Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].N#N.[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:12]=1>CN(C=O)C>[CH2:1]([O:5][C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Reactant: CCCCO
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(Cl)cc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a solution of n-butanol (0.633 g, 8.54 mmol) in anhydrous DMF (50 mL) at 0° C. under the N2, NaH (0.307 g, 12.8 mmol) was added quickly. The obtained suspension was stirred for 0.5 h at 0° C. 2,4-Dichloro-6-(morpholin-4-yl)pyrimidine (2 g, 8.54 mmol) was added to the suspension. After the suspension was warmed to room temperature and stirred for 12 h, the reaction mixture was quenched with ice/brine and extracted with 200 mL EtOAc. The extract was washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure. The crude residue was purified using flash chromatography (silica; EtOAc/Hexane: 1/6) to yield 1.4 g of 2-n-butoxy-4-chloro-6-(morpholin-4-yl)pyrimidine (white solid, 60%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[O:21].CCN(CC)CC>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:20](=[O:21])[NH:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])[C:9]#[N:10]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC(C(=O)Nc1ccc(F)cc1F)C(=O)c1ccc[nH]1

Procedure:
Reaction of 2.4 g of 2-pyrroloylacetonitrile with 3.1 g of 2,4-difluorophenyl isocyanate in the presence of 2.0 g Et3N in 25 ml of glyme and isolation similarly to the preceding examples, followed by trituration with and recrystallization from ethanol gives β-oxo-α-(2,4-difluorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 169°-171°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]=[C:28]=[O:29].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:26][NH:27][C:28](=[O:29])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCCC1c1cccc(O)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a solution of 2-{2-[2-(3-hydroxyphenyl)-1-pyrrolidinyl]ethyl}-1H-isoindole-1,3(2H)dione (0.71) in dry tetrahydrofuran (35 ml) was added methyl isocyanate (0.13 ml) followed by milled potassium carbonate (0.38 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 45 mins, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated, and the residue was triturated with petroleum ether. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/heptane). The appropriate fractions were collected and concentrated to afford 0.78 g (94%) of product. Recrystallization from dichloromethane/petroleum ether gave the analytical sample, mp 96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1>CCO.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Solvent: CCO
Solvent: C1COCCO1
Product: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 20.1, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester in EtOH/dioxane was converted to yield Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester as a dark brown oil, MS: 396 (MH+, 1Cl).
Reaction SMILES: O1C2C=CC([CH:10]3[C:22]4[C:13](=[N:14][C:15]5[CH:16]=[C:17](C(OCC)=O)[C:18]6[O:25][CH:24](C(OCC)=O)[O:23][C:19]=6[C:20]=5[CH:21]=4)[C:12](=[O:36])[O:11]3)=CC=2OC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH2:43]>C1COCC1>[O:43]1[C:18]2[CH:17]=[CH:16][C:15]([C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]5[O:25][CH2:24][O:23][C:19]5=4)[N:14]=[C:13]4[C:12](=[O:36])[O:11][CH2:10][C:22]=34)=[CH:20][C:19]=2[O:23][CH2:24]1
Reactant: O
Reactant: CCOC(=O)c1cc2nc3c(cc2c2c1OC(C(=O)OCC)O2)C(c1ccc2c(c1)OCO2)OC3=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OCc2c1nc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl 9-(1,3-benzodioxole-5-yl)-1,3-dioxolo[4,5- f]furo[3,4-b]quinoline-7(9H)-one dicarboxylate (2.4 g) was added gradually to a suspension of LAH (lithium aluminium hydride (2.0 g) in THF (50 ml) at 0° C. The mixture was stirred at room temperature for one hour, followed by addition of water to stop the reaction. The resulting precipitate was filtered off through Celite®. The filtrate was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) and, with addition of 10% Pd-C (2.5 g), stirred at room temperature overnight. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform (300 ml), followed by addition of manganese dioxide (20 g). The mixture was stirred at room temperature for 3 hours. The manganese dioxide was filtered off through Celite®. The filtrate was concentrated under reduced pressure. The resulting crude crystals were washed with diisopropyl ether to yield the title compound (0.9 g). Some portions of the compound were recrystalized from THF to be used for elemental and instrumental analysis.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[CH:10]=2)=O)C.[NH3:18]>CO>[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[CH:10]=2)(=[O:3])[NH2:18]
Reactant: N
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Solvent: CO
Product: COc1ccc2cc(C(N)=O)cnc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
