Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:31][NH:32][C:19](=[O:21])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.5 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain a white solid, which was dried in vacuum at 50° C. to obtain the title compound (25 mg, yield 14%). LC-MS (ESI) m/z: 362 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.58 (s, 3H), 4.52-4.54 (d, J=7.2 Hz, 1H), 4.94-4.97 (m, 1H), 6.69-6.70 (m, 1H), 6.96-6.97 (m, 1H), 7.04-7.08 (m, 3H), 7.18-7.22 (m, 2H), 7.36-7.38 (m, 2H), 7.51-7.55 (t, J=8.0 Hz, 1H), 12.2 (s, 1H).
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:33])=O>O1CCCC1>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:33])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a cooled (-10°) and stirred solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-hydroxyacetate (102 g., 0.250 mole) in tetrahydrofuran (2000 ml.) were added in succession pyridine (27.1 ml., 0.287 mole) and thionyl chloride (25.2 ml., 0.287 mole); the thionyl chloride addition was done over ca 15 minutes. The mixture was stirred for 30 minutes at -10° and filtered. Concentration of the filtrate left a yellow oil which was partially purified by absorption on a pad of silica gel (800 ml.) and elution with chloroform (ca 3000 ml.). Concentration of the eluates gave an oil (92.9 g., 100%) which was found to contain a minimum of 90% of the title ester as a mixture of epimers.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([F:33])[C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([F:33])[C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3F)cc2)CC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-4-methyl-piperidine (164 mg, 0.48 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine (110 mg, 0.48 mmol).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([O-:11])=[O:10])(=O)C.[Na+:12].[OH-].[Na+].CCO>O>[NH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([O-:11])=[O:10].[Na+:12]
Reactant: CC(=O)NCCOCC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCOCC(=O)[O-]
Temperature: 100 °C

Procedure:
52 g of sodium 5-acetylamino-3-oxapentanoate were dissolved in 200 ml of water. 11.4 g of NaOH were added at 20° C., and the reaction mixture was then heated at 100° C. for 8 h until precursor was no longer detectable. Then 200 ml of EtOH were added and the pH was adjusted to about 6, resulting in pure crystals of sodium 5-amino-3-oxapentanoate. The crude product resulting after removal of the solvent by distillation as a mixture with sodium acetate weighing 63.3 g (corresponding to 100% of theory) could be employed without prior precipitation for the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[CH3:6][Si:7]([C:10]1([Na])[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:9])[CH3:8]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:11]1[CH:12]=[CH:13][CH2:14][C:10]=1[Si:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: COCCCl
Reactant: C[Si](C)(C)C1([Na])C=CC=C1
Solvent: C1CCOC1
Product: COCCC1=C([Si](C)(C)C)CC=C1
Temperature: -78 °C
Yield: 84 %

Procedure:
A solution of 18.9 g (200 mmol) of chloroethyl methyl ether in 100 ml of THF was gradually dropwise added to a solution of 32 g (200 mmol) of trimethylsilyl-cyclopentadienylsodium in 400 ml of THF while being stirred in an argon atmosphere at −78° C. After completion of the addition, the reaction mixture was heated under reflux overnight. Then THF was distilled off under a reduced pressure, and the obtained solid was filtered off and subjected to vacuum distillation (80° C./1 mmHg) to give about 33 g of [(2-methoxy)ethyl]-trimethylsilylcyclopentadiene (TMSCpCH2CH2OMe). Yield: 85%. The chemical structure was confirmed by the following data obtained by 1H-NMR using CDCl3.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH:17]=[CH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>C(#N)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17][CH2:18][N:24]([CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:19])[CH2:23][CH:20]1[CH2:22][CH2:21]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CC1
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CC1CC1
Reaction time: 16 h
Yield: 43.9 %

Procedure:
A solution of 444 mg (1.71 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester and 74 ml (0.85 mmol) cyclopropylmethylamine in 5 ml acetonitrile was stirred for 1 h at room temperature, then for 16 h at 80°0 C. Concentration in vacuo and flash chromatography (gradient: 0-100% MeOH in EtOAc) afforded 220 mg (44%) of the title compound as a yellow oil. MS m/e (%): 590 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 49.2 %

