Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([CH2:16][OH:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: COCCCc1cc(CO)c2ccccc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCCCc1cc(C=O)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [2-(3-methoxypropyl)quinoline-4-yl]methanol from the previous step (1 eq.) in CH2Cl2 (0.05 M) was added Dess-Martin periodinane (1.1 eq.) portionwise. The resulting suspension was stirred at RT for 3 h. The reaction was quenched with MeOH and H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound which was purified further by way of flash chromatography (SiO2, 2:1 (v/v) Hex:EtOAc).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (300 mg, 0.62 mmol) was dissolved in a 4.0 M solution of HCl in 1,4-dioxane (10 mL). After being stirred at room temperature for 1 h, the solution was concentrated to give 260 mg of desired product. MS calculated for C19H27F3N4O: (M+H) 385.2; found 385.2.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.C1C(=O)N([Cl:32])C(=O)C1>C(Cl)(Cl)Cl>[Cl:32][C:23]1[C:22](=[O:24])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Cl)C(=O)OC1)C2=O
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (I-16, Step A) (2.1 g, 6.2 mmol) in chloroform (50 mL) was added NCS (1.00 g, 7.49 mmol) at rt and the resulting solution was heated at 60° C. overnight. After removing the volatiles the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to give the title compound. LC/MS: (M+1)+: 371.11, 372.99.
Reaction SMILES: [NH:1]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>C(OCC)(=O)C.CO.[Pd]>[NH:1]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 80 %

Procedure:
The Boc-Gly-Phe-Leu-OBzl (1.7 g) obtained in Example 19 was dissolved in a mixed solution of ethyl acetate (30 ml) and methanol (30 ml), and added with 5% Pd—C (1.5 g) to perform catalytic reduction. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give the title compound (1.15 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10](=[O:19])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:19])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:33]([C:32]3[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:37][CH:36]=3)=[O:34])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2nonc2-c2noc(=O)n2-c2cccc(Cl)c2)cc1
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (50 mg, 0.18 mmol) and 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid (49 mg, 0.2 mmol) in dichloromethane (3.5 mL) was treated with 4-dimethylaminopyridine (13 mg, 0.1 mmol) and N,N-diisopropylethylamine (93 μL, 0.54 mmol). After the reaction mixture turned clear, it was treated with bromotris(pyrrolydino)phosphonium hexafluorophosphate (50 mg, 0.11 mmol) and additional N,N-diisopropylethylamine (93 μL, 0.54 mmol). The reaction mixture was stirred for 16 h, treated with additional bromotris(pyrrolydino)phosphonium hexafluorophosphate (50 mg, 0.11 mmol), and stirred for another 6 h. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with 0.1 M HCl (2×25 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated. Purification of the crude reaction mixture by preparative LCMS gave the desired product (22 mg, 24%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN1CCCC1.O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)COc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 70 °C
Reaction time: 5 h
Yield: 325.7 %

Procedure:
4-Nitronaphthalen-1-ol (0.70 g, 3.7 mmol) in N-methylpyrrolidine (6 ml) is treated with potassium carbonate (1.0 g) and methyl bromoacetate (0.169 g, 1.1 eq). The mixture is stirred at 70° C. for 5 h. The mixture is then diluted with water and extracted with ethyl acetate. The organic layer is repeatedly washed with water, dried over Na2SO4, and evaporated to dryness to provide (4-nitronaphthalen-1-yloxy)-acetic acid methyl ester (0.94 g). MS: 262 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[CH:6]=O)[CH2:3][CH2:2]1.[N+:16]([CH3:19])([O-:18])=[O:17].Cl.CN.C([O-])(=O)C.[Na+]>>[CH:1]1([C:4]2[C:5](/[CH:6]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:3][CH2:2]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)nc1C1CC1
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: O=[N+]([O-])/C=C/c1ccc(C(F)(F)F)nc1C1CC1
Reaction time: 4 h
Yield: 16.7 %

