Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][N:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCCCNCCC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A solution of 1.01 g (0.005 mole) of 3-butylamino-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-90:10) gave 1.6 g of 3-[butyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-propionic acid tert-butyl ester (IV-44)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[C:12]([N:17]=1)=[N:13][CH:14]=[CH:15][CH:16]=2.CC(C)=[O:20].I([O-])(=O)(=O)=O.[Na+]>O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[C:12]([N:17]=1)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:20]
Reactant: CC(C)=O
Reactant: CSc1ccccc1-c1nc2ncccc2o1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CS(=O)c1ccccc1-c1nc2ncccc2o1
Temperature: 25 °C

Procedure:
A solution of 0.5 g. of 2-(2-methylthiophenyl)oxazolo[4,5-b]pyridine in 50 ml. of acetone was treated with 3 g. of sodium metaperiodate. After stirring over the weekend at room temperature, the mixture was diluted with 30 ml. of water. The acetone was distilled out and the resulting precipitate was recrystallized to give 2-(2-methylsulfinylphenyl)oxazolo[4,5-b]pyridine, m.p. 153.5°-155.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1CC[CH2:14][N:13]1[CH3:17].C(OC(N1CCC[C@@H]1C(C1C2C(=CC=C(Br)C=2)NC=1)=O)=O)C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:14])[CH3:17]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Product: CN(C)CCc1c[nH]c2ccc(Br)cc12

Procedure:
(R)-5-Bromo-3-[(N-methylpyrrolidin-2-yl)methyl] 1 H-indole: (63%) from (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole (Example 1a).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][CH:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8].[OH-].[Na+].[C:18](OC(=O)C)(=[O:20])[CH3:19]>O>[CH3:8][CH:7]([NH:6][C:18](=[O:20])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(N)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C)Cc1ccccc1

Procedure:
Seventy three and six tenths g (0.2 moles) of rac. amphetamine sulfate was suspended in 150 ml of water and to the stirred suspension, a solution of twenty g (0.5 moles) of sodium hydroxide in 200 ml of water was added. The liberated oil was collected by three extractions with 200-ml portions of toluene. The combined extracts were dried over anhydrous K2CO3, then the drying agent removed by filtration. To the filtrate, 100 ml of acetic anhydride (1.0 mole) was added in portions and the resulting solution refluxed for two hours. The toluene, excess anhydride and acetic acid were distilled in the rotary evaporator and the residual oil distilled in a simple Claisen still collecting the fractions that boiled at 120°-126°/7 mm, yield 63.3 g (89%) of a colorless oil that spontaneously set to a mass of crystals, mp 91°-93°.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1.O>O1CCOCC1>[CH:5]([NH:8][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1)([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.25 mL, 2.0 mmol) was added dropwise (exothermic) to a solution of isopropylamine (210 μL, 2.0 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. Then 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol) was added. The resulting mixture was then heated at 90° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:4) afforded the title compound (170 mg, 78%) which was obtained as a white solid after trituration from diisopropylether/ethyl acetate. MS: m/e=348.3 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:34])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:34])[NH:15][C:9]=2[CH:10]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M47) (270 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (129 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([CH:15]1[CH2:20][S:19][C:18]([CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]2)([CH3:21])[S:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([CH:15]1[CH2:16][S:17][C:18]([CH:22]2[CH2:23][CH2:24][CH:25]([CH:28]=[O:29])[CH2:26][CH2:27]2)([CH3:21])[S:19][CH2:20]1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C1CSC(C)(C2CCC(CO)CC2)SC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C1CSC(C)(C2CCC(C=O)CC2)SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl sulphoxide (376 μl.) in dichloromethane (2 ml.) was added over 5 minutes to a solution of oxalyl chloride (210 μl.) in dichloromethane (3 ml.) at -70° C. After stirring for a further 5 minutes a solution of 5-t-butyl-2-(4-hydroxymethylcyclohexyl)-2-methyl-1,3-dithiane (650 mg.) in dichloromethane (2 ml.) was added. The reaction mixture was stirred for 30 minutes. Triethylamine (1.5 ml.) was added and the mixture allowed to warm to 25° C. over 3 hours. Water (25 ml.) was added and the crude product obtained by dichloromethane extraction. After washing with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine and then drying over anhydrous magnesium sulphate the solution was evaporated to give 5-t-butyl-2-(4-formylcyclohexyl)-2- methyl-1,3-dithiane as a gum.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([OH:25])CO)=[CH:18][C:17]=3[CH3:26])[N:12]=2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].C1COCC1.O>[Cl-].[Na+].O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[O:25])=[CH:18][C:17]=3[CH3:26])[N:12]=2)=[CH:7][C:6]=1[C:27]([F:28])([F:29])[F:30])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(O)CO)ccc1-c1noc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C=O)ccc1-c1noc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A solution of 49 mg (0.12 mmol) of 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)ethane-1,2-diol and 37 mg (0.17 mmol) of sodium periodate in 9 mL of 2:1 v:v THF/H2O mix solvent. After stirring at rt for 4 h, the mixture was poured into brine and extracted with EtOAc (3×10 mL). Organic layers were combined, dried over MgSO4, and concentrated. Chromatography on Biotage 40S cartridge using 1:9 v/v EtOAc/hexanes as the eluant afforded 40 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.44 (d, J=5.9, 6H), 2.78 (s, 3H), 4.79 (m, 1H), 7.16 (d, J=9.0, 1H), 7.84-7.86 (m, 2H), 8.28 (d, J=8.5, 1H), 8.32 (dd, J=2.2, 8.9, 1H), 8.44 (d, J=2.1, 1H), 10.09 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:21][CH:20]=2)[CH2:10][CH2:9][CH2:8]1)[CH2:3][CH:4]1[CH2:6][O:5]1.FC(F)(F)C(O)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:23][CH:24]=2)[CH2:10][CH2:9][CH2:8]1)[CH2:3][CH:4]([OH:39])[CH2:6][OH:5]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC3CO3)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC(O)CO)c3ccccc32)cc1
Reaction time: 4 h

