Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 72.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 1.15 ml (4.96 mmol) of lauroyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.05 g of the desired compound (72.2%, colorless powder), mp: 71.0°-72.0° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([CH3:15])[CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C@H:17]1[O:22][C@@H:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:23][C@H:21]1[O:22][C@@H:17]([CH3:16])[CH2:18][N:19]([CH2:13][C@H:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:15])[CH2:20]1
Reactant: C[C@H](CCl)Cc1ccc(C(C)(C)C)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H](Cc1ccc(C(C)(C)C)cc1)CN1C[C@@H](C)O[C@@H](C)C1

Procedure:
The reaction of (a) with cis-2,6-dimethylmorpholine gives the known (S)-fenpropimorph.
Reaction SMILES: BrC1C=CC(Br)=CC=1C1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)=[N:12][N:13]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33]([NH:13][NH:12][C:11](=[O:10])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)=[O:34]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)cc(Cl)c2)cc1
Yield: 60 %

Procedure:
By the general method for the synthesis of 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole in Example 3, the reaction of 3,5-dichlorobenzoyl chloride (20.0 g, 0.010 mole) with 4-octoxybenzoyl hydrazide (25.24 g, 0.010 mole) gave the intermediate 3,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide (25 g, 60% yield). Cyclocondensation of the intermediate 3,5-dichloro-N′-[4-(octyloxy)benzoyl ]-benzohydrazide (16.0 g) with POCl3 (83 mL) gave 2-(3,5-dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (11.16 g, 73% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][NH2:10])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:28])=O)=[CH:22][CH:21]=1>C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]([NH:9][N:10]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[CH3:28])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCc1nc(NN)cc(-c2ccccc2OC)n1
Solvent: CCO
Product: CCc1nc(NN=C(C)c2ccc(C)cc2)cc(-c2ccccc2OC)n1

Procedure:
The title compound was prepared from [2-ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (100 mg, 0.41 mmol) and 4-methylacetophenone (55 μL, 0.41 mmol) in 1.0 mL of ethanol by a procedure similar to example 1, step 4 yielding 117 mg (79%) of a yellow solid. HPLC Purity: 95%.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]([C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:8].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=1)#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:18]2[CH2:17][CH2:16][C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([C:7]([O:6][CH3:5])=[O:8])=[CH:23][CH:22]=3)([OH:21])[CH2:20][CH2:19]2)=[CH:28][CH:27]=1)#[N:25]
Reactant: COC(=O)c1ccc(OCC2(O)CCNCC2)cc1
Reactant: N#Cc1ccc(CC=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Temperature: 0 °C
Yield: 39.1 %

Procedure:
Acetic acid (11.5 mL) was added to a dichloromethane solution (450 mL) of the compound (17.7 g) obtained in Step 6 and the compound (19.4 g) obtained in Step 1 of Example 1 at room temperature and the mixture was stirred at the same temperature for thirty minutes. Sodium triacetoxyborohydride (56.6 g) was added to the mixture under cooling with ice-water and the mixture was stirred at the same temperature for thirty minutes and further stirred at room temperature for five hours. The solvent was removed under reduced pressure and insoluble matter (16.1 g) precipitated by adding water (250 mL) and ethyl acetate (250 mL) was collected by filtration. To the obtained insoluble matter (13.0 g) was added water (50 mL) and saturated aqueous sodium hydrogencarbonate solution (150 mL) and the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was crystallized from ether-hexane to obtain the titled compound (10.3 g) as crystals. The physical data of the obtained compound accord with those of the compound of Example 3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][SH:17])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Fc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CSc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,5-dibromopyridine (1.0 eq.) and (4-fluoro-phenyl)-methanethiol (1.2 eq.) in DMF (0.2M) at 0° C. was added portionwise NaH (1.3 eq.). The mixture was stirred for 1 h at rt, poured in water and extracted with Et2O. The organic extract was washed with water (2×), brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[S:48][CH:49]=[CH:50][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[S:48][CH:49]=[CH:50][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminothiazole (160 mg, 1.60 mmol), and the resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with water and ethyl acetate. The organic layer was further washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded crude 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide as a yellow solid. Recrystallization from 2/1 hexanes/ethyl acetate afforded pure 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide (114 mg, 44%) as a white solid: mp 195–196° C.; EI-HRMS m/e calcd for C18H22N2OS2 (M+) 346.1174, found 346.1171.
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].[H-].[Na+].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>O1CCCC1.C(OCC)C>[CH3:13][N:14]([CH3:18])[C:15]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:16]
Reactant: CC1=NC(C)(C)SC1=NO
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=NC(C)(C)SC1=NOC(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.0 g (0.019 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are added portionwise to a suspension of 0.9 g of sodium hydride in 20 ml of tetrahydrofuran. The sodium hydride was liberated shortly before its use from a 55% suspension in oil by two-fold extraction with a small amount of absolute pentane. After completion of the hydrogen evolution, the mixture is stirred at room temperature for an additional 1 hour. 2.05 g (0.019 mol) of dimethylcarbamoyl chloride are added dropwise, and the reaction mixture is stirred at room temperature for 16 hours. The residue is then taken up in diethyl ether, and the organic phase is washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is subsequently distilled off, and the residue is recrystallized from diethyl ether/n-hexane to yield 5-oxo-2,2,4-trimethyl-3-thiazoline O-(dimethylcarbamoyl) oxime, m.p. 92°-95° C.
Reaction SMILES: [F:1][C:2]([C:17]([F:20])([F:19])[F:18])([O:6][C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3](F)=[O:4].C[Si](C)(C)[O-:23].[K+:26]>CCOCC>[F:1][C:2]([C:17]([F:18])([F:19])[F:20])([O:6][C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[C:3]([O-:4])=[O:23].[K+:26]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 72 %

