Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[N+:23]([O-])=O)([O-])=O.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:23][C:15]1[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=1[O:13][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(N)cc2N)c(N)c1
Yield: 24 %

Procedure:
The dinitro compound obtained from Example 7 (22.1 g, 0.035 mole) was mixed with 10% Pd/C (2.2 g) in ethyl acetate/ethanol (6/4 by volume, 88 g) solvent. Hydrogenation was carried out with 50-60 psi of hydrogen pressure at ambient temperature for about 6 hrs. After reaction, the solution was filtered to remove the metal residue and the solvent was removed in vacuo. The final diamino product was purified by distillation, 4.75 g of (24% yield) clear, viscous liquid was obtained. Bp. 120° C./0.02 mm. H1NMR (CDCl3): δ7.61 (d, J=8.0 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 6.02 (dd, J=2 Hz, 8 Hz, 1H), 4.11 (t, J=13.5 Hz, 2H), 3.55 (s, br, 4H, --NH2); F19NMR (CDCl3): -71.3 (m, 2F), - 77.5 (m, 1F), -80.2 (m, 3F), -82.3 to -86.0 (m, 4F), -124.0 (m, 2F), -146.2 (m, 1F).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][CH2:17][C:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][CH2:17][C:18]3([CH2:21][OH:22])[CH2:20][CH2:19]3)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: NCC1(CO)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnn2cc(Br)cc2c1NCC1(CO)CC1
Yield: 73.7 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 45 mg, 0.164 mmol), (1-(aminomethyl)cyclopropyl)methanol HCl salt (25.9 mg, 0.189 mmol) and DIPEA (0.072 mL, 0.410 mmol) in NMP (0.5 mL) was heated to 110° C. for 1 hr. The reaction mixture was purified on preparative HPLC to afford the title compound (41 mg, 74%). HPLC (condition G): retention time=2.73 min. LCMS (condition B): m/z 339.1, 341.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](I)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:16]([OH:19])[C:17]#[CH:18]>C(NCC)C.[Cu]I.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>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:18]#[C:17][CH2:16][OH:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
To a stirred solution of 3,5-bistrifluoromethyliodobenzene (which may be prepared as described by S. D. Ross et al, J. Amer. Chem. Soc. (1953), 75, 4967-4969; 340.1 g) in anhydrous diethylamine (665 ml), cooled to 10° C. and under an inert atmosphere, there were added successively copper (I) iodide (1.81 g) and dichlorobis(triphenylphosphine)palladium (3.51 g). 2-Propyn-1-ol (57.8 g) was then added dropwise over 20 minutes and the reaction mixture was then maintained, with stirring, at 25° to 30° C. for 4 hours. The reaction mixture was then maintained overnight, with stirring, at ambient temperature. The solvent was removed by evaporation under reduced pressure (water-pump) and the crystalline residue was partitioned between diethyl ether (670 ml) and water (200 ml). The ether layer was separated, washed with water (2×200 ml), dried over anhydrous sodium sulphate and evaporated under reduced pressure (water-pump). The solid residue thus obtained was distilled to give 1-(3,5-bistrifluoromethylphenyl)-prop-1-yn-3-ol, in the form of a white crystalline solid (231.7 g), m.p. 58°-60° C., b.p. 87°-91° C./1 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH4+].[OH-]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[OH:24])[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Temperature: 120 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (2.43 g), 2-amino-5-fluorophenol (2.43 g) and p-toluenesulfonic acid (190.0 mg) were dissolved in dioxane (50.0 ml) and heated at 120° C. for 4 h under nitrogen. The reaction mixture was allowed to cool and treated with 3M NH4OH. The resultant suspension was filtered, the solid was washed with ether and dried in vacuo at 60° C. over P2O5.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[N:5][N:4]=[C:3]1[SH:10].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[C:21]2[N:25]([C:26]=1[C:27](O)=O)[CH:24]=[CH:23][O:22]2.O=P(Cl)(Cl)Cl>C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[C:21]2[N:25]([C:26]=1[C:27]1[S:10][C:3]3=[N:4][N:5]=[C:6]([CH:7]([CH3:9])[CH3:8])[N:2]3[N:1]=1)[CH:24]=[CH:23][O:22]2
Reactant: O=C(O)c1c(-c2ccc(F)cc2F)nc2occn12
Reactant: CC(C)c1nnc(S)n1N
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc2sc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 0 °C
Yield: 15 %

