Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([C:34]([O:36]C)=O)[C:17]([C:20]4[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:8]2)[CH:2]=1.O.[NH2:39][NH2:40].C1(C)C=CC=CC=1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([C:34]([NH:39][NH2:40])=[O:36])[C:17]([C:20]4[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:21]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:8]2)[CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: NNC(=O)c1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 135 °C

Procedure:
A solution of 7a (160 mg, 0.300 mmol) and hydrazine hydrate (286 μL, 9.18 mmol) in ethanol:toluene (2.70 mL of an 8:1 mixture, respectively) was heated to 100° C. in a sealed microwave vial for 10 min, An additional aliquot of hydrazine hydrate (200 μL, 6.42 mmol) was added, and the resulting mixture was heated to 135° C. in a sealed microwave vial for 15 min. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The combined organics were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 9a. m/z (ES) 523 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3ccccc32)c1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
To a solution of 2-phenyl-1H-indole (4.64 g, 24.0 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.96 g, 24.0 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(bromomethyl)benzoate (5.0 g, 21.8 mmol) was added to the obtained mixture, and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 3-[(2-phenyl-1H-indol-1-yl)methyl]benzoate (3.67 g). Then, to a solution of the product in tetrahydrofuran (37 mL) was added lithium aluminum hydride (0.41 g, 10.7 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, sodium hydrogensulfate decahydrate (6.9 g, 21.4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (2.63 g, yield 79%) as a yellow oil. 1H NMR (CDCl3) δ: 1.57 (1H, m), 4.62 (2H, d, J=2.1 Hz), 5.37 (2H, s), 6.66 (1H, s), 6.93 (1H, m), 7.07 (1H, s), 7.11-7.20 (3H, m), 7.22-7.31 (2H, m), 7.33-7.48 (5H, m), 7.67 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:10]=1[OH:11])[CH:6]=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:28](=[O:30])[CH3:29])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:29][C:28]([C:20]2[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=2)=[O:30])[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:10]=1[OH:11]
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc(C(F)(F)F)c1O

Procedure:
The procedure described in Example 8 was repeated using 2.2 g of 3-methoxy-4-hydroxy-5-trifluoromethylbenzaldehyde and 2.1 g of 3',4',5'-trimethoxyacetophenone. Yield 2.6 g (61%), m.p. 190°-192° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>C(Cl)Cl>[CH2:14]([NH:16][C:17]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=1)=[O:18])[CH3:15]
Reactant: Cc1nn(-c2cccnc2)cc1N
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1cn(-c2cccnc2)nc1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To a solution of 3-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.1 g, 0.574 mmol) in DCM (5.74 ml) was added ethyl isocyanate (0.041 g, 0.574 mmol) and the reaction mixture was stirred at ambient temperature for 40 minutes. The reaction mixture had turned from a clear solution to a suspension with white solid material. The reaction mixture was concentrated and purified using silica gel chromatography (0-20% MeOH/DCM) to yield the title compound as a white solid (0.135 g, 95%): mp 197-200° C.; 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.3 Hz, 1H), 8.48-8.37 (m, 1H), 8.32 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.52 (br s, 1H), 7.41-7.25 (m, 1H), 5.79 (br s, 1H), 3.33-3.23 (m, 2H), 2.29 (d, J=2.9 Hz, 3H), 1.16 (dd, J=8.7, 5.7 Hz, 3H); ESIMS m/z 246 ([M+H]+), 244 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCCCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 10.9 g. of p-n-octylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 16.5 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-octylbenzyliden)amino]benzonitrile which is obtained has a melting point of 32.5°-32.8°C. and a clearing point of 68.8°C. Up to 54.4°C. the compound is smectic. UV (ethanol): ε280 = 24200 (shoulder at 312 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5](=[O:8])[CH2:6]Cl.[C:13]([OH:16])(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:6][C:5]([C:4]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=1)=[O:8])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: O=C(CCl)c1ccc(Cl)c(Cl)c1
Product: CC(=O)OCC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
Following the procedure of Example 1, 5 grams of 3,4-dichlorophenacyl chloride are reacted with 5 grams of acetic acid to obtain 3,4-dichlorophenacyl acetate, m.p. 68°-70° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][C:16]=1[NH2:24])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CC(OC)(C)C>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:25])=[O:2])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][C:16]=1[NH2:24])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](CSc1ccc(C(=O)O)cc1N)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CSc1ccc(C(=O)O)cc1N)C(=O)O
Yield: 88.7 %

Procedure:
