Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][CH:41]=[CH:42][C:35]=12)[NH2:29].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]4[NH:40][CH:41]=[CH:42][C:35]=34)=[C:26]([F:25])[CH:27]=2)[N:3]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1.05 g (2.89 mmol) of benzyl 3-(2-amino-6-chloropyrimidin-4-yl)piperidine-1-carboxylate (from example LXXII) and 0.75 g (2.89 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XIX) are suspended in 35 ml of water and 4 ml of ethanol. 0.29 ml (3.47 mmol) of 37% strength hydrochloric acid is added. The mixture is stirred at 100° C. for 18 hours. After cooling, the mixture is neutralized using a saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate (in each case 30 ml). The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified on a silica gel column using dichloromethane/methanol 20:1. This gives 1.38 g (86% of theory) of product.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[Br:24]Br.[OH-].[Na+]>CC(O)=O>[Br:24][C:3]1[C:4]([CH3:23])=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:6][C:2]=1[Br:1]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(Br)c3C)c(C)nc12
Temperature: 110 °C
Yield: 55.3 %

Procedure:
To a solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (4.00 g, 10.20 mmol) and AcOH (40 mL) is added Br2 (0.57 mL, 11.21 mmol) and the solution heated at 110° C. overnight. Br2 (0.57 mL, 11.21 mmol) is added and the solution heated at 110° C. for 2 hours. The solution is poured into 5 M NaOH (200 mL) and ice (200 mL). The slurry is extracted with EtOAc (2×150 mL). The combined organic layers are washed with water (200 mL), 20% NaHSO3 (200 mL), sat. NaHCO3 (200 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (5%-15% EtOAc gradient) furnish the title compound (2.66 g, 5.64 mmol, 55%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.72-1.91 (m, 4H), 2.12 (s, 3H), 2.43 (s, 3H), 2.50 (s, 3H), 3.25-3.35 (m, 1H), 6.69 (s, 1H). LC/MS (m/z): calcd. for C18H21Br2N3S (M+H)+: 470.0; found: 470.3.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC[C@@H]1[C@H](CC(=O)OC)CC[C@@H]1O
Solvent: CO
Product: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)OC

Procedure:
The intermediate methyl (-)-(1S,2R,3S)-3-hydroxy-2-pentyl-1-cyclopentane acetate presented a [α]20D =-16° (c=1.805, methanol)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH2:12].[CH2:13]([O:15][C:16](=[O:24])[C:17]#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16](=[O:24])[C:17]([NH:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[Cl:1])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14]
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=C(Nc1cc(C(=O)OC)ccc1Cl)C(=O)OCC
Temperature: 90 °C

Procedure:
To a solution of 22 (5.00 g, 26.9 mmol) in ethanol (50 mL) was added but-2-ynedioic acid diethyl ester (5.02 g, 29.5 mmol) at room temperature. The reaction mixture was heated at 90° C. for 18 h and then cooled to room temperature. The solvent was removed under reduced pressure. The crude residue was washed with a solution of 1:1 Hexanes/diethyl ether (100 mL) to afford a white solid (23, 9.08 g, 95.1%). 1H NMR (DMSO-d6, 300 MHz) δ ?9.80 (s, 1H), 7.65-7.66 (m, 2H), 7.38 (s, 1H), 5.54 (s, 1H), 4.13-4.22 (m, 4H), 3.83 (s, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:13][CH2:14][CH3:15])=[N:9][C:8](=S)[N:7]([CH2:17][CH3:18])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[OH-].[Na+].[Ni]>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][CH2:14][CH3:15])[N:9]=[CH:8][N:7]3[CH2:17][CH3:18])[CH2:3][CH2:2]1
Reactant: CCNc1nc(=S)n(CC)c2nc(C3CC3)[nH]c12
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CCNc1ncn(CC)c2nc(C3CC3)nc1-2
Temperature: 25 °C