Procedure:
A 5 mL round-bottomed flask equipped with a reflux condenser outfitted with a nitrogen inlet adapter was charged with 4-amino-5-isopropyl-4H-1,2,4-triazole-3-thiol (0.15 g, 0.95 mmol, Enamine) and 6-(2,4-difluorophenyl)imidazo[2,1-b]oxazole-5-carboxylic acid (0.25 g, 0.95 mmol) in POCl3 (3.5 mL, 38 mmol) to give a tan suspension. The reaction mixture was heated at about reflux for about 18 h, allowed to cool, and then poured over stirring ice water. The mixture was diluted with DCM and the layers were separated. The organic layer was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to provide a white solid (0.055 g) which was dissolved in a minimal amount of hot ACN and left to cool to ambient temperature for about 2 h. The resulting crystals were isolated by filtration, washed with ACN, and dried under vacuum to give the title compound (0.020 g, 5%): LC/MS (Table 1, Method b) Rt=1.95 min; MS m/z: 387.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H]>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:10]([OH:11])=[O:9])=[CH:18][CH:19]=1
Reactant: COc1ccc(C=C2OC(=O)c3ccccc32)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CCc2ccccc2C(=O)O)cc1

Procedure:
To 280 ml of an ethanol solution containing 20.0 g (79.3 mmol) of 3-(4-methoxybenzylidene)phthalide were added 16.6 ml (119 mmol) of triethylamine and Raney nickel (available from Kawaken Finechemical, developed nickel catalyst NTD-65, 24 ml), and the resulting mixture was stirred at 80° C. for 2.5 hours under pressure with hydrogen (10 atm).
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH2:20][C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)[N:13]=1)=[O:11])([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[CH3:1][C:2]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:30]2[CH2:31][C:28]([F:32])([F:27])[CH2:29]2)=[C:14]([O:19][CH2:20][C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)[N:13]=1)=[O:11])([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]
Reactant: FC1(F)CNC1
Reactant: CC1(COc2nc(C(=O)NC(C)(C)c3nccs3)ccc2Br)COC1
Agent: Cl
Product: CC1(COc2nc(C(=O)NC(C)(C)c3nccs3)ccc2N2CC(F)(F)C2)COC1

Procedure:
The title compound was synthesized in analogy to Example 288b, using 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide (Example 281c) and 3,3-difluoroazetidine hydrochloride as starting materials, MS (EI): m/e=439.3 [M+H]+.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].Cl.Cl[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:12]=1)=[O:10]>CO>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]([NH:5][C:4]([NH2:6])=[NH:3])=[O:10])=[CH:12]1
Reactant: O=C(Cl)c1cn(-c2ccc3ccccc3n2)c2ncccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2ccc3ccccc3n2)c2ncccc12

Procedure:
0.477 g (20.73 mmol) of sodium (washed beforehand in toluene) was gradually added to 40 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolving with stirring, 2.021 g (20.74 mmol) of guanidine hydrochloride were added and the mixture was stirred at a temperature in the region of 20° C. for 2 h. The reaction mixture was filtered and then concentrated to dryness under reduced pressure (2.7 kPa), and the residue was subsequently taken up in a mixture of 70 cm3 of tetrahydrofuran and 70 cm3 of dichloromethane under an argon atmosphere at a temperature in the region of 20° C. 3.46 mmol of 3-chlorocarbonyl-1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride were added thereto with stirring. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The solid residue was taken up in 100 cm3 of water and stirred for 2 h and then the insoluble material was filtered off. The solid obtained was dried and then triturated in 20 cm3 of cyclohexane. The solid was filtered off and then dried at a temperature in the region of 20° C. under reduced pressure (2.7 kPa), and 0.921 g of N-[1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine was thus obtained in the form of a light yellow solid melting at 242° C. 1H N.M.R. spectrum (300 MHz, (CD3)2SO, δ in ppm): from 6.20 to 7.30 (very broad unresolved peak, 2H), 7.39 (dd, J=8 and 5 Hz, 1H), 7.63 (broad t, J=7.5 Hz, 1H), 7.84 (broad t, J=7.5 Hz, 1H), 8.03 and 8.07 (2 broad d, J=7.5 Hz, each 1H), 8.48 (dd, J=5 and 1.5 Hz, 1H), 8.64 (d, J=9 Hz, 1H), 8.89 (dd, J=8 and 1.5 Hz, 1H), 9.06 (s, 1H), 9.21 (d, J=9 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.C1(C)C=CC(S(O[C@@H:35]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]2)(=O)=O)=CC=1>>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][C@H:35]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 0.665 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.822 g of tert-butyl 3(R)-(toluene-4-sulphonyloxy)pyrrolidine-1-carboxylate are reacted. The title compound is obtained as a white foam. Rf=0.14 (1:1 EtOAc-heptane). Rt=4.91.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][NH2:11])=O)=[CH:4][C:3]1=[O:12].[CH3:13][N:14]=[C:15]=[S:16].[OH-].[Na+]>CO.O>[SH:16][C:15]1[N:14]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:12])[CH:4]=2)=[N:10][N:11]=1
Reactant: Cn1ccc(C(=O)NN)cc1=O
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(S)nnc1-c1ccn(C)c(=O)c1
Reaction time: 0.25 h

