Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -10 °C

Procedure:
Ethyl 2,2-di(tertiary-butylperoxy)-1-cyclohexanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (24.41 g, 0.2500 moles) to 95% ethyl 2-oxo-1-cyclohexanecarboxylate (17.92 g, 0.1000 moles) at room temperature in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled to −10° C. via a dry ice-acetone bath and 78% sulfuric acid (15.09 g, 0.1200 moles) added dropwise to the solution with temperature at −10° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4 and filtered through a Buchner funnel to give a resulting peroxide (24.92 g, 74.92%). The resulting peroxide crystallized and was subsequently re-crystallized with hexanes, analyzed for purity by Gas Chromatography, as presented in Example 1, (95% by area) and it's 10 hr half life temperature was determined to be 93.31° C. by G.C.: m.p. 36-38°; 13C NMR (75 MHz, CDCl3) δ 171.8 (C═O), 106.1 (O—C—O, cyclic), 79.0 (C(CH3)3), 78.9 (C(CH3)3, 59.5 (CH2CH3), 44.3 (CH, Cyclic), 27.6 (CH2, cyclic), 26.3 ((CH3)3), 26.2 ((CH3)3), 2.17 (CH2, cyclic), 21.4 (CH2, cyclic), 13.8 (CH3CH2—O); IR (NaCl, CHCl3) ν 1735, 1370, 1200, 880 Cm−1; Analysis calculated for C17H32O6: C, 61.42; H, 9.70; O, 28.88; found: C, 61.05; H, 9.82: O, 28.22.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][C:24]=4[F:35])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[F:35][C:24]1[CH:25]=[C:26]([C:29]2[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=2)[CH:27]=[CH:28][C:23]=1[C:20]1([C:17]2[N:13]3[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]3=[N:19][N:18]=2)[CH2:21][CH2:22]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)c(F)c2)cn1
Yield: 69.1 %

Procedure:
A solution of the compound (368 mg, 0.70 mmol) obtained in Example 80-1) and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (200 mg, 69%) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:21]#[N:22])([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>>[C:21]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])#[N:22]
Reactant: CCOC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Reactant: CNCCc1cccc(C(=O)OC)c1
Product: CCOC(=O)C(C#N)(CCCN(C)CCc1cccc(C(=O)OC)c1)c1ccc(OC)c(OC)c1

Procedure:
Reaction of 1c with 2d produced 3u. MS found M+H=483. The oxalate salt of 3u was recrystallized from ethyl acetate; mp 89-91° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18](O)=[O:19])=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:28][CH:27]=1>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:19][N:36]=[C:25]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([NH2:33])(=[O:34])=[O:35])=[CH:30][CH:31]=5)[N:24]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)cc1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (heptane/diethyl ether) as an off-white solid (186 mg, 77%). MS (ISP) 486.3 [(M+H)+]; mp 288° C.
Reaction SMILES: [C:1]1([CH:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>C(N(CC)CC)C>[C:1]1([CH:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)N1CC(CO)OC1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CN(C(C)(C)C)C(c3ccccc3)O2)cc1

Procedure:
To a solution of dl-2-phenyl-3-t-butyl-5-hydroxymethyloxazolidine (12.05 g.) in triethylamine (120 ml.) 13 is added p-toluenesulfonylchloride (14.5 g.). After 6 days at room temperature the mixture is added to water (500 ml.) and extracted with ether (2×200 ml.). The ether solution is washed with water, dried with anhydrous magnesium sulfate and evaporated to dryness. The residue is recrystallized from hexane to afford 2-phenyl-3-t-butyl-5-p-toluenesulfonyloxymethyloxazolidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[C:11](=[O:20])[CH2:10][CH2:9]2.C([O:25][N:26]=O)CCC.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[C:11](=[O:20])[C:10](=[N:26][OH:25])[CH2:9]2
Reactant: CCCCON=O
Reactant: COCCOc1cc2c(cc1OCCOC)C(=O)CC2
Agent: Cl
Solvent: CO
Product: COCCOc1cc2c(cc1OCCOC)C(=O)C(=NO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of 5,6-Bis-(2-methoxy-ethoxy)-indan-1-one (2.6 g, 9.28 mmol) in the methanol (20 ml) was added n-butylnitrite (1.25 ml, 10.2 mmol) followed by concentrated HCl (0.8 ml). The solution was stirred at room temperature overnight during which time a precipitate was formed. The precipitate was collected and dried to yield product as a yellow solid (1.11 g, 38.58%). LC-MS: m/e 310 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:15][CH2:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18]>ClC1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:20][CH2:19][N:17]([CH3:18])[CH2:16][CH2:15]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccccc1N
Reactant: CN(CCCl)CCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: CCCCOc1ccccc1N1CCN(C)CC1
Yield: 99 %

