Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)=[N:6][CH:7]=1.F[C:22]1[CH:23]=[C:24]([C@H:28]2OC(=O)N[C@@H:29]2C2C=NC(C#CC3C=CC=CC=3)=CC=2)[CH:25]=[CH:26][CH:27]=1.BrC1C=CC(CBr)=NC=1>>[F:19][C:15]1[CH:14]=[C:13]([C@@H:12]2[O:11][C:10](=[O:20])[NH:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([C:29]#[C:28][C:24]3[CH:25]=[CH:26][CH:27]=[CH:22][CH:23]=3)=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1.[F:19][C:15]1[CH:14]=[C:13]([C@H:12]2[O:11][C:10](=[O:20])[NH:9][C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([C:29]#[C:28][C:24]3[CH:25]=[CH:26][CH:27]=[CH:22][CH:23]=3)=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1N[C@H](c2ccc(Br)cn2)[C@@H](c2cccc(F)c2)O1
Reactant: O=C1N[C@H](c2ccc(C#Cc3ccccc3)nc2)[C@@H](c2cccc(F)c2)O1
Agent: BrCc1ccc(Br)cn1
Product: O=C1N[C@@H](c2ccc(C#Cc3ccccc3)cn2)[C@H](c2cccc(F)c2)O1
Product: O=C1N[C@H](c2ccc(C#Cc3ccccc3)cn2)[C@@H](c2cccc(F)c2)O1
Reaction time: 0.25 h
Yield: 15 %
Yield: 11 %

Procedure:
Prepared from (4R,5R)-4-(5-bromopyridin-2-yl)-5-(3-fluorophenyl)oxazolidin-2-one using the same procedure as that used to prepare (4R,5R)-5-(3-fluorophenyl)-4-(6-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one from 5-bromo-2-(bromomethyl)pyridine. The two enantiomers were purified via chiral preparative liquid chromatography (Chiralpak AS 21×250 10 μm, A=0.1% Diethylamine/Heptane, B=Ethanol, Isocratic 45% B for 15 min, Flow Rate=15 mL/min) providing 8.5 mg (15%) (4S,5S)-5-(3-fluorophenyl)-4-(5-(phenylethynyl)pyridin-2-yl)oxazolidin-2-one and 6.2 mg (11%) (4R,5R)-5-(3-fluorophenyl)-4-(5-(phenylethynyl)pyridin-2-yl)oxazolidin-2-one. 1H NMR (500 MHz, CDCl3) δ ppm 8.79 (1H, d, J=1.53 Hz), 7.90 (1H, dd, J=8.09, 1.98 Hz), 7.51-7.62 (2H, m), 7.32-7.45 (5H, m), 7.14-7.24 (2H, m), 7.08 (1H, td, J=8.32, 1.98 Hz), 5.77 (1H, s), 5.57 (1H, d, J=5.80 Hz), 4.90 (1H, d, J=5.19 Hz). Chiral LC for (4S,5S)-5-(3-fluorophenyl)-4-(5-(phenylethynyl)pyridin-2-yl)oxazolidin-2-one; example 409 (Chiralpak OJ-H analytical column, 4.6×100 mm, 5 μm, Mobile Phase: A=100% Heptane with 0.1% Diethylamine, B=100% Ethanol, Flow rate: 2.0 mL/min, 40% A Isocratic) 4.57 min. Chiral LC for (4R,5R)-5-(3-fluorophenyl)-4-(5-(phenylethynyl)pyridin-2-yl)oxazolidin-2-one; example 410 (Chiralpak OJ-H analytical column, 4.6×100 mm, 5 μm, Mobile Phase: A=100% Heptane with 0.1% Diethylamine, B=100% Ethanol, Flow rate: 2.0 mL/min, 40% A Isocratic) 9.94 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[N:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 38 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (120 mg, 0.4 mmol), using 1-(6-chloro-3-pyridinyl)-1-ethanone instead of 4-fluoroacetophenone, was converted to the title compound (64 mg, 38%) which was obtained as a light yellow solid. MS: m/e=417.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.C1C=CC(/C(/C2C=CC([N+]([O-])=O)=CC=2)=N/O)=CC=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=1>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([C:9]2([C:13]([NH:59][CH:57]([C:54]3[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=3)[CH3:58])=[O:15])[NH:8][CH2:12][CH2:11][S:10]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Agent: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Product: CC(NC(=O)C1(S(=O)(=O)c2ccc(-c3ccccc3)cc2)NCCS1)c1ccc(F)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and 1-(4-fluorophenyl)ethanamine, the title compound was obtained in 85% purity by HPLC.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[C:30](#[N:34])[CH:31]=[CH:32][CH3:33].N12CCCN=C1CCCCC2>C(#N)C.CO>[C:30]([CH2:31][CH:32]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[CH3:33])#[N:34]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Reactant: CC=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(CC#N)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (15 mg, 0.037 mmol) and 2-butenenitrile (3.8 mg, 0.056 mmol) in acetonitrile (0.5 mL) and methanol (0.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 μL, 0.037 mmol). The mixture was stirred at 60° C. overnight. The reaction mixture was stirred at 60° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=469.1.
Reaction SMILES: [CH2:1]=O.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CCO>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:1])[CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C=O
Reactant: CN1CCNCC1
Solvent: CCO
Product: CC(=O)c1ccc(O)c(CN2CCN(C)CC2)c1
Yield: 55 %