Procedure:
The procedure of Example 1 was followed using perfluoro-2-methyl-3-oxahexanoyl fluoride (16.6 g, 50 mmol), potassium trimethylsilanolate (6.41 g, 50 mmol), and dry ether (300 mL). Potassium perfluoro-2-methyl-3-oxahexanoate (12.3 g initially and 0.9 g by concentrating the filtrate under vacuum; total: 13.2 g, 72% yield) was isolated as a white solid: 19F NMR (D2O) δ -81.0 ##STR12##
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH:20](Cl)Cl>CC(C)=O>[OH:10][C:9]1[CH:8]=[C:7]([O:11][CH2:18][O:19][CH3:20])[CH:6]=[CH:5][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: COC(Cl)Cl
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(C(C)=O)c(O)c1
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
A mixture of 2,4-dihydroxy acetophenone (2.0 g, 13.2 mmol) and oven-dried potassium carbonate (4.0 g, 30.0 mmol) in dry acetone (30 mL) was stirred for 10 min. Methoxymethylene chloride (MOMCl) (1.62 mL, 17.2 mmol) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 24 h. Solvent was evaporated under reduced pressure and water (25 mL) was added. The mixture was extracted with chloroform (3×100 mL) and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was column chromatographed on silica gel eluting with 20% ethyl acetate in hexanes to afford acetophenone 6a (2.2 g, 87% yield) as a very low melting solid. Rf=0.51 (25% EtOAc-hexanes): mp 38-39° C. IR (KBr) 2959, 2829, 1632, 1579, 1504, 1367, 1262, 1142 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.7 Hz, 1H), 6.51 (m, 2H), 5.15 (s, 2H), 3.42 (s, 3H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.6, 164.7, 163.4, 132.3, 114.6, 108.0, 103.6, 93.8, 56.2, 26.1; EIMS (m/z, rel intensity) 196 (M+, 100), 181 (6), 164 (9), 151 (32), 137 (24).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:3]=1[C:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.O>[Pd].C(O)(=O)C>[CH2:22]([C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:2]=1[OH:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(C(=O)CCCCC)c1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCc1ccc(O)c(CCCCCC)c1
Reaction time: 16 h
Yield: 41.1 %

Procedure:
A mixture of 31.04 g of 1-(2-hydroxy-5-tetradecylphenyl)-1-hexanone, 8.4 g of 5% palladium on carbon, 5 ml of concentrated hydrochloric acid, 95 ml of water and 100 ml of glacial acetic acid was hydrogenated in a Parr apparatus for 16 hours, then filtered and the solvents removed. The residue was chromatographed on silica gel, eluting with hexane:ethyl acetate (40:1), giving 12.3 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]CC1C=CC=CC=1)=O.[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:20])=[CH:31][CH:30]=1
Reactant: CN1C(C(=O)OCc2ccccc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Reactant: Nc1ccc(Cl)cc1
Product: CN1C(C(=O)Nc2ccc(Cl)cc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 52 %

Procedure:
Prepared analogous to Example 1 from benzyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4-chloro-aniline with a yield of 52% of theory.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C=O)s2)cc1
Yield: 82 %

