Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>C(O)CO.[S]>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20]([OH:1])=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [S]
Solvent: OCCO
Solvent: O
Product: Oc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A solution of 4.76 g (85.3 mmol) of potassium hydroxide in 20 ml of ethylene glycol is added dropwise over the course of 2 hours at 180° C. to 7.26 g (21.3 mmol) of 2-(3-benzyloxyphenyl)-5-bromopyrimidine and 0.035 g (1.08 mmol) of sulfur in 60 ml of ethylene glycol. The mixture is kept at 180° C. for a further 3 hours, poured into water and acidified by means of 37% strength hydrochloric acid, and the solid which precipitates is isolated by filtration. Purification by chromatography (silica gel/hexane: ethyl acetate=32) gives 4.77 g of 2-(3-benzyloxyphenyl)-5-hydroxypyrimidine. ##STR28##
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([CH2:12][C:13]#[N:14])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][C:23]#[N:24].O>O1CCCC1>[NH2:24][C:23]1[N:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C:12]([C:13]#[N:14])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1
Reactant: N#CC=C(Br)c1ccccc1
Reactant: N#CCc1n[nH]c(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccccc2)cc(N)n2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.2 %

Procedure:
A solution of 0.18 g (0.001 mol) 5-phenyl-1H-1,2,4-triazole-3-acetonitrile in 7 ml tetrahydrofuran was treated at −70° C. with 1.56 ml (0.0025 mol) butyllithium (1.6 M in hexane). After one hour 0.21 g (0.001 mol) 3-bromo-3-phenyl-2-propenenitrile was added, stirring was continued for one hour, the mixture warmed to room temperature over night and water was added. Extraction with diethylether, chromatography on silicagel with dichloromethane/methanol 99/1 and crystallisation from diethylether gave 3.6 mg 5-amino-2,7-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitril as white cystals. MS m/e (%): 312 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[CH3:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1c([N+](=O)[O-])cnc(Cl)c1[N+](=O)[O-]
Product: Cc1c([N+](=O)[O-])cnc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-4-methyl-3,5-dinitropyridine. (Czuba, Rocz. Chem., 1967, 41, 479) and 4-aminophenylethyl alcohol.
Reaction SMILES: ClC1C=CC=C2C=1CCN2[C:11]([O:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:17][Cl:18])[CH:12](CC=O)O.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH2:23]([N:22]1[CH2:21][CH2:20][O:19][CH:11]([CH2:17][Cl:18])[CH2:12]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=CCC(O)C(CCl)(OCCNCc1ccccc1)N1CCc2c(Cl)cccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCC1CN(Cc2ccccc2)CCO1
Temperature: 150 °C
Yield: 54 %

Procedure:
41.25 g of 2-[2-(4-chloro-2,3-dihydroindol-1-yl)-2-oxoethyl-2-(2-benzylaminoethoxy)-3-chloropropan-1-ol previously obtained are placed in a 250 ml round-bottomed flask equipped with a condenser, and then 50 ml of concentrated sulfuric acid (d=1.84) are added dropwise. The temperature increases, and the water formed condenses in the condenser. The reaction medium is then heated for one hour at 150° C., then cooled to ambient temperature (20° C.), before being poured slowly onto ice; the reaction medium is brought to pH=10 with 40% NaOH, and then extracted with toluene (2×150 ml), and the organic phases are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. 4-Benzyl-2-chloromethylmorpholine is isolated (20.30 g, light brown oil, yield=54%) and is used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)=[O:10])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1cccc(Cl)n1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cccc(Cl)n3)CC2)nn1

Procedure:
Following the procedure of Example 14, making variations only as required to use 6-chloropyridine-2-carboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white flaky solid (12% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.87, 7.82, 7.70, 7.43, 7.00, 3.80-4.00, 3.50, 1.70, 1.53, 0.95. MS (ES+) m/z 417 (M+1).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:9]1[CH2:10][C:11]1[C:23](OS(C(F)(F)F)(=O)=O)=[CH:22][CH:21]=[CH:20][C:12]=12)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:19][C@:13]12[C:16]([CH3:17])([CH3:18])[C@H:9]([NH:8][CH2:15][CH2:14]1)[CH2:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]2=1
Reactant: CC1(C)[C@H]2Cc3c(OS(=O)(=O)C(F)(F)F)cccc3[C@]1(C)CCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)[C@H]2Cc3ccccc3[C@]1(C)CCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Pd/C (0.20 g) is added to a solution of (2R,6S)-trifluoro-methanesulfonic acid 3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-yl ester (0.50 g) in ethanol (10 mL). The resulting mixture is shaken under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst is separated by filtration and Pd(OH)2 (0.2 g) is added to the filtrate (the benzyl group was not completely removed after the treatment in the presence of Pd/C). The mixture is shaken for another 16 h in hydrogen atmosphere (50 psi) at room temperature. The catalyst is separated and the filtrate is concentrated under reduced pressure to give the crude product that is used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Cl:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH2:23]([O:22][C:20]([C:19]1[C:18]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[Cl:9])=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Br)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc(F)cc1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 125.6 %

