Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[N:18][OH:19])=[CH:12][CH:11]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[O:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2F)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4F)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(2-fluoro-phenoxy)-phenyl)-acetohydroximoyl chloride (210 mg, 0.622 mmol) described in Manufacturing Example 83-1-3 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 16 hours at room temperature. Water was added at room temperature to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (41.7 mg, 49.2%).
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:7](OCC)C.[CH3:12][C:13]1[CH2:17]C[C:15](=O)[CH:14]=1.[Cl-].[NH4+]>C(OCC)C.O>[C:1]([C:4]1[CH2:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)([CH3:7])([CH3:3])[CH3:2]
Reactant: CC1=CC(=O)CC1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC1=CCC(C(C)(C)C)=C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a nitrogen atmosphere, dehydrated diethylether (350 ml) was added to a tert-butylmagnesium chloride/diethyl ether solution of 2.0 mol/lit. concentration (450 ml, 0.90 mol) to thereby obtain a solution. A solution of 3-methylcyclopentenone (43.7 g, 0.45 mmol) in dehydrated diethyl ether (150 ml) was dropped into the above solution while maintaining its temperature at 0° C. by cooling with ice. The mixture was agitated at room temperature for 15 hr. A solution of ammonium chloride (80.0 g, 1.50 mol) in water (350 ml) was dropped into the reaction mixture while maintaining its temperature at 0° C. by cooling with ice. Water (2500 ml) was added to the obtained solution, and agitated. An organic layer containing the reaction product was separated and washed with water. A 10% aqueous hydrochloric acid solution (82 ml) was added to the organic layer while maintaining its temperature at 0° C. by cooling with ice, and agitated at room temperature for 6 hr. The organic layer of the reaction mixture was separated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in sequence, and dried over anhydrous magnesium sulfate (drier). The drier was filtered off, and the solvent was distilled off from the filtrate. Thus, a liquid was obtained. 14.6 g of light-yellow liquid (1-tert-butyl-3-methylcyclopentadiene) was obtained by vacuum distillation (45 to 47° C./10 mmHg) of the above liquid. The analytical value thereof was as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([C:21]2[CH:22]=[C:23]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=2)[C:10]=1[CH2:32][CH2:33]Cl>>[CH3:31][NH:30][S:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:11]2[C:10]3[CH2:32][CH2:33][N:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[C:9]=3[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:12]=2)[CH:22]=1)(=[O:29])=[O:28]
Reactant: CNS(=O)(=O)c1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: Nc1ccncc1
Product: CNS(=O)(=O)c1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1

Procedure:
Using 4-aminopyridine instead of 3-aminopyridine, and 3-[6-chloro-5-(2-chloro-ethyl)-2-morpholin-4-yl-pyrimidin-4-yl]-N-methyl-benzenesulfonamide instead of 4-[4-chloro-5-(2-chloro-ethyl)-6-phenyl-pyrimidin-2-yl]-morpholine, in the same manner as Example 1-A-37, the desired compound was obtained as a yellow solid (yield 9%).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][NH:8][C:9]([C:11]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[C:25](=[O:31])[NH:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:19])[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:12]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:27]1([NH:26][C:25]([C@@H:21]2[CH2:22][CH2:23][CH2:24][N:20]2[C:18](=[O:19])[CH2:17][O:16][C:14]2[N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:38])=[O:5])=[O:10])[CH:15]=2)=[O:31])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 5 h