Procedure:
A stirred solution of 2-butoxybenzenamine (6.50 g) in chlorobenzene (50 ml) was treated with 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (7.70 g) according to the method of Intermediate 40. Concentration in vacuo of the dichloromethane extracts gave the title compound as a red oil (9.67 g).
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].C([B-](F)(F)F)=C.[K+].Br[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:28]([CH2:34][CH2:35][CH3:36])=[N:27][C:21]=3[C:22]([NH2:26])=[N:23][C:24]=2[CH:25]=1.[OH-].[Na+]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:32][CH:31]([CH3:33])[CH2:30][N:29]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([CH:1]=[CH2:2])=[CH:25][C:24]=3[N:23]=[C:22]([NH2:26])[C:21]=2[N:27]=[C:28]1[CH2:34][CH2:35][CH3:36]
Reactant: CCN(CC)CC
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCCO
Solvent: O
Product: C=Cc1ccc2c(c1)nc(N)c1nc(CCC)n(CC(C)C)c12

Procedure:
Triethylamine (3.0 equivalents), potassium vinyltrifluoroborate (1.0 equivalent) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.2 equivalent) were added to a solution of 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 equivalent) in n-propanol (30 ml/g). The reaction mixture was heated at reflux under a nitrogen atmosphere until it was complete (between four and 18 hours) and then poured into water (3 volumes). The pH of the mixture was monitored and adjusted to pH 12 with the addition of 10% aqueous sodium hydroxide if needed. The mixture was extracted with ethyl acetate, and the combined organic fractions were filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10), followed by recrystallization from acetonitrile to provide 1-(2-methylpropyl)-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:12][C:6]1[N:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([NH:1][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1
Temperature: 30 °C
Yield: 58.4 %

Procedure:
To a solution of 2-amino-7-chloro-1,8-naphthyridine (5.4 g) in pyridine (60 cc), benzoyl chloride (4.2 g) is added slowly, maintaining the temperature in the region of 30° C. After the solution has been maintained for 3 hours at a temperature in the region of 20° C., the product is precipitated in distilled water (340 cc). The solid produced after drying in the air is dissolved in boiling ethanol (88 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×5 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)benzamide (4.95 g) is thus produced, m.p. 198° C. EXAMPLE 9
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O.C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=1)=[O:19])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C(=O)c1ccc(OC)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A suspension of NaH (12.8 mmol, 512 mg) in DMSO (23 mL) was added 4′-methoxy-2-phenylacetophenone (12.8 mmol, 2.89 g) in 10 ml toluene dropwise under argon. After 30 minutes of stirring, ethyl bromoacetate (1.4 mL, 1 eq.) in 10 mL of toluene was added and the mixture was stirred at rt overnight. The reaction was quenched by addition of 2N HCl (4 mL), and then 60 mL of water. The mixture was extracted with CH2Cl2 (3×30 mL), dried over MgSO4 and concentrated under vacuum overnight to afforded 4.0 g (99%) of 4-(4-methoxy-phenyl)-4-oxo-3-phenyl-butyric acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2].[OH-].[Na+]>CCO>[CH3:9][C:8]1[C:3]2[C:1]([NH2:2])=[N:14][S:11](=[O:13])(=[O:12])[NH:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NS(N)(=O)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2-cyano-3-methylphenyl)sulfamide (Example 24a) (211 mg, 1.0 mmol) in EtOH was treated with NaOH (2.0 N, 1.0 mL, 2.0 mmol) and the resultant solution was heated to 100° C. and stirred at that temperature for 0.5 h. After cooling to room temperature, the clear reaction solution was filtered and the filtration was carefully neutralized with 10% AcOH while with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, washed with warm water and 20% EtOH in water to give the title product 5-Methyl-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ2.59 (s, 3H), 6.85-6.87 (d, J=8.4 Hz, 1H), 6.92-6.94 (d, J=7.2 Hz, 1H), 7.24 (s, 1H), 7.37 (t, J=7.6 Hz, 1H), 8.24 (s, 1H), 10.76 (s, 1H). MS 212 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:28][C:29]1[NH:30][CH:31]=[CH:32][N:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:28][C:29]4[N:33]([C:14]=2[CH2:15]3)[CH:32]=[CH:31][N:30]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3nccn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 2-aminoimidazole sulfate.
Reaction SMILES: [CH3:1]/[C:2](/[C:5]1[N:10]=[C:9]2[O:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13]([C:14](=[O:17])[NH:15][CH3:16])[C:8]2=[CH:7][C:6]=1[C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:3]\[CH3:4]>CCO.[Pd]>[CH:2]([C:5]1[N:10]=[C:9]2[O:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13]([C:14](=[O:17])[NH:15][CH3:16])[C:8]2=[CH:7][C:6]=1[C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])([CH2:3][CH3:4])[CH3:1]
Reactant: C/C=C(\C)c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Pd/C (50 mg, 0.047 mmol, 10%) was added to a stirring solution of (E)-tert-butyl 3-(6-(but-2-en-2-yl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (118 mg, 0.236 mmol) in EtOH (4.7 ml) at rt. The reaction was placed in a Parr bomb and charged with 50 PSI of H2 and the mixture was allowed to stir for 16 h at rt. Celite was added to the reaction mixture and the slurry was filtered through a pad of Celite washing with EtOAc. The filtrate was concentrated to give the expected product tert-butyl 3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (118 mg, 0.235 mmol, 100% yield) consistent by LCMS. LC-MS retention time: 2.38 min; m/z (MH+): 503. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 2 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: CCCCCC.S(Cl)([Cl:10])(=O)=O.[CH2:12]([N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]1[NH:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C:37]([F:40])([F:39])[F:38])[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+]>CCOCC.C(O)(=O)C>[CH2:12]([N:15]1[C:20](=[O:21])[C:19]([Cl:10])=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]=[C:16]1[NH:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C:37]([F:40])([F:39])[F:38])[CH:13]=[CH2:14]
Reactant: C=CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(=O)O
Product: C=CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Reaction time: 1 h
Yield: 86.3 %

