Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[N:7]([C:34]2[CH:35]=[C:36]([CH2:40][C:41](OCC)=[O:42])[CH:37]=[CH:38][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:46][CH2:47][CH:48]([OH:51])[CH2:49][OH:50]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[N:7]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][C:41]([NH:46][CH2:47][CH:48]([OH:51])[CH2:49][OH:50])=[O:42])[CH:35]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c(Nc3nccc(-c4cccnc4)n3)c2)c1
Reactant: NCC(O)CO
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2cccc(CC(=O)NCC(O)CO)c2)cc1Nc1nccc(-c2cccnc2)n1
Yield: 54.2 %

Procedure:
Using the same method as for Example 21, ethyl 2-(3-(3-t-butyl-5-(3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)ureido)-1H-pyrazol-1-yl)phenyl)acetate (137 mg, 0.23 mmol) and 1-amino-2,3-dihydroxypropane (49 mg, 0.54 mmol) were combined to yield 1-(3-t-butyl-1-(3-(2-(2,3-dihydroxypropylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)urea (81 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.29 (dd, J=2.2, and 0.8 Hz, 1H), 8.95 (s, 1H), 8.86 (s, 1H), 8.69 (dd, J=4.8, and 1.6 Hz, 1H), 8.51-8.47 (m, 2H), 8.38 (s, 1H), 8.10 (brt, J=5.8 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.51 (ddd, J=8.4, 4.7, and 0.8 Hz, 1H), 7.47-7.42 (m, 3H), 7.36 (m, 1H), 7.31 (brd, J=7.6 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.05 (dd, J=8.5, and 2.1 Hz, 1H), 6.41 (s, 1H), 4.76 (d, J=4.8 Hz, 1H), 4.51 (t, J=5.8 Hz, 1H), 3.53 (s, 2H), 3.48 (m, 1H), 3.30-3.18 (m, 3H), 2.96 (m, 1H), 2.19 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 650.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]2[CH:11]=[CH:12][NH:13][C:7]=12)=[O:5])[CH3:2].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH:12]([O:5][CH2:4][CH3:6])[O:3][CH2:1][CH3:2])[C:7]=1[NH2:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2cc[nH]c12
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cnn(CC(OCC)OCC)c1N

Procedure:
Synthesis of 1H-Imidazo[1,2-b]pyrazole-7-carboxylic acid ethyl ester, K-8. To a solution of crude K-7 (2 g) in absolute ethanol (10 mL) was added aqueous 20% sulfuric acid solution (12 mL) and the resulting mixture was refluxed for 1 h. The cooled reaction mixture was concentrated to remove the solvent and the mixture was poured to ice and adjusted to pH 8 with sodium bicarbonate. The insoluble material was filtered off and filtrate was extracted with methylene chloride (2×60 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give 1.2 g of a dark brown residue. This residue was purified by column chromatography using CH2Cl2 to 2% MeOH/CH2Cl2 to afford 280 mg of product K-8. 1H NMR.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1.[H][H]>[Pd].O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [H][H]
Reactant: CCCCCC(C)=CCC#CCC#CCCCCCCCl
Agent: [Pd]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(C)=CCC=CCC=CCCCCCCCl

Procedure:
A mixture of 11.0 g. of 1-chloro-14-methyl-nonadeca-7,10-diyn-13-ene, 1.5 g. of 5% palladium on barium sulfate, and 80 ml. of pyridine was shaken in a Parr rocker under 40 lb. of hydrogen pressure for about 1.3 hrs., at which time two moles of hydrogen had been absorbed. The reaction mixture was then poured into water and extracted with ether. The extract was washed with water, dilute hydrochloric acid, saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated leaving a residue comprising 1-chloro-14-methyl-7,10,13-nonadecatriene. The residue was distilled in a rocking short-path distillation apparatus, collecting 7.6 g. of a mixture comprising 1-chloro-14-methyl-7,10,13-nonadecatriene at a bath temperature of 180°C. and a pressure of 0.005 mm.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:15][C:16]([N:18]1[CH:23]([CH3:24])[CH2:22][CH:21]([OH:25])[CH2:20][CH:19]1[CH3:26])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[OH-].