Procedure:
To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g), toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g), and purged with argon. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixture was stirred in an oil bath at 110° C. for 3 hr. The oil bath was removed, and water (125 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hr, and filtered through celite. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene, and the organic layers were combined. The organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (41.8 g). The obtained solid was directly used for the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.[CH2:33]([O:35][C:36]([C:38]1([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][CH:42]=2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([C:38]1([C:41]2[CH:46]=[CH:45][C:44]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([N:16]4[CH2:21][CH2:20][N:19]([S:22]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=5)(=[O:23])=[O:24])[CH2:18][CH2:17]4)=[O:15])=[CH:4][CH:3]=3)=[CH:43][CH:42]=2)[CH2:39][CH2:40]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)N1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)N4CCN(S(=O)(=O)c5ccc(Cl)c(Cl)c5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[4-(3,4-dichloro-benzenesulfonyl)-piperazin-1-yl]-methanone and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>ClCCl>[C:17]([O:14][CH2:13][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane solution containing 2.52 g (0.011 mol) 2-carbobenzoxyamino-2-methyl-1-propanol and 1.17 g (0.015 mol) acetyl chloride was added dropwise with stirring 1.11 g (0.011 mol) triethylamine. The reaction was stirred at ambient temperature overnight and the dichloromethane was removed under reduced pressure. The triethylamine hydrochloride residue was triturated in anhydrous ether. Following filtration, the ether was removed under reduced pressure to afford 2.38 g (0.009 mol), 82%, crude 2-carbobenzoxyamino-2-methyl-1-propyl acetate as a pale yellow liquid, pmr (CDCl3) δ 7.2 (s, 5H), 5.4 (bs, 1H), 5.0 (s, 2H), 2.0 (s, 3H) and 1.2 (s, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(F)c([N+](=O)[O-])c2)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium (I g) was added to a mixture of 5 g of 4methoxyphenylboronic acid, 6.6 g of 5-bromo-2-fluoronitrobenzene and 30 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried, and concentrated to give a brown oily solid. The solid was chromatographed on silica gel (5% ethyl acetate in hexane) to give crude 4-fluoro-4′-methoxy-3-nitrobiphenyl as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11]O)[CH2:2][CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:32]I.N1C=CN=C1>ClCCl>[I:32][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1ccccc1CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccccc1CCI
Temperature: 30 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Into a 50-mL round-bottom flask was placed 2-(2-propylphenyl)ethan-1-ol (240 mg, 1.46 mmol, 1.00 equiv), PPh3 (498 mg, 1.90 mmol, 1.30 equiv), I2 (446 mg), imidazole (129 mg) and dichloromethane (20 mL). The resulting solution was stirred for 16 h at 30° C. The reaction was then quenched by the addition of 100 mL of NaHSO3 (aq.). The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). Purification afforded 200 mg (50%) of 1-(2-iodoethyl)-2-propylbenzene as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1>>[CH3:29][O:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][NH:18][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCCOc1ccc(-c2ccnc(Cl)n2)cc1
Product: CCCOc1ccc(-c2ccnc(NCCc3ccc(O)c(OC)c3)n2)cc1