Procedure:
The title compound of example 31.1 (1.0 g, 5.98 mmol) was stirred in methanol (6 mL) at 60° C. Methyl isothiocyanate (481 mg, 6.58 mmol) was dissolved in methanol (2 mL) and added to the reaction mixture which was stirred for 15 min. After 15 min a solution of sodium hydroxide (263 mg) in water (2 mL) was added to the reaction mixture which was kept stirring at 60° C. overnight. The reaction mixture was then concentrated in vacuo to remove the methanol and the remaining residue was stirred in 3 M HCl (aq) to precipitate the product which was collected by vacuum filtration (off-white powder, 1.2 g, 90%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=[CH:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1=CC=CNC=C1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and azepine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.86 (s, 1H), 3.3-3.8 (m, 16H), 1.95 (m, 4H), 1.75 (m, 4H); MS (DCI) m/z 434 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:17][C:18]([O:20]C)=O)[C:13](OC)=[O:14])=[C:4](Cl)[N:3]=1.[BH4-].[Li+].[OH2:25]>C(O)(C)(C)C>[OH:20][CH2:18][CH2:17][CH:12]([CH2:13][OH:14])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:25])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: O
Reactant: COC(=O)CC(Cn1cnc2c(Cl)nc(N)nc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)(C)O
Product: Nc1nc2c(ncn2CC(CO)CCO)c(=O)[nH]1
Reaction time: 1 h

Procedure:
Dimethyl 2-(2-amino-6-chloropurin-9-ylmethyl)succinate (8.00 g, 0.0244 mol) was dissolved in 200 ml of tert. butanol at 50° C., lithium borohydride (2.66 g, 0.122 mol) was added in portions, and the mixture was stirred for 1 h. Then 100 ml of water was added and the stirring was continued over-night, the inorganic salts were filtered off and the solution was evaporated to dryness in vacuum. The residue was found to contain 78 mole-% of 2-amino-6-tert.butoxy-9-[4-hydroxy-2(hydroxymethyl)butyl]purine together with the 6-chloro compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][C:64]([N:66]2[CH2:70][CH2:69][CH2:68][CH2:67]2)=[O:65])[CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][C:64](=[O:65])[N:66]2[CH2:67][CH2:68][CH2:69][CH2:70]2)[CH2:58][CH2:57]1)=[O:5]
Reactant: O=C(COC1CCNCC1)N1CCCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CCCC1
Reaction time: 2 h

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 2-(piperidin-4-yloxy)-1-(pyrrolidin-1-yl)ethanone (106) (0.142 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH+) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.168 g, 50.9%); 1H NMR (400.132 MHz, CDCl3) δ 1.90-1.56 (m, 6H), 2.01-1.93 (m, 2H), 3.16-3.07 (m, 1H), 3.57-3.42 (m, 6H), 3.72 (septet, J=3.6 Hz, 1H), 4.06-4.00 (m, 1H), 4.12 (q, J=11.9 Hz, 2H), 4.26 (s, 2H), 7.02 (t, J=8.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.79-7.70 (m, 3H), 8.47-8.44 (m, 1H), 10.01-9.97 (m, 1H); m/z (LC-MS, ESI+), RT=1.66 (M+H 493).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:33]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:26]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]4=[O:33])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCCCC4=O)cc3F)CC2)c(C)c1
Yield: 19 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and azepan-2-one (58 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (41 mg) was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[C:54]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1B(O)O)(=[O:56])[CH3:55]>>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]([F:53])=[C:40]([CH:26]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[C:4]2[N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:6]=[C:2]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=3[C:54](=[O:56])[CH3:55])[N:3]=2)[CH:45]=1)[CH3:48]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)c1ccccc1B(O)O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(C)=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1