200 mg (0.540 mmol) of N-tert-butoxycarbonyl-3-(4-carboxy-2-aminophenylthio)-L-alanine methyl ester was added to a system consisting of 5 ml TBME and 20 ml buffer solution (0.1M sodium chloride; 3 mM sodium phosphate pH 7.0) under vigorous stirring. 100 μl of Alcalase 2.5 L [a subtilisin Carlsberg from Novo Nordisk] was added and the pH maintained at 7.0 under vigorous stirring by the controlled addition (pH-static) of 0.1N sodium hydroxide solution. After a consumption 5.847 ml of titrating agent (108% of theory; after 1.5 h) the reaction mixture was washed twice with 25 ml TBME, acidified to pH 2.5 with 25% HCl and extracted with 3×25 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, the solvent evaporated and the residue dried on a HV to give 187 mg (0.479 mmol) N-tert-butoxycarbonyl-3-(2-amino-4-carboxyphenylthio)-L-alanine as yellow crystals (yield: 93.4%). Analytical data: HPLC-purity: 96.4%% (area). 1H-NMR (DMSO, 400 MHz) 1.378 (s, 9H, OC(CH3)); 2.982 (dd, 1H, SCH2, J=13.2 Hz, J=9.6 Hz); 3.150 (dd, 1H, SCH2, J=13.2 Hz, J=4.4 Hz); 3.950 (m, 1H, COCHNH); 5.542 (m, 2H, —NH2); 7.067 (dd, 1H, CONHCH, J=8.0 Hz, J=1.6 Hz); 7.201 (d, 1H, arom. SCCH, J=8.0 Hz); 7.298 (d, 1H, arom. SCCHCH, J=8.0 Hz); 7.323 (d, 1H, arom. CHCNH2, J=1.6 Hz); 12.73 (bs, 2H, 2 —COOH). IR: 3445 and 3347 cm−1 (—NH, —NH2); 2977 and 2930 cm−1 broad (—COOH); 1720 and 1692 cm−1 (COOH —C═O, carbamate —C═O); 1608 cm−1 (—COO−); 1509 cm−1 (amide —CO—NH); 1486 cm−1 (aromate); 1247 and 1163 cm−1 (COOH). ISN-MS: m/z=355.1 [M−H+]. OR [α]D=+13.00° (EtOH; c=1.0).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:10]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:9]=[C:8]([I:16])[C:4]=2[CH:5]=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[CH3:25][C:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([Si:29]([CH3:31])([CH3:30])[O:13][CH2:12][C:11]([N:10]1[C:3]2[C:2]([F:1])=[CH:7][N:6]=[CH:5][C:4]=2[C:8]([I:16])=[CH:9]1)([CH3:14])[CH3:15])([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(CO)n1cc(I)c2cncc(F)c21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-1-yl)-2-methyl-propan-1-ol (Preparation 72, 4.5 gm, 13.47 mmol) in DCM (90 mL) were added 2,6-lutidine (3.91 mL, 33.65 mmol) and tert-butyl dimethylsilyl trifluoromethanesulfonate (4.62 gm, 17.51 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM. The organic layer was washed with water, brine, dried over sodium sulphate, and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with 10-12% EtOAc in Hexane to afford the title compound as off white solid (45%, 2.7 g).
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: c1ccncc1
Solvent: O
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: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[O:5])[CH2:11][CH2:10][C:12](=[O:13])[CH3:14]
Reactant: O=Cc1ccccc1Br
Reactant: C=CC(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)c1ccccc1Br
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 90 g of bromobenzaldehyde, 41 g of methyl vinyl ketone, 24.2 g of 3-benzyl-4-methyl-5-hydroxyethylthiazolium chloride is added with 45 ml of triethylamine. A marked exothermicity is observed, at the end of which the reaction mixture is heated to 70° C. under stirring for 4 h. The resulting mixture is cooled and partitioned between 800 ml of ether and 400 ml of H2O. The aqueous phase is reextracted and the combined organic phases are washed with 10% HCl and with brine, then dried over Na2SO4 and the solvent is evaporated off. 110 g of an orange oil are obtained (93% yield). 1H NMR (CDCl3), δ: 2.22 (s, 3 H), 2.89 (t, 2 H), 3.15 (t, 2 H), 7.18-7.65 (m, 4 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([CH3:18])[CH2:4][CH2:3]1.CN(C)C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:41]([C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)([O-:43])=[O:42].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:18][C@@H:5]1[CH2:4][CH2:3][C@@H:2]([O:1][C:48]([C:47]2[CH:46]=[CH:45][C:44]([N+:41]([O-:43])=[O:42])=[CH:52][CH:51]=2)=[O:49])[CH2:7][N:6]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CN(C)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a THF (909 ml) solution of benzyl (2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate (34 g, 136 mmol), 4-(dimethylamino) phenyldiphenylphosphine (58.3 g, 191 mmol), and 4-nitrobenzoic acid (29.6 g, 177 mmol) was added, under N2, DEAD (30.0 ml, 191 mmol) dropwise at −15 to −25° C. over 20 min. The reaction was allowed to warm to RT overnight. The reaction was concentrated in vacuo, removing most THF, then diluted with Et2O (500 mL). The mixture was cooled at 0° C. and washed with 1 N HCl (5×200 mL). The combined aqueous phases were back-extracted twice with Et2O. The combined organic phases were subsequently washed twice more with 1 N HCl. The organics were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-40% ethyl acetate in hexanes), providing the titled compound as a light yellow oil which slowly solidified. LRMS m/z (M+H) 399.3 found, 399.1 required.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10](O)=[O:11])[CH:7]=[CH:6][N:5]=1.[H][H].B(F)(F)F.CCOCC.Cl>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: [H][H]
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
