Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])(C(OCC)=O)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCCCC(=O)O)N=C2c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (10 g) is dissolved in diethyl carbonate (150 ml) in a nitrogen stream, and 60% sodium hydride (2.0 g) is added with stirring at room temperature. The mixture is refluxed under heating for 2 hours and cooled to 50° C. with ice water. Ethyl bromovalerate (7.9 ml) is added. After stirring at 100° C. for 2 hours, the reaction mixture is poured on ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) and crystallized from isopropyl ether and ethyl acetate to give 8.3 g of (±)-ethyl 5-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl) valerate as white powdery crystals. (±)-Ethyl 5-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)valerate (8.2 g) is dissolved in a mixture of ethanol (90 ml) and water (30 ml), and barium hydroxide 8 hydrate (19 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 6N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether and recrystallized from chloroform and methanol to give 3.2 g of (±)-5-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)valeric acid as white powdery crystals, melting point 257°-260° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]1([CH2:18]Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCC1CCCCC1
Product: COC(=O)c1ccc(OCC2CCCCC2)cc1
Yield: 63.4 %

Procedure:
Using the general method of Compound 80 Part A, methyl 4-hydroxybenzoate (3.0 g, 19.7 mmole) was reacted with cyclohexylmethyl bromide (2.8 mL, 20.1 mmole) to provide 3.1 g of methyl 4-cyclohexylmethoxybenzoate as a white crystalline solid, m.p. 62°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:13][NH:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:13][CH:11]2[CH3:10])=[CH:4][N:3]=1
Reactant: CC1CN1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Yield: 16.7 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (352 mg, 2.17 mmole) in 4 mL of dry acetonitrile is 0.4 mL (4.34 mmol) of 2-methyl-aziridine followed by 300 mg (2.17 mmol) of potassium carbonate. The reaction is heated at 60° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 66 mg (17% yield) of 2-Chloro-5-(2-methyl-aziridin-1-ylmethyl)-pyridine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.15 (d, 3H, J=5.4 Hz), 1.34 (d, 1H, J=6.6 Hz), 1.47–1.55 (m, 2H), 3.35 (abq, 2H, J=5.8 Hz), 7.25 (d, 1H, J=6.3 Hz), 7.65 (dd, 1H, J=8.3 and 2.5 hz), 8.27 (d, 1H, J=1.7 Hz); MS 183.2 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1
Reactant: CC1CN2CC(C)OC2(CCCCCO)O1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCCCCC12OC(C)CN1CC(C)O2
Temperature: 0 °C
Yield: 462 %

Procedure:
In an oven dried 100 mL round-bottom flask equipped with a pressure equalizing addition funnel and a reflux condenser were added 5-(2,6-Dimethyl-tetrahydro-oxazolo[2,3-b]oxazol-7a-yl)-pentan-1-ol (22.9 g, 0.01 mol) followed by chloroform 50 mL and triethylamine 12.12 g, 0.12 mol). The reaction content was cooled to 0° C. under nitrogen. While stirring a solution of methacryloyl chloride (11.44 g, 0.11 mol) in chloroform was added slowly. After completion of the acid chloride the reaction was stirred one hour at 0° C., then allowed to warmed to room temperature and then stirred over night at room temperature. The triethylamine salt was filter off through Celite® (World Minerals, Santa Barbara, Calif.), the filtrate concentrate at reduced pressure. NMR (proton) showed this material to be the desired material contaminated with triethyl amine salt. This material was then washed with hexanes (2×125 ml), the hexanes washes combined concentrated giving 13.74 g of product.
Reaction SMILES: C(N[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]#[N:21])(=O)C1C=CC=CC=1.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Cl:22][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]#[N:21]
Reactant: N#Cc1c(NC(=O)c2ccccc2)ccc2ccccc12
Reactant: Cl
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: N#Cc1c(Cl)ccc2ccccc12

Procedure:
33.6 g (0.2 mole) of 2-aminonaphthalene-1-carbonitrile (cf. Example 1) in 250 ml of absolute acetonitrile were added at 65° C. to a suspension of 32.3 g (0.24 mole) of copper(II) chloride (anhydrous) and 30.9 g (0.3 mole) of tert-butylnitrile in 800 ml of absolute acetonitrile. After the end of gas evolution, 2,000 ml of 20% strength hydrochloric acid were added to the cooled reaction mixture, and the precipitate was isolated, washed and dried. 31.7 g (70% of theory) of the title compound of melting point 82°-83° C. (active ingredient example 1001) were obtained in this manner.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1)(=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:6]([CH2:5][OH:4])=[CH:7][N:8]=[CH:9]2)=[CH:13][C:14]=1[F:20])#[N:19]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CO)cc1F
Reaction time: 4 h

