Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[OH:27][C@@H:28]([CH2:41][NH2:42])[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[OH:27][C@@H:28]([CH2:41][NH:42][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(N2CCCCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H), 2.60-2.95 (m, 5H), 3.50-4.10 (m, 9 H), 4.89 (brs, 1 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.2 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.01 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 2 H), 7.51 (s, 1 H), 10.60 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 289.1 ((M+2 H)2+, 100%), 577.1 (MH+, 50%); HRMS Calcd. for C30H37N6O4S (MH+): 577.2597. Found: 577.2625.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:14])[NH:7][C:6]=2[N:15]=1.[CH3:17][C:18]1[CH:23]=CN=C(N)[C:19]=1C.C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH3:37][OH:38]>>[Cl:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:5]1[C:37](=[O:38])[NH:1][C:2]([NH:3][C:4](=[O:16])[C:18]([CH3:23])([CH3:19])[CH3:17])=[N:15][C:6]=1[NH:7]2
Reactant: Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Reactant: Cc1ccnc(N)c1C
Reactant: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Reaction time: 48 h
Yield: 40 %

Procedure:
Compound 8 (300 mg, 1.27 mmol), 2-dimethyl propanoic anhydride (713.32 mg, 3.83 mmol), dimethyl aminopyridine (7 mg, 0.06 mmol), triethylamine (514.05 mg, 5.08 mmol) were weighed together in a 50 mL round bottom flask. This flask was placed in an oil bath at 60° C. with stirring for 2 days. Then, to the reaction mixture was added 1 g silica gel. The DMF was removed using oil pump and a silica gel plug was made. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform, 1% methanol in chloroform and 5% methanol in chloroform. Fractions containing the product 9 (TLC) were pooled and evaporated to give solid compound. The overall yield was 40%. TLC Rf 0.45 (chloroform-methanol 10:1), m.p. 185.8-190.1° C., 1H NMR: δ 1.27 (s, 9H, pivaloyl); 7.19-7.40 (m, 3H, phenyl); 11.15 (s, 1H, 9-NH, exch); 11.94 (s, 1H, 9-NH, exch); 12.12 (s, 1H, 3-NH, exch).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[C:12]([CH3:23])[CH:11]=1.CON(C)[C:27](=[O:29])[CH3:28]>C1COCC1>[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15])=[C:12]([CH2:23][C:27](=[O:29])[CH3:28])[CH:11]=1
Reactant: CON(C)C(C)=O
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Br)cc1CC(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 2M solution of LDA (35.2 mL, 70.3 mmol) in THF (176 mL) cooled to −78° C. was treated with slow addition of 4-bromo-N,N-diethyl-2-methylbenzamide (19 g, 70.3 mmol) in dry THF (176 mL). The reaction was allowed to stir at −78° C. for 1 hour before it was quenched with N-methoxy-N-methylacetamide (22.43 mL, 211 mmol) and allowed to slowly warm to room temp. The reaction was stirred overnight and then partitioned between 1N HCl (200 mL) and EtOAc (400 mL). The aqueous layer was further extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was an oil out of which the product precipitated. The oil was decanted off and the solid was washed with hexanes and dried using a buchner funnel to afford 4-bromo-N,N-diethyl-2-(2-oxopropyl)benzamide: LC-MS: (M+H)+ 312.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](C(OC)=O)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:20][Mg]Br.C([O:25][CH2:26][CH3:27])C>O1CCCC1.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:26]([OH:25])([CH3:27])[CH3:20])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: CCCCc1nc(=O)c2cc(C(=O)OC)ccc2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.075 g of methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate in 5 ml of dry tetrahydrofuran, cooled to 0° C., is added dropwise 0.51 ml of a solution of 3.OM methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 0.5 hours and then at room temperature for 1 hour followed by quenching with 10 ml of saturated ammonium chloride solution. The resulting reaction mixture is diluted with 10 ml of water and extracted with ethyl acetate. The combined organics are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 100:0.25 chloroform-reethanol to yield 0.055 g of the desired product as a white solid, m.p. 190°-192° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[CH3:42]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:36]4[CH:37]=[CH:38][N:33]=[C:34]([CH3:42])[CH:35]=4)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Br)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: Cc1cc(-c2cccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CCC(F)(F)C4)C3)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(3-Bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 188 step 4) and 2-picoline-4-boronic acid. Off-white solid (60%). MS (EI): 543.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:22][NH2:23]>O1CCOCC1.O1CCCC1>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[N:22][NH2:23])#[N:2]
Reactant: Cc1cc(C)cc(C(=O)NCCC#N)c1
Reactant: NN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=NN)NCCC#N)c1
Temperature: 100 °C