[Na+]>S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:8]([O:15][C:16]([N:18]1[CH:19]([CH3:26])[CH2:20][CH:21]([O:25][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22][CH:23]1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1CC(O)CC(C)N1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(OCC(=O)OC(C)(C)C)CC(C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To 10 ml of toluene was dissolved 1.91 g of N-benzyloxycarbonyl-2,6-dimethyl-4-hydroxypiperidine, and to this solution were added 1.70 g of tert-butyl bromoacetate, 0.08 g of tetrabutylammonium sulfate and 1 ml of water, and then aqueous solution of sodium hydroxide in an ice bath. The solution was stirred overnight at room temperature, washed with water and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:1 v/v) was obtained 1.11 g of N-benzyloxycarbonyl-4-tert-butoxycarbonylmethyloxy-2,6-dimethylpiperidine, which was an oily product (yield: 41%).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[N:18]=[C:19]([CH:21]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42](=[NH:44])[NH2:43])=[CH:38][CH:37]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12].[N+](C1C=CC([O:65][C:66](=O)[O:67][CH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][CH3:71])=CC=1)([O-])=O.C1COCC1.C(N(CC)CC)C>C(O)(=O)C>[CH3:5][C:6]([CH3:55])([CH3:54])[CH2:7][O:8][C:9](=[O:53])[C:10]([CH3:52])([CH3:51])[C:11]([O:13][CH2:14][O:15][C:16]1[N:17]([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[N:18]=[C:19]([CH:21]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]([NH2:43])=[N:44][C:66]([O:67][CH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][CH3:71])=[O:65])=[CH:40][CH:41]=2)[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH2:31][CH2:32][OH:33])[C:23]=2[F:34])[N:20]=1)=[O:12]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Reactant: CCC(C)(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)COC(=O)N=C(N)c1ccc(NC(c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c2cc(OC)cc(OCCO)c2F)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a mixture of 2,2-dimethylmalonic acid 5-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-metho xyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester 2,2-dimethylpropyl ester acetate (270 mg), carbonic acid 2,2-dimethylbutyl ester 4-nitrophenyl ester (141 mg), and THF (10 mL), triethylamine (0.17 mL) was added, and the resulting mixture was stirred at room temperature for 26 hours. Acetic acid (0.3 mL) was added to the reaction solution, and the resulting mixture was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound.
Reaction SMILES: [CH:1]1[C:16]2=[C:17]3[C:4]([CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][C@@H:10]3[C@H:15]2[CH2:14][CH2:13][NH:12][CH2:11]3)=[CH:3][CH:2]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:34]>ClCCCl.C(O)C.CCOCC.C(O)(=O)C>[ClH:34].[ClH:34].[CH3:20][N:12]1[CH2:11][C@H:10]2[C@H:15]([C:16]3[CH:1]=[CH:2][CH:3]=[C:4]4[C:17]=3[N:8]([CH2:7][CH2:6][CH2:5]4)[CH2:9]2)[CH2:14][CH2:13]1
Reactant: c1cc2c3c(c1)[C@@H]1CCNC[C@@H]1CN3CCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CC[C@H]2c3cccc4c3N(CCC4)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-cis 5,6,8a,9,10,11,12,12a-octahydro-4H,8H-quino[1,8-bc]-2,7-naphthyridine free base from EXAMPLE 124 (50 mg, 0.22 mmol) in 10 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.05 mL, 0.58 mmol) and sodium triacetoxyborohydride (0.19 g, 0.87 mmol) and a couple drops of acetic acid. The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue (40 mg, 0.16 mmol) was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.25 mL, 0.5 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford the title compound of EXAMPLE 126 as an off white powder. LRMS (ES)+: 243.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[Br:18].NC1C2C(=[O:34])C3C(=CC=CC=3)C(=O)C=2C(Br)=CC=1.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(O)=CC=1>NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:34])=[CH:4][C:3]=1[Br:18]
Reactant: Nc1c(Br)ccc2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: Nc1c(O)ccc2c1C(=O)c1ccccc1C2=O
Agent: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
