Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([O:37][CH3:38])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:39])[C:28]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:46](=[O:47])[C:44]2[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:28]3[C:29]([F:39])=[CH:30][C:31]([C:33]4([O:37][CH3:38])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:45]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: COC1(c2cc(F)c(-c3nc(C(=O)O)ccc3F)c(F)c2)COC1
Product: COC1(c2cc(F)c(-c3nc(C(=O)Nc4cnn(C)c4[C@@H]4CC[C@@H](N)[C@@H](F)CO4)ccc3F)c(F)c2)COC1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-methoxyoxetan-3-yl)phenyl)-5-fluoropicolinic acid (see WO2012/225062) gave 203. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.31 (dd, J=8.7, 4.0 Hz, 1H), 8.19 (t, J=8.9 Hz, 1H), 7.95 (s, 1H), 7.49 (d, J=9.3 Hz, 2H), 4.96 (dd, J=8.1, 4.0 Hz, 1H), 4.81 (d, J=1.7 Hz, 4H), 4.65-4.37 (m, 1H), 3.97-3.73 (m, 2H), 3.72 (s, 3H), 3.41-3.25 (m, 2H), 3.15 (s, 3H), 3.12-2.99 (m, 1H), 2.22-2.12 (m, 1H), 1.81-1.71 (m, 1H), 1.70-1.60 (m, 1H), 1.57-1.52 (m, 3H). LCMS (ES+) m/z 550 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@@H:23]([NH2:35])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C(O)C>[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH2:24][C@@H:23]([NH:35][C:2]2[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 82.6 %

Procedure:
A solution of 4,5-dichloro-3-nitropyridin-2-amine (0.0365 g, 0.000175 mol) (Johansson, H; Lawitz, K; Nikitidis, G; Sjoe, P; Storm, P. PCT Int. Application WO2004/01661-1), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentanamine (0.0947 g, 0.000263 mol) and DIPEA (0.0907 g, 0.000702 mol) in ethanol (10.0 mL) was refluxed overnight. The reaction was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.0768 g, 82%) as a yellow solid.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].[Mg].C(Cl)(C)C.[C:13]([CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1I)[C:19]#[N:20])#[N:14].[Cu]C#N.[CH:28]1[N:29]=[CH:30][N:31]2[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[C:32]=12>O1CCCC1>[C:13]([CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:33]1([OH:37])[CH2:34][CH2:35][CH2:36][N:31]2[CH:30]=[N:29][CH:28]=[C:32]12)[C:19]#[N:20])#[N:14]
Reactant: O=C1CCCn2cncc21
Reactant: N#CCc1cc(C#N)ccc1I
Agent: N#C[Cu]
Agent: CC(C)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: N#CCc1cc(C#N)ccc1C1(O)CCCn2cncc21
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
In a dried flask under Ar atmosphere are placed 1.05 mmol of isopropylmagnesium chloride.lithium chloride in tetrahydrofuran solution (prepared from magnesium, dry lithium chloride and isopropyl chloride in THF according to A. Krasovskiy and P. Knochel; Angewandte Chemie International Edition 2004, 43, 3333-3336). The solution is cooled to −15° C. and 1 mmol of 3-cyanomethyl-4-iodo-benzonitrile is added in one portion. The reaction mixture is stirred for 15 minutes at −10° C. and 0.02 ml of a copper (I) cyanide.2 lithium chloride solution (10M in tetrahydrofuran) as well as 1.1 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridine-8-one [426219-51-4] are added. The reaction mixture is stirred for 1 hour at 0° C., then quenched by addition of aqueous saturated ammonium chloride solution and extracted with diethyl ether (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:34][N:35]=[C:36]=[O:37]>C(Cl)Cl>[CH3:34][NH:35][C:36](=[O:37])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Reactant: CN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=NCc2ccccc2)CC1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (2.0 g) in CH2Cl2 (40 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 g) followed by the dropwise addition of methyl isocyanate (0.39 g) in CH2Cl2 (10 ml). The reaction was monitored via TLC and after 3 hours the solution was concentrated and the precipitate was collected and recrystallized from acetonitrile to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.85 grams).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Brc1ccccn1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(c4ccccn4)CC3)c2[N+](=O)[O-])cc1
Temperature: 165 °C