Procedure:
2-Amino-5-bromopyridine (5.0 g, 28.90 mmol), phenylboronic acid (7.05 g, 57.80 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.01 g, 1.45 mmol), and 2M Na2CO3(aq) (24 mL, 48 mmol) were combined in 150 mL of dimethoxyethane and heated to reflux for 1 hour. Upon cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine. The solvent was removed to give an amber oil which was chromatographed on silica gel eluting with hexanes/ethyl acetate (1:1) to afford 5-phenylpyridin-2-amine (2.42 g) as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]2)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH:6]=[N:7][C:2]([O:29][CH:26]3[CH2:27][CH2:28][N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[CH2:25]3)=[N:3][C:4]2=[O:16])=[CH:10][CH:11]=1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Reactant: OC1CCN(c2ccc(F)cc2)C1
Solvent: ClC(Cl)Cl
Product: O=c1nc(OC2CCN(c3ccc(F)cc3)C2)ncn1Cc1ccc(Cl)cc1
Yield: 3.8 %

Procedure:
The synthesis was performed using a chloroform solution (2 mL) of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (67 mg, 0.26 mmol) synthesized in Reference Synthesis Example 11 and 1-(4-fluorophenyl)pyrrolidin-3-ol (71 mg, 0.39 mmol) synthesized in Reference Synthesis Example 46 in a similar manner to Synthesis Example 79 to obtain the title compound (4.0 mg, yield: 4%).
Reaction SMILES: IC.[Br:3][C:4]1[CH:13]=[CH:12]C2N[C:9](=O)[NH:10][C:6]=2[CH:5]=1.CC(C)([O-])C.[K+].Cl.C[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[Br:3][C:4]1[CH:13]=[CH:12][C:25]2[N:24]([CH3:26])[C:22](=[O:23])[N:10]([CH3:9])[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Br)cc2[nH]1
Reactant: CC(=O)N(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Product: Cn1c(=O)n(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (2.41 g) was added to a suspension of 5-bromo-1,3-dihydro-benzoimidazol-2-one (1.65 g) and potassium tert-butoxide (1.91 g) in DMA (20 ml). The mixture was stirred overnight at room temperature. The mixture was poured to 2.5N aqueous HCl (80 ml) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. Heptane (50 ml) was added to the residue and the mixture was filtered. The residue was washed with diethyl ether and dried in vacuo to give the title compound (1.1 g) as a light brown solid. MS (m/e)=241.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:22])=[C:6]([NH:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)Nc1cc(Cl)nc(N)n1
Solvent: CCO
Product: CC(C)(C)Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
9 g of 2-amino-4-tert-butylamino-6-chloropyrimidine are suspended in 90 ml of ethanol. 24.70 g of meta-chloroperbenzoic acid are added dropwise as solution in 250 ml of ethanol. The reaction mixture is stirred at room temperature for 7 hours 30 minutes. It is evaporated to dryness. The residue is taken up in 100 ml of water. The pH is adjusted to 1 by adding concentrated hydrochloric acid. After 1 hour's stirring the precipitate is filtered off on sintered glass and then discarded. The filtrates are adjusted to pH 8 by adding concentrated sodium hydroxide and are then extracted with 3×100 ml of dichloromethane. The organic phase is separated off, dried over sodium sulfate, filtered on paper and evaporated to dryness. The residue obtained is recrystallized from 60 ml of acetonitrile. 1.30 g of 2-amino-4-tert-butylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.Cl.[NH2:24]O.O>C(O)(=O)C>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:24][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3C)cnc21
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccccc4C)c3cnc21
Yield: 44.1 %

Procedure:
4-Chloro-1-ethyl-5-(2-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (5.40 g) was refluxed for 2 hours in 300 ml of glacial acetic acid containing 10 ml of concentrated hydrochloric acid and 10 g of hydroxylamine hydrochloride. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed four times with water and once with saturated sodium bicarbonate solution. It was then evaporated and chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane) to give 2.21 g of product, mp 168°-170°. This product was recrystallized from ethyl acetate together with the product of another run to give analytically pure material, mp 170°-171° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[C:5]([F:12])[CH:4]=1.C(=O)([O-])O.[K+].O.Br[CH2:20][C:21]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)=O>C1COCC1>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:9][CH:20]=[C:21]([C:23]3[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=3)[N:8]=2)=[C:5]([F:12])[CH:4]=1
Reactant: CC(C)n1ncnc1C(=O)CBr
Reactant: N=C(N)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a rapidly stirred mixture of 4-bromo-2-fluoro-benzamidine hydrochloride (9.84 g, 38.8 mmol), potassium hydrogen carbonate (15.6 g, 154.8 mmol), THF (98 mL) and water (16 mL) at reflux was added a solution of 2-bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.0 g, 38.8 mmol) in THF (19 mL) over 15 min. The resulting mixture was stirred for 18 h at reflux before concentrating in vacuo. The resultant residue was treated with water and the solid formed collected by filtration, washed (water, then 1:1 diethyl ether:cyclohexane then diethyl ether) to give 5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole as a brown solid (10.1 g, 74%). 1H NMR δ (ppm) (CDCl3): 8.21-8.14 (1H, m), 7.90 (1H, s), 7.80 (1H, s), 7.47-7.38 (2H, m), 7.26 (1H, s), 5.91 (1H, br, s), 1.59 (6H, d, J=6.63 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([C:12]1([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3([C:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:11])[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)=[N:32][CH:33]=1)#[N:38]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NNC(=O)C1(c2ccc(-c3ccc(C#N)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.6 %