Procedure:
To a solution of 1.33 g ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid tert-butyl ester in 20 ml dichloromethane were added 3.8 ml TFA. After stirring for 5 h it was concentrated and codistilled twice with toluene to give the crude product. Yield: 1.58 g
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:5][CH:4]1[C@H:6](O)C)[CH3:2].CN([CH:12]=[O:13])C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:15].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O>[CH2:1]([C@H:3]1[CH2:5][C@@H:4]1[CH2:6][C:12]([OH:13])=[O:15])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC[C@H]1CC1[C@@H](C)O
Reactant: CN(C)C=O
Agent: c1cc[nH+]cc1
Solvent: O
Product: CC[C@H]1C[C@@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250-mL, one-necked, round bottomed flask equipped with a magnetic stirrer, and under nitrogen, was charged with 1.65 g (14.3 mmol) of alcohol 21 and 40 ml of dry DMF. Pyridinium dichromate 18.8 g (3.5 eq.; 50.1 mmol) was added in one portion. The reaction mixture was stirred overnight at 25° C. and then poured into 200 ml of water and extracted with ether (4×80 ml). The organic layers were concentrated under reduced pressure, and the residue was then dissolved in chloroform (50 ml) and extracted with a 10% aqueous NaOH (2×25 ml). The combined aqueous layers were washed twice with 25 ml of chloroform, followed by acidification with a 10% aqueous HCl. Extraction with ether (4×50 ml), drying over MgSO4, filtration and concentration under reduced pressure afforded the desired compound (1R,2S)-2-ethylcyclopropylacetic acid (22) as a colorless oil (737 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:18]=2)[N:9]=1.[CH3:35][C:36]([CH3:38])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:36]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:18]=2)[N:9]=1)([CH3:38])[CH3:35]
Reactant: CC(C)=O
Reactant: c1ccc2c(CNc3cc(-c4cc5nccn5c(N5CC6CC5CN6)n4)ccn3)cccc2c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(NCc3cccc4ccccc34)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 92 mg (0.2 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-Naphthalen-1-ylmethyl-amine in 5 mL chloroform was treated with 0.12 g (2.0 mmol) acetone, 41 mg (0.66 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1(N)CCCCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C:13](=[O:15])[NH:18][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.4 %

Procedure:
To a solution of N-(benzyloxycarbonyl)glycine (13.21 g), 1-hydroxybenzotriazole hydrate (9.39 g) in dimethylformamide (92 ml) were added cyclohexylamine (7.95 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.32 g), and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed successively with water, aqueous sodium hydrogencarbonate solution, 10% hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (16.799 g).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:21])[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.Br[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH:26]1([CH2:25][CH2:24][CH2:23][N:18]2[CH2:19][CH2:20][CH:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH3:21])=[CH:13][CH:12]=3)[CH2:16][CH2:17]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: BrCCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC2CCN(CCCC3CCCCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(p-toluidino)piperidine trifluoroacetate (0.7726 g) dissolved in N,N-dimethylformamide (10 mL) were added (3-bromopropyl)cyclohexane (0.57 g) and potassium carbonate (1.02 g). The reaction solution was heated with stirring at 80° C. for 5 hours. Dichloromethane was added to the reaction solution, and the insolubles were filtered off, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography [silica gel, dichloromethane-methanol-aqueous ammonia (95:5:0.3)] to give the title compound as a while solid (0.4879 g).
Reaction SMILES: N[C:2](N)=[S:3].[N+]([O-])([O-])=O.[NH4+].O1[CH2:27][CH:11]1[CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][S:22][CH2:23][CH:24]2OC2)[CH:16]=1.[S:28](=O)(=O)(O)O>C1(C)C=CC=CC=1.CO>[S:3]1[CH2:2][CH:24]1[CH2:23][S:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][S:13][CH2:12][CH:11]2[S:28][CH2:27]2)[CH:16]=1
Reactant: NC(N)=S
Reactant: O=S(=O)(O)O
Reactant: c1cc(CSCC2CO2)cc(CSCC2CO2)c1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: c1cc(CSCC2CS2)cc(CSCC2CS2)c1
Yield: 81 %

