Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(N)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N:12]1[C:19]([Cl:20])=[N:18][C:16](Cl)=[N:15][C:13]=1[Cl:14]>CC(C)=O>[CH:1]1([C:16]2[N:18]=[C:19]([Cl:20])[N:12]=[C:13]([Cl:14])[N:15]=2)[CH2:2][CH2:3]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC1CC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)nc(C2CC2)n1

Procedure:
A mixture of 28.5 g of cyclopropylamine and 50.5 g of triethylamine was added drop-by-drop to a stirred solution of 92.3 g of cyanuric chloride in 1.5 liters of dry acetone at room temperature. Then the acetone was evaporated and the residue was treated with a 1:1 v:v mixture of ice water and ether. The ether phase was separated and dried (MgSO4), and the ether was evaporated to give 2-cyclopropyl-4,6-dichloro-1,3,5-triazine (9A), as a white solid, m.p.: 106°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8]1=[N:12][C:11]([CH3:13])=[N:10][N:9]1[C:19]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:26]
Reactant: Cc1nc(-c2ccc(Cl)cc2)n[nH]1
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 0 °C
Yield: 49.1 %

Procedure:
2.0 g (10.3 mmol) of 3-(4-Chlorophenyl)-5-methyl-1,2,4-triazole is dissolved in 50 ml of tetrahydrofuran (THF) (freshly distilled from lithium aluminum hydride) mechanically stirred in a 250 ml round-bottom 3-necked flask equipped with a septum and nitrogen inlet and cooled in an ice bath. 13.6 ml (22.7 mmol) of n-butyllithium (1.67 mol/liter in hexane) is injected with a syringe and the mixture is stirred in the ice bath for 30 minutes. 2.12 g (20.6 mmol) of benzonitrile is added in a little THF. After stirring for 30 minutes in the ice bath and for 30 minutes at room temperature, the mixture is poured into a chilled stirred mixture of 100 ml of 2.5 M ammonium chloride and 200 ml of chloroform. The layers are separated and the aqueous layer washed with chloroform. The combined chloroform layers are washed with water and dried (Na2SO4). The chloroform is removed under vacuum and the residue is recrystallized from toluene to yield 1.5 g of the title compound, m.p. 173°-175°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=2[CH2:11]1.Cl.[N:28]1([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][CH2:34][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:38][CH:39]=2)[CH:7]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N)c1
Reactant: O=C(O)Cc1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NC(=O)Cc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 54.9 %

Procedure:
Synthesized from pivalic acid 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and [4-(2-piperidin-1-ylethoxy)phenyl]acetic acid hydrochloride (140 mg) according to an analogous synthetic method to Preparation Example 154,the title compound (93 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1I)[CH2:15][N:16]([CH3:20])[CH2:17][CH:18]=[CH2:19])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C([Li])CCC.CCCCCC.[CH2:38]([Sn:42](Cl)([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH3:41].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]([F:26])([F:25])[C:3]([C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[Sn:42]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:15][N:16]([CH3:20])[CH2:17][CH:18]=[CH2:19])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C=CCN(C)Cc1ccc(I)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCN(C)Cc1ccc([Sn](CCCC)(CCCC)CCCC)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Compound 12 (470 mg, 945 μmol) was dissolved in freshly distilled THF (5 mL) under nitrogen atmosphere and cooled to −78° C. n-butyllithium 1.6M in hexane solution (886 μL, 1.42 mmol) was then added and the mixture stirred 30 min at −78° C. Tributyltin chloride (462 mg, 1.42 mmol) in solution in THF (2 mL) was added and the mixture let to warm to room temperature overnight. A 0.1M ammonium chloride solution (5 mL) was added to the reactionnal mixture. The organic layer was isolated and the aqueous layer was extracted with dichloromethane (2×5 mL). The organic layers were combined and dried over sodium sulfate. After solvent evaporation under reduced pressure, the residue was purified over silica gel with heptane/acetone (98/2) as eluant to give 524 mg (794 μmol, 84% yield) of a yellowish oil.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH-:20].[Na+]>>[CH:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:20])=[CH:6]1)([CH3:17])[CH3:16]
Reactant: Cc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-methyl-1H-indol-3-yl)-ethanone (1.50 g, 5.57 mmol) in a 20% aqueous sodium hydroxide solution (20 mL) was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (150 mL) and ethyl acetate (150 mL), and then treated with a 1N aqueous hydrochloric acid solution (50 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid (1.19 g, 98%) as a yellow solid: mp 185-186° C.; EI-HRMS m/e calcd for C13H15NO2 (M+) 217.1103, found 217.1110.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2].O=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=2)[N:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CCC(CC)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C