Procedure:
A mixed solution of the compound (100 g, 249 mmol) obtained in Example 60-1), 2-chloro-5-cyanopyridine (44.8 g, 323 mmol), potassium carbonate (68.7 g, 497 mmol), and tetrakis(triphenylphosphine)palladium (14.4 g, 12.4 mmol) in 1,2-dimethoxyethane (800 mL) and water (200 mL) was stirred at 100° C. for 8 h, then at 80° C. for 14 h, and further at 100° C. for 5 h. The reaction mixture was cooled to room temperature, insoluble substances were filtered off, dichloromethane was added to the filtrate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution in this order. The solvent was distilled off under reduced pressure, and the residue was washed with dichloromethane and hexane and then purified by silica gel column chromatography (ethyl acetate:methanol=1:1) to obtain the title compound (24.1 g, 26%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])OCC.O.[NH2:15][NH2:16]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[NH:15][NH2:16]
Reactant: CCOC(=O)Nc1ccccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Nc1ccccc1F
Reaction time: 72 h

Procedure:
A mixture of ethyl N-(2-fluorophenyl)carbamate (8.3 g, 45.4 mmol) and hydrazine hydrate (13.6 g, ca. 14 ml) in 40 ml of absolute ethanol is heated to reflux. After 3 days, the reaction mixture is concentrated, and the solid is filtered, washed with water and with ether and dried to give 4-(2-fluoro-phenyl)semicarbazide.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[OH:26].C(N(CC)CC)C.Cl.C(N(CC)CC)C>O1CCCC1>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[O:26][C:9](=[O:10])[CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(C)c1O
Reactant: O=C(Cl)CC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC(=O)CC(c1ccccc1)c1ccccc1
Yield: 91.2 %

