Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)(=[O:4])[NH:2][NH2:3].[CH3:17][C:18]1([CH3:34])[CH2:23][CH:22]([NH:24][C:25](=[O:31])[C:26](OCC)=[O:27])[CH2:21][C:20]([CH3:33])([CH3:32])[NH:19]1>CO>[CH3:17][C:18]1([CH3:34])[CH2:23][CH:22]([NH:24][C:25](=[O:31])[C:26]([NH:3][NH:2][C:1]([O:5][CH:6]2[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]2)=[O:4])=[O:27])[CH2:21][C:20]([CH3:33])([CH3:32])[NH:19]1
Reactant: CN1C(C)(C)CC(OC(=O)NN)CC1(C)C
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CN1C(C)(C)CC(OC(=O)NNC(=O)C(=O)NC2CC(C)(C)NC(C)(C)C2)CC1(C)C
Temperature: 50 °C

Procedure:
Into a 100 ml 3-neck flask was added 7.3 grams (0.0318 mole) of 1,2,2,6,6-pentamethyl-4-piperidinyl carbazate, 12.9 grams (0,032 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate in methanol and 15 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with reflux condenser. The flask was placed in a hot oil bath and heated to reflux. The methanol was distilled off through the Dean Stark trap and the residue was heated for 4 hours at 75°-80° C. Liquid chromatography of the residue indicated that the reaction had proceeded to 85-90% of completion. The reaction was cooled to 50° C. and 50 ml of methanol was added to dissolve the product. The methanol solution was cooled in the freezer (-10° C.) overnight and the next day the crystals that formed were filtered off and air dried. The dry crystals weighed 3.1 grams and melted at 165°-170° C. A liquid chromatography scan indicated the presence of only one component. The infrared spectrum of the product contained a weak carbonyl peak at 1740 cm-1 and strong, sharp carbonyl peaks at 1600 and 1685 cm-1. A second crop of 4.5 grams was obtained by concentrating the filtrate to about 25 ml, cooling and filtering off the solids that formed. The filtrate was stripped to dryness, leaving 7.0 grams of product which was contaminated with small amounts of the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:82]([CH3:84])[CH3:83])[C:10]([CH3:81])=[C:11]([S:77]([CH3:80])(=[O:79])=[O:78])[C:12]=2[C:13]2[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([NH:42][C@@H:43]([CH2:62][S:63][C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)[CH2:44][CH2:45][N:46]6[CH2:51][CH2:50][CH:49]([C:52]([O:54]C(P(=O)(O)O)CC)=[O:53])[CH2:48][CH2:47]6)=[C:38]([S:70]([C:73]([F:76])([F:75])[F:74])(=[O:72])=[O:71])[CH:37]=5)(=[O:35])=[O:34])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH:16]=[C:17]([F:19])[CH:18]=2)=[CH:4][CH:3]=1.O[CH:86]([CH3:94])[CH2:87][P:88](=[O:93])([O:91]C)[O:89]C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:82]([CH3:83])[CH3:84])[C:10]([CH3:81])=[C:11]([S:77]([CH3:80])(=[O:78])=[O:79])[C:12]=2[C:13]2[CH:14]=[C:15]([N:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:27]=[CH:28][C:29]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([NH:42][C@@H:43]([CH2:62][S:63][C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)[CH2:44][CH2:45][N:46]6[CH2:47][CH2:48][CH:49]([C:52]([O:54][CH2:94][CH2:86][CH2:87][P:88](=[O:89])([OH:93])[OH:91])=[O:53])[CH2:50][CH2:51]6)=[C:38]([S:70]([C:73]([F:74])([F:76])[F:75])(=[O:71])=[O:72])[CH:37]=5)(=[O:35])=[O:34])=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)[CH:16]=[C:17]([F:19])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCC(OC(=O)C1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)Nc3ccc(N4CCN(c5cc(F)cc(-c6c(S(C)(=O)=O)c(C)n(C(C)C)c6-c6ccc(Cl)cc6)c5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)P(=O)(O)O