Procedure:
Intermediate 50 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 380. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.0 (d, 1H), 7.1-7.0 (m, 4H) 6.8 (s, 1H), δ 6.7-6.6 (m, 3H), δ 4.0 (t, 2H), δ 3.7 (s, 3H), 3.5 (t, 2H), δ 2.7 (t, 2H), δ 1.8-1.7 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:35].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:28][CH2:29][S:30](=[O:35])[CH2:31][CH2:32]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCSCC2)cc1Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCS(=O)CC2)cc1Cl
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.1 g, 0.2 mmol) in methanol (20 mL) at 0° C. was added a solution of potassium peroxymonosulfate (0.13 g, 0.2 mmol) in water (5 mL). After 5 minutes, the reaction was quenched by addition of aqueous 5% sodium bisulfite solution. The mixture was extracted with methylene chloride/methanol, and the organic phase dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.064 g (62% yield) of N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a pale yellow powder; NMR (DMSO-d6/TFA) 11.2 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (m, 2), 7.6 (m, 1), 7.4 (m, 3) 4.7 (s, 2), 3.7 (m, 2), 3.5 (m. 2), 2.9 (br s, 4) ppm.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19]>>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[S:3][CH:4]=2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1ccc(-c2csc(Br)n2)cc1
Product: CC(C)(CO)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 175 °C
Yield: 68.2 %

Procedure:
2-Bromo-4-(4-nitrophenyl)-1,3-thiazole (1.0 g, 3.5 mmol), prepared in the previous step, and 2-amino-2-methyl-propan-1-ol (2.0 mL, 21.0 mmol) were placed in a sealed tube and heated to 175° C. for 18 h. The crude product was pre-adsorbed onto silica gel and purified using a stepwise gradient of 1-5% methanol:methylene chloride to give 2-{[4-(4-nitrophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (700 mg, 69%), MS (ES) m/z 294[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(OCC)(=O)C.C1COCC1.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(F)cn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of 5-fluoropyridine-2-carbaldehyde (18.49 g, 148 mmol) in ethyl acetate (850 mL), THF (250 mL) and hexanes (300 mL) were added (R)-(+)-2-methyl-2-propanesulfinamide (19.71 g, 163 mmol) and anhydrous copper(II) sulfate (59.0 g, 370 mmol). The mixture was stirred at ambient temperature. After 18 h, the mixture was filtered through Celite. The filtered cake was washed with ethyl acetate and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane 98% dichloromethane/methanol) gave the title compound (33.7 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:16])=[N:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[BrH:17]>>[BrH:17].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH3:16])=[N:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c[nH]c(=O)nc2C)cc1
Agent: Br
Product: Cc1nc(=O)[nH]cc1-c1ccc(O)cc1
Temperature: 0 °C

Procedure:
1.5 g of 5-(4-methoxyphenyl)-4-methyl-2-(1H)-pyrimidinone are heated with 12.5 ml of 47% hydrobromic acid at 100° C. for 24 hours. The mixture is then cooled to 0° C., and the product which has crystallised out is filtered off with suction and washed with cold ethanol. 1.3 g of 5-(4-hydroxyphenyl)-4-methyl-2-(1H)-pyrimidinone hydrobromide are obtained. Melting point above 300° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1)#[CH:2].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.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>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](\[C:20]2[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]3[S:4][C:5]([CH3:8])=[CH:6][CH:7]=3)=[CH:18][CH:19]=2)/[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Reactant: C#Cc1ccc(C)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(C)s3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Ethynyl-5-methylthiophene (176 mg, 1.442 mmol) and diisopropylamine (0.475 mL, 3.39 mmol) were added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (420 mg, 0.721 mmol; prepared as described in example 34) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (11.0 mg, 0.0576 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25.3 mg, 0.0361 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 19:1) yielding methyl (E)-[2-methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]phenoxy]acetate as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].C(N(C(C)C)C(C)C)C>O1CCCC1>[CH2:28]([N:30]([CH2:31][CH3:32])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])[CH3:29]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CCNCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), diethylamine (250 ul, 2.42 mmole), N-ethyldiisopropylamine (282 ul, 1.62 mmole) and propylphosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (5 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4,N4-diethyl-1-methyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (140 mg, 81.3%) as a white solid. Mp.: 165-7° C. MS: m/z=427.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:22]([NH2:21])=[S:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A solution of 2 g (11.47 mmol) (3-Amino-propyl)-carbamic acid tert-butyl ester in 20 ml THF was treated with 1.62 ml (11.47 mmol) Benzoyl isothiocyanate and stirred for 1 h at room temperature. After removal of the volatiles the residue was suspended in 50 ml methanol and 4.8 g (34.4 mmol) K2CO3 in 50 ml water was added. The mixture was stirred at room temperature for 16 h, concentrated, and extracted with ethyl acetate. The combined organic layers were washed with NaHCO3 sat., brine, dried with MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate/heptane. The combined product fractions were evaporated under reduced pressure to yield 1.48 g (74%) of the title compound.