Procedure:
To a solution of rac-8-ethyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate HC)(13 mg, 0.041 mmol) in DCE (2 ml) was added ethyl 7-oxoheptanoate (24.84 mg, 0.144 mmol) followed by sodium triacetoxyborohydride (69.9 mg, 0.330 mmol). The reaction mixture was left to stir at room temperature under an atmosphere of nitrogen. Water (10 ml) was added and the resulting mixture was extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (10 ml) to afford the title product;
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].ClCCl.C([O:20][C:21]([C:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1)=[O:22])C>[Cu]Cl.CCCCCC>[C:10]([O:14][C:26]([C:23]1([C:21]([OH:22])=[O:20])[CH2:25][CH2:24]1)=[O:27])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(C(=O)O)CC1
Reaction time: 96 h

Procedure:
At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (12.7 ml) was added to a dichloromethane solution (40 ml) of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (6.37 g), and heated at reflux for 3 hours. Hexane (50 ml) was added to the reaction solution, and the precipitate was filtered off. After the filtrate was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After hexane was added to the resulting residue, the precipitate was filtered off, and the filtrate was concentrated. The resulting residue was dissolved in tetrahydrofuran (25 ml), and 1 N aqueous sodium hydroxide solution (25 ml) was added, and stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, 1 N aqueous sodium hydroxide solution (15 ml) was added to the residue, and washed with dichloromethane. A 10% aqueous citric acid solution was added to the aqueous layer to render it acidic, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.80 g).
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1C=CC=CC=1>[CH:19](=[N:1][CH2:2][P:3](=[O:18])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=P(CN=Cc1ccccc1)(Oc1ccccc1)Oc1ccccc1

Procedure:
A solution of diphenyl aminomethylphosphonate (102.8 g) and benzaldehyde (41.6 g) in benzene (1000 ml) is heated at reflux in a Dean-Stark apparatus until water separation ceases. The resulting solution is evaporated under reduced pressure to yield diphenyl N-benzylideneaminomethylphosphonate.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[CH:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:3]1[C:4]2[C:17]3[C:12]([C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]=2[CH2:1][CH2:2]1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: C1=Cc2c(c3ccccc3c3ccccc23)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)c1c(c3ccccc32)CCC1
Reaction time: 48 h

Procedure:
A mixture of 2 g cyclopentaphenanthrene, 0.2 g 10% palladium on carbon and 50 mL toluene was stirred under hydrogen (69 kPa) until hydrogen uptake ceased, about 48 h. Catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated. The crude product remaining weighed 1.97 g. It was further purified by recrystallization from heptane at −40° C. to give 1.8 g colorless plates. Spectroscopic and chemical analysis confirmed the identity of the desired compound.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH:27]([CH3:29])[O:26][CH:25]([CH3:30])[CH2:24]5)=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:31])=[C:8]([C:32]([O:34]CC)=[CH2:33])[C:7]2=[O:37])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[C:32]([C:8]1[C:7](=[O:37])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH:25]([CH3:30])[O:26][CH:27]([CH3:29])[CH2:28]4)=[CH:19][N:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CC(C)OC(C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CC(C)OC(C)C4)cn3)nc2n(C2CCCC2)c1=O
Yield: 38.5 %

Procedure:
8-Cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-6-(1-ethoxy-vinyl)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.055 g, 0.109 mmol) was dissolved in ethyl acetate (3 mL) and 1 N aqueous HCl (2 mL) and stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane and aqueous NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and the solvent evaporated to give 6-acetyl-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.020 g, 38.4%). MS (APCI) Calc'd for M+1: 477.3. Found: 477.2. 1H NMR δ (400 MHz, CDCl3) 8.79 (s, 1H), 8.1 (d, J=9.0 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 7.90 (s, 1H), 7.30 (dd, J=3.1, 9.3 Hz, 1H), 5.87 (m, 1H), 3.83 (m, 2H), 3.37 (d, J=10.0 Hz, 2H), 2.54 (s, 3H), 2.46 (dd, J=11.7, 11.7, 2H), 2.37 (s, 3H), 2.32 (m, 2H), 2.05 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H), 1.27 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[C:36]=4[CH3:42])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.Cl[CH2:44][O:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:44][O:45][CH3:46])[C:36]=4[CH3:42])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(OCOC)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of EXAMPLE 158B (0.6 g), chloro(methoxy)methane (0.18 g) and cesium carbonate (0.9 g) was suspended in N,N-dimethylformamide (15 mL). After it stirred at room temperature for 30 minutes, the crude product was purified by preparative HPLC using a 250×50 mm C18 column and eluting with 20-100% CH3CN vs. 0.1% trifluoroacetic acid in water.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21]>CN(C=O)C>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:21]
Reactant: COc1cc(C=O)c(O)c(OC)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1c(C=O)cc(OC)cc1OC)OCC
Yield: 67 %