Procedure:
Compound A2 (0.13 mmol, 50 mg), and 2-bromo-pyridine (0.53 mmol, 53 μL) were dissolved in DMF (1 mL) and triethylamine (0.46 mmol, 63 μL). The reaction was heated in a microwave at 165° C. for 40 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by prep-TLC provided Compound A9 as a yellow solid (12 mg, 20%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.10 (s, 1H), 8.35 (s, 1H), 8.13 (m, 1H), 7.89 (d, 2H), 7.81 (d, 2H), 7.42 (m, 1H), 6.64 (d, 1H), 6.55 (m, 1H), 5.58 (heptet, 1H), 3.78 (m, 2H), 3.60 (m, 2H), 3.00 (s, 3H), 2.02 (m, 2H), 1.91 (m, 2H). LCMS (ESI), m/z 471.4 (M+H+, 100%).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1.CO>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[C:9]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:10]1)([OH:28])=[O:27]
Reactant: COC(=O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 100 °C
Yield: 99.3 %

Procedure:
2N NaOH solution (2.0 mL) was added to a solution of methyl 3-cyclohexyl-1-(5-methoxy-5-oxopentyl)-1H-indole-6-carboxylate (410 mg, 1.1 mmol) in THF/Methanol mixture (2.0 mL/2.0 mL). The reaction mixture was heated at 100° C. under microwave condition for 15 min, after which it was concentrated and the pH was adjusted to 4–5 with 1N HCl solution. A precipitate formed which was collected by filtration to give the product as a white powder, (375 mg, 99% yield). MS m/z 344(MH+). 1H NMR (300 MHz, CD3OD) δ ppm 1.24–1.98 (m, 10 H) 2.00–2.15 (m, 2 H) 2.25–2.39 (m,2H) 2.84 (m, 1 H) 4.16–4.30 (m, 2 H) 4.56–4.72 (m, 2 H) 7.22 (m, 1H) 7.58–7.78 (m, 2H) 8.10 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH2:19][CH3:18])[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccccc2)c1C#N
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)nc(-c2ccccc2)c1C#N
Yield: 29 %

Procedure:
To a stirred solution of 0.2 g (0.86 mmol) 2-amino-4-(methylthio)-6-phenyl-5-pyrimidinecarbonitrile in 10 ml ethanol was added 0.33 ml (0.89 mmol) sodium ethylate solution (2.7M in ethanol) and the mixture heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and dichloromethane and the organic phase dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1) afforded 60 mg (29%) 2-amino-4-ethoxy-6-phenyl-pyrimidine-5-carbonitrile as a white crystalline solid. MS m/e (%):240 (M+, 100), 239 ([M—H]+, 50), 170 (56).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH2:18][C:19]([NH2:21])=[O:20].Cl.O>C(O)C.C(OCC)(=O)C>[CH2:6]([C:7]1[CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:21]=[C:19]([OH:20])[N:18]=1)[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: NC(N)=O
Reactant: CCCCCCC(=O)CC(=O)CCCCCC
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCc1cc(CCCCCC)nc(O)n1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
Pentadecane-7,9-dione (60.0 g, 250 mmol) and 30 g (500 mmol) of urea were dissolved in 3750 mL of ethanol, and under a nitrogen atmosphere, 75 mL of concentrated hydrochloric acid was added, and the mixture was gradually heated until reflux, and allowed to reflux for 18.5 hours. After cooling down to room temperature, water and ethyl acetate were added, the oil phase was extracted, and washed with a saturated sodium bicarbonate solution and saturated saline in this order, and dried over magnesium sulfate and concentrated. The resultant concentrate was purified by a silica gel column (hexane•ethyl acetate) to obtain 31.2 g of 4,6-dihexylpyrimidin-2-ol.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[S:17][C:16]([C:18]([O:20]CCCC)=[O:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[OH-].[Na+].CO.O>C1COCC1>[CH3:3][C:2]([CH3:25])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CCCCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 50 ml round bottomed flask with a stirring bar was added n-butyl 5-(4-(1,1-dimethylethoxycarbonyl)-piperazin-1-yl)-thiophene-2-carboxylate (490 mg, 1.33 mmol) and 4.2 mL of a 2.5M NaOH solution in 3:1 MeOH/H2O. THF (2 mL) was added to keep the reaction homogeneous. The reaction was stirred at room temperature and followed by HPLC. After 2 days, the reaction was concentrated in vacuo, acidified with 10% citric acid and extracted with EtOAc (3×). The combined organics were washed with water (1×), brine (1×), dried (Na2SO4), filtered, and the solvents removed in vacuo. The product was azeotroped with benzene (3×) and dried in vacuo over 2 days to yield 5-(4-(1,1-dimethylethoxycarbonyl)-piperazin-1-yl)-thiophene-2-carboxylic acid as a dark green solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>C1COCC1>[CH:11]1([CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][OH:2])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C(c1ccccc1)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCC(c1ccccc1)C1CCCCC1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a stirring solution of 2-cyclohexyl-2-phenyl-acetic acid methyl ester (2.2 g, 0.0094 mole) in THF (20 mL) was added 19 mL of a lithium aluminum hydride solution (1.0 M in THF) at 0° C. The reaction mixture was stirred overnight and 10% KOH (8 mL) was added. The mixture was filtered, and then washed with ether. Ether (60 mL) was added to the filtrate and the ethereal solution was washed with water (50 mL). The ether layer was dried over sodium sulfate, filtered, and concentrated to give 1.86 g (97% yield) of the title compound as an oil. 1H-NMR (400 MHz, CDCl3) δ 7.37-7.15 (m, 5H), 3.97 (t, 1H, J=6.0 Hz), 3.86 (t, 1H, J=9.0 Hz), 2.59 (q, 1H, J=4.0 Hz), 1.96-1.03 (m, 11H). The primary alcohol was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1N2CCN(CC2)C1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:11](=[CH2:12])[C:10]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: CO
Product: C=C(C(=O)OC)C(O)c1ccc(Br)cc1
Yield: 47.2 %