Reactant: COP(=O)(CC(C)O)OC
Product: Cc1c(S(C)(=O)=O)c(-c2cc(F)cc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(C(=O)OCCCP(=O)(O)O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c(-c2ccc(Cl)cc2)n1C(C)C

Procedure:
2-(1-((R)-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carbonyloxy)propylphosphonic acid (17). 17 was prepared from 13 and dimethyl 2-hydroxypropylphosphonate according to general procedure V. 1H NMR (300 MHz, CD3OD): δ 7.97 (d, J=2.1 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.36-7.08 (m, 13H), 6.85-6.43 (m, 4H), 5.26 (s, 1H), 4.54-4.44 (m, 1H), 4.01 (s, 1H), 3.58-2.92 (m, 16H), 2.87 (s, 3H), 2.76 (s, 3H), 2.70-2.55 (m, 1H), 2.26-1.85 (m, 8H), 1.46 (d, J=7.1 Hz, 6H), 1.38 (d, J=5.9 Hz, 3H). MS (ESI): m/z 1281.34 (M+H)+.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.[Cl-].[NH4+]>O1CCCC1>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][C:13]1[O:12][C:11]([CH:7]2[O:8][CH2:9][CH2:10][O:6]2)=[CH:15][CH:14]=1
Reactant: c1coc(C2OCCO2)c1
Reactant: Fc1cccc(CBr)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cccc(Cc2ccc(C3OCCO3)o2)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (2.66M hexane solution, 25.5 mL, 67.88 mmol) was added dropwise to a solution of 2-(1,3-dioxolan-2-yl)furan (8272 mg, 59.03 mmol) in tetrahydrofuran (160 mL) that had been cooled to −78° C. solution under nitrogen atmosphere, which was then stirred for 10 minutes. To this solution was added a solution of 3-fluorobenzyl bromide (14.50 g, 76.73 mmol) in tetrahydrofuran (60 mL) dropwise, which was then stirred for 1 hour at −78° C., and for 1.25 hours at room temperature. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and a mixture of the title compound and 2-(1,3-dioxolane-2-yl)furan (8033 mg), which is the starting material, was obtained.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[N:21]([CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1Cc2c(ccc3c2CCC(=O)N3)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1Cc2c(ccc3c2CCC(=O)N3)O1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The compound obtained in Example 160 (0.691 g, 2.32 mmol) and sodium azide (1.51 g) were suspended in dimethylformamide (14 ml) and stirred at 120° C. for 2 hours. The suspension was cooled and poured into water, followed by extraction with chloroform. The chloroform phase was washed with water and dried over sodium sulfate. When the solvent was distilled off under reduced pressure, 0.553 g of the pale yellow crystals of the title compound was obtained (97.4%, mp.: 157°-158° C.).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].CN(C)[CH2:10][C:11]1C=CC=CC=1.[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH2:21].C(=O)C>C(Cl)Cl>[CH:10](=[N:21][C:20]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:19]=1[CH3:18])[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CN(C)Cc1ccccc1
Agent: CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC=Nc1c(C)cccc1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
180 g (3 mols) of sodium sulphate and 3 ml of dimethylbenzylamine were added to 121 g (1 mol) of 2,6-dimethylaniline in 200 ml of methylene chloride. 88 g (2 mols) of acetaldehyde were added to the mixture at 0° C. The mixture was stirred at 0° C. for 4 hours and was filtered, and the filtrate was concentrated in vacuo at a maximum bath temperature of 20° C. 140 g (95.2% of theory) of N-ethylidene-2,6-dimethylaniline were obtained as a reddish oil.
