Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C.C1(C)C(S(C2C=CC(C(N)C(C3C=CC=CC=3)N)=CC=2)(=O)=O)=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccccc1S(=O)(=O)c1ccc(C(N)C(N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
(3S)-3-tert-Butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.49 g, 5.0 mmol), 90% formic acid (0.224 ml, 5.25 mmol), and triethylamine (0.730 ml, 5.25 mmol) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl-1,2-diphenylethylenediamine (3.4 mg, 0.005 mmol, s/c=1000) in ethyl acetate (7.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quantitatively analyzed by HPLC to confirm production of a desired compound, (2R, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4phenylbutane (1.50 g; yield: 99.9%). The production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was found to be 9.0:1.
Reaction SMILES: BrBr.[F:3][C:4]1[CH:10]=[C:8]([NH2:9])[C:7]([CH3:11])=[CH:6][CH:5]=1.C([Br:19])C1C=CC=CC=1>>[F:3][C:4]1[CH:10]=[C:8]([NH:9][Br:19])[C:7]([CH3:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(F)cc1N
Reactant: BrCc1ccccc1
Agent: BrBr
Product: Cc1ccc(F)cc1NBr

Procedure:
Bromine (0.5 mole) is added over 1 hour to stirred 5-fluoro-o-toluidine (0.5 mole) at 100° C illuminated with a high wattage lamp. The crude benzyl bromide is used as prepared.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])[CH2:3][OH:4].N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.CCOCC>[C:31]([O:4][CH2:3][C:2]([CH3:1])=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])(=[O:33])[CH3:32]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CO
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene-1-ol (1.6 g, 5 mmol) and pyridine (9.6 ml, 7.3 mmol) in 15 ml of anhydrous methylene chloride is stirred in an ice bath and a solution of acetyl chloride (0.37 ml, 5.25 mmol) in 5 ml of anhydrous methylene chloride is added dropwise. The mixture is stirred at 0° C. for 11/2 hours and at room temperature for 30 minutes and then taken up in 250 ml of ether. The solution is washed with ice cold 5% aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated to give the crude product; recrystallization from ethanol affords the titled compound.
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[CH2:18][CH2:19][CH3:20].[NH2:22][C:23]([NH2:25])=[O:24].C(O)(=O)C>ClC1C=CC=CC=1>[C:11]1([P:7](=[O:8])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]([NH:22][C:23]([NH2:25])=[O:24])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCC=O
Reactant: NC(N)=O
Reactant: CCOP(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: CCCC(NC(N)=O)P(=O)(c1ccccc1)c1ccccc1
Temperature: 110 °C

Procedure:
When a mixture of 0.50 mole of ethyl diphenylphosphinite 0.55 mole of n-butyraldehyde, and 0.25 mole of urea in 150 ml of chlorobenzene is warmed at 110° C. for 3 hr, there is only a slow reaction. The mixture is cooled to room temperature and 0.25 mole of acetic acid is added dropwise in ~10 minutes. The temperature increases to 65° during this addition; the urea dissolves and then a white solid product separates. The addition of another 0.25 mole of acetic acid causes no additional heat of reaction. The reaction mixture is warmed at 65°-80° for 9.5 hr and filtered, giving 44.4g. Recrystallization from ethylene glycol gives 26.5g of a white solid: mp 241°-244°; 31P nmr (CF3CO2H) -44.4 ppm; ms M+ = 316 (theory 316).
Reaction SMILES: [O:1]1CC(O)O[CH2:3][CH:2]1O.[CH3:9][NH2:10].[N+:11]([CH:13](S(C1C=CC(C)=CC=1)(=O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])#[C-:12]>C1COCC1.CN(C=O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[N:11]=[CH:12][N:10]([CH3:9])[C:3]=1[CH2:2][OH:1]
Reactant: CN
Reactant: [C-]#[N+]C(c1ccccc1OC)S(=O)(=O)c1ccc(C)cc1
Reactant: OC1COC(O)CO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ncn(C)c1CO
Reaction time: 1.25 h
Yield: 56.8 %