Procedure:
2-Cyclopropyl-6-(trifluoromethyl)nicotinaldehyde (130 mg, 0.604 mmol) was diluted with nitromethane (229 μL, 4.23 mmol) followed by the addition of methylamine hydrochloride (24.5 mg, 0.363 mmol) and sodium acetate (29.7 mg, 0.363 mmol). After stirring for 4 hours, the reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield (E)-2-cyclopropyl-3-(2-nitrovinyl)-6-(trifluoromethyl)pyridine (26 mg, 0.101 mmol, 16.7% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14](=[O:22])[CH2:15]P(=O)([O-])OCC)[CH:2]([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:29]/[C:30](/[CH:37]=O)=[CH:31]\[C:32]([O:34][CH2:35][CH3:36])=[O:33].O>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14](=[O:22])[CH:15]=[CH:29][C:30]([CH3:37])=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C=C(\C)C=O
Reactant: CCOP(=O)([O-])CC(=O)c1cc(OC)ccc1OCC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(C)C=CC(=O)c1cc(OC)ccc1OCC(C)C
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
3 g (8.4 mmol) of ethyl [2-(2-isobutoxy-5-methoxyphenyl)-2-oxoethyl]-phosphonate dissolved in 20 ml of tetrahydrofuran are added dropwise to a suspension of 1.41 g (12.6 mmol) of potassium tert-butoxide in 30 ml of tetrahydrofuran, heated to 50° C. Heating is continued for 20 minutes at 50° C., the mixture is then cooled to 0° C. and 1.8 g (12.6 mmol) of ethyl 3-methyl-4-oxocrotonate dissolved in 20 ml of tetrahydrofuran are added dropwise. The reaction mixture is then stirred for 72 hours at 25° C. Water is added and the resulting mixture is extracted with ether. After drying (Na2SO4), the solvent is evaporated off and the residue is purified by flash chromatography (dichloromethane) (2.58 g of yellow oil; 89%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].O.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)c(CO)c1
Reaction time: 20 h
Yield: 80.6 %

Procedure:
In a flask under a nitrogen atmosphere, 81.60 grams (0.346 mole) of 2,3-dichloro-5-nitrobenzoic acid was dissolved in 325 mL of tetrahydrofuran, and this solution was cooled to below 10° C. To this solution was slowly added 400 mL (0.400 mole) of a 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran. Upon completion of the addition the temperature of the reaction mixture was allowed to rise to ambient conditions, at which it was stirred for about 20 hours. At the conclusion of this period, 40 mL of water was slowly added to the reaction mixture. This was followed by the addition of 220 mL of 10% aqueous hydrochloric acid. Addition of the water had caused the mixture to become cloudy, but addition of the acid restored the clarity of the solution. The solvent was concentrated under reduced pressure, leaving a residue which was then dissolved in approximately 1500 mL of ethyl acetate. This solution was washed in succession three times with water, four times with an aqueous solution of sodium bicarbonate, once with water, and finally with a saturated aqueous solution of sodium chloride. The solution was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 61.90 grams of 2,3-dichloro-5-nitrophenylmethanol as a solid residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19].C1(=O)[NH:25]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.C(OCC)(=O)C.C1(=O)NC(=O)C2=CC=CC=C12.[K]>[NH2:25][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(CN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.9 %

Procedure:
A mixture of compound 65b (1.08 g, 3.11 mmol) and potassium phthalimide (0.634 g) in DMF (10 mL) was stirred at rt overnight. Additional potassium phthalimide (0.063 g) was added and stirring was continued for 4 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried, and concentrated. The residue was dissolved in ethanol (20 mL) and hydrazine (0.34 mL) was added. The reaction mixture was refluxed for 1 h, and then cooled and filtered. The filtrate was concentrated to give compound 65c (1.04 g). ESI-MS m/e 282 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16]([NH2:18])=O)[CH:4]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH3:1][N:2]([CH3:19])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16]#[N:18])[CH:4]=1
Reactant: CN(C)c1cc(C(N)=O)nn1Cc1ccccc1F
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CN(C)c1cc(C#N)nn1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.33 g of 5-(dimethylamino)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxamide 1-10-1 (5.07 mmol, 1.0 eq.) were dissolved in 74 mL of dry THF. 1.03 mL of pyridine (12.7 mmol, 2.50 eq.) were added. Then 1.79 mL of trifluoroacetic anhydride (12.7 mmol, 2.50 eq.) were added dropwise. The reaction mixture was stirred for 24 hours at rt. Then the reaction mixture was partitioned between water and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane/ethyl acetate) to provide 406 mg (1.66 mmol, 33%) of analytically pure target compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[S:14])[NH:12][NH2:13])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[OH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[CH:26]=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[S:14])[NH:12][N:13]=[CH:26][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[OH:15])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: NNC(=S)Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(NC(=S)NN=Cc2c(O)ccc3ccccc23)c1
Yield: 49 %