Procedure:
At room temperature, hexane solution of sulfuryl chloride (1.2 M, 0.56 ml, 0.67 mmol) was added to a mixture of 3-allyl-2-(2,5-bis(trifluoromethyl)phenyl)amino-6-trifluoromethyl-4-(3H)-pyrimidinone (0.29 g, 0.67 mmol) and acetic acid (6 ml), followed by stirring for 1 hour. After completion of the reaction, ether (30 ml) and saturated sodium bicarbonate aqueous solution (10 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (20 ml×2). The organic layers were combined, washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under a reduced pressure from the resulting filtrate. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=3:1), 3-allyl-2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 67] was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 33) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a white solid as a mixture of diastereomers (2.01 g, 94%); ES+-HRMS m/e calcd for C28H33N5O5F2 [M+H+] 558.2523 found 558.2521. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.80-1.19 (m, 6H) 1.23 (s, 3H) 1.29 (s, 3H) 1.61 (br s, 5H) 1.75-1.91 (m, 1H) 2.06-2.21 (m, 1H) 3.71 (dd, J=8.5, 5.8 Hz, 1H) 3.90-4.21 (m, 3H) 4.33 (quin, J=5.8 Hz, 1H) 5.52 (dd, J=10.9, 3.9 Hz, 1H) 6.02 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.28-7.54 (m, 3H) 7.57 (d, J=2.1 Hz, 1H) 8.27 (d, J=2.7 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:8][C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([OH:3])=[O:2].[OH:20]O>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:8](=[O:20])[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1S2
Reactant: OO
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1S2=O
Reaction time: 8 h

Procedure:
3-Carboxythianthrene-5,5-dioxide ((60 mg), acetic acid acid (2.0 ml) and 30% hydrogen peroxide (0.10 ml) were boiled under reflux for 10 mins., filtered and allowed to stand overnight at 0° C. 3-Carboxythianthrene-5,5,10-trioxide crystallised out, was filtered off and dried at 156° C. at 2mm. Hg, m.p. 340°-343° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>C(=S)=S>[C:19]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 3.00 g (16.6 mM) of 9,10-dihydrophenanthrene in 40 ml of dry carbon disulfide, 2.73 g (20.5 mM) of anhydrous aluminum chloride was added while being cooled on an ice-common salt bath. Under cooling on the bath, 1.27 ml (17.9 mM) of acetylchloride was gradually added dropwise to the mixture at -4° to -2° C., followed by stirring for 1 hour and 30 minutes at room temperature without cooling on the bath. After the reaction, the reaction mixture was poured into a mixture of 50 g of ice and 15 ml of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and distilled-off the solvent under reduced pressure to obtain 3.57 g of oily 2-acetyl-9,10-dihydrophenanthrene (Yield: 96.5%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C(F)(F)F)c1

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 0.705 ml of 3-(trifluoromethyl)aniline in place of the 2-fluoroaniline. 228 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(trifluoromethyl)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[C:6]2[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C:5]=12)(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[C:1]([C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[C:6]2[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C:5]=12)#[N:2]
Reactant: CC(C)(C)OC(=O)N1Cc2nn(COCC[Si](C)(C)C)c(C(N)=O)c2C1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2nn(COCC[Si](C)(C)C)c(C#N)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the product obtained in Step D (500 mg, 1.307 mmol) in DMF (10 mL) was added cyanuric chloride (482 mg, 2.61 mmol). The resulting mixture was stirred at RT under N2 overnight, quenched with saturated NaHCO3 and extracted with EtOAc (2×100 mL). The organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on a silica gel Biotage 40S® column, eluting with 0 to 20% ethyl acetate in hexanes to give the title compound as a colorless gum. LC-MS: 265.1 (M-Boc).