Procedure:
To 5-(N-methyl-N-oxiranylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.62 g) is added trifluoroacetic acid (1.22 ml) under ice-cooling and the mixture is stirred for 4 hours. The reaction solution is neutralized with aqueous sodium carbonate solution, and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is dissolved in methanol (10 ml). Thereto is added 40% aqueous sodium hydroxide solution (10 ml) and water (10 ml), and the mixture is stirred at room temperature overnight. Methanol is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-[N-methyl-N-(2,3-dihydroxypropyl)amino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as colorless amorphous.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:44][C:45]1[N:46]=[CH:47][S:48][CH:49]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]=2[N:3]1[CH2:44][C:45]1[N:46]=[CH:47][S:48][CH:49]=1
Reactant: ClCc1cscn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3cscn3)C(=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.106 mmol), potassium carbonate (59 mg, 0.424 mmol) and 4-(chloromethyl)thiazole HCl salt (54 mg, 0.318 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at 80° C. for one hour. The reaction mixture was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 0:100) to give the desired product as an off-white solid (54 mg, 90% yield). 1H-NMR (500 MHz, CDCl3) δ 8.70 (1H, s), 7.61 (1H, s), 7.28 (1H, s), 7.12-7.27 (7H, m), 7.03-7.12 (2H, m), 5.23 (2H, s), 4.99 (1H, br s), 4.86 (2H, s), 2.10-2.60 (4H, m), 2.41-2.06 (1H, m), 1.65-1.79 (1H, m), 1.00-1.45 (9H, br m). LCMS (Method A) RT=7.11 min, M+H+=569.14.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:39])[C@@H:28]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[CH3:40][NH2:41]>O1CCCC1>[CH3:38][N:30]([C@@H:28]([CH3:29])[C:27]([NH:26][CH2:25][CH2:24][CH2:23][C:22]#[C:21][C:14]1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[N:16][C:11]([NH:41][CH3:40])=[N:12][CH:13]=1)=[O:39])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCNc1nc(On2nnc3ccccc32)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reactant: CN
Solvent: C1CCOC1
Product: CCCNc1nc(NC)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To (S)-tert-butyl (1-((5-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (K3, 50 mg), a 2.0 mol/L solution of methylamine in tetrahydrofuran (1 mL) was added at room temperature, the reaction vessel was sealed, and then the mixture was stirred at 50° C. for 5 hours by using a microwave reaction system. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 40 to 0% hexane in ethyl acetate) to obtain oily (S)-tert-butyl methyl(1-((5-(2-(methylamino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)carbamate (K4, 35 mg).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:16][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])([C:12]([F:13])([F:14])[F:15])[C:8]([F:11])([F:10])[F:9])=[O:28]
Reactant: C=C(F)C(=O)Cl
Reactant: Cc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccccc1C)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 21 g (0.081 mol) of 2-tolylhexafluoro-2-propanol and 8.2 g (0.08 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 9.8 g (0.09 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 40 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 4 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.02 g of hydroquinone monomethyl ether. 19.6 g (73 percent of theory) of 2-tolylhexafluoro-2-propyl α-fluoroacrylate having a boiling point of 58° to 60° C. (under 0.27 mbar) were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[S:27][C:26]([C:28]([O:30]C)=[O:29])=[CH:25][CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:32])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 40.2 %