35.59 g of sodium borohydride was suspended in 3 liters of tetrahydrofuran, and the suspension was stirred by a mechanical stirrer. The suspension was cooled with ice water, and 98.83 g of 2-chloro-4-pyridinecarboxylic acid was added little by little. The mixture was heated to room temperature, and stirred until evolution of hydrogen ceased. A solution of 148 ml of boron trifluoride etherate in 1000 ml of tetrahydrofuran was added dropwise at room temperature for 3 hours. After the addition, the mixture was stirred for 20 hours. The reaction solution was cooled with ice water, and adjusted to pH 1 to 2 with 1.5N hydrochloric acid. The tetrahydrofuran was evaporated under reduced pressure, and a 4N aqueous solution of sodium hydroxide was added to adjust the pH of the mixture to 10 to 11. The solution was then extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The aqueous layer was further extracted with ethyl acetate twice, and the organic layers were washed with a saturated aqueous solution of sodium chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 75.0 g (yield 83%) of 2-chloro-4-pyridinemethanol.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:14]([CH3:27])=[C:13]([CH3:28])[N:12]=1.O>O1CCCC1>[CH3:28][C:13]1[C:14]([CH3:27])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, tetrahydrofuran (THF) (150 mL) was cooled to 0° C. Sodium hydride (9.30 g, 233 mmol), available as a 60% dispersion in mineral oil, was added with stirring. A solution of phenol (21.1 g, 225 mmol) in THF (80 mL) was added dropwise over a period of one hour. A solution of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol (44.5 g, 155 mmol) in THF (80 mL) was then added dropwise over a period of 40 minutes. The reaction was allowed to warm to room temperature and heated at reflux overnight. An analysis by thin layer chromatography (TLC) indicated that the reaction was incomplete. Additional reagent was prepared as described above by adding phenol (7.1 g, 75 mmol) to sodium hydride (3.2 g, 80 mmol) in THF (50 mL), and the reagent was added to the reaction solution at room temperature. The reaction was heated at reflux overnight and then allowed to cool to room temperature. Water (50 mL) was added, and the solvent was removed under reduced pressure. The aqueous solution was extracted with ethyl acetate. The organic solution was washed with water (3×) and brine (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the crude product. The crude product was purified twice by column chromatography on silica gel (eluting sequentially with 50:50 hexane:ethyl acetate and 25:75 hexane:ethyl acetate) to provide 40.24 g of 5-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-ylamino)pentan-1-ol as a yellow oil.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([CH:29]3C[CH2:30]3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([B-](F)(F)F)=C.[K+]>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([CH:29]=[CH2:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C2CC2)CC1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Product: C=Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc([C@]3(C)COC(=O)N3)ccc12

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-vinylnaphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-cyclopropylnaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 214) in 48% yield using potassium vinyltrifluoroborate (0.0675 g, 0.000504 mol) as reagent.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[NH:17][CH:18]2[CH2:23][CH2:22][N:21](C(OCC)=O)[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[OH-].[K+]>CC(O)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3cnccc3n2Cc2ccc(C)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccc(Cn2c(NC3CCNCC3)nc3cnccc32)o1
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 20.5 parts of ethyl 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-imidazo[4,5-c]pyridin-2-yl]amino]-1-piperidinecarboxylate, 40 parts of potassium hydroxide and 240 parts of 2-propanol was stirred overnight at reflux temperature. After evaporation, the residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 15 parts (88%) of 1-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-1H-imidazo[4,5-c]pyridin-2-amine; mp. 185.6° C. (int. 25).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1OC.OCCC1C=C([F:44])C=C(F)C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:44][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:29][CH2:30][C@H:31]([CH3:34])[CH2:32][CH2:33]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F
Reactant: OCCc1cc(F)cc(F)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cc(F)cc(F)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-{2-[3-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 1-(2-hydroxy-ethyl) -3,5-difluoro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C([Sn]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(CCCC)CCCC)CCC.[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1>CN(C=O)C.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>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:23]1[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Clc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cccs2)nn1
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of tri-n-butylstannylthiophene (6.26 g, 16.78 mmol), 3,6-dichloropyridazine (5.00 g, 33.56 mmol), tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and few crystals of 1,2-ditert-butyl of 2,6-di-tent-butyl-4-methylphenolo in dry DMF (50 mL) was deareated twice with nitrogen. The reaction mixture was heated at 80° C. for 6 hours and, after cooling, poured onto water (100 mL). A white precipitate was collected, washed several times with water and dried under vacuum. This solid was taken up with ether (25 mL) and filtered to afford 3.01 g of almost pure product. Finally, this solid was crystallized from MeOH—H2O to give the pure target compound as white crystals (1.56 g, 7.90 mmol, 47.3% yield). Mp 155° C.; 1H NMR (CDCl3) δ 7.75 (1H, d, 2J=11.0), 7.68 (1H, d, 2J=3.6), 7.54 (1H, d, 2J=5.0), 7.51 (1H, d), 7.18 (1H, dd).