Procedure:
To a solution of 5-(acetoxymethyl)-1-(4-cyano-3-fluorobenzyl) imidazole, as described above in Step E, (19.8 g, 72.5 mmol) in 5:1 THF/water (430 mL) at ambient temperature was added lithium hydroxide monohydrate (3.33 g, 79.4 mmol). After 4 hours, the solution was adjusted to pH 7 with 1.0 N hydrochloric acid and concentrated in vacuo. The residue was concentrated from toluene in vacuo (3×100 mL) to give the titled product as a pale solid.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]([NH2:30])=[O:29]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:21]3[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[O:29][CH:15]=2)[CH:9]=1
Reactant: NC(=O)Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: O=C(O)COc1ccc(Br)cc1-c1coc(Cc2c(Cl)cccc2Cl)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(2,6-dichlorophenyl)acetamide according to GP5 and GP3: LC/MS (an 10p8) Rt 2.75 min, m/z 456/458/460 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: N#Cc1ccsc1CBr
Yield: 46.3 %

Procedure:
2-Methyl-thiophene-3-carbonitrile [see Beaton, et al.; Tetrahedron Lett. 39, 10, 1998, 1227-1230] (1.36 g, 11 mmol), N-bromosuccinimide (2.56 g, 14.4 mmol), and a catalytic amount of benzoyl peroxide were stirred in benzene (30 mL) at 80° C. for 2 h. The solution was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (10% EtOAc/hexanes) gave 1.03 g (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.39 (d, 1H, J=5.6 Hz), 7.17 (d, 1H, J=5.6 Hz), 4.79 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(=O)(OC)OC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[N:18]=[C:17]([O:28][CH3:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(OC)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Temperature: 120 °C
Reaction time: 5 h
Yield: 128.8 %

Procedure:
A suspension of 5-{5-[4-(benzyloxy)phenyl]-3-hydroxy-1H-pyrazol-1-yl}-2-methoxypyridine (800 mg), dimethyl carbonate (0.9 mg) and potassium carbonate (888 mg) in DMF (8 ml) was stirred at 120° C. for 5 hours. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give 5-{5-[4-(benzyloxy)phenyl]-3-methoxy-1H-pyrazol-1-yl}-2-methoxy-pyridine (1.069 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:30][CH3:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:23]=[CH:22][N:21]([CH2:30][CH3:31])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CCI
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, using 3-(4-bromophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one from Example 60 above and iodoethane.
Reaction SMILES: [NH3:1].[C:2](#[N:5])[CH:3]=[CH2:4]>O>[C:2]([CH2:3][CH2:4][NH:1][CH2:4][CH2:3][C:2]#[N:5])#[N:5]
Reactant: N
Reactant: C=CC#N
Solvent: O
Product: N#CCCNCCC#N
Reaction time: 10 h

Procedure:
The reaction takes place in a tube reactor which has an internal diameter of 36 mm and a length of 70 cm. At the lower end of the reactor there is a glass frit G 4, manufactured by the Schott Company, Mainz. It is designated 160 D and has a 30 mm diameter. The glass frit functions as a distribution device. The tube has a total volume of 700 ml. and the effective reaction volume (the space used during the reaction) equals 500 ml. 9 liters of gaseous ammonia are fed into the reactor per hour. The gas flows through the glass frit and reacts with the acrylonitrile. In order to monitor the gas conversion, the amount of unreacted gas is determined using a gas meter. 52 ml of acrylonitrile and 3.8 ml of water are pumped hourly into the upper end of the reactor at a rate which corresponds to a space velocity of 0.1 hr-1. After 10 hours of residence time, the reaction mixture is removed at a point above the distribution device located at the lower end of the tube reactor. The yield of bis-(2-cyanoethyl)-amine obtained is 91 %.
Reaction SMILES: [CH2:1]([C:4]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CO.[Br:14]Br.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:4]1([CH2:1][CH2:2][CH2:3][Br:14])[CH2:5][CH2:6]1
Reactant: C=CCC1(CC(=O)OC)CC1
Reactant: BrBr
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC1(CCCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 3.4 ml (3.4 mmol) of borane/THF complex solution (1 M in THF) were added dropwise to 1542 mg (10 mmol) of methyl [1-(prop-2-en-1-yl)cyclopropyl]acetate in 10 ml of anhydrous THF. After 30 min at 0° C., the reaction was stirred at RT for a further 30 min, and 22 μl (0.54 mmol) of methanol were then added. At −5° C., 0.62 ml (12 mmol) of bromine and 2971 mg (16.5 mmol) of sodium methoxide solution (30% in methanol) were then successively added dropwise to the reaction mixture. Once the reaction had reached room temperature, 10 ml of saturated sodium bicarbonate solution were added, the organic phase was separated off and the aqueous phase was extracted three more times with tert-butyl methyl ether. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 683 mg (2.9 mmol, 29% of theory) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.C(N(CC)CC)C.[F:35][C:36]([F:41])([F:40])[C:37](O)=[O:38]>ClCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH:23][C:37](=[O:38])[C:36]([F:41])([F:40])[F:35])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NNC(=O)C(F)(F)F)c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (257 mg, 0.67 mmol) obtained in Step 2 of Example 56 was dissolved in dichloromethane (8.0 mL), and the mixture was cooled to 0° C. after adding triethylamine (0.19 mL, 1.34 mmol). Thereafter, anhydrous trifluoroacetic acid (0.19 mL, 1.34 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and a 3 mol/L aqueous sodium hydroxide solution was added to the resulting residue to adjust the pH at 4. The precipitated white solid was then filtered off to obtain (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)-N′-(2,2,2-trifluoroacetyl)benzoic hydrazide (300 mg, 93%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I