Procedure:
The procedure described in example 7 was followed here, using 4-(3-carboxyphenyl)-3-thiosemicarbazide in place of 4-(4-carboxyphenyl)-3-thiosemicarbazide and 2-hydroxy-1-naphthaldehyde in place of 3,5-dichloro-2-hydroxybenzaldehyde to give the title compound (49%) as a solid. MS (ES−) m/e 364 [M−H]−.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.[CH3:58][O:59][C:60](=[O:73])[C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][CH2:69][CH2:70][CH2:71]Cl)=[CH:63][CH:62]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:82]([OH:89])(=[O:88])/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86]>CN(C)C=O>[C:82]([OH:89])(=[O:88])/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86].[CH3:58][O:59][C:60](=[O:73])[C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][N:48]2[CH2:47][CH2:46][CH:45]([C:43]([C:51]3[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=3)([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[OH:44])[CH2:50][CH2:49]2)=[CH:63][CH:62]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)c1ccc(OCCCCCl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 65 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 9.1 g (0.03 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 7.3 g (0.03 mole) of 4-(4-chlorobutoxy)benzoic acid methyl ester, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 125 ml of dimethylformamide gave a gum as residue. The gum was converted to the fumaric acid salt and the solid was recrystallized from acetonitrile-dimethylformamide to yield 12.2 g (65%) of title compound as a white solid, mp 186°-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[F:12][C:13]([F:23])([F:22])[C:14]1[C:15]([Cl:21])=[N:16][C:17](Cl)=[N:18][CH:19]=1.ClCCCl.C(O)(C)(C)C.CCN(CC)CC>CCOCC.[Cl-].[Cl-].[Zn+2]>[Cl:21][C:15]1[C:14]([C:13]([F:22])([F:12])[F:23])=[CH:19][N:18]=[C:17]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][C:5](=[O:11])[NH:6]3)[N:16]=1
Reactant: Nc1cccc2c1CC(=O)N2
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1Cc2c(cccc2Nc2ncc(C(F)(F)F)c(Cl)n2)N1
Temperature: 25 °C

Procedure:
4-amino-oxindole (2.75 g, 18.6 mmol) was added portionwise to a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (4.03 g, 1 eq) and ZnCl2 (18.6 mL of a 1M solution in ether) in 1:1 DCE/t-butanol (60 mL) at 0° C. After 15 minutes a solution of Et3N (2.85 mL, 1.1 eq) in 1:1 DCE/t-butanol (20 mL) was added dropwise. The reaction was allowed to warm to RT overnight. The reaction was then concentrated and the product triturated from methanol as a grey solid 3.05 g (50%). 1H NMR (DMSO-d6, 400 MHz) δ 3.43 (s, 2H), 6.64 (m, 1H), 7.14 (m, 2H), 8.74 (s, 1H), 10.32 (s, 1H), 10.43 (s, 1H); HPLC ret. time: 5.859 min. LRMS (M+) 329.1, 331.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22](=[O:24])[N:21]([CH3:25])[C:20]([N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[N:19][C:18]=3[N:17]([CH3:33])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)C1C=CC=CC=1>[Pd]>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[C:20]1[N:21]([CH3:25])[C:22](=[O:24])[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=3[F:34])=[CH:16][N:17]([CH3:33])[C:18]=2[N:19]=1)[CH2:31][CH3:32]
Reactant: CCCN(CCC)c1nc2c(c(-c3ccc(OCc4ccccc4)cc3F)cn2C)c(=O)n1C
Agent: [Pd]
Product: CCCN(CCC)c1nc2c(c(-c3ccc(O)cc3F)cn2C)c(=O)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.9 %

Procedure:
To a solution of 5-[4-(benzyloxy)-2-fluorophenyl]-2-(dipropylamino)-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (194 mg, 0.419 mmol) was added 10% palladium on carbon (50 mg), and the mixture was stirred at room temperature for 15 hours under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 25% hexane/ethyl acetate mixture. The desired fractions were concentrated in vacuo, and the resulting crystals were washed with diethyl ether to give 42 mg (27%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][OH:9].[N:10]1[C:17](F)=[N:16][C:14](F)=[N:13][C:11]=1F>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][O:9][C:11]1[N:13]=[C:14]([O:9][N:8]=[C:3]2[N:4]([CH3:7])[CH2:5][CH2:6][N:2]2[CH3:1])[N:16]=[C:17]([O:9][N:8]=[C:3]2[N:4]([CH3:7])[CH2:5][CH2:6][N:2]2[CH3:1])[N:10]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CN1CCN(C)C1=NO
Solvent: c1ccncc1
Product: CN1CCN(C)C1=NOc1nc(ON=C2N(C)CCN2C)nc(ON=C2N(C)CCN2C)n1
Temperature: 42 °C
Reaction time: 15 h