Procedure:
The product of step (i) (11.85 g) was dissolved in 2N NaOH (270 ml) and 10N NaOH (27 ml) and heated to 65° C. Within 1.25 hours 50% Ni—Al alloy (518 mmoles of Ni and 1125 mmoles of Al) (60.8 g) was added under vigorous string at 65-70° C. After a further 0.75 hr at the same temperature the reaction mixture was cooled to room temperature and treated with chloroform (400 ml). The nickel was filtered off and washed with 350 ml of chloroform and 150 ml of water. The filtrate was separated and the chloroform layer evaporated to dryness. The residue (19.64 g) was dissolved in acetone (100 ml), treated with 2 portions of charcoal (0.15 g) filtered, and evaporated. The residue was treated with diethylether (100 ml) and crystals collected (6.10 g), mp 80-96° C. A second crop gave 1.25 g. A recrystallized sample from diisopropylether had mp 103-105° C.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>CN(C)C=O>[NH:24]1[CH:25]=[C:21]([CH2:20][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[N:22]=[CH:23]1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 5.80 g. portion of diphenylacetonitrile and 1.5 g. of 50% sodium hydride were reacted for 30 minutes in 20 ml. of dimethylformamide, and 2.29 g. of 4-chloromethylimidazole hydrochloride in 20 ml. of dimethylformamide was added. The reaction mixture was stirred at ambient temperature for about 15 minutes, the solvent was evaporated from the mixture under vacuum, and the residue was worked up as described in Example 1 to obtain 3.0 g. of the desired product as the free base, which was identified by 60 mHz nuclear magnetic resonance analysis in CDCl3, showing the following characteristic peaks: δ9.05 (broad m, 1H); 7.32 (m, 11H); 6.60 (s, 1H); 3.68 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[CH3:28][C:29]([CH:35]1[CH2:40][O:39][CH2:38][CH2:37][NH:36]1)([CH3:34])[CH2:30][C:31]([OH:33])=[O:32]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:35]2[C:29]([CH3:34])([CH3:28])[CH2:30][C:31]([OH:33])=[O:32])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)(CC(=O)O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(C)(C)CC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 41 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with 3-methyl-3-(morpholin-3-yl)butanoic acid hydrochloride (1.34 g, 6 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (1.5 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:45]([O:47]CC1C=CC=CC=1)=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]>C(O)(=O)C>[NH2:1][C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:35])[NH2:36])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH3:40][C:45]([OH:47])=[O:46].[CH3:40][C:45]([OH:47])=[O:46]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)CC
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](N)CCCNC(=N)N)[C@@H](C)CC)C(=O)O

Procedure:
510 mg of Z-D-Arg-Ile-Leu-Arg-Ile-OBzl are catalytically hydrogenated in 15 ml of 90% acetic acid in analogy to Example 1b.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[N:12]([CH2:15][C:16](OCC)=[O:17])=[C:13]=[O:14]>C(Cl)Cl>[O:14]=[C:13]1[NH:12][CH2:15][C:16](=[O:17])[N:10]1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:11]
Reactant: COC(=O)c1cccc(N)c1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Product: O=C(O)c1cccc(N2C(=O)CNC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13 mmol of methyl-3-aminobenzoate were dissolved in 20 ml DCM and 1.7 ml of ethyl isocyanatoacetate added. The reaction mixture was stirred at rt for 1 h. The solvent was evaporated and the resulting crude taken up in 50 ml acetone. 50 ml of aq. HCl (25%) were added and heated to reflux for 8 h. After evaporation of the organic layer the resulting solid was filtered off, washed with water and dried under vacuum. MS(ISO): 219.2 (M−H+)
Reaction SMILES: [C:1]([CH:3]([C:13](=O)[CH2:14][CH3:15])[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)#[N:2].[NH2:17][NH2:18]>CCO>[NH2:2][C:1]1[NH:18][N:17]=[C:13]([CH2:14][CH3:15])[C:3]=1[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: CCC(=O)C(C#N)Cc1ccc(C#N)cc1
Reactant: NN
Solvent: CCO
Product: CCc1n[nH]c(N)c1Cc1ccc(C#N)cc1
Reaction time: 0.5 h

Procedure:
To a 500 ml, four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged 4-(2-cyano-3-oxopentyl)benzonitrile (25) (5 g, 23.6 mmol) and 50 ml of EtOH. The solution was stirred and hydrazine (1.65 g, 33 mmol, 64%, 1.4 eq) was added. The batch was stirred at 65° C. for 3 hours. The solvent was concentrated by vacuum and the residue was slurried with 50 ml of MTBE at room temperature for 30 min. The precipitate was collected by vacuum filtration and the solid was washed with MTBE to give product 26 as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:17][B:16](B2OC(C)(C)C(C)(C)O2)[O:15]1.ClCCl.C([O-])(=O)C.[K+]>O1CCOCC1.C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:11][N:10]([CH3:12])[C:8]([C:5]1[N:6]=[CH:7][C:2]([B:16]([OH:17])[OH:15])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(B(O)O)cn1
Temperature: 120 °C
Yield: 63.1 %