3-Ethoxycarbonyl-7-methoxyquinoline (28 g, 120 mmol) was added to a methanol solution saturated with ammonia. The suspension was stirred at ambient temperature in a glass pressure vessel for 2 weeks. The white solid was collected by filtration, washed with methanol and dried under vacuum to give 3-carbamoyl-7-methoxyquinoline (21 g, 86%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35]C(OC(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.C(N(C(C)C)CC)(C)C.[Cl:73][C:74]1[CH:79]=[CH:78][C:77]([S:80](Cl)(=[O:82])=[O:81])=[CH:76][CH:75]=1>O1CCCC1>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][S:80]([C:77]2[CH:78]=[CH:79][C:74]([Cl:73])=[CH:75][CH:76]=2)(=[O:82])=[O:81])[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NS(=O)(=O)c2ccc(Cl)cc2)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 23 h
Yield: 70 %

Procedure:
100 mg (0.11 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3) and 300 μl (1.71 mmol) of diisopropylethylamine are dissolved in 5 ml of tetrahydrofuran, mixed with 238 mg (1.13 mmol) of 4-chlorobenzenesulfonic acid chloride and stirred for 23 hours at room temperature. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography on 25 g of silica gel 60 (hexane/acetone 2:1→1:2) yields 75 mg (70%) of N-(N-(N-(N-(4-chlorobenzenesulfonyl)-L-alanyl)-L-alanyl)-L -prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien-21-yl] ester, and, after recrystallization from dichloromethane/diisopropyl ether, 47 mg (44%) of crystalline product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30]([O:32][CH:33](OCC)OCC)[CH3:31]>>[C:16]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[C:2]=1[N:1]=[CH:33][O:32][CH2:30][CH3:31])#[N:17]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC=Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
A mixture of 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (10 g) and p-toluenesulphonic acid hydrate (0.1 g) in triethylorthoformate (40 ml) was heated at reflux for 1 hour. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution was added. The organic phase was removed, dried over anhydrous magnesium sulphate and evaporated to give a colourless solid which was recrystallised from a mixture of ethyl acetate and hexane to give 4-cyano-5-ethoxymethyleneamino-1-(2,3,4-trichlorophenyl)pyrazole (11.0 g), m.p. 131°-132° C., in the form of colourless crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH2:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40].Cl>O1CCCC1>[CH2:39]([S:41]([N:23]1[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:24]1)(=[O:43])=[O:42])[CH3:40]
Reactant: CCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Reaction time: 1.5 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile (0.100 g, 0.244 mmol) in tetrahydrofuran (2 mL) containing N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) was added ethanesulfonyl chloride (0.023 mL, 0.24 mmol). After stirring for 1.5 hours, the reaction mixture was poured into dilute HCl and extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford product, used without further purification in Step 5 (111 mg, 91%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)Oc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)Oc1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (80 mg, 0.270 mmol) in EtOH was added hydantoin (27 mg, 0.270 mmol) and piperidine (27 μL, 0.270 mmol). The mixture was heated at 70° C. for several hours. The solid produced was isolated by filtration to yield 5-((5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=379)
Reaction SMILES: C[Si](C)(C)Cl.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH3:7].Br[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18].Cl>C(OCC)(=O)C.[Zn]>[OH:8][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)C(C)Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)C(C)(O)c1ccccc1
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 8.6 g of zinc powder (130 mmol) in 53 ml of ethyl acetate. After 2.5 ml of trimethylchlorosilane (19.5 mmol) had been added, the mixture was heated at 65° C. for 30 min, then left to cool to 60° C., following which 10.5 g of acetophenone (87 mmol) were added, and over the course of 6 min, 17.4 g of methyl 2-bromopropionate (104 mmol) were then added dropwise, the temperature being maintained at 65° C. by external cooling. The mixture was stirred at 60° C. for 25 min, and following cooling to 0° C., acidified with 70 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 70 ml of 0.5 N hydrochloric acid and finally washed with 30 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was removed by distillation under reduced pressure. Methyl 3-hydroxy-2-methyl-3-phenylbutyrate was obtained in a yield of 15.5 g (91% of theory) with a boiling point of 64° C. (0.03 mbar). The diastereomer ratio of the product was 2:1.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[CH:6]1([P:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)([SH:14])=[S:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([P:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)([S:14][CH2:1][CH2:2][CH2:3][CH3:4])=[S:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCCCBr
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Product: CCCCSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