Procedure:
305 g of thiourea, 3000 ml of methanol, 1500 ml of toluene, 10 g of ammonium nitrate, and 325 g of 1,3-bis(β-epoxypropylthiomethyl)benzene were mixed and reacted at 20° C. for 9 hours in a nitrogen atmosphere. During the reaction, no polymer was deposited. After the reaction, 3800 ml of toluene and 460 ml of 10% aqueous solution of sulfuric acid were put to the reaction vessel to extract the reaction product. Then, the extracted product was washed with 300 ml of water four times, and toluene was removed by distillation. As a result, 288 g of 1,3-bis(β-epithiopropylthiomethyl)benzene (in formula (7), p=1, q=1) was obtained. The yield was 81%. The results are shown in Table 2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: Oc1ccncc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-hydroxypyridine (10 g, 105 mmol), ethyl 4-bromobutyrate 12-1 (15.0 ml, 105 mmol) and Cs2CO3 (34.2 g, 105 mmol) in DMF (100 ml) was stirred at room temperature for 24 h. The reaction was filtered and the filtrate diluted with ethyl acetate (300 ml) and washed with water (4×100 ml) and brine (100 ml) then dried (Na2SO4), filtered, and evaporated. The resulting oil was purified by chromatography on silica gel (3% CH3OH/CH2Cl2) to give 12-2 as a colorless glass.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[S:10][C:9]([N:11]([CH3:15])[C:12](Cl)=[O:13])=[N:8][C:7]=1[CH3:16])(=[O:5])=[O:4].C(N(CC)CC)C.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>O1CCOCC1>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[S:10][C:9]([N:11]([CH3:15])[C:12]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[CH:37][CH:36]=2)=[O:13])=[N:8][C:7]=1[CH3:16])(=[O:5])=[O:4]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc(N(C)C(=O)Cl)sc1S(=O)(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(N(C)C(=O)Nc2ccc(N3CCOCC3)cc2)sc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
12.0 g (40.3 mmol) of 5-[(dimethylamino)sulphonyl]-4-methyl-1,3-thiazol-2-yl(methyl)carbamoyl chloride and 4.08 g (40.3 mmol) of triethylamine were dissolved in 150 ml of dioxane, and 7.18 g (40.3 mmol) of 4-morpholinoaniline, dissolved in 60 ml of dioxane, were added dropwise. The mixture was stirred at room temperature for 12 h, and the resulting precipitate was filtered off and dissolved in a dichloromethane/water (1:1) solvent mixture. The organic phase was separated off, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCOCC1.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN(C)CCO
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reaction time: 1.5 h

Procedure:
A suspension of 9.0 g of 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylic acid in 240 ml of dioxane was treated in succession with 6.7 ml of 2-(dimethylamino)ethanol, 15.7 g of 1H-1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate and 263 mg of 4-dimethylaminopyridine, whereupon the mixture was heated to boiling under reflux for 80 minutes under argon, treated with 1.58 g of 1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate and heated for a further 1 hour. The mixture was then left to cool and the separated crystals were filtered off under suction. After stirring with 890 ml of methylene chloride, 475 ml of water and 70 ml of saturated sodium hydrogen carbonate solution for 90 minutes the organic phase was separated and evaporated. The residue was dissolved in 100 ml of methanol, whereupon the solution was acidified with etheral hydrochloric acid, filtered and the product was precipitated by cooling in an ice bath. There was obtained 2.9 g of 2-(dimethylamino)ethyl 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate as yellowish crystals with a m.p. of 225°-228°.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O=C1C2C(C(OCC)=O)=CC=CC=2NC(C2C=CN=CC=2)C1C1C=CN=CC=1.O.[NH2:57][NH2:58]>>[N:19]1[CH:20]=[CH:21][C:16]([CH:4]2[NH:5][C:6]3[C:11]4[C:2](=[N:57][NH:58][C:12](=[O:14])[C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH:3]2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccncc1)C(c1ccncc1)N2
Reactant: NN
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccncc1)C(c1ccncc1)N2
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccncc1)C2c1ccncc1
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of methyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (60 mg, 0.17 mmol) in hydrazine monohydrate (7 mL) was heated to reflux for 4 hr. Then the mixture was cooled to room temperature and solvent was removed in vacuum to give crude product. The crude product was purified by pre-HPLC to give 8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (15 mg, yield 68%) as a light yellow solid. 1H-NMR (400 MHz, DMSO) δ 4.46-4.48 (d, J=8.4 Hz, 1H), 4.90-4.92 (d, J=8.4 Hz, 1H), 7.16-7.20 (m, 3H), 7.32-7.34 (d, J=5.2 Hz, 2H), 7.40-7.42 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.59-7.63 (t, J=8.0 Hz, 1H), 8.40-8.40 (d, J=5.2 Hz, 2H), 8.44-8.45 (d, J=5.2 Hz, 2H). LC-MS (ESI) m/z: 342 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28]C(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].[C:33](OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH2:21]1)(=[O:28])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Reaction time: 1 h