Procedure:
A mixture of the product from step (vii) (35.68 g) and phosphorus pentachloride (36.86 g) was stirred under a water-aspirator vacuum and heated at 100° C. giving rise to a yellow oil. The oil was further stirred at 100° C. under vacuum for a further 30 min. The boiling phosphorus oxychloride liberated was collected by distillation to leave a dark brown oil which was cooled to room temperature and dissolved in dry 1,4-dioxane (50 ml). This solution was transferred rapidly via cannula to a stirring solution of hydrazine in tetrahydrofuran (1.0M, 882 ml) under nitrogen at room temperature. An exotherm was produced raising the reaction temperature to ˜40° C. The resultant opaque yellow solution was further stirred for 16 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulphate and solvent removed under reduced pressure to give the subtitle product as a red oil (34.7 g). This was not purified but used directly in the next step
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1.O>CS(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
0..87 g (5 mmol) of 2-n-butyl-benzimidazole is dissolved in 20 ml of dimethylsulphoxide and 0.61 g (5.5 mmol) of potassium tert.butoxide is added with stirring. After 1/2 hour, 4'-bromomethyl-2-(1-triphenylmethyl-1H-tetrazol-5-yl)-biphenyl is added and the mixture is stirred for 3 hours at ambient temperature. It is poured into about 50 ml of iced water and extracted by shaking 3 times using 30 ml of ethyl acetate each time. The ethyl acetate phase is extracted by shaking using 20 ml of water, dried over sodium sulphate and evaporated to dryness. The crude product is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol=100:1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(Cl)Cl.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:46].[Mg+2]>CO>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH2:31][CH3:32])=[O:46])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CCSc1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Agent: [Mg+2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCS(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Reaction time: 2 h

Procedure:
To a solution of N-cyclopropyl-1-[3-(4-ethylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 18, in a 1:1 mixture of methylene chloride and methanol (9 ml/mmol), was added at 0° C. magnesium monoperoxyphthalate hexahydrate (MMPP, 0.5 molareq) and the resulting mixture was stirred in the cold for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 90:9:1 mixture of methylene chloride, ethanol and 28% aqueous ammonium hydroxide to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1>O1CCCC1>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Diethyl malonate (74 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 18 g) in dry tetrahydrofuran under an inert atmosphere. The resulting suspension was stirred at reflux for one hour. The mixture was cooled to 60° C. and a solution of 2-chloro-5-nitropyridine (50 g) in dry tetrahydrofuran was added. The resulting red solution was stirred at reflux for 3 hours then allowed to stand at room temperature overnight. The volume of solvent was reduced by evaporation, water was added to the residue and the mixture was acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, washed with water, dried (anhydrous magnesium sulphate), filtered and evaporated. The crude product was triturated in a mixture of cyclohexane and diethyl ether to yield diethyl 2-(5-nitropyridin-2-yl)malonate (56.5 g) as a yellow solid, m.p. 91.5°-93.5° C.
Reaction SMILES: [CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])OC)([CH3:3])[CH3:2].C([Si](C(C)C)(C(C)C)OCCCC)(C)C.[ClH:28]>>[CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[Cl:28])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CO[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCCO[Si](C(C)C)(C(C)C)C(C)C
Product: CC(C)[Si](Cl)(C(C)C)C(C)C
Yield: 99 %

Procedure:
The procedure of Example 13 was repeated except that triisopropylmethoxysilane was replaced by 83.3 g (0.2 moles) of triisopropyl-n-butoxysilane. The latter was reacted with 35% hydrochloric acid. There was obtained 38 g of triisopropylchlorosilane (yield; 99%).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=1.Br[CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+]>C(O)C.C(N(CC)CC)C>[C:29]([CH2:28][CH2:27][CH2:26][NH:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)/[CH:12]=[CH:13]/[C:14]1[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=1)([OH:31])=[O:30]
Reactant: CCCc1csc(/C=C/c2cccc(N)c2)n1
Reactant: CCOC(=O)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCc1csc(/C=C/c2cccc(NCCCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 63.5 %

Procedure:
To 20 ml of toluene were added 732 mg of 2-(trans-3-aminostyryl)-4-propylthiazole, 1170 mg of ethyl 4-bromobutyrate and 606 mg of triethylamine, and the reaction was carried out at 100° C. for 21 hours. After the reaction mixture was cooled to room temperature, 10 ml of ethanol and 10 ml of an aqueous 5% sodium hydroxide solution were added and the mixture was stirred at room temperature for 1.5 hours to effect hydrolysis of the ester. After completion of the reaction, ethanol was evaporated under reduced pressure and the residue was adjusted to pH 1-2 with addition of 10% hydrochloric acid, followed by extraction with ethyl ether. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the solid formed was recrystallized from ethyl ether to give 629 mg (yield 64%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)=[N:7][NH:6][C:5](=[O:21])[CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:22]([O:1][CH2:2][CH:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)=[N:7][NH:6][C:5](=[O:21])[CH2:4]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CCc2cc(C3=NNC(=O)CC3CO)ccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1CC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2C
Yield: 46.8 %