Procedure:
A mixture of 5-bromo-N,N-dimethylpyridine-2-carboxamide (23 g, 98 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (27 g, 110 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Aldrich, Catalog No. 379670) (1:1) (4.8 g, 5.9 mmol), 1,1′-bis(diphenylphosphino)ferrocene (Aldrich, Catalog No. 177261) (3.3 g, 5.9 mmol), and potassium acetate (30 g, 300 mmol) in 1,4-dioxane (600 mL) was degassed with nitrogen and was heated at 120° C. for 16 hrs. The mixture was cooled to room temperature and diluted with ethyl acetate (600 mL) and water (600 mL). The aqueous layer was concentrated in vacuo to give a solid residue. The solids were taken up in acetonitrile and filtered to remove the residual insoluble salts. The acetonitrile was removed in vacuo to give {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (12 g, 60%). LCMS calculated for C8H12BN2O3 (M+H)+: m/z=195.1; found: 195.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:24])=[C:4]([CH3:25])[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:24])=[C:4]([CH3:25])[N:3]=1
Reactant: Cc1nc(C)n2nc(/C=C/c3nc(N4CCCC4)nn3C)nc2c1C
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(C)n2nc(CCc3nc(N4CCCC4)nn3C)nc2c1C
Yield: 62.1 %

Procedure:
(E)-5,7,8-Trimethyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-c]pyrimidine (32 mg) and Pd/C (10 mg) were stirred in ethanol (0.4 ml) under hydrogen for 1 h. The mixture was filtered and concentrated to give the product (20 mg, 62.5%) as a white waxy solid. MS: m/z=341.4 (M+H+)
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.[CH2:15]([C@H:17]([NH:21][C:22](=[O:28])OC(C)(C)C)[C:18](=[O:20])[CH3:19])[CH3:16].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:15]([C@@H:17]1[NH:21][C:22](=[O:28])[CH2:1][C@@:18]1([OH:20])[CH3:19])[CH3:16]
Reactant: CC(C)NC(C)C
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1NC(=O)C[C@]1(C)O
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of diisopropylamine (7.50 g) in tetrahydrofuran (110 mL) was ice-cooled under a nitrogen atmosphere, and 1.6 mol/L n-butyllithium-hexane solution (45.4 mL) was added. The mixture was stirred at the same temperature for 30 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (7.17 ml) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hr. A solution of tert-butyl [(1S)-1-ethyl-2-oxopropyl]carbamate (9.75 g) in tetrahydrofuran (60 mL) was added, and the mixture was stirred at the same temperature for 5.5 hr. A saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→30%) and the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (285 mL), and diisopropylethylamine (22.2 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=3→13%), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as colorless crystals (yield: 4.69 g, 68%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20](=[CH2:22])[CH3:21])[CH3:15].Cl>>[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20]([C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])([CH3:22])[CH3:21])[CH3:15]
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Reactant: COc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h

Procedure:
0.8 g of anhydrous aluminum chloride is added to 5 ml of 4-fluoranisole and 0.9 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester. After 40 hours of stirring at room temperature, it is added to ice-cooled 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 1N hydrochloric acid and water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (1:1), 1 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, melting point 38-390° C., is obtained.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:34])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][CH2:20][C:21]3[N:22]([C:27](OC(C)(C)C)=[O:28])[C:23]([CH3:26])=[CH:24][CH:25]=3)[CH:17]=2)[CH:12]=[CH:11]1)(C)(C)C.O.C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH3:26][C:23]1[N:22]2[C:27](=[O:28])[N:19]([C:16]3[CH:17]=[C:18]4[C:13]([CH:12]=[CH:11][N:10]4[CH2:9][C:8]([OH:7])=[O:34])=[CH:14][CH:15]=3)[CH2:20][C:21]2=[CH:25][CH:24]=1
Reactant: Cc1ccc(CNc2ccc3ccn(CC(=O)OC(C)(C)C)c3c2)n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2n1C(=O)N(c1ccc3ccn(CC(=O)O)c3c1)C2
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
NaH (2.0 equiv., 60% in mineral oil) was suspended at 0° C. in THF (6 ml). A solution of tert-butyl 2-((1-(2-tert-butoxy-2-oxoethyl)-1H-indol-6-ylamino)methyl)-5-methyl-1H-pyrrole-1-carboxylate (0.797 mmol, 1.0 equiv.) in THF (2 ml) was added, and the mixture was stirred for 14 h at 25° C. The reaction mixture was hydrolysed with water (50 ml) and diluted with ethyl acetate (100 ml). The aqueous phase was adjusted to an acidic pH value with acetic acid and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was crystallized from the residue with hexane. Yield: 81%
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[N+:22]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C1COCC1.[Pd]>[CH:1]1([CH2:7][NH:8][C:9]2[C:10]([NH2:22])=[CH:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Nc2ccccc2)ccc1NCC1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Nc2ccccc2)ccc1NCC1CCCCC1
Reaction time: 0.05 h
Yield: 75.2 %