Procedure:
A suspension of (S)-6-phenyl-4-(piperidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydrochloride salt (Example 44, 12.2 mg, 0.033 mmol) in CH2Cl2 (0.3 mL) was added acetic anhydride (3.72 μL, 0.04 mmol) followed by DIPEA (0.017 mL, 0.1 mmol). The reaction was stirred for 1 h at which time the starting material had been consumed as judged by HPLC. The solvents were removed and the product purified via reverse phase preparative HPLC. LCMS: 378 (M+H)+; HPLC (conditions E): retention time=7.41 min; 1H NMR (MeOD, 400 MHz) δ 8.17 (d, J=13 Hz, 1H), 7.97 (dd, J=1.7, 12.3 Hz, 1H), 7.75 (m, 3H), 7.40 (m, 3H), 7.27 (m, 1H), 4.38 (m, 1H), 3.83-3.94 (m, 2H), 3.42 (m, 2H), 2.21 (s, 3H), 1.98 (m, 1H), 1.87 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH:11]([CH2:16][N+:17]([O-:19])=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])C(OCC)=O)[CH3:2].O.[Na+].[Cl-].C(OC)(C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:11]([CH2:16][N+:17]([O-:19])=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(CC(C)C)C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(CC(C)C)C[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
10.0 g (34 mmol) of 2-(3-methyl-1-nitromethyl-butyl)-malonic acid diethyl ester (XII, R1=ethyl) were dissolved in 140 mL of DMSO. Water (10.4 mL) and solid NaCl (14.6 g) were added and the mixture was heated for 6 hours at 150° C. After complete conversion, the reaction mixture was cooled to 25° C. and 150 mL of methyl tert-butyl ether were added. 100 mL of water were added slowly. The heterogeneous mixture was stirred for 5 minutes prior to layer separation. The aqueous layer was washed once with 75 mL of methyl tert-butyl ether. The organic layers were combined and washed once with 50 mL of water. The combined organic layers were dried and the volatiles were removed under reduced pressure to give 7.0 g of 5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl; 93% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([N:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:20]=3)=[CH:15][C:14]2=[O:32])[CH2:11][OH:12])=[CH:6][C:5]=1[F:33].[I-].[Na+].[CH3:36][S:37][CH2:38]Cl>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([N:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:20]=3)=[CH:15][C:14]2=[O:32])[CH2:11][O:12][CH2:36][S:37][CH3:38])=[CH:6][C:5]=1[F:33]
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](CO)c1ccc(Cl)c(F)c1
Reactant: CSCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCOC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Temperature: 0 °C
Yield: 99.9 %

Procedure:
Sodium hydride (44 mg, 1.10 mmol) was added to 1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]pyridine-2-one (0.49 g, 1.10 mmol) in DMF (10 mL) at 0° C., which was left to stir at 0° C. In a separate vial, sodium iodide (0.17 g, 1.10 mmol) and chlorodimethyl sulfide (0.11 g, 1.10 mmol) were transferred, which was then added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The mixture was quenched carefully with water before diluting with ethyl acetate. The phases were separated. The organic phase was washed with saturated sodium bicarbonate, water, and followed by brine. The mixture was dried over sodium sulfate before removing the solvent to leave an oil. The oil was purified by CombiFlash (24 g column, 0-10% MeOH/DCM over 20 minutes) to furnish (S)-1-(1-(4-chloro-3-fluorophenyl)-2-((methylthio)methoxy)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (555 mg) as a solid (M+1=506).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C.O>[Br:1][C:18]1[N:17]=[C:16]([O:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[C:9]([CH3:12])([CH3:10])[CH3:11])[C:21]([NH2:22])=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccccc1Oc1nc(Br)ccc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.3 %

Procedure:
A solution of N-bromosuccinimide (2.32 g, 13.0 mmol) in DMF (20 ml) was added to a cold (−20° C.) solution of 1b (2.76 g, 11.4 mmol) in DMF (25 ml). The reaction rapidly turned dark red. HPLC analysis after 5 min showed that the reaction was complete. The reaction was quenched with a freshly prepared solution of sodium thiosulfate (40 ml, 10% aqueous). A precipitate formed. The mixture was warmed to rt and was diluted with water (60 ml). The solid was filtered, washed with water and dried overnight under reduced pressure to give 123a (3.82 g, 96% yield) as brown solid. [M+H]+=321.14. 1H NMR (500 MHz, CDCl3) δ ppm 1.40 (s, 9H), 3.91 (s, 2H), 6.93 (m, 2H), 7.00 (d, J=8.07 Hz, 1H), 7.12 (t, J=7.73 Hz, 1H), 7.20 (t, J=7.73 Hz, 1H), 7.41 (d, J=8.07 Hz, 1H).