Procedure:
The title compound was prepared from 5-bromo-thiophene-2-carbaldehyde (2.0 g, 10.5 mmol) and (4-methoxyphenyl) boronic acid (1.6 g, 11 mmol) using the procedure of Example 159, step 1 with 82% yield (1.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[CH:3]=1.[Cl-].[NH4+].C1COCC1>[Zn].CO>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:12][CH:11]=3)[N:5]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1c(Cl)cc(-c2ccc([N+](=O)[O-])cc2)nc1-c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
A mixture of 4-chloro-6-(4-nitrophenyl)-2-(4-phenoxyphenyl)nicotinonitrile (136.3 mg, 0.319 mmol), zinc dust (312 mg, 4.78 mmol), ammonium chloride (256 mg, 4.78 mmol), THF (3 mL) and methanol (3 mL) was stirred at room temperature for 15 min, and filtered. The filtrate was concentrated and partitioned with dichloromethane and saturated sodium bicarbonate. The organic layer was separated and concentrated. Silica gel chromatography, eluting with 0-40% ethyl acetate in hexanes, gave pure 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile as yellow solid (51 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-8.04 (4H, m), 7.70 (1H, s), 7.40 (2H, t, J=8.03 Hz), 7.18 (1H, t, J=7.40 Hz), 7.08-7.14 (4H, m), 6.76 (2H, δ, J=8.78 Hz), 4.04 (2H, s); MS (ES+) m/z: 398 (M+H); LC retention time: 4.551 min (analytical HPLC Method A). Additional impure product was also obtained from the chromatography (48.1 mg).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ccccc2n1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 377.04 g/mol.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=4)=[C:21](F)[CH:20]=3)[C:9]([C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>C1COCC1>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:35])[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=4)=[CH:23][CH:24]=3)[C:9]([C:11]([NH:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3c(C(=O)NCC(F)(F)F)cn4ncnc(N)c34)cc2F)n1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3c(C(=O)NCC(F)(F)F)cn4ncnc(N)c34)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (100 mg, 0.2 mmol) in THF (5 mL) was added 1M solution of oxalic acid (0.2 mL, 0.2 mmol, 225 mg was dissolved in 2.5 mL of THF to make a 1M solution) and the mixture was stirred at rt for 16 h. The solid was filtered using a 0.2 uM membrane filter, dried in high vacuum oven to give (60 mg, 51%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.60 (t, 1H), 8.36 (t, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.66 (t, 1H), 7.30 (d, 1H), 7.11 (d, 1H), 6.96 (bd, 1H), 6.89 (d, 1H), 3.98 (m, 2H), 2.50 (s, 3H); ES-MS m/z 503.30 (MH)+, HPLC RT (Method A) 2.64 min. DSC mp.=210.36° C. Anal. Calcd for C22H18F4N8O2: C2H2O4: C, 48.66%; H, 3.40%; N, 18.91%. Found: C, 48.62%; H, 3.24%; N 18.69%.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: CC(C)C(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (example 149) (115 mg, 0.279 mmol) and triethylamine 0.558 mmol) in anhydrous DMF (2 ml) was stirred at RT for 1 hour. After this time, isobutyryl chloride (35 μl, 0.335 mmol) was added and stirring was continued at RT overnight. The reaction was partitioned between water and EtOAc and the aqueous phase was extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (60 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:24]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)=[O:25])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: O=C(Cl)c1ccsc1
Product: Cc1nc(-c2sc(NC(=O)c3ccsc3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and thiophene-3-carbonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][N:32]=[N:31][CH:30]=1)CCC>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:34]=[CH:33][N:32]=[N:31][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnnc4)ncc3O2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and 4-(tributylstannyl)pyridazine (60 mg) in N,N-dimethylformamide (1 mL) is sparged with argon for 10 min and Pd(PPh3)3 (16 mg) is added. The resulting mixture is heated in an oil bath to 120° C. for 7 h. Ethyl acetate and water are added and the organic phase is separated, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 95:5→90:10). The crude product is triturated with diethyl ether, filtered off, and dried to give the title compound. LC (method 7): tR=1.35 min; Mass spectrum (ESI+): m/z=383 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([NH:8][C:9]1[N:27]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)[N:11]2[N:10]=1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>>[CH3:2][C:1]1[S:37][C:6]([NH:8][C:9]2[N:27]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=4)[N:11]3[N:10]=2)=[CH:5][N:4]=1
Reactant: CC(=O)NCC(=O)Nc1nc2cccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1ncc(Nc2nc3cccc(-c4cccc(S(C)(=O)=O)c4)n3n2)s1
Yield: 43.2 %

Procedure:
A solution of 2-acetamido-N-(5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (46 mg, 0.12 mmol, 1 equiv) and Lawesson's reagent (190 mg, 0.48 mmol, 4.0 equiv) was heated under reflux for 6 hr. The reaction mixture was concentrated in vacuo, and the resulting residue was diluted with water and ethyl acetate. The product was collected by filtration and purified by preparative HPLC to afford product (20 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.71 (t, J=1.6 Hz, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.60 (m, 1H), 7.37 (dd, J=7.2, 1.3 Hz, 1H), 7.28 (s, 1H), 3.33 (s, 3H), 2.52 (s, 3H).