Reaction SMILES: [C:1]1([CH:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:30]2[O:34][C@H:33]([C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C@@H:32]([OH:40])[C@H:31]2[OH:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:48]1([S:54](Cl)(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:1]1([CH:7]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH:27]([CH3:29])[CH3:28])[S:54]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:56])=[O:55])=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:30]2[O:34][C@H:33]([C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C@@H:32]([OH:40])[C@H:31]2[OH:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCNC(C)C)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN(C(C)C)S(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared from (2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(isopropylamino)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (80 mg, 0.12 mmol) (Preparation 12) and benzenesulphonyl chloride (0.0017 ml, 0.14 mmol) by a similar method to that of Example 8.
Reaction SMILES: [F-:1].[Cs+].[CH2:3]([Sn:7](C1SC=CC=1)([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].ClCCl>C1(C)C=CC=CC=1.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>[Sn:7]([F:1])([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [F-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC[Sn](F)(CCCC)CCCC
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Step a) Under inert atmosphere, to a mixture of chromophore 1, 1 mol % catalysator Pd(PPh3)4, 1 equivalent of CsF in toluene, 1.2 equivalent of tributylstannyl-thiophene were added. The reaction mixture was stirred at 120° C. for 12 h. After cooling to room temperature, dichloromethane was added. The white salt (Bu3SnF) formed during the reaction was filtered off and the solvent removed under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel with (4/6) dichloromethane/ethylacetate to give the pure thiophene derived squarylium dye 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9][CH3:10])N.[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[S:9][CH3:10]
Reactant: CSc1ccc(N)cc1Cl
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(O)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
The product from stage (ii) (11.5 g, 66.2 mmol) was dissolved in the minimum THF (˜15 mL) and water (500 mL) was added with vigorous stirring, followed by conc H2SO4 (25 mL). The mixture was cooled in an ice-water bath and a solution of NaNO2 (5.0 g, 72.5 mmol) in iced water (10 mL), was added via pipette under the surface of the reaction mixture. The reaction was stirred at 0° C. for 1.5 h and the resulting yellow/brown solution was decanted from the remaining solid into a dropping funnel containing ice (˜200 g). This solution was added at a steady rate over 7 min to a vigorously stirred mixture of Cu(NO3)2 (230 g, 0.99 mol) and Cu2O (8.52 g, 67.4 mmol) in water (1 L) at room temperature. After the addition was complete the mixture was stirred for a further 15 min before being extracted with ether (500 mL). The residual red/brown solid in the reaction flask was taken up in MeOH (100 mL) and diluted with ether (300 mL) before being poured into the aqueous layer from above. The ether layer was separated and the combined organic layers were extracted with 1M NaOH (3×100 mL). The aqueous extracts were acidified with conc. HCl and then extracted with ether (2×150 mL). The ether layers were then washed with brine, dried (MgSO4) and the solvent was removed in vacuo to give the phenol (5.465 g, 47%) as a brown crystalline solid; δH (400 MHz, CDCl3) 2.44 (3H, s), 5.08 (1H, br), 6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d); MS m/z (ES−) 173 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:13]1[C:14](=[O:15])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:2]=2[F:1])=[C:10]([CH2:17][CH2:18][CH3:19])[N:11]=[C:12]1[CH3:16]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
A mixture of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.04 g), 1-bromo-3,3-dimethylbutan-2-one (1.53 g), potassium carbonate (1.59 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
p-Aminoacetophenone (87.6 g.) is heated with 1-bromohexadecane (198 g.) in dry hexamethyl phosphoramide (300 ml.) containing anhydrous potassium carbonate (90 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (20 ml.). The amber solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides the product of the Example.
