53]1[CH2:52][N:51]2[C:50]3[CH:49]=[C:48]([C:68]([O:70][CH3:71])=[O:69])[CH:47]=[CH:46][C:45]=3[C:44]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[C:58]2[C:57]2[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=2[O:55][CH2:54]1)(=[O:32])=[O:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)CCCS(=O)(=O)NCc1ccccc1)COc1ccccc1-3
Temperature: 200 °C
Yield: 23 %

Procedure:
DIPEA (2 eq.), K2CO3(4 eq.) and tert-butyl benzyl[(3-chloropropyl)sulfonyl]carbamate (was added to a solution of methyl (7S)-14-cyclohexyl-7-[2-(methylamino)ethoxy]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.08 M) in MeCN. The mixture was heated in the microwave at 200° C. for 30 min. The resulting mixture was filtered, concentrated in vacuo, and the residue purified by RP-HPLC (WATERS XTERRA column, C18, 5 um, 19×150 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (23%) as a white powder. (ES+) m/z 674 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](=[O:28])=[O:27].CC(C)=O.[Li+:33].CC([N-]C(C)C)C.C1COCC1>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2[C:26]([O-:28])=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:33]
Reactant: O=C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nc(-c3ccccc3)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C([O-])c1cc2c(Cl)nc(-c3ccccc3)nc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of the N-sulfonyl compound 24 (1.504 g, 4.07 mmol) in dry THF (150 mL), cooled by dry ice/acetone, is added LDA-THF (3.8 mL, 1.5M solution in cyclohexane, 5.7 mmol). After 45 min, carbon dioxide is bubbled into the solution for 5 min, then the cooling bath is removed. When the solution has reached ambient temp., the solvents are evaporated, yielding 1.73 g of the salt 27 [containing (iPr)2NCO2Li] as pale yellow solid. The salt is used without purification in the next step. 1H-NMR (D6-DMSO): δ=6.44 (s, 1H), 7.50-7.75 (m, 6H), 8.33-8.40 (m, 2H), 8.53 (dd, J=8.0, 1.6 Hz, 2H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][C:11]1[O:15][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])=[N:13][C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>CN(C)C=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:12]2[N:13]=[C:14]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])[O:15][C:11]=2[CH2:10][CH2:9][CH2:8][C:7]2[O:29][CH2:4][CH2:5][N:6]=2)=[CH:23][CH:24]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCC(=O)NCCCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCC2=NCCO2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
Sodium hydride (60%, oil, 130mg) was gradually added to a N,N-dimethylformamide solution (30ml) of N-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutyramide (870mg) at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was poured into ice water. And this was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO,). 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-oxazolin-2-yl)propyl]oxazole (615mg, 78%) was obtained by evaporating the solvent. This was recrystallized from acetone-isopropyl ether to give colorless prisms. mp 88-89° C.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 68.1 %

Procedure:
Powdered sodium hydroxide (1 g, 28.77 mmol) was added to a solution of 3-nitro phenol (2 g, 14.35 mmol) in DMF (15 ml) and cooled in an ice-bath. Ethyl bromoacetate (3.2 ml, 28.77 mmol) was added, and the reaction mixture was heated at 90° C. for 7 hr. The reaction mixture was cooled and quenched with ice water. The product was extracted with ethyl acetate, washed with water and dried. Concentration under reduced pressure gave (3-nitrophenoxy)-acetic acid ethyl ester (2.2 g, 68%) as oil.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][NH:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[C:12](#[N:15])[CH:13]=[CH2:14]>>[OH:9][CH:6]([CH2:7][OH:8])[CH2:5][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:14][CH2:13][CH2:12][NH2:15]
Reactant: C=CC#N
Reactant: OCC(O)CNCC(O)CO
Product: NCCCN(CC(O)CO)CC(O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bis-(2,3-dihydroxypropyl)amine (16.5 g., 0.1 mole) and acrylonitrile (6.4 g., 0.12 mole) is mixed in an ice bath and then warmed to room temperature. After standing for 2 hours, the mixture was then heated at 45° C.-55° C. for 3 hours. The excess acrylonitrile is removed by gentle warming under reduced pressure. The residue was taken up in ethyl alcohol, mixed with sponge nickel catalyst and hydrogenated under 200 psi hydrogen using good agaitation. After filtration of catalyst the solvent and excess acrylonitrile is removed by stripping under reduced pressure to leave the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[CH3:12]I>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: Oc1ccc(Br)cc1F
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Br)cc1F
Yield: 80 %