Procedure:
Methyl 5-[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-thiophenecarboxylate (16.0 mg, 0.035 mmol) in methanol (1.5 mL) was stirred with 1 M aqueous sodium hydroxide (176 μL, 0.176 mmol) at room temperature for 17 hours. After the stirring, 1 M hydrochloric acid (176 μL, 0.176 mmol) was added, and the precipitated solid was recovered by filtration to give 6.2 mg of the desired product as yellow crystals (yield 40%).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][C@H:6]([C:10]([O:12]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:11])[CH2:7]2)[O:3]1>[Pd].CC(C)=O>[O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][C@H:6]([C:10]([OH:12])=[O:11])[CH2:7]2)[O:3]1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@H]1C[C@@H]2CN(C1)C(=O)O2
Agent: [Pd]
Solvent: CC(C)=O
Product: O=C(O)[C@H]1C[C@@H]2CN(C1)C(=O)O2

Procedure:
320 mg of the compound obtained in Example 12a, 17 ml of acetone and 70 mg of Pd/C catalyst at 20% by weight are mixed together.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:13][CH2:2][CH2:3][N:4]=2)=[CH:11][CH:10]=1
Reactant: O=C(NCCO)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1ccc(C2=NCCO2)cc1

Procedure:
To a slurry of 18.10g (0.1 moles) of N-(2-hydroxy-ethyl)-p-hydroxybenzamide in 100 ml of ethyl acetate was added a solution of 23.80g (0.2 moles) of thionyl chloride in 25 ml of ethyl acetate. Thionyl chloride addition was slow enough to maintain the reaction temperature below 50° C. After 2 hours at room temperature the precipitate was collected by vacuum filtration and then dissolved in 200 ml of water. The solution was neutralized with 5% sodium hydroxide solution. The white precipitate which formed was collected by vacuum filtration and then dried in a vacuum oven at ≈70° C. overnight. This material was identified by NMR and IR spectroscopy as the desired 2-(p-hydroxyphenyl)-oxazoline. An 87% yield was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:22][CH2:21][CH2:20][OH:23])=[O:18])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Reactant: OCCO
Solvent: O
Product: COC(=O)CCCCCOc1ccc(NC(=O)OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
6-(4-Isocyanato-phenoxy)-hexanoic acid methyl ester 36 (15 g, 57 mmol) was added to ethylene glycol (50 ml) at room temperature. The reaction was exothermic and the temperature rose to 46° C. The reaction mixture was allowed to cool to room temperature and later stirred at room temperature for 16 hours. Water (150 ml) was added and crude 37 was filtered, dried and recrystallised from toluene to get pure 37 (12 g, 84%) as a white powder. M.p: 69.5-71.5° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[CH2:21][O:22][CH3:23])[CH:16]=[C:15]([CH:24]=O)[CH:14]=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C>CCOC(C)=O.[Pd]>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH3:24])[CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: COC/C=C/c1cc(C=O)cc(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(C)cc(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl cyclopropyl{3-formyl-5-[(1E)-3-methoxy-1-propen-1-yl]benzyl}carbamate (1 eq.) from the previous step and 10% w/w palladium over charcoal (0.1 eq.) were suspended in EtOAc (0.1 M). The vessel was then evacuated and purged with H2. Under a balloon-filled H2 atmosphere, the reaction suspension was stirred at RT for 3 h. The reaction suspension was then quenched with dichloromethane and filtered through a bed of celite. Concentration of the filtrate in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7](=O)[NH:6][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(Cl)(Cl)=O.C[N:22](C)C=O>>[NH2:22][C:7]1[N:6]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]=1[Br:1]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nc(C2CC2)[nH]c(=O)c1Br
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C2CC2)nc(N)c1Br
Temperature: 125 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-bromo-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidine-carboxylate (i.e. the product of Step B) (1.07 g, 3.7 mmol) in N,N-dimethylformamide (15 mL) was added thionyl chloride (0.54 mL, 7.5 mmol). The reaction mixture was stirred for 2 h. The solvent was removed with a rotary evaporator. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate and dried (Na2SO4). The solvent was removed with a rotary evaporator. The residue was dissolved in tetrahydrofuran (2 mL), and a methanolic solution of ammonia (7 N, 2 mL) was added. The reaction mixture was placed in a sealed vial and heated in a microwave reactor at 125° C. for 2 h. The reaction mixture was allowed to stand over the weekend. Dichloromethane was added and the reaction mixture was filtered. The solvent was removed with a rotary evaporator. The residue was purified by MPLC (10→30% ethyl acetate in hexanes as eluant) to afford the title product, a compound of the present invention, as a white solid (0.52 g).
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.[CH3:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1>>[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:33]1[C:32](=[O:36])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][CH:22]=3)=[CH:30][CH:29]=2)[CH:35]=[N:34]1)[CH3:12]
Reactant: Cc1nc(-c2ccc(-n3cn[nH]c3=O)cc2)cs1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: Cc1nc(-c2ccc(-n3cnn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)cs1

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(2-methyl-4-thiazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-thiazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 31).