The progress of the bromination may be followed by thin layer chromatography or high pressure liquid chromatography so as to insure that the byproducts, 1-amino-2-bromoanthraquinone and 1-amino-4-bromoanthraquinone, represent less than 1% of the product mixture. This is essential, since hydroxylation of these two products results in 1-amino-2-hydroxyanthraquinone and 1-amino-4-hydroxyanthraquinone respectively. Both products are isolated along with the desired 1-amino-2-bromo-4-hydroxyanthraquinone and therefore give rise to a product with unsatisfactory quality.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 115 and isolated as a white solid (48 mg, 69%). 1H NMR (CDCl3): 8.79 (dd, J=1.8, 4.5 Hz, 2H), 8.30 (dd, J=1.8, 4.5 Hz, 2H), 7.97 (s, 1H), 7.46 (s, 1H), 6.99 (dd, J=1.5, 8.1 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])=[CH:11][C:10]=1[O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28].[Mn]([O-])(=O)(=O)=O.[K+].[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][C@H:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][OH:16])=[CH:11][C:10]=1[O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28]
Reactant: COCCCOc1cc(C[C@@H](C(=O)O)C(C)C)ccc1OC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](CO)C(C)C)ccc1OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A 100-ml flask is charged under inert atmosphere (nitrogen) with 500 mg (13.18 mmol) of lithium aluminium hydride and 15 ml of THF. The suspension is heated to 40° C., and 2.045 g (6.59 mmol) of (R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-butanoic acid dissolved in 5 ml of THF are added. The mixture is maintained at 40° C. and stirred for two hours, monitoring the course of the reaction by TLC (ethyl acetate:mixture of hexanes 7:3; Rf acid=0.5; Rf alcohol=0.6; spot detecting system with potassium permanganate and UV at 254 nm). At the end of reaction the mixture is cooled to room temperature and 0.5 ml of water, 0.5 ml of a 15% w/w solution of NaOH and another 0.5 ml of water are added dropwise. The mixture is diluted with toluene, filtered on Celite and concentrated to constant residue, obtaining 1.90 g (yield 97%) of product in the form of a colourless dense oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:22])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
4-(4-Chloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (26 g) was dissolved in CH2Cl2 (350 mL). 4M HCL/Dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was concentrated. The white solid was washed with Et2O. After the white solid was treated with 1N NaOH (200 mL) and extracted with Ethyl acetate (3×100 mL), the combined organic phase was dried over Na2SO4 and concentrated to give 17.79 g of desired product (99% yield). 1H-NMR (for HCl salt) (300 MHz, MeOD): δ 2.80-2.90 (m, 4H), 3.20-3.80 (m, 4H), 7.29-7.36 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>>[O:23]1[CH:27]=[CH:26][C:25]([NH:28][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])=[N:24]1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Nc1ccon1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccon1

Procedure:
Same procedure as described in preparation 133a was used from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (854 mg, 2.17 mmols) and isoxazol-3-amine (0.48 ml, 6.50 mmols). The title compound was obtained (919 mg, 55% purity, 64%).
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12](=[NH:15])[N:11]([CH2:16][C:17](OC)=O)[N:10]=1.O=P(Cl)(Cl)[Cl:23]>ClC1C=CC=CC=1>[Cl:23][C:17]1[N:15]=[C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])=[N:10][N:11]2[CH:16]=1
Reactant: COC(=O)Cn1nc(-c2ccccc2F)ccc1=N
Reactant: O=P(Cl)(Cl)Cl
Agent: Br
Solvent: Clc1ccccc1
Product: Fc1ccccc1-c1ccc2nc(Cl)cn2n1
Temperature: 120 °C
Yield: 85.5 %

Procedure:
To a solution of methyl 2-(3-(2-fluorophenyl)-6-iminopyridazin-1(6H)-yl)acetate hydrobromide (0.5 g, 1.46 mmol) in chlorobenzene (20 mL) is added POCl3 (7.30 mmol). The reaction mixture is heated at 120° C. for 4 hours, cooled, concentrated under reduced pressure to dryness and sat. aqueous NaHCO3 (25 mL) is added. The mixture is extracted with CH2Cl2 (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via silica chromatography (hexanes to EtOAc) to afford the title compound (0.309 g, 85%) as a white solid: Rf 0.39 (1:4 EtOAc:hexanes); LCMS (m/z)=248.2, 250.2 [M+H]+, tR=2.51 min.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]([OH:37])[CH2:6][C:7]2[N:8]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=[CH:10][N:11]=2)=[CH:34][CH:33]=1
Reactant: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