Procedure:
According to the procedure for Intermediate 93.4, Intermediate 66.3 was coupled with 2-acetylphenylboronic acid to afford Intermediate 111.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:20])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCO>CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([NH:11][C:12](=[O:20])[CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(NC(=O)CN2CCOCC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1c(N)cccc1NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(2-Methyl-3-nitrophenyl)-2-morpholinoacetamide (0.25 g, 0.9 mmol) was dissolved in 20 ml of MeOH, and to this was added a slurry of 10% Pd/C (0.025 g) in a minimal amount of EtOH. The reaction vessel was evacuated and purged with H2, and the reaction was stirred at room temperature for 16 hours. The mixture was purged with N2 for 30 minutes and then filtered through a pad of celite. Solvent evaporation afforded N-(3-amino-2-methylphenyl)-2-morpholinoacetamide as a gray solid. MS m/z=250.1 [M+H]+; Calc'd for C13H19N3O2: 249.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](I)[CH:14]=[C:15]([F:21])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH2:29])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[CH:29]/[C:13]2[CH:14]=[C:15]([F:21])[CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])=[CH:26][CH:25]=1
Reactant: Oc1nc(Nc2ccc(Cl)c(Cl)c2)nc2c(I)cc(F)cc12
Reactant: C=Cc1ccc(C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(/C=C/c2cc(F)cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1
Temperature: 120 °C

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-6-fluoro-8-iodoquinazolin-4-ol (45 mg) and palladium acetate (13.5 mg) in dimethylformamide (1.3 mL) was added 4-methylstyrene (26 μL), diisopropylethylamine (200 μL) and tri-o-tolylphosphine (12 mg). The resulting mixture was heated at 120° C. for 3 h. The mixture was then cooled to room temperature and the supernatant was removed by pipette from the settled black solids. The solvent and the excess volatile reagents were removed in vacuo, providing the crude product as a brown solid. This residue was triturated with 50% (v/v) methanol/dichloromethane (3 mL) and the resulting yellow solid was dried in vacuo to afford the title compound (25.1 mg). 1H NMR (300 MHz, DMSO-d6): δ11.24 (brs, 1H), 9.12 (brs, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.04 (dd, J=3 & 10.2 Hz, 1H), 7.91 (d, J=16.8 Hz, 1H), 7.62-7.56 (m, 4H), 7.47 (d, J=16.8 Hz, 1H), 7.36 (dd, J=2.4 & 9 Hz, 1H), 7.31 (d, J=6 Hz, 2H), 2.34 (s, 3H). MS (APCI+): m/z 440.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:8][CH2:9][CH3:10])[N:3]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[N:6]([CH2:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:20])[C:5](=[O:7])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:8][CH2:9][CH3:10])[N:3]=1
Reactant: CCCC1(c2ccccc2)N=C(C)NC1=O
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 70 °C
Yield: 55.7 %

Procedure:
(+/−)-2-Methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (541 mg, 2.5 mmol) and 2-bromo-1-(4-nitro-phenyl)-ethanone (707 mg, 2.8 mmol) and potassium carbonate (698 mg, 5 mmol) are dissolved in 5 mL acetone and the reaction mixture is heated at 70° C. for 10 min in the microwave oven (Biotage Initiator). The mixture is cooled to room temperature filtered and the filtrate evaporated. The residue is subjected to flash chromatography (cyclohexane/ethyl acetate-gradient, ethyl acetate 0-100% in 20 min) to yield (+/−)-2-methyl-3-[2-(4-nitro-phenyl)-2-oxo-ethyl]-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (528 mg, 56%). LC/MS at 254 nm; [M+H] 380; Rt 2.959 min.