Procedure:
To a soln. of 1,4-dioxane-2,5-diol (120 mg, 0.995 mmol) in THF (8 ml) was added methylamine (2.8 ml, 0.664 mmol) at r.t. The resulting mixture was stirred at r.t for 75 min. Then 1-(isocyano(tosyl)methyl)-2-methoxybenzene (200 mg, 0.664 mmol) was added while keeping reaction mixture at <30° C. by a water bath. The reaction mixture was stirred at r.t overnight. Evaporated to leave white solid, dissolved in DMF, and purified by Pre-HPLC to afford (4-(2-methoxyphenyl)-1-methyl-1H-imidazol-5-yl)methanol (84 mg, 0.377 mmol, 38.6% yield) as a colorless oil. 1H-NMR (MeOD), δ: 8.97 (1H, s), 7.55 (1H, t, J=7.5 Hz), 7.47 (1H, d, J=8.0 Hz), 7.22 (1H, d, 8.0 Hz), 7.15 (1H, t, J=7.5 Hz), 4.67 (2H, s), 4.05 (3H, s), 3.89 (3H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[Li+].[CH3:10][CH:11]([N-]C(C)C)C.ICC>C1COCC1>[CH2:10]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)c1cccs1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1ccc(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophencarboxylic acid (4.00 g, 30.9 mmol) in THF (24 mL) is added dropwise via a syringe to a stirred solution of LDA (32.5 mL, 2 M in toluene) in THF (40 mL) cooled to −78° C. The temperature of the reaction is maintained at −78° C. for 10 min before iodoethane (4.87 g, 30.9 mmol) is added. The mixture is stirred at −78° C. for 1 h and is then allowed to warm to rt overnight. The reaction is quenched by the addition of water. The mixture is acidified and extracted three times with diethyl ether. The org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on reversed phase silica gel to give the title compound (1.10 g) as a brownish solid; LC-MS: tR=0.80 min, 1H NMR (CDCl3): δ 1.34 (t, J=7.3 Hz, 3H), 2.90 (q, J=7.6 Hz, 2H), 6.84 (d, J=3.5 Hz, 1H), 7.73 (d, J=3.8 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[C:55]([O:59][C:60](=[O:68])CN1C=CC(N)=N1)([CH3:58])([CH3:57])[CH3:56].N1C=CC=CC=1>C(Cl)Cl.O>[C:55]([O:59][C:60](=[O:68])[CH2:48][N:45]1[CH:46]=[CH:47][C:43]([NH:42][C:40](=[O:41])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:29]([Cl:28])[CH:30]=2)[CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)=[N:44]1)([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)Cn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 55.8 %

Procedure:
Triphenylphosphine (1.66 g, 6.33 mmol) was dissolved in methylene chloride (40 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (1.27 g, 7.17 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 1.40 g, 4.22 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for 30 min. After such time, (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (833 mg, 4.22 mmol) and pyridine (1.03 mL, 6.33 mmol) were added and it was stirred at 25° C. for 16 h. The reaction was then diluted with water (30 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (1.20 g, 56%) as a white solid: ESI-LRMS m/e calcd for C24H32ClN3O5S [M+] 509.2, found 510.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:13]3[CH2:14][CH:10]([CH2:11][N:12]3C(OC(C)(C)C)=O)[CH2:9][CH:8]=2)[O:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:13]3[CH2:14][CH:10]([CH2:11][NH:12]3)[CH2:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1cc(C2=CCC3CC2N(C(=O)OC(C)(C)C)C3)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=CCC3CNC2C3)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A solution of tert-butyl 4-(3-methyl-5-isoxazolyl)-6-azabicyclo[3.2.1] oct-3-ene-6-carboxylate (80 mg, 0.28 mmol) in 10 mL of dichloromethane was treated with trifluoroacetic acid (2 mL) with ice bath cooling. After stirring 2 h and warming to ambient temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was made basic with 10% potassium hydroxide solution and extracted with chloroform (2×10 mL). The extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product as a viscous oil (30 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccncc1F
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNc2cnccc2C(=O)O)c(OC)c1
Yield: 61 %

Procedure:
The title compound was prepared in 61% yield from 2,4-dimethoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.20 (s, 1H), 7.80 (d, 1H, J=5.0 Hz), 7.54 (d, 1H, J=5.0 Hz), 7.18 (d, 1H, J=8.3 Hz), 6.59 (d, 1H, J=2.4 Hz), 6.48 (dd, 1H, J=8.3, 2.4 Hz), 4.40 (s, 2H), 382 (s, 3H), 3.74 (s, 3H). [M+H] calc'd for C15H16N2O4, 259. found 259.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(#N)C.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(N(CC)CC)C>[C:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(C=O)cc1
Reaction time: 2 h