Procedure:
To a cold (0° C.) solution of 1,3-dimethyl-2-imidazolidinone oxime (prepared according Kitamura, Mitsuru; Chiba, Shunsuke; Narasaka, Koichi, Bulletin of the Chemical Society of Japan (2003), 76(5), 1063-1070) (5.3 g, 0.041 mol) in dry pyridine (25 ml) within 15 minutes is dropwise added cyanuric fluoride (1.49 g, 0.011 mol). The mixture is then heated for 2 h at 42° C. and then stirred for 15 h at room temperature. The pyridine is evaporated under reduced pressure, the residue is chromatographed (silica gel, CH2Cl2—CH3OH 20:1 to 10:1) and the pure fractions are crystallized from ethyl acetate hexane to afford 2.4 g of the title compound as white crystalls, mp. 143-145° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Te:9](Cl)(Cl)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-:20].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Te:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc([Te](Cl)(Cl)c2ccc(OC)cc2)cc1
Agent: [Na+]
Product: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Yield: 81 %

Procedure:
The bis-(p-methoxyphenyl)tellurium dichloride (8.00 g, 19.4 mmol) was stirred at 95° in aqueous sodium hydroxide (100 ml, 5%) for 1 h. After cooling in an ice bath the white solid was filtered and dried under vacuum over phosphorus pentoxide to give bis-(p-methoxyphenyl)telluroxide (5.60 g, 81%), m.p. 187°-189° (lit., 190°-191°) νmax (Nujol) 1585,1575,1490,1460,1401,1380,1295,1247,1180,1172,1109,1068,1026,823,811 and 789 cm-1.
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[NH2:16][CH2:17][CH2:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>ClCCl>[NH2:16][CH2:17][CH2:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([F:7])=[O:22]
Reactant: FC1=CC(F)=NN(F)N1
Reactant: NCCc1nc(Cl)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: NCCc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 5.0 g (24.8 mmol) of 2-(aminoethyl)-6-chloronicotinic acid in 125 ml of dichloromethane. The mixture is stirred for 3 hours at ambient temperature and then filtered. The solid is rinsed with 50 ml of dichloromethane and the filtrate is washed twice with 60 ml of ice-cold water. The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 5.01 g of product are obtained in the form of an orange oil. Yield=99%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][C:12]3([CH3:27])[CH3:26])=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[Si](C)(C)C>O1CCOCC1.CCOCC>[CH3:27][C:12]1([CH3:26])[CH2:13][NH:14][CH2:15][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:31]=[C:2]([C:38]3[CH:37]=[CH:36][N:35]=[C:34]([O:33][CH3:32])[CH:39]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:28]([NH2:29])=[O:30]
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: COc1cc(B(O)O)ccn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)I
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(-c2cc3c(N[C@@H]4CNCC4(C)C)c(C(N)=O)cnn3c2)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution of benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpyrrolidine-1-carboxylate (35 mg, 0.072 mmol) in 1,4-dioxane (0.3 mL), was added (2-methoxypyridin-4-yl)boronic acid (14.3 mg, 0.094 mmol), X-Phos (3.43 mg, 7.2 μmol) and potassium phosphate (2 M, 0.115 mL, 0.23 mmol). The reaction vial was purged with nitrogen, sealed and heated at 100° C. for 18 h. The reaction was diluted with ethyl acetate (50 mL), washed with aq. sodium bicarbonate and brine. The organic layer was dried and concentrated. The residue was suspended in acetonitrile (5 mL), was added iodotrimethylsilane (36.0 mg, 0.180 mmol) at 0° C., stirred at rt for 1 h. To the suspension was added ether (30 mL), stirred for additional 2 h, filtered and rinsed the collected solid with ether and dried to give the hydroiodide salt of the title compound (15 mg, 0.030 mmol, 41.0% yield) as a yellow solid. 1H NMR (500 MHz, METHANOL-d4) δ 8.15 (s, 1H), 8.09 (d, J=5.4 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.58 (s, 3H), 7.31 (d, J=1.5 Hz, 1H), 7.25 (dd, J=5.4, 1.5 Hz, 1H), 7.09 (d, J=1.0 Hz, 1H), 4.61-4.54 (m, 1H), 4.30 (br. s., 1H), 3.94 (s, 3H), 3.73 (dd, J=11.9, 6.9 Hz, 1H), 3.12-3.04 (m, 2H), 1.97 (s, 2H), 1.24 (d, J=14.4 Hz, 6H), MS (ES+) m/z: 380.2, 381.3 (M+H); LC retention time: 0.84 min (analytical HPLC Method I).