Procedure:
A solution of formaldehyde (37% w/w, 8.2 mL) was added to a solution of 4′-Hydroxy acetophenone (100 mmol), and N-methylpiperazine (110 mmol) in EtOH. Heated at reflux overnight. The solvent was evaporated on celite and the residue was purified by flash chromatography and crystallized from heptane to give the title product as white needles in 55% yield. 1H-NMR (DMSO-d6) δ 7.76 (dd, 1H), 7.74 (s, 1H), 6.81 (d, 1H), 3.69 (s, 2H), 2.47 (br, 4H), 2.46 (s, 3H), 2.35 (br, 4H), 2.17 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH:19]1[CH2:21][CH2:20]1)[C@@H:6]([OH:18])[C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[N+:2]=[N-:3].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOC(C)=O.O>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:9][CH2:8][C@@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[C@H:6]([OH:18])[C@@H:5]([CH:19]2[CH2:20][CH2:21]2)[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)[C@H](O)[C@H](CN=[N+]=[N-])C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](CN=[N+]=[N-])C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of tert-butyl [(1R,2R,3S)-4-azido-3-cyclopropyl-2-hydroxy-1-(hydroxymethyl)butyl]carbamate (0.435 g, 1.45 mmol) in anhydrous pyridine (5 mL) was added 4-dimethylaminopyridine (0.055 g, 0.20 mmol) and para-toluenesulfonyl chloride (0.55 g, 2.8 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was diluted with EtOAc (40 mL) and H2O (3 mL). The layers were separated, the organic layer was washed with H2O (3×3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (40 g silica gel column, eluting with 0-30% EtOAc/hexanes) to afford the sub-title compound (506 mg, 77%). LCMS (ESI) calc. for C15H23N4O4S [M+H-Boc+H]+ m/z=355.2. found 355.1
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[OH:10][C:11]1([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]1.O=[C:19]1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:1]1[CH:19]=[C:16]([C:11]2([OH:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=[N:2]1)[CH3:9]
Reactant: N#CC1(O)CCCC1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(C2(O)CCCC2)nn1
Reaction time: 48 h
Yield: 98 %

Procedure:
Ethyl azidoacetate (2.58 g, 20 mmol) was dissolved in tert-butanol (15 mL), and 1-hydroxycyclopentanecarbonitrile (2.20 g, 20 mmol) was added. A solution of sodium ascorbate (0.792 g, 4 mmol) in water (10 mL) followed by a 0.3 M solution of copper sulfate (0.67 mL) was added to the mixture, and stirring continued at room temperature for a further 48 hours. The solution was evaporated to dryness in vacuo and the residue was dissolved in EtOAc (50 mL), dried (MgSO4), filtered and evaporated in vacuo to afford the title compound as green-yellow crystals in 98% yield, 4.69 g. MS m/z 238 [M−H]−
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH3:10])[N:4]=1.[OH2:11].[CH3:12]O>>[Cl:9][C:7]1[CH:6]=[C:5]([CH3:10])[N:4]=[C:3]([O:11][CH3:12])[N:8]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: O
Reactant: CO
Agent: [Na]
Product: COc1nc(C)cc(Cl)n1
Reaction time: 0.5 h

