Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]([F:19])[CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([NH:22][C:13]([C@@H:12]1[CH2:16][CH:17]([F:19])[CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:15])[CH3:21]
Reactant: O=C(O)[C@@H]1CC(F)CN1C(=O)OCc1ccccc1
Reactant: CCN
Product: CCNC(=O)[C@@H]1CC(F)CN1C(=O)OCc1ccccc1

Procedure:
With 3.02 g of the compound obtained in Step 11-2 and 1.16 g of an aqueous solution of 70% ethyl amine as starting material, 1.92 g of the title compound (colorless solid) was obtained by a similar method to Step 10-1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:27]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Si:40](Cl)([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42].[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])([C:22]([F:25])([F:23])[F:24])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:27]=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)cc(C=O)n2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 0.33 g (0.82 mmol) of 1-benzyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-1H-indole-2-carbaldehyde (example 23) in 3 mL of DMF at 0° C. were added 0.15 mL (0.99 mmol) of DBU, followed by 0.17 mL (0.99 mmol) of TESCl. The mixture was stirred at RT overnight and then poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 0.389 g (92%) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole-2-carbaldehyde, MS: 516 (MH+).
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:3]([OH:5])=[O:4].[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][SH:18]>>[C:9]([CH2:8][CH2:7][CH2:6][CH:2]([S:18][CH2:17][CH2:16][C:15]([O:14][CH3:13])=[O:19])[C:3]([OH:5])=[O:4])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCCC(Br)C(=O)O
Reactant: COC(=O)CCS
Product: COC(=O)CCCC(SCCC(=O)OC)C(=O)O

Procedure:
5-Carbomethoxypentanoic acid (12), wherein alk is methyl, was reacted with thionyl chloride and then N-bromosuccinimide (NBS) followed by base hydrolysis to give 2-bromo-5-carbomethoxypentanoic acid (13). Compound (13) was reacted with methyl-3-mercaptopropionate (m=1, R1 '=H and R2 '=OCH3) to yield 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanoic acid (14). Compound (14) reacted first with diborane and then with dimethylsulfoxide and trifluoroacetic anhydride to afford 5-carbomethoxy-2-[(2-carbomethoxyethyl)thio]-pentanal (15). Compound (15) was reacted under Wittig conditions with tridecyltriphenylphosphonium ylid to yield methyl-5-[(2-carbomethoxyethyl)thio]-6(Z)-nonadecenoate (16) which was saponified to afford a compound of the formula (IV) wherein m is 1, R1 is hydrogen, and R2 is hydroxyl.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=1)(=[O:21])=[O:20])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)O)cc1
Yield: 95.4 %