Procedure:
Forty-six and thirty-seven hundredths grams (a 10% excess) of 3,3-diphenylpropionic acid chloride in 120 ml tetrahydrofuran are placed into a 500 ml round-bottom flask which is equipped with a mechanical agitator. Eighteen and three-tenths grams 2,6-dimethylphenol with 16.7 grams triethylamine in 150 ml tetrahydrofuran are added, dropwise, to this solution while stirring. The mixture is stirred for 12 hours at room temperature. The precipitated triethylamine-hydrochloride is sucked off and the tetrahydrofuran is evaporated in vacuo. The residue is taken up in ether and washed three times with water. The solvent is dried with sodium sulfate and then evaporated in vacuo. There remain 45.0 grams 3,3-diphenylpropionic acid-2,6-dimethylphenyl ester [91.2% yield]. Forty-five grams of this ester are dissolved in a 500 ml flask in 200 ml nitrobenzene. Eighteen and two-tenths grams aluminum chloride are added and the substance is stirred, excluding any humidity, with a KPG agitator. The mixture is heated to 100° C. and the components are left to react at this temperature for 1 day. The nitrobenzene is distilled off in vacuo, the residue is taken up with ether and crushed ice is added. Subsequently, the ether phase is washed well with water, dried with sodium sulfate and the ether is evaporated except for a small amount. Thirty-two grams [71.3%] 4-hydroxy-3,5-dimethyl-β,β-diphenylpropiophenone crystallize out. Ten grams of this compound are dissolved in 80 ml dry acetone for the etherification and 25 grams water-free potash (100% excess) are added. Twelve and twenty-five hundredths grams (200% excess) diethylamine-ethylchloride, dissolved in 150 ml acetone, are added dropwise, with the exclusion of humidity, to this solution. The solution is boiled under reflux for 1 day. The potash is filtered off, the acetone evaporated in vacuo and the residue taken up in ether. The ether solution is washed in water and dried with sodium sulfate. The hydrochloride salt is precipitated with ethereal hydrochloric acid. After recrystallization from a methanol/ether solution, 9.55 grams [67.8%] 4-[2-(N,N-diethylamino)-ethoxy] -3,5-dimethyl-β,β-diphenylpropiophenone hydrochloride (Melting point of 95°-97° C.) and 4-[2-(N,N-diethylamino)-ethoxy] -3,5-dimethyl-β,β-diphenylpropiophenone fumarate (Melting point 226° C. [decomposition]), are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][C:34]=1[F:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:33]5[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][C:34]=5[F:42])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(N)=O)cc1F
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42 mg, 0.10 mmol), 4-bromo-3-fluorobenzamide (24 mg, 0.11 mmol), Pd-FibreCat 1007 (10 mg), K2CO3 (1M, 240 mL), and DMF (1 mL) were combined in a scintillation vial and heated at 80° C. for 3 hr. The mixture was filtered and purified using reverse-phase preparative HPLC to provide 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro-2′-methylbiphenyl-4-carboxamide (ESI-MS m/z calc. 428.5. found 429.5 (M+1); retention time 3.30 min).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]#[N:7])=[N:2]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:1]1[CH:5]=[N:4][C:3]([C:6]#[N:7])=[N:2]1
Reactant: N#Cc1nc[nH]n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: N#Cc1ncn(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1H-1,2,4-triazole-3-carbonitrile (1.00 g, 10.63 mmol) in DCE (10 mL) was added 3,4-dihydro-2H-pyran (1.94 ml, 21.26 mmol) and p-toluenesulfonic acid (183 mg, 1.06 mmol). The resulting mixture was stirred at room temperature under nitrogen for 15 minutes. Saturated aqueous sodium bicarbonate solution (25 mL) was added and the product extracted into DCM (25 mL×3). The combined organics were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 0-10% methanol gradient in DCM) to give the title intermediate as a yellow oil: 1H NMR (500 MHz, CDCl3) delta 1.81-1.63 (3H, m), 2.11-1.95 (2H, m), 2.19 (1H, dd, J=8.1, 5.6 Hz), 3.87-3.65 (1H, m), 4.18-3.97 (1H, m), 5.53 (1H, dd, J=8.5, 2.9 Hz), 8.37 (1H, s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O>[CH:10]1([CH2:9][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrCC1CCCCC1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnn(CC2CCCCC2)c1
Reaction time: 0.08 h
Yield: 20.7 %

Procedure:
To a solution of pyrazole (1.00 g, 14.7 mmol) in of dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 450 mg, 11 mmol). After 5 min, bromomethylcyclohexane (2.4 mL, 17 mmol) was added by syringe and the mixture was maintained overnight. The reaction mixture was quenched with methanol, diluted with water, and extracted with ether (2×). The combined organic layers were dried over magnessium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 500 mg (27%) of 1-cyclohexylmethyl-1H-pyrazole. To a solution of 1-cyclohexylmethyl-1H-pyrazole (490 mg, 3.00 mmol) in tetrahydrofuran (10 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (1.5 mL, 3.8 mmol). The reaction mixture was maintained at −78° C. for 1 h and was treated with dimethylformamide (1.0 mL, 13 mmol). The reaction mixture was allowed to warm to rt, maintained overnight, and was quenched with methanol. The reaction mixture was diluted with water and was extracted with ether (2×). The combined organic layers were dried over magnessium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 390 mg (68%) of 2-cyclohexylmethyl-2H-pyrazole-3-carbaldehyde.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[N:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:8]=1)#[N:2].S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+]>[C:1]([C:3]1[C:4](=[O:19])[N:5]([CH3:24])[C:6](=[O:18])[N:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:8]=1)#[N:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C)c1Nn1cc(C#N)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1Nn1cc(C#N)c(=O)n(C)c1=O

Procedure:
To a mixture of 5-cyano-1-(2,6-dimethylanilino)-2,4-pyrimidinedione (0.1 mol) and 80 ml of 5% sodium hydroxide solution, with stirring, is slowly added dimethyl sulfate (0.1 mol). The reaction mixture is stirred for about 2-4 hours and then filtered, washed with water and dried to yield 5-cyano-1-(2,6-dimethylanilino)-3-methyl-2,4-pyrimidinedione.