Procedure:
A solution of 3-iodo-4-methylaniline (1.22 g, 5.25 mmol), 3-(trifluoromethyl)benzoic acid (0.95 g, 5 mmol), HOBt (0.68 g, 5 mmol), and EDCl (1.05 g, 5.5 mmol) in THF (20 mL) was stirred overnight at rt. Water was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (3:1 hexane/ethyl acetate) yielding the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=1[C:6](OC)=[O:7])[CH3:2].[NH2:17][OH:18]>CO>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=1[C:6]([NH:17][OH:18])=[O:7])[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: NO
Solvent: CO
Product: CCOc1ccc([N+](=O)[O-])cc1C(=O)NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-ethoxy-5-nitrobenzoate (6.099 g, 26.99 mmol) and 50% wt/v aqueous hydroxylamine (40 ml) were taken up in MeOH (100 ml) and stirred at RT overnight. The resulting precipitated yellow solid was collected by filtration, washed with IPA and dried in vacuo The filtrate was evaporated in vacuo and the residue was triturated with IPA (25 ml). The solid that didn't dissolve was filtered off, washed with a minimum quantity of IPA and dried in vacuo. The two crops of solid were suspended in H2O (300 ml) and the pH was lowered to 2 by careful addition of concentrated HCl. The solid was filtered off, washed with MTBE and dried in vacuo to give 3.9 g of crude 2-ethoxy-5-nitro-N-hydroxybenzamide. The IPA mother liquors from above were combined with the crude 2-ethoxy-5-nitro-N-hydroxybenzamide and evaporated in vacuo. The residue was triturated with CH2Cl2 (25 ml) and the solid was filtered off and dried in vacuo to give 2-ethoxy-5-nitro-N-hydroxybenzamide (2.39 g, 39%) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 87.7 %

Procedure:
To a biphasic solution of 4-amino-1-benzylpiperidine (6.0 g, 31.6 mmol), K2CO3 (8.71 g, 63.1 mmol) in CH2Cl2 (200 mL) and water (100 mL) was added benzoyl chloride (4.86 g, 34.7 mmol) in 20 mL of CH2Cl2 at 0° C. with stirring. After stirring for 4 h at room temperature, the layers were separated. The organic layer was washed with water, dried over MgSO4 and filtered. The solvent was removed in vacuo to obtain 1-benzyl-4-benzamidopiperidine (8.16 g, 87% yield) as a white solid. It was used in the next step without purification.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[OH:21].[OH-].[Na+]>CC(C)=O>[OH:21][C:20]1[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][C:15]=1[NH:14][C:11]([NH2:12])=[S:10]
Reactant: Cc1ccc(N)c(O)c1
Reactant: N#C[S-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: Cc1ccc(NC(N)=S)c(O)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.2 mole of benzoyl chloride is added dropwise to a solution of 0.22 mole of ammonium thiocyanate in 100 ml of anhydrous acetone. The mixture is boiled to reflux for 5 minutes after the addition is complete, and a solution of 0.2 mole of 6-amino-m-cresol in 50 ml of anhydrous acetone is then added dropwise so as to maintain gentle refluxing. Stirring and heating are continued for 5 minutes after the addition, the reaction mixture is poured into 1.5 l of ice-cold water, and the crystals obtained are drained and suspended in 300 ml of 10% strength sodium hydroxide solution. The mixture is is brought to boiling for 10 minutes, and the solution is filtered on glass wool and acidified strongly with concentrated hydrochloric acid. The solution is brought back to pH 8 with ammonia solution. The crystals which precipitate on cooling are drained, washed with water and recrystallized in ethanol. (M.p. 175°-7° C.) Yld: 65%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24](O)[C:25](O)=[O:26])=[CH:22][CH:21]=1)[CH:17]=[CH2:18]>>[CH2:16]([O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24]2[C:7]3[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=3[O:15][C:25]2=[O:26])=[CH:22][CH:21]=1)[CH:17]=[CH2:18]
Reactant: C=CCOc1ccc(C(O)C(=O)O)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: C=CCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A mixture of 309 g (1.50 mol) of 2,4-di-tert-butyl-phenol and 192 g (1.00 mol) of 4-allyloxymandelic acid (prepared in accordance with EP-B-182 507, Example 1, page 4) is stirred under nitrogen for 2 hours at 140°-150° C. Then the mixture is stirred under low vacuum (50 mbar) for 1.5 hours; at 150° C. Excess 2,4-di-tert-butylphenol is distilled off under a high vacuum. Crystallisation of the residue from xylene and ethanol gives 230.1 g (61% ) of 3-(4-allyloxyphenyl)-5,7-di-tert-butylbenzofuran-2-one of m.p. 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([C:39]([F:42])([F:41])[F:40])[C:32]3[N:36]=[C:35]([CH3:37])[NH:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[C:32]6[N:36]=[C:35]([CH3:37])[NH:34][C:33]=6[CH:38]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C(F)(F)F)c5nc(C)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
140 mg (0.510 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.