Butyllithium (1.6M in hexanes) (4.24 mL, 6.78 mmol) was added dropwise to 2-methyl-1-trityl-1H-imidazole (Intermediate 85) (2.0 g, 6.16 mmol) in THF (30 mL) cooled to −78° C. over a period of 20 minutes under nitrogen. The resulting dark red solution was stirred at −78° C. for 30 minutes then a solution of 4-Chlorobenzaldehyde (0.867 g, 6.16 mmol) in THF (10 mL) added dropwise. The reaction was allowed to warm slowly to 0° C. then quenched with saturated NH4Cl (50 mL) and extracted with TBME (2×). The combined extracts were washed with brine, dried over MgSO4, concentrated by evaporation then purified by flash silica chromatography, elution gradient 20 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanol (1.810 g, 63.1%) as a colourless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][O:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:34][O:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][N:40]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:18]([O:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:19]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: COC(=O)CCCNc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.600 ml) and DMF (0.01 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.393 g) in anhydrous dichloromethane (5 ml). The reaction was stirred at room temperature for 1 h then a solution of 4-(2-fluoro-phenylamino)-butyric acid methyl ester (0.422 g) in dichloromethane (1.5 ml), DMAP (0.006 g) and DIPEA (0.522 ml) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:cyclohexane (4:1 v/v), to give the title compound as a colourless gum (0.287 g).
Reaction SMILES: [Al](Cl)(Cl)Cl.[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>ClCCl.C(OCC)C>[F:12][C:13]1[CH:18]=[C:17]([C:5](=[O:11])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[CH:16]=[CH:15][C:14]=1[F:19]
Reactant: O=C1C=CC(=O)O1
Reactant: Fc1ccccc1F
Agent: Cl[Al](Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)/C=C/C(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
Aluminum chloride anhydrous (32.6 g, 0.245 mol.) was added at room temperature and under dry nitrogen atmosphere, to a solution of maleic anhydride (9.6 g, 0.098 mol.) and difluorobenzene (20 ml, 0.195 mol.) in dry dichloromethane. The reaction mixture was heated to reflux for 4 hours; then cooled and quenched with ice/37% hydrochloric acid (100 g/100 mL). Dichloromethane (200 mL) was added, the phases separated and the aqueous layer was extracted twice with dichloromethane (50 mL), the collected organic extracts were washed with 2N HCl and then with brine. The resulting solution was dried (Na2SO4) and evaporated in vacuo to provide the crude product, as deep yellow oily material, which was dissolved in diethyl ether (60 mL). The organic phase was extracted with saturated sodium bicarbonate solution (150 mL), the collected aqueous layers were washed with diethyl ether and cooled at 0° C., then to the alkaline aqueous solution, 37% hydrochloric acid was added on stirring until the pH was 2. The obtained suspension was extracted with ethyl acetate (3×100 mL); the collected organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to provide a yellow solid (11 g). Crystallisation from toluene provided the pure titled compound (7.6 g, 40%) melting at 107-108° C.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:16][NH2:17])[CH2:5][CH2:4]1)=[O:2].[Cl:23][C:24]1[C:25](=[O:31])[NH:26][N:27]=[CH:28][C:29]=1Cl.C(N(CC)CC)C.C(O)CC>O>[Cl:23][C:24]1[C:25](=[O:31])[NH:26][N:27]=[CH:28][C:29]=1[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:8][CH2:7]2)[CH:14]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COc1ccc(CN)cc1OCCCN1CCN(C=O)CC1
Solvent: O
Solvent: CCCO
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cn[nH]c(=O)c2Cl)cc1OCCCN1CCN(C=O)CC1
Reaction time: 14 h
Yield: 47 %

Procedure:
A mixture comprising 11.58 g of 3-[3-(4-formylpiperazin-1-yl)-propoxy]-4-methoxybenzylamine, 5.0 g of 4,5-dichloro-3(2H)-pyridazinone, 4.6 g of triethylamine, 50 ml of n-propanol and 50 ml of water, was refluxed under heating with stirring for 14 hours. The solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.21 g of the above-identified compound as slightly yellow white solid.