Procedure:
To a solution of N1-cyclohexylmethyl-2-nitro-N4-phenyl-benzene-1,4-diamine (0.06 g, 0.18 mmol) in THF (5.00 mL) was added 10% palladium on activated carbon (60 mg). The reaction flask was equipped with a septum and was placed under vacuum for 3 min. The flask was then placed under hydrogen atmosphere (balloon inflated with hydrogen) and the reaction mixture was stirred for 16 h. The palladium was filtered off through a plug of diatomaceous earth and washed with EtOAc. The solvent was removed via rotary evaporation. The resulting residue was flash chromatographed (30% EtOAc/hexanes), providing N1-cyclohexylmethyl-N4-phenyl-benzene-1,2,4-triamine as a purple foam (0.04 g, 75.6% yield). M+, 294.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19](I)[CH:18]=[N:17][C:13]=3[N:14]([CH3:16])[N:15]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH2:30]([OH:33])[C:31]#[CH:32]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19]([C:32]#[C:31][CH2:30][OH:33])[CH:18]=[N:17][C:13]=3[N:14]([CH3:16])[N:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cnc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Under an argon atmosphere, a mixture of N-(4-chlorobenzyl)-6-iodo-1-methyl4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide (Preparation 23, 0.053 g), dichlorobis(triphenylphosphine)palladium (II) (4.1 mg), copper(I) iodide (18.3 mg), and diethylamine (1.5 mL) is treated with a solution of propargyl alcohol (11 μL). The reaction mixture is stirred at room temperature overnight. The mixture is diluted with EtOAc and then filtered through a Celite-packed, sintered-glass funnel. The cake is washed with CHCl3 until the washings are colorless. The organic filtrate is washed with aqueous saturated ammonium chloride and water, dried (Na2SO4) and concentrated in vacuo. The crude solid is triturated with ether, filtered and washed with ether to give 0.032 g (71%) of the title compound as a light brown solid. Physical characteristics: mp 201-206° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.21, 4.39, 4.54, 5.51, 7.40, 8.52, 9.0, 9.7; IR (drift) 3368, 1660, 1612, 1597, 1551, 1479, 1410, 1397, 1377, 1353, 1256, 1036, 812, 674, 650 cm−1; MS (EI) m/z 382 (M+, 6); HRMS (FAB) m/z 383.0917 (C19H15ClN4O3+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.C(N(CC)CC)C.[CH3:34][N:35]1[C:39]([C:40](Cl)=[O:41])=[CH:38][C:37]([CH3:43])=[N:36]1>O1CCCC1>[CH3:34][N:35]1[C:39]([C:40]([NH:1][C:2]2[CH:26]=[CH:25][CH:24]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:41])=[CH:38][C:37]([CH3:43])=[N:36]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CCOCC4)cn3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CCOCC5)cn4n3)c2)n(C)n1
Yield: 26.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]tetrahydro-2H-pyran-4-carboxamide (200 mg, 0.57 mmol), triethylamine (237 mL, 1.70 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (180 mg, 1.13 mmol) and tetrahydrofuran (6.0 mL) as starting materials and in the same manner as in Example 96, the title compound (73 mg, 27%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][CH2:23][CH2:24]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C=C([N+]([O-])=O)C=1C(=O)C1C=CC=CC=1)C(O)=O)C=C>>[CH2:22]([O:21][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([NH2:18])[C:9]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]([OH:15])=[O:14])[CH:23]=[CH2:24]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: C=CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: C=CCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 3-allyloxy-4-benzoyl-5-nitrobenzoic acid, and following the procedure described, 3-allyloxy-5-amino-4-benzoylbenzoic acid is obtained with a melting point of 206.5°-207.5° C.