Procedure:
A solution of 13.6 g of 6-(5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one, 5.8 g of acetic anhydride and 10 ml of triethylamine in 300 ml of chloroform was heated under reflux on a water bath for 3 hours. The reaction mixture was washed with water, dried over potassium carbonate and concentrated under reduced pressure. The residue was dissolved into a small amount of ethyl acetate. After the solution was allowed to stand, the precipitated crystals were filtered off and recrystallized from isopropanol to give 7.3 g of 6-(5-acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as needles, melting at 149°-153° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:43][CH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49](Cl)=[N:50][OH:51])=[CH:47][CH:46]=1>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]2[O:51][N:50]=[C:49]([C:48]3[CH:53]=[CH:54][C:45]([CH2:44][Cl:43])=[CH:46][CH:47]=3)[CH:30]=2)=[N:27][C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:35][CH:36]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ON=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CCl)cc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83.8 %

Procedure:
Triethylamine (899.0 mg, 1.238 mL, 8.884 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate 8 (4.05 g, 8.074 mmol) and 4-(chloromethyl)-N-hydroxy-benzimidoyl chloride (2.063 g, 8.494 mmol) in DCM (12 mL). The mixture was stirred at RT for 22 h then partitioned between DCM and an ice/water solution. The combined organic extract was dried over MgSO4 and concentrated under reduced pressure then purified by chromatography on silica gel (eluent 30-50% EtAc/petrol) yielding tert-butyl N-tert-butoxycarbonyl-N-[3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate as colourless crystals (4.53 g, 79%). 1H NMR (400 MHz, CDCl3) δ 1.41 (18H, s), 4.66 (2H, s), 7.37 (1H, s), 7.54 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0 Hz), 8.66 (1H, s)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[N:3]=[N:4][C:5]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: Clc1ccc(Cl)nn1
Product: c1cc(N2CCOCC2)nnc1N1CCOCC1
Yield: 80 %

Procedure:
3,6-Dichloropyridazine (25.0 g, 0.168 mol) was dissolved in morpholine (120 mol), for reflux condition for 24 hours. After cooling, the deposited crystal was filtered, to give 3,6-dimorpholinopyridazine in white crystal (33.7 g as a yield of 80%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=[O:2]>C(O)C.[Pd]>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2]
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NNC=O)cc1
Yield: 81.9 %

Procedure:
30 g of the 1-formyl-2-(4-nitrophenyl)hydrazine was then catalytically reduced in 1.6 liters of ethanol in the presence of palladium-on-carbon as a catalyst at room temperature. The reaction mixture was filtered, and the filtrate was evaporated to dryness to obtain 20.5 g of 1-formyl-2-(4-aminophenyl)hydrazine as a white solid. Melting Point: 123°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), N-methylpiperazine (117 mg, 1.17 mmol) and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition, the mixture was stirred at room temperature for 5 h. Dichloromethane was removed under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (48 mg, yield 22%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.02 (s, 3H), 3.60-3.81 (m, 8H), 4.36-4.38 (d, J=7.6 Hz, 1H), 4.47 (s, 2H), 4.80-4.82 (d, J=7.6 Hz, 1H), 6.93-6.97 (m, 2H), 7.12-7.15 (m, 2H), 7.22-7.24 (m, 1H), 7.43-7.45 (m, 2H), 7.52-7.57 (m, 3H), 7.64-7.68 (m, 1H). LC-MS (ESI) m/z: 470 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[F:9][C:10]([F:17])([F:16])[C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH:12]=[C:11]([C:10]([F:17])([F:16])[F:9])[CH:15]=[N:14]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnn(-c2ncc(Br)cn2)c1
Temperature: 85 °C
Yield: 98.4 %

Procedure:
To a mixture of 5-bromo-2-chloropyrimidine (4.32 g, 21.5 mmol), 4-(trifluoromethyl)-1H-pyrazole (2.92 g, 21.5 mmol), and dried potassium carbonate (8.90 g, 64.4 mmol) was added anhydrous dimethylformamide (31.5 mL). The resulting suspension was heated at 85° C. for 4 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 12.4 g of crude yellow solid. The crude material was put through a plug of silica eluting with 15% ethyl acetate in heptanes to give 5-bromo-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (6.2 g, 99%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.83 (s, 2H), 8.02 (s, 1H).