Procedure:
To 61 g of 4-hydroxybenzaldehyde, 400 ml of acetonitrile and 84 ml of triethylamine were added to effect the dissolution. The resulting solution was cooled to 0° C. by ice-methanol and thereto 48.4 ml of methacrylic acid chloride was gradually added dropwise. After 2 hours, the reaction solution was extracted by liquid separation with water and ethyl acetate and then subjected to silica gel column chromatography to produce the objective compound. The objective compound obtained was immediately used in the following reaction.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])C)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)(=[O:22])C>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:22])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 4 h
Yield: 51 %

Procedure:
500 ml of glacial acetic acid, 50.8 g of 4-acetoxy-4'-acetylbiphenyl, 0.8 g of cobalt(II) acetate and 12.0 g of manganese(II) acetate were refluxed in a 1 l double-walled flanged reactor equipped with an intensive stirrer and baffles, and the mixture was gassed with air via a valve in the base. After 4 hours, the mixture was cooled and the product was filtered off under suction, washed with water and dried. 26.1 g (51% yield) of 4-acetoxybiphenyl-4'-carboxylic acid having a purity of >98% (HPLC) were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=1>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=3[C:12]([OH:14])=[O:13])[CH2:3]2)[N:32]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1ccccc1-c1nc(CI)c(C)o1
Product: Cc1ccccc1-c1nc(COC2CCCC(OCc3cccc(C)c3C(=O)O)C2)c(C)o1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(2-methylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 63 of molecular weight 449.55 (C27H31NO5), MS(ESI): 450.20 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13](Cl)=[O:14].[OH-].[NH4+:17]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:17])=[O:14]
Reactant: [NH4+]
Reactant: O=C(Cl)/C=C1\CCc2c(Cl)cc(F)cc21
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)/C=C1\CCc2c(Cl)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
A solution of (E)-2-(4-chloro-6-fluoro-1-indanylidene)acetyl chloride (4.0 g, 0.015 mol) [as prepared in example 1 g] in dichloromethane (36 ml) was added dropwise to an ice-cold mixture of 30% aqueous ammonium hydroxide (2.0 ml, 0.03 mol) and dichloromethane (100 ml) and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate solution was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate:hexanes (2:1) as eluent. Trituration of the resulting solid with pentane gave 1.47 g (43%) of (E)-2-(4-chloro-6-fluoro-1-indanylidene)acetamide as a white solid: m.p. 182°-184° C.
Reaction SMILES: [S-2].[Na+].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:15][C:16]1[CH:37]=[CH:36][C:19]([O:20][CH:21]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:22](O)[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=1.O>CS(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21]([O:28][C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[CH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:36][CH:37]=1
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [S-2]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C=C(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
39 g (0.5 mole) of sodium sulfide were added to 47.8 g (0.1 mole) of the tosylate of 1,1-bis-(4-chlorophenoxy)-3,3-dimethylbutan-2-ol in 200 ml of dry dimethyl sulfoxide, and the mixture was stirred at 120° C. until the starting compound was no longer detectable by high-pressure liquid chromatography (HPLC). Thereafter, the mixture was cooled, water was added, the mixture was extracted twice with the same volume of ethyl acetate, the extracts were dried and the solvent was distilled off under reduced pressure.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[CH3:9].[N+:17]([O-])([OH:19])=[O:18]>CCOC(C)=O>[CH2:8]([C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:5](=[O:7])[CH3:6])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(N)cc1
Solvent: CCOC(C)=O
Product: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To 5 mL acetic anhydride, was added 4-ethylaniline (0.50 mL, 4.02 mmol). The mixture was cooled to 0° C., then fuming red nitric acid (0.35 mL) was added, dropwise. The mixture was stirred at rt for 15 h, then was diluted with EtOAc. The organic phase was washed with sat. NaHCO3, water and brine, dried (Na2SO4) and concentrated to afford 555 mg of Intermediate 180.1, which was used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([OH:29])[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.C([O-])([O-])=O.[K+].[K+]>C1(=O)CCCCC1>[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:29][C:14]1[CH:13]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=1
Reactant: CCCCCCCCCCOc1cc(O)cc(OCCCCCCCCCC)c1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCCCCCCCOc1cc(OCCCCCCBr)cc(OCCCCCCCCCC)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
A mixture of 9 (2.70 g, 6.64 mmol), 1,6-dibromohexane (15.0 ml, 98.4 mmol), K2CO3 (2.29 g, 16.6 mmol) in cyclohexanone (50 ml) was heated for 16 h under reflux. The mixture was allowed to cool to RT, the inorganic salts are filtered off, followed by rinsing with acetone. The solvent and the excess 1,6-dibromohexan are distilled off in vacuo, and the residue is purified by means of column chromatography (silica gel, chloroform/petroleum ether 1:2). 2.62 g (69%) of compound 10 could be isolated in form of a light yellow oil. IR (film) 2895, 2810, 1575 cm−1; 1H-NMR (CDCl3) δ 6.05 (s, 3H), 3.94-3.86 superimposed signals (3.91, t, 6.4 Hz, 2H and 3.90, t, 6.7 Hz, 4H), 3.42 (t, 6.7 Hz, 2H), 1.95-1.83 (m, 2H), 1.81-1.69 (m, 6H), 1.52-1.21 (m, 32H), 0.88 (t, 6.8 Hz, 6H); MS (FD) m/z 571 (M+ for Br81), 569 (M+ for Br79). Anal. calc. for C32H57BrO3: C, 67.46; H, 10.08. Found C, 67.67; H, 10.12.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:18](Br)[CH:19]=[CH2:20].C(N(CC)CC)C.[C:29]1([CH3:38])[CH:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][CH:30]=1>CN(C=O)C.O>[CH2:18]([N:16]1[CH:17]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:14]=[C:15]1[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:38])=[CH:30][CH:31]=1)=[O:36])[CH:19]=[CH2:20]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCn1cc(-c2ccccc2)nc1C(=O)c1ccc(C)cc1
Yield: 15.4 %