Procedure:
To anhydrous methanol (10 ml) was added sodium (230 mg, 10 mmol) and the mixture was stirred under an argon atmosphere until a clear solution had formed. This solution was added dropwise over two hours with stirring to a solution of 2,4-dichloro-6-methylpyrimidine (1.79 g, 11 mmol) in anhydrous methanol (10 ml) under cooling so that the temperature remained below 10° C. Stirring was continued for 30 minutes, then water was added (2 ml), the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (pre-packed silica column, gradient of heptane/ethyl acetate). 750 mg was obtained (4.75 mmol, 47%). MS (APCI) m/z=159.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH3:18][C:19]1([CH3:27])[O:23][C@:22]([CH2:25]O)([CH3:24])[CH2:21][O:20]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:24][C@@:22]1([CH3:25])[CH2:21][O:20][C:19]([CH3:27])([CH3:18])[O:23]1)=[O:15])[CH:7]=[CH:6]2
Reactant: CC1(C)OC[C@](C)(CO)O1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@@]3(C)COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 32.2 g, 0.14 mol) and ((4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)methan-1-ol (15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC) (23 g, 0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give the title compound (37.5 g, 96.5% yield) as a white solid, mp 65–66° C. 1H NMR (CDCl3) δ 7.75 (d, J=8.7 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.46 (dd, J=8.4 and 1.7 Hz, 1H), 7.15 (m, 2H), 4.27 (m, 1H), 4.19 (m, 2H), 4.03–3.92 (m, 2H), 3.96 (s, H), 3.69 (dd, J=8.4 and 6.0 Hz, 1H), 1.64 (d, J=7.1 Hz, 3H), 1.40 (s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.8, 127.1, 126.1, 125.9, 119.0, 109.7, 105.5, 73.4, 66.2, 64.8, 55.2, 45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 362 (M+NH4)+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1.[CH:16]1([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][CH2:17]1.O>CN(C=O)C>[CH:16]1([CH2:19][N:20]([CH2:4][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH2:14][O:13][CH2:12][CH2:11][C:9]=3[N:10]=2)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCC1CC1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1nc2c(c(=O)[nH]1)COCC2)CC1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of NaH (11.96 g, 299 mmol) in 260 mL DMF at 0° C. was sequentially added 2-(chloromethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (20 g, 100 mmol) and tert-butyl cyclopropylmethylcarbamate (17.07 g, 100 mmol) in small portions in order to maintain the internal temperature at or below 5° C. The reaction mixture was allowed to warm to room temperature slowly with continued stirring over 12 h. The reaction was cooled to 0 C and water was added slowly (˜250 mL total). The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated to a red oil. The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes and eluting with 100% ethyl acetate via a sharp gradient. The title compound was obtained as an off-white solid (20.79 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:3]=1.[CH2:24]([Br:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.S1(CCCC1)(=O)=O>C(OCC)(=O)C>[Br-:31].[CH2:24]([N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N+:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCCCCCCn1nc(C)cc1C
Reactant: BrCc1ccccc1
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC[n+]1c(C)cc(C)n1Cc1ccccc1
Product: [Br-]
Temperature: 100 °C
Reaction time: 11 h
Yield: 49.2 %

Procedure:
A mixture of 48.1 g (0.150 mol) of 3,5-dimethyl-1-hexadecyl-pyrazole, 25.6 g (0.150 mol) of benzyl bromide and 200 ml of sulfolane is stirred and heated to 100° C., and then kept at this temperature for 11 hrs. The reaction mixture is allowed to cool down overnight. It is then stirred and 100 ml of ethyl acetate is added. The crystalate is filtered off, washed with ethyl acetate, and vacuum dried at 50° C./12 Torr to yield about 36.3 g of 2-benzyl-3,5-dimethyl-1-hexadecyl-pyrazolium bromide; m.p. 166°-167° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](C=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=O.[K+].[OH-:25].[Na+].[C:27]([OH:31])(C)(C)C>O>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([C:27]([OH:31])=[O:25])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)O
Reactant: [OH-]
Reactant: O=Cc1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4'-Trifluoromethyl-2-biphenylcarbaldehyde (1.08 g, 4.32 mmol) in tert-butanol (15 mL) at 80° C. was added a solution of potassium permanganate (0.89 g, 5.62 mmol) in water (25 mL). After stirring at 80° C. for two hours, the mixture was cooled, a solution of 3N sodium hydroxide was added (2 mL) and the manganese dioxide was filtered off. The filtrate was diluted with water (15 mL) and acidified with 6N hydrochloric acid to precipitate the title compound (1.05 g, 91.2%). Dissolution in 0.3N sodium hydroxide (15 mL), followed by charcoal treatment, filtrating, and precipitation with 6N hydrochloric acid gave the purified 4-Trifluoromethyl-2-biphenylcarboxylic acid compound (0.85 g, 85%). 'H NMR (CDCl3): 7.5 (m, 7, ArH), 8.0 (m, 1,3-H), 9.5 (broad s, 1, CO2H).
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:10]3=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=[C:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][CH:21]([CH:23]=[CH2:24])[CH3:22])=[O:19]>N1C=CC=CC=1.ClCCl.O>[CH3:22][CH:21]([O:20][C:18](=[O:19])[NH:15][C:13]1[CH:14]=[C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:16][C:10]2=[N:11][CH:12]=1)[CH:23]=[CH2:24]
Reactant: C=CC(C)OC(=O)Cl
Reactant: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(C)OC(=O)Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Temperature: 25 °C