Procedure:
A solution of 2.46 g (13.3 mmol) of 4-bromobenzaldehyde, 1.0 mL (11.1 mmol) of methyl acrylate and 125 mg (1.11 mmol) of 1,4-diazobicyclo[2.2.2]octane in 5 mL MeOH was stirred at ambient temperature for 46 hr. The solvent was evaporated and the residue taken up in EtOAc. The organics were washed with 0.5 N HCl (aq), then with brine, and concentrated. The residue was purified by silica gel chromatography (120 g of silica gel eluting with 0-30% EtOAc in hexanes over 45 minutes) to give 1.42 g (40%) of methyl 2-[(4-bromophenyl)(hydroxy)methyl]-2-propenoate as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J=2 Hz, 2H), 7.27 (d, J=2 Hz, 2H), 6.33 (s, 1H), 5.82 (s, 1H), 5.51 (d, J=5 Hz, 1H), 3.72 (s, 3H), 3.07 (d, J=5 Hz, 1H). ESI-LCMS m/z 293 (M+Na)+.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:21]([O:22][CH3:23])=[C:20]3[C:15]([C:16](=[O:45])[C:17]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][C:34]=4[CH3:44])=[O:30])=[CH:18][N:19]3[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:14][C:13]=2[F:46])[CH2:7]1)C.O1CCOCC1.[Li+].[OH-].Cl>C(OCC)(=O)C>[F:46][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([O:22][CH3:23])[C:12]=1[N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([CH2:5][C:4]([OH:47])=[O:3])[CH2:7]1)[N:19]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH:18]=[C:17]([C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:35][C:34]=1[CH3:44])=[O:30])[C:16]2=[O:45]
Reactant: CCOC(=O)C[C@@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CC(F)(F)F)c3c2OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1c(N2CCC[C@@H](CC(=O)O)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Yield: 101 %

Procedure:
72 mg (0.107 mmol) of the compound of Example 20 are stirred with 2.6 ml of dioxane and 533 μl of LiOH (1M solution in water, 5 eq.) at RT overnight. The mixture is acidified with 1N HCl and diluted with ethyl acetate. It is extracted by shaking twice with water and once with a saturated NaCl solution. The organic phase is dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under HV. 70 mg of the title compound (99% of theory) are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.BrP(Br)Br>C(Cl)Cl.C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC(c1ccc2occc2c1)c1ccccn1
Agent: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: c1ccc(Cc2ccc3occc3c2)nc1
Reaction time: 1.5 h