Procedure:
2-Fluoro-4-bromophenol (1) (382.0 g, 2.0 mols) was dissolved in ethanol (1,000 ml), followed by adding potassium hydroxide (113.0 g, 2.0 mols) to the solution, sufficiently agitating the mixture, dropwise adding thereto methyl iodide (312.3 g, 2.2 mols), refluxing it for 4 hours, distilling off most of the ethanol, distilling the residue under reduced pressure and collecting a fraction of 65°-66° C. (4.5 mmHg) to obtain 2-fluoro-4-bromoanisole (2) (328.0 g). This compound was reacted with Mg (38.9 g) in diethyl ether to obtain 3-fluoro-4-methoxyphenylmagnesium bromide (3), followed by dropwise adding thereto cyclohexanone (157.0 g, 1.6 mol) at 7° C. or lower, agitating the mixture at room temperature for about 30 minutes, adding thereto 6N--HCl (350 ml), refluxing the mixture for one hour, washing the resulting organic layer with water, distilling off diethyl ether and recrystallizing the residue from ethanol to obtain (3'-fluoro-4'-methoxyphenyl)-cyclohexene-1 (4) (180.4 g) having a m.p. of 49.0°-50.0° C. This compound (112.0 g, 0.55 mol) was dissolved in xylene (700 ml), followed by adding p-chloranil (267.0 g, 1.1 mol) to the solution, refluxing the mixture for 4 hours, filtering off the resulting tetrachlorohydroquinone, washing the filtrate with 2N--NaOH aqueous solution, distilling off the solvent, subjecting the residue to column chromatography with a column filled with activated alumina and recrystallizing the resulting material from ethanol to obtain 3-fluoro-4-methoxybiphenyl (5) (69.2 g) having a m.p. of 84.5°-86.0° C.
Reaction SMILES: Cl.C(C1C=CC2[NH:14][CH:13]([CH2:15]C(OC)=O)[C:12](=[O:20])N(C)CC=2C=1)(O)=O.O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:14][CH:13]([C:15]1[NH:24][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH2:12][OH:20]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(CO)c1nc2ccccc2[nH]1

Procedure:
HCl (Maekawa; Ohtani, Agric. Biol. Chem., 40, 1976, 791) and 0.88 g of methyl 7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate are dissolved in 30 ml of DMF and treated with 0.49 g of 1-hydroxybenzotriazole and 0.58 g of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide.hydrochloride and 1.55 g of diisopropylethylamine.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C@H:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[Br:31])[NH:16]2)[OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(Cl)=[O:44]>C(Cl)Cl>[Br:31][C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:21]=1[C@H:17]1[N:16]2[C:43](=[O:44])[O:14][C@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([CH3:2])[CH:4]=3)[C@@H:15]2[CH2:20][CH2:19][CH2:18]1
Reactant: O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCC[C@@H](c2cc(C(F)(F)F)ccc2Br)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@H]2OC(=O)N3[C@H](c4cc(C(F)(F)F)ccc4Br)CCC[C@@H]23)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To (R)-[3,5-bis(trifluoromethyl)phenyl]{(2S,6S)-6-[2-bromo-5-(trifluoromethyl)phenyl]piperidin-2-yl}methanol (280 mg, 0.509 mmol) in DCM (5 mL) was added DIPEA (0.9 mL, 0.509 mmol) and phosgene (252 mg, 0.509 mmol). The reaction mixture was stirred at room temperature for 30 minutes before the solvent was removed and the reaction was diluted with ethyl acetate (15 mL) and aqueous KOH (15 mL). The organic was dried over sodium sulfate, filtered, and concentrated before purification by preparative TLC to yield (1R,5S,8aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-methyl-5-(trifluoromethyl)phenyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (200 mg, 0.347 mmol). MS ESI calc'd. for C22H16BrF9NO2 [M+H]+ 576.0 and 578.0, found 576.1 and 578.1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=1.[Li+].[BH4-]>C1COCC1>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[C:10]#[N:11])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(C#N)c(OCCNC(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cc(CO)ccc1C#N
Temperature: 70 °C

Procedure:
3-(2-tert-Butoxycarbonylamino-ethoxy)-4-cyano-benzoic acid methyl ester from Step 2 (346 mg, 1.08 mmol) was dissolved in THF (5.5 ml). LiBH4 in THF (2M, 1.1 ml, 2.16 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1
Reactant: COc1cc(-c2ncc(Br)cc2[N+](=O)[O-])c(F)cn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2ncc(Br)cc2N)c(F)cn1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 5-bromo-5′-fluoro-2′-methoxy-3-nitro-2,4′-bipyridine (0.22 g, 0.67 mmol) in EtOAc (15 mL) was added tin(II) chloride dihydrate (0.76 g, 3.37 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the residue was purified on basic alumina (0-15% EtOAc in hexanes) to afford a residue as 5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (1H, d, J=2.0 Hz), 8.13 (1H, d, J=1.5 Hz), 7.29 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=4.9 Hz), 3.95 (3H, s).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C(NC(C)C)(C)C.[Li].F[B-](F)(F)F.[CH+:17]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=[CH:18]1>O1CCCC1>[CH:22]1([CH2:2][C:1]#[N:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=[CH:23]1
Reactant: CC#N
Reactant: c1ccc[cH+]cc1
Agent: F[B-](F)(F)F
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CCC1C=CC=CC=C1
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a solution of anhydrous acetonitrile (3.12 mL, 56.2 mmol, 1 eq.) in tetrahydrofuran (281 mL, 0.2 M) was added lithium diisopropylamine (1.8 M in heptane/ethylbenzene/tetrahydrofuran, 31.2 mL, 56.2 mmol, 1 eq.) at −78° C. After 20 minutes at −78° C., tropylium tetrafluoroborate (10 g, 56 mmol, 1 eq.) was added. After 10 minutes, the reaction was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide a brown oil, which was purified by silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) to provide #61 (1.88 g, 25%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.69-6.71 (m, 2H), 6.27-6.32 (m, 2H), 5.28-5.33 (m, 2H), 2.61 (d, J=7.2 Hz, 2H), 2.26-2.34 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[CH:26][C:27](O)=[N:28][CH:29]=1>COCCOC>[F:21][C:18]([F:19])([F:20])[CH2:17][N:4]([CH2:3][CH2:2][O:1][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:29][N:28]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cn1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(C(F)(F)F)cn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 5-trifluoromethyl-2-pyridinol, using dry DME as reaction solvent: MS (ESI) m/z 458 (M+1).