Procedure:
80 mg 2-phenyl-3H-imidazo[4,5-b]pyridin-6-ylamine (0.38 mmol,) in 3 ml dry pyridine were treated with a solution of 3-buten-2-yl chloroformate in dichloromethane. The mixture was stirred at room temperature over night, diluted with 1 ml water and stirred for another hr. The solvents were evaporated and the residue was dispersed in water with sonication, filtered, and the filter residue washed thoroughly with water and ether.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1>>[NH2:37][C@@H:34]1[CH2:35][CH2:36][N:32]([CH2:29][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:8]4[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=4[CH3:13])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:31])[CH:15]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=2)[CH2:33]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: N[C@@H]1CCNC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CC[C@@H](N)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and (R)-pyrrolidin-3-ylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH3:28])=[C:10]2[C:29]([O:31][CH3:32])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>C(Cl)Cl>[CH3:32][O:31][C:29]([C:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:14]([C:15](=[O:16])[NH:33][CH2:34][CH2:35][CH2:36][N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[C:13](=[O:27])[NH:12][C:11]=1[CH3:28])=[O:30]
Reactant: NCCCn1ccnc1
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCn2ccnc2)C1c1ccc(F)c(F)c1
Yield: 83.9 %

Procedure:
A solution of 6-(3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine (100 mg, 0.22 mmol) and 1-(3-aminopropyl)imidazole (40 ml, 0.34 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 hours. The solvent was removed in vacuum. The residue was separated on preparative TLC (CHCl3/MeOH=100/15) to get the title compound (80 mg, 84% yield) as a white solid. Hydrochloride of title compound was made with HCl in ether. Calcd for C20H21N5O4F2+0.3H2O: C, 54.74%; H, 4.99%; N, 15.89%. Found: C, 54.92%; H, 4.65%; N, 15.77%. M.P. of the salt: 221-224° C.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]23CCC(CCC)(CC2)C[CH2:13]3)[CH2:8][C:7]1=[O:23])[CH2:2]CCC.C(C1COC(=O)C1)(=O)C.[BrH:33]>>[C:7]([CH:6]([CH2:11][CH2:10][CH2:9][CH2:12][CH3:13])[CH2:1][CH2:2][Br:33])(=[O:23])[CH3:8]
Reactant: Br
Reactant: CCCCCC1CCC(C23CCC(CCC)(CC2)CC3)CC1=O
Agent: CC(=O)C1COC(=O)C1
Product: CCCCCC(CCBr)C(C)=O

Procedure:
A mixture of 33 g of 2-n-pentyl-5-(4-n-propylbicyclo[2.2.2]octyl)-cyclohexanone [obtainable by the method of P. Place et al., Tetrahedron 34, 1931 (1978) by reacting 3-acetylbutyrolactone with n-pentyl halide/NaH, subsequently reacting the product with hydrogen bromide to give 3-acetyl-1-bromo-n-octane, converting the latter into the corresponding ethylene ketal, reacting the corresponding Grignard compound with 4-cyano-1-n-propylbicyclo[2.2.2]octane and subsequently subjecting the product to an aldol condensation and catalytically hydrogenating the cyclohex-2-enone to give the target product], 20 ml of 80% hydrazine hydrate and 20 g of KOH in 240 ml of diethylene glycol is boiled under reflux for 2 hours. The reflux condenser is then replaced by a distillation column, the temperature is increased slowly to 200° C. and the mixture is kept at this temperature for 6 hours. After cooling, it is diluted with 300 ml of water, acidified and extracted with toluene. Customary working up of the organic phase gives 1-n-propyl-4-(trans-4-n-pentylcyclohexyl)-bicyclo[2.2.2]octane.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([O:13][CH3:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C

Procedure:
To a cloudy mixture of 3-bromo-2-chloro-5-nitropyridine (Atlantic Scitech, Linden, N.J., 5.10 g, 21.48 mmol) in 50 mL anhydrous methanol at 0° C. (ice/water bath) was added sodium methoxide 5.4 M in methanol (7.96 mL, 43.0 mmol) dropwise by addition funnel. The reaction became clear then a thick precipitate formed. The ice/water bath was removed and the reaction warmed to ambient temperature, quenched with water and sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with DCM 2 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-bromo-2-methoxy-5-nitropyridine (5.07 g, 21.76 mmol, quantitative yield) as a light yellow solid. m/z (ESI, +ve ion) 233 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J=2.3 Hz, 1H), 8.63 (d, J=2.5 Hz, 1H), 4.15 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-methyl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A15) (3.40 g, 10.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as light gray solid (3.0 g, 97%).
Reaction SMILES: [CH2:1]([N:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:31]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-dibenzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 113, 48.0 mg, 0.10 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 42.0 mg (93%) of the title compound as a colorless solid.