Procedure:
A solution of benzofuran-5-yl(pyridin-2-yl)methanol (500 mg, 2220 μmol) in DCM (10 mL) at 0° C. was treated with tribromophosphine (314 μL, 3330 μmol) and stirred for 1.5 h. The mixture was diluted with CHCl3, washed with sat. aqueous KHCO3, dried over MgSO4, and evaporated. A suspension of the crude material and 10% Pd—C (50 mg) in EtOAc (5 mL) and MeOH (3 mL) was stirred under 1 atm H2 at 24° C. for 1 h. The solids were filtered off (Celite) and washed with EtOAc. The filtrate was evaporated and purified by flash chromatography (hexanes to EtOAc to 5% MeOH in DCM) to give 2-(benzofuran-5-ylmethyl)pyridine as a yellow foam. 1H NMR (400 MHz, CD3OD) δ ppm 8.71 (br. s, 1H), 8.17 (t, J=7.6 Hz, 1H), 7.70-7.64 (m, 3H), 7.50-7.48 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 6.76 (s, 1H), 4.71 (s, 2H). MS (ESI) m/z: Calculated: 209.1; Observed: 210.0 (M++1).
Reaction SMILES: C([S-])C.[Na+].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:12]=1)#[N:6].[CH2:21]([OH:23])[CH3:22]>ClCCl>[CH2:21]([O:23][C:5](=[NH:6])[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:12]=1)[CH3:22]
Reactant: CCOC(=O)c1cn2cc(C#N)ccc2n1
Reactant: CCO
Agent: CC[S-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)c1ccc2nc(C(=O)OCC)cn2c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
470 mg of sodium ethanethiolate are added to a solution of 1 g of ethyl 6-cyanoimidazo[1,2-a]pyridine-2-carboxylate (J. Med. Chem. (1998), 41(22), 4317) in a mixture of 15 mL of ethanol and 10 mL of dichloromethane cooled to 0° C. The reaction mixture is stirred for 5 hours at 25° C. and filtered, and the filtrate is evaporated to dryness. The residue is chromatographed on silica, eluting with a mixture of dichloromethane and methanol (98/2) to give 625 mg of ethyl 6-[ethoxy(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](Cl)=[O:11]>O1CCCC1>[CH3:16][N:15]([CH3:17])[C:13]([N:9]([CH3:8])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])=[O:14]
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 146.9 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, 7.4 g (0.08 mole) of aniline was dissolved. The mixture was cooled below 0° C., and a solution prepared by dissolving 6.4 g (0.04 mole) of 2,4,4-trimethylallophanoyl chloride in 10 ml of anhydrous tetrahydrofuran was added dropwise under stirring. The reaction was continued at a room temperature for 1 hour, then the solvent was removed by distillation under a reduced pressure, and water was added to form an insoluble matter. The insoluble matter was obtained by filtration and was recrystallized from ethanol to obtain 13.0 g (yield 73%) of 1,1,3-trimethyl-5-phenylbiuret having a melting point 89.5°-90.5° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH:16]([C:18]([CH3:20])=[O:19])=[CH2:17].[OH-].[K+]>C1COCC1.C(O)C>[O:19]=[C:18]1[CH2:16][CH2:17][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:20]1
Reactant: C=CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To the solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.87 mmol, 1 eq) in THF (250 ml) was added methyl vinyl ketone (7.63 mmol, 1.3 eq) at 0° C., followed by slow addition of 3 N KOH in ethanol (7.7 ml). The reaction was then stirred at 25° C. for 16 h. The reaction mixture was concentrated to one-third of the volume of solvent and then acidified with 0.5 N HCl at 0° C. The aqueous layer was extracted with ethyl acetate (2×100 ml), and the organics dried over Na2SO4 and concentrated. The crude material was used in the next step without further purification. Yield: 91%
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:26]([OH:32])[C@H:27]([OH:31])[C:28]([OH:30])=[O:29].C(O)(C(F)(F)F)=O>C1COCC1>[C:28]([CH:27]([OH:31])[CH2:26][O:32][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19])([OH:30])=[O:29]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Reactant: O=C(O)[C@@H](O)CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)C(=O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.1 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1h-pyrrol-2-yl)-meth-(z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indole-2-one (166 mg, 0.5 mmol), L-glyceric acid (432 mg, 1.5 mmol), and TFA (399 mg, 3.5 mmol) in 3 mL of THF was stirred at room temperature for 4 h and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) followed by 1% of acetic acid in ethylacetate-hexane (1:1) to afford 15 mg (8%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-carboxy-2-hydroxy-ethyl ester as a red solid. MS m/z (relative intensity, %) 371 (100, [M+1]+.).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][C:15]([O:18][CH2:19][CH3:20])([CH3:17])[CH3:16])(=O)=O)=CC=1.[OH:23][C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1>>[CH2:19]([O:18][C:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][CH2:12][CH:11]([O:23][C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1)[CH3:21])[CH3:20]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CCOC(C)(C)CCCC(C)OS(=O)(=O)c1ccc(C)cc1
Product: CCOC(C)(C)CCCC(C)Oc1ccc2c(c1)OCC2

Procedure:
5-ethoxy-1,5-dimethylhexyl p-toluenesulfonate and 6-hydroxy-2,3-dihydrobenzofuran are reacted to produce 6-[(5-ethoxy-1,5-dimethylhexyl)-oxy]-2,3-dihydrobenzofuran of boiling point (bulb-tube) 127° C./0.02 mmHg; nD24 = 1.5023.
Reaction SMILES: CS(O[CH:6]([CH3:29])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[N:30]([CH:6]([CH3:29])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1)=[N+:31]=[N-:32]
Reactant: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)-1-methylethyl methanesulfonate 283 mg) and sodium azide (271 mg) in DMF (3 mL) was stirred at 60° C. overnight. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (249 mg).