Procedure:
The compound of Example 10 (300 mg, 0.47 mmol) was dissolved in 10 mL of MeOH and then 10% Pd/C (150 mg) was added. The reaction was hydrogenated under normal pressure overnight, filtered through Celite, rinsed with MeOH (3×10 mL) and concentrated in vacuo to give the desired compound (242 mg, 84%) which was used without further purification. ES—MS (M+H)+540.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.C(P(O)(=O)O)CC.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:26]([C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)=[O:27])[CH2:17][CH2:18]1
Reactant: Cc1cc(C(=O)O)no1
Reactant: N[C@H]1CC[C@H](Oc2ccnc3c(Br)cccc23)CC1
Agent: CCCP(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](Oc3ccnc4c(Br)cccc34)CC2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-[(8-Bromoquinolin-4-yl)oxy]cyclohexylamine (321 mg, 1.0 mmol), and 5-methylisoxazole-3-carboxylic acid (153 mg, 1.2 mmol) were put in pyridine (4.0 mL) and propanephosphonic acid cycloanhydride (637 mg, 2.0 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water was added until a precipitate formed. After a further 10 minutes the precipitate was filtered off with suction and washed with water. After drying, the desired compound was obtained at 92% yield (400 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]([C:27]1([NH:38][CH2:39][CH3:40])[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)=[O:26].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:24][C:25]([C:27]1([N:38]([CH2:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][C:15]=2[O:21][CH3:22])[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:23])[CH2:39][CH3:40])[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:28]1)=[O:26]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CCNC1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Yield: 19.2 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (360 mg, 0.93 mmol, prepared as described in Example 62) was added portionwise over 2 hours to a solution of tert-butyl 3-(aminocarbonyl)-3-(ethylamino)azetidine-1-carboxylate (294 mg, 1.21 mmol) and diisopropylethylamine (0.5 ml, 2.79 mmol) in DMF (1 ml) at 120° C. The resulting product was purified on preparative HPLC (standard basic conditions) to give tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-1-carboxylate as a solid (100 mg, 19%); Mass Spectrum: (M+H)+ 559. This was dissolved in 1,4-dioxan (3 ml) and a solution of concentrated hydrochloric acid (5 ml) in 1,4-dioxan (25 ml) was added dropwise. The reaction mixture was stirred overnight and concentrated under reduced pressure. The residues were triturated with a mixture of methanol/dichloromethane/diethylether to give a hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-3-carboxamide as a solid (89 mg, 100%); 1H NMR Spectrum: (CDCl3) 1.16 (t, 3H), 2.59 (q, 2H), 3.41 (d, 2H), 3.76 (d, 2H), 3.89 (s, 2H), 3.98 (s, 3H), 5.47 (brs, 1H), 7.15 (m, 2H), 7.24 (s, 1H), 7.77 (s, 1H), 7.90 (s, 1H), 8.44 (m, 1H), 8.72 (s, 1H); Mass Spectrum: (M+H)+ 459.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 2,4-difluoroaniline (10 g, 77 mmol) and triethylamine (12.95 mL, 93.00 mmol) in THF (50 mL) was added ethyl 2-chloro-2-oxoacetate (9.05 mL, 81.0 mmol) drop wise at 0° C. A white solid precipitated instantly. The reaction mixture was stirred at rt for 1 h. The solvent was evaporated, and Et2O was added. The solution was washed with 1N HCl (20 mL), saturated NaHCO3 and then brine, then the organic layer dried over MgSO4, filtered and concentrated to give Intermediate 11A (15.8 g, 68.9 mmol, 89.0% yield) as a white crystalline solid. HPLC/MS (Method L) RT=1.58 min, [M+H]+ 230.0.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[N:3]=[CH:2]1.[OH-].[Na+].[ClH:22]>CO>[ClH:22].[ClH:22].[NH:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[N:3]=[CH:2]1
Reactant: COC(=O)/C=C/c1ccccc1NCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1ccccc1NCc1c[nH]cn1
Reaction time: 20 h

Procedure:
To a solution of methyl (E)-3-[2-(4-imidazolylmethylamino)phenyl]propenoate (0.7 g) in methanol (7 ml) was added 1N sodium hydroxide aqueous solution (3 ml) and the mixture was stirred for 20 hours. After removal of methanol from the reaction mixture, water was added to the residue. The mixture was adjusted to pH 6 with acetic acid. The mixture was salted out and extracted with ethyl acetate 8 times. The extracts were combined and dried over magenessium sulfate. Removal of the solvent afforded an orange oil, which was dissolved in methanol (5 ml). To the solution was added an ethereal solution of hydrogen chloride. The resultant precipitate was colIected by filtration, washed with ether twice and dried to give (E)-3-[2-(4-imidazolylmethylamino)phenyl]propenoic acid dihydrochloride (0.29 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[N:4]=1.O.[NH2:22][NH2:23].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:22][NH2:23])=[O:15])[N:4]=1
Reactant: NN
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)NN)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.10 Gram of 2-(4,6-dimethoxypirimidin-2-yl)oxybenzoic acid was dissolved in 10 ml of tetrahydofuran, and 0.77 g of N,N'-carbonyldimidazole was added. After stirring at room temperature for 20 minutes, the reaction solution was cooled to 0° to 5° C. 0.72 Gram of hydrazine monohydrate was added with keeping this temperature. After stirring at 0° to 5° C. for 30 minutes, the reaction solution was pourd into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was washed with diethylether to obtain 0.95 g of 2-(4,6-dimethoxypirimidin-2-yl)oxybenzohydrazide [present compound (1)].
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[F:18])[S:6]1(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[F:18])[S:6]1(=[O:19])=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1
Yield: 79.5 %

Procedure:
2-tert-Butyl-5-(2-fluoro-4-methylphenyl)isothiazol-3(2H)-one 1