n-Butyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain n-butyl dicyclohexylphosphinodithioate, a viscous liquid, b.p. 167°-175° C at 0.15 mm., which on testing lasted 900 hours longer than the control. The total number of hours required to reach failure was 2.8 times that of the control.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[C:59]([CH3:64])=[N:60][O:61][C:62]=1[CH3:63])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[C:59]([CH3:64])=[N:60][O:61][C:62]=2[CH3:63])=[O:57])[CH2:49][CH2:48]1
Reactant: Cc1noc(C)c1N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as starting materials in 30% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.41 (m, 2H), 9.00 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.02 (m, 2H), 2.98 (m, 4H), 2.80 (m, 2H), 2.32 (m, 2H), 2.20 (s, 3H), 2.12 (m, 4H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C30H33ClN9O3 (M+H)+: m/z=602.2.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:34])[NH:9][C:10]2[C:11]3[N:12]([CH:31]=[CH:32][N:33]=3)[N:13]=[C:14]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:14]2[CH:15]=[C:10]([NH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:34])[C:11]3[N:12]([CH:31]=[CH:32][N:33]=3)[N:13]=2)[CH2:18][CH2:19]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(NC(=O)Nc3ccccc3)c3nccn3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Nc2cc(NC(=O)Nc3ccccc3)c3nccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl(trans)-4-(8-(3-phenylureido)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (6.3 mg, 0.135 mmol) from 1a in dichloromethane (2 mL) was added TFA (1 mL). After stirring at RT for 2 hours, the reaction solution was concentrated in vacuo. The residue was purified by SCX column (300 mg, eluting with 2M ammonia in methanol) to give the title compound as a TFA salt 3.2 mgs (64%). 1H NMR (500 MHz, MeOH) δ ppm 7.64 (1H, s), 7.47 (2H, m), 7.31 (2H, m), 7.06 (2H, m), 6.71 (2H, m), 3.63 (1H, m), 2.71 (1H, m), 2.15 (2H, m), 1.91 (2H, m), 1.28-1.33 (4H, t). LC/MS, m/e 366.27 (M+1). HPLC Rt, 2.18 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:9][CH2:10]1
Reactant: O=C1CCCN1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one (143 mg, 0.64 mmol) from above step B, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (×4). The organic fractions were combined, filtered and evaporated to give 115 mg of 1-(4-oxocyclohexyl)pyrrolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:25][CH:26]=1)=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:18][C:19]([C:21]3[CH:26]=[N:25][C:24]([O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[N:23][CH:22]=3)=[O:20])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=C(CBr)c1cnc(OCC2CC2)nc1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc(OCC2CC2)nc1

Procedure:
180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 211.66 mg (0.78 mmol) of 2-bromo-1-(2-cyclopropylmethoxypyrimidin-5-yl)ethanone were used in the reaction. After purification by chromatography on silica gel (eluent: 80/20 DCM/MeOH), 160 mg of (8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:19][CH2:18][C:11]3[N:12]=[N:13][C:14]([NH:16][NH2:17])=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:25])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:19][CH2:18][C:11]3[N:12]=[N:13][C:14]([NH:16][N:17]=[C:23]([CH3:25])[CH3:22])=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:20][CH:21]=1
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1)C2
Reactant: CC(C)=O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1)C2

Procedure:
A suspension of 3.1 g of crude 6-(p-chlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 30 cc of acetone is heated on a water bath for 1 hour. The title compound has a M.P. of 221°-223° (decomp., from ethanol).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[C:34]1[CH3:47].C(=O)=O.CC(C)=O>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:47])=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cc1ncc(C(=O)c2cnc(C)n2C)n1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-BuLi (1.63 M in hexane, 0.124 mL, 0.203 mmol) was added dropwise under argon at ˜−70° C. to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (81.6 mg, 0.19 mmol, Intermediate 10) in THF (1.9 mL). After 2 additional minutes, an opaque milky suspension of bis(1,2-dimethyl-1H-imidazol-5-yl)methanone (42.4 mg, 0.194 mmol, Intermediate 11) in LaCl3-2LiCl (0.5 M in THF, 0.381 mL, 0.19 mmol) and THF (2.5 mL) was added rapidly dropwise over 1.5 minutes. The resulting yellow slurry was stirred in the dry ice/acetone bath for 10 minutes, and was then transferred to an ice bath and stirred overnight as the bath warmed to room temperature. The reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL) and diluted with DCM (˜5 mL) and MeOH (˜2 mL), and the suspension was partitioned with 0.75 M aqueous tetrasodium EDTA (4 mL) and 9:1 DCM/MeOH (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN gradient with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.86 (d, J=2.53 Hz, 1H), 7.63-7.70 (m, 2H), 7.58 (d, J=8.59 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.37 (m, 1H), 6.42 (t, J=1.99 Hz, 1H), 6.14 (s, 2H), 5.82 (br. s., 1H), 4.29 (s, 2H), 4.08 (s, 3H), 3.38 (s, 6H), 2.26 (s, 6H); MS m/e 568.3 [M+H]+.