Reaction SMILES: [C:1]([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([O:3]CC)=[O:2].[OH-].[Na+]>CO.CCOC(C)=O>[C:1]([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCC(CCP(=O)(OCC)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC(CCP(=O)(OCC)OCC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
A solution 0.61 g (1.44 mmol) of (±)-diethyl 3-(carboethoxy)pentadecyl phosphonate (from Example 27, Step A) in 10 mL of MeOH was treated with 4.3 mL of 1 N NaOH. The resulting mixture was stirred at rt for 2 h then heated to 50° C. for 16 h. The reaction was diluted with 75 mL of EtOAc, washed with 50 mL of 2 N HCl, 50 mL of sat'd NaCl, dried and concentrated to give 0.62 g of the title compound: ESI-MS 393.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)[C:31]1=[O:35])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Reaction time: 9.5 h
Yield: 21.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.5 g), 1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and cesium carbonate (powder: 9.7 g) were added to N,N-dimethylformamide (150 ml), and the mixture was heated at 80° C. with stirring for 9.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (400 ml). Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:ethyl acetate/acetone=2/1) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 9; 1.03 g) as a pale yellow powder.
Reaction SMILES: [CH3:1]S(C)(=O)=C.[CH3:6][O:7][CH:8]([CH2:21][CH3:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH:19]2[CH:16]([CH2:17][C:18]2=[O:20])[CH2:15][CH2:14]1>CS(C)=O>[CH3:6][O:7][CH:8]([CH2:21][CH3:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH:19]2[CH:16]([CH2:17][C:18]32[CH2:1][O:20]3)[CH2:15][CH2:14]1
Reactant: C=S(C)(C)=O
Reactant: CCC(CCCCC1CCC2CC(=O)C12)OC
Solvent: CS(C)=O
Product: CCC(CCCCC1CCC2CC3(CO3)C12)OC
Temperature: 40 °C

Procedure:
A 250 ml, 3-necked round bottomed flask is equipped with a magnetic stirrer. The reaction is conducted under a positive nitrogen pressure, maintained with an oil filled bubbler. The reaction vessel is charged with dimethyloxosulfonium methylide (36 ml of 0.932M solution, 0.034 moles) in dimethyl sulfoxide. 4-(5-Methoxyheptyl)bicyclo[3.2.0]heptan-6-one (7.7 g, 0.032 moles) is added neat to the stirring solution by a syringe. The reaction vessel is heated in a 40° C. water bath for 60 minutes and then a sample is removed and analyzed by infra-red spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and tetradecanoic acid to yield (3aR,4S,7aR)-4-tetradecanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=2.01 min; UPLC Method I
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26])[CH:17]=1
Reactant: CC(Oc1cc(F)ccc1CO)c1ccccc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(Oc1cc(F)ccc1COc1ccnn1-c1cc(C#N)ccn1)c1ccccc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-(1-phenylethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C24H19FN4O2, 415; Found, 415.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:24][CH2:25][CH2:26][CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[N:28]1([CH2:27][CH2:26][CH2:25][NH:24][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)([CH3:23])[CH3:22])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Product: CC(C)(NCCCn1ccnc1)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
N-[1-(4′-Benzyloxybiphenyl-4-yl)-1-methylethyl]-3-(imidazol-1-yl)propylamine was hydrogenated, using palladium on charcoal as catalyst, in IMS at atmospheric pressure to give 4′-{1-[3-(imidazol-1-yl)propylamino]-1methylethyl}biphenyl-4-ol, m.p. 178-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43]Br)=[CH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22][CH2:43][CH2:42][O:41][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])=[CH:40][CH:39]=2)=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OCCBr)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
3.3 g (100 mmol) of 1,4-dihydro-2.6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl ester, 3.5 g (10 mmol) of the bromoethoxy compound from step 1b), and 2.8 g (20 mmol) of potassium carbonate are heated at boiling in 50 ml of acetonitrile while stirring and under reflux. After approximately 20 hours, the reaction mixture is filtered and the filtrate is concentrated by evaporation under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, and the organic phase is concentrated by evaporation in vacuo. Crude 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-tertiary butoxycarbonylaminoethyl)-phenoxy]-ethyl}-ester 5-methyl ester is thus obtained and is used further in crude form.