Procedure:
Potassium t-butoxide (2.59 g, 23.1 mmol) was dissolved in DMF (100 ml), and thereto was added 4-phenyl-1H-imidazole (3.00 g, 21 mmol) with stirring. The mixture was stirred at room temperature for 30 minutes, and thereto was added allyl bromide (3.50 g, 31.5 mmol). The mixture was stirred at 40° C. for 4 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in pyridine (24 ml), and thereto were added successively triethylamine (17.9 g, 17.7 mmol) and 4-toluoyl chloride (3.7 g, 16.3 mmol), and the mixture was stirred at 60° C. for 5 hours. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N diluted hydrochloric acid, and saturated saline, and dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (760 mg, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H].O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCOCC2=O)cc1
Temperature: 40 °C

Procedure:
60 g (0.27 mol) of 4-(4-nitrophenyl)-3-morpholinone (VII) are suspended in 480 g of ethanol, admixed with 3 g of palladium on activated carbon (5%) and contacted with 5 bar of hydrogen at 80° C. for one hour. After hydrogenation has ended, the suspension is admixed with 80 g of ethanol and 270 g of water and heated to 40° C., and the catalyst is filtered off. The solution is concentrated under reduced pressure and the remaining solid is dried to constant weight at 50° C. under reduced pressure.
Reaction SMILES: [CH2:1]([CH:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[NH2:22])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4]1)[CH3:2].Cl[C:27](Cl)([O:29][C:30](=O)[O:31][C:32](Cl)(Cl)Cl)Cl>ClCCl>[CH2:1]([CH:3]1[C:7]2[C:8]([O:12][C:13]3[N:18]=[CH:17][C:16]([N:19]4[C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[NH:22][C:27]4=[O:29])=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4]1)[CH3:2].[CH3:5][O:4][C:3]1[CH:7]=[CH:6][CH:11]=[C:32]([O:31][CH2:30][O:29][CH3:27])[CH:1]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC1OCc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c21
Solvent: ClCCl
Product: CCC1OCc2cccc(Oc3ccc(N4C(=O)NC(C)(C)C4=O)cn3)c21
Product: COCOc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 791 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 149, 17.2 mg, 0.050 mmol) was dissolved in Dichloromethane (3 mL) to give a pale yellow solution that was cooled at 0° C. TEA (0.035 mL, 0.252 mmol) was added followed by a dropwise addition of a solution of triphosgene (6.43 mg, 0.023 mmol) in dichloromethane (0.5 ml) and the reaction mixture was stirred at 0° C. for 20 minutes. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 10 g and cyclohexane/ethyl acetate from 2:1 to 1:2 as eluents affording the title compound Example 45 (15.3 mg) as a white solid.