Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1>>[CH3:24][O:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 22 using 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 5-amino-2-methoxypyridine (Aldrich), and isolated as a yellow solid (80%). LCMS (API-ES) m/z 310 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.74 (br. s., 1H) 8.77 (dd, J=5.02, 2.51 Hz, 1H) 8.53 (br. s., 1H) 8.29 (br. s., 1H) 8.08-8.23 (m, 1H) 7.84 (br. s., 1H) 7.71 (br. s., 1H) 6.88 (ddd, J=7.78, 4.27, 4.02 Hz, 1H) 6.82 (dd, J=8.78, 4.27 Hz, 1H) 3.84 (d, J=5.02 Hz, 3H) 2.42 (d, J=4.02 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1cccc(Cl)c1
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1cccc(Cl)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
2.34 g of 5-(3-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.39 g of 3-chloro-5-(3-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xx) of the present invention).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12]C)=[CH:6][CH:5]=2.B(Br)(Br)Br.[OH-].[Na+]>O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([OH:12])=[CH:6][CH:5]=2
Reactant: COc1ccc2[nH]c(C)c(C)c2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]c2ccc(O)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 2,3-dimethyl-5-methoxyindole (175 mg, 1 mmol), (J. Chem. Soc. 1957, 3175–3180) in methylene (5 ml) cooled at −60° C. was added boron tribromide (210 μl, 2.2 mmol) dropwise. After completion of addition, the mixture was left to warm up to ambient temperature and was stirred for 1 hour. Water was added and the pH was adjusted to 6 with 2N sodium hydroxide. The mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give 2,3-dimethyl-5-hydroxyindole (124 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:33](Cl)(Cl)=[O:34]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:33]2=[O:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2Cn2c(=O)oc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {2′-[(2-hydroxy-phenylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 30.0 g. of 4-(p-chlorocinnamamido)benzoic acid, ethyl ester, 500 mg. of 10% palladium on carbon, and 150 ml. of tetrahydrofuran is hydrogenated in a Parr apparatus, over a 2 hour period, repressurizing until hydrogen uptake is complete. The mixture is filtered, and the filtrate is evaporated. The solid is crystallized from 175 ml. of ethanol, giving 26.8 g. of the desired product as white crystals, m.p. 163°-165° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]3)=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[F:27][C:24]([F:25])([F:26])[CH:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=3[CH:11]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc2cc(OCCN3CCC(C(F)(F)F)CC3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(OCCN3CCC(C(F)(F)F)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-trifluoromethylpiperidine hydrochloride (1 g, 5.3 mmol) in THF (20 mL) was added methylbromoacetate (0.52 mL, 5.5 mmol) and triethylamine (2.2 mL, 15.8 mmol). The reaction was heated at reflux for 4 h and then diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester as a brown oil (1.19 g, 98%). MS 226 (M+H)+. To a solution of (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester (1.19 g, 5.3 mmol) in THF (15 mL) at 0° C. was added portion wise lithium aluminium hydride (0.4 g, 10.6 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4-trifluoromethylpiperidin-1-yl)-ethanol as a brown oil (1.0 g, 99%). MS 198 (M+H)+. To a solution of diisopropylazodicarboxylate (0.58 mL, 2.28 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (1.14 g, 3.4 mmol). The reaction was stirred at RT for 10 mins. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.47 g, 2.3 mmol) and 2-(4-trifluoromethylpiperidin-1-yl)-ethanol (0.45 g, 2.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (548 mg, 62%). MS 386 (M+H)+. To a solution of 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (548 mg, 1.42 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 2.84 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 358 (M+H)+ which was used directly for coupling with H2N-Leu-P1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=O.[CH3:17][C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([NH:24][C:21]1[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][N:22]=1)=[O:7]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1

Procedure:
It will be appreciated by those skilled in the art that the sequence of steps in the processes described above may be performed in a different order for example 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid may be reacted with 5-methylpyrazine-2-amine to give (S)-3-hydroxy-5-(1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)benzamide, for example as described below. The conversion of (S)-3-hydroxy-5-(1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)benzamide into 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide may be carried out as described in WO2007/007041.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][CH2:14][O:15][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>CCO>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:2]3[C:11]4[CH:10]=[C:9]5[O:12][CH2:13][CH2:14][O:15][C:8]5=[CH:7][C:6]=4[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:27]=2)[CH:23]=[N:24]1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)OCCO3
Reactant: Nc1ccc2cn[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc2cn[nH]c2c1)OCCO3
Yield: 75.9 %

Procedure:
A mixture of 1.00 g (4.07 mmol) of 9-chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile and 0.649 g (4.88 mmol) of 6-aminoindazole in 25 mL of EtOH was refluxed under N2 for 5.7 h. Satd NaHCO3 was added and the solvent was removed. The residue was slurried with H2O, filtered, washed with H2O and cold EtOH and dried. The crude product was boiled with EtOH, filtered and dried in vacuo (50° C.) to yield 1.06 g of 9-(1H-indazol-6-ylamino)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile as tan crystals: mass spectrum (electrospray, m/e): M+H 344.3.