Procedure:
To a stirred suspension containing 2 (1.1 g, 6.0 mmol) and K2CO3 (1.0 g, 7.2 mmol) in DMF (100 mL), bromoacetaldehyde diethyl acetal (0.93 mL, 6.0 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 3 (1.2 g, 67%) as a clear oil. 1H NMR (500 MHz, CDCl3): δ: 10.50 (1H, s, CHO), 6.88 (1H, d, J4,6=2.9 Hz, H-6), 6.74 (1H, d, J4,6=2.9 Hz, H-4), 4.83 (1H, t, J4,6=5.3 Hz, CH), 4.14 (2H, d, J4,6=5.3 Hz, CH2), 3.88 (3H, s, OMe), 3.83 (3H, s, OMe), 3.77-3.71) (2H, m, CH2CH3), 3.63-3.58 (2H, m, CH2CH3), 1.24 (6H, t, J=7.1 Hz, 2×CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=O)=[C:14]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.C(Cl)CCl.C1C=CC2N(O)N=[N:41]C=2C=1.[OH-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:41])=[O:21])=[C:14]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: O=C(O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-2-oxo-2H-quinolizine-7-carboxylic acid (Example 53, 21 mg) in THF was added EDC (20 mg), HOBt (10 mg) and ammonium hydroxide (0.1 mL) at room temperature. After stirring for 2 h, the mixture was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (methylene chloride/methanol=20/1) to give the title compound (17 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:29]([CH3:28])[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:27])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNCc1cccnc1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CN(Cc1cccnc1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with methyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[OH-:29].[Na+].CO>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[N:6]([C:8]([C:11]([NH2:12])=[O:29])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(N)=O)cnc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (25 mgs) from Example XXXI(1) step 1b, 6N NaOH (0.1 mL), MeOH (0.1 mL) and dioxane (1 mL) in a vial was heated to 100° C. for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. Upon addition of 1M HCl a precipitate forms. The precipitate was collected by filtration and dried to provide 35 mgs of crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1>CN(C=O)C.O>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([CH:3]3[CH2:4][N:1]([C:21]4[C:16]([Cl:15])=[N:17][CH:18]=[CH:19][N:20]=4)[CH2:2]3)=[N:6][C:7]=2[CH:13]=1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1nccnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Temperature: 100 °C

Procedure:
A mixture of 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared by Preparation 2) (1.0 g, 4.83 mmol) and 2,3-dichloro-pyrazine (0.71 g, 10.4 mmol) was dissolved in DMF (20 mL) and heated for 2 h at 100° C. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to afford the product as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([C@@:8]23[CH2:17][N:16]([S:18]([C:21]4[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=4)(=[O:20])=[O:19])[CH2:15][CH2:14][C:13]2=[CH:12][C:11]2[N:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[N:29]=[CH:30][C:10]=2[CH2:9]3)=[O:7])[CH2:3][CH2:2]1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]([C@@:8]23[CH2:17][N:16]([S:18]([C:21]4[CH:22]=[N:23][C:24]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[CH:25][CH:26]=4)(=[O:20])=[O:19])[CH2:15][CH2:14][C:13]2=[CH:12][C:11]2[N:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[N:29]=[CH:30][C:10]=2[CH2:9]3)=[O:7])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(OCC1CC1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: O=C(OCC1CC1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid cyclopropylmethyl ester and morpholine to give the title compound (0.063 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.78 (dd, 1H), 7.49-7.40 (m, 3H), 7.16 (t, 2H), 6.61 (d, 1H), 6.41 (d, 1H), 4.40 (dd, 1H), 3.95-3.85 (m, 2H), 3.81 (t, 5H), 3.66 (t, 4H), 3.31 (d, 1H), 2.95-2.87 (m, 1H), 2.58 (d, 1H), 2.49-2.41 (m, 3H), 1.20-1.10 (m, 1H), 0.57-0.48 (m, 2H), 0.33-0.22 (m, 2H).
Reaction SMILES: BrC(=O)[CH:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:4][CH3:5].[C:18]([NH:21][C:22]([NH2:24])=[S:23])(=[NH:20])[NH2:19].[CH2:25](O)C>>[NH:21]([C:22]1[S:23][C:4]([CH2:5][CH3:25])=[C:3]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[N:24]=1)[C:18]([NH2:19])=[NH:20]
Reactant: CCC(C(=O)Br)c1ccc2c(c1)CCC(=O)N2
Reactant: CCO
Reactant: N=C(N)NC(N)=S
Product: CCc1sc(NC(=N)N)nc1-c1ccc2c(c1)CCC(=O)N2

Procedure:
A mixture of 6-(α-bromobutanoyl)-3,4-dihydrocarbostyril (7 g), amidinothiourea (2.9 g) and absolute ethanol (250 ml) is stirred at reflux overnight. The reaction mixture is cooled to ice bath temperature and the solid filtered, washed, dried and suspended in aqueous sodium hydroxide. The neutralized solid is filtered, washed with water, dried in vacuo and recrystallized from 50% aqueous DMF and boiling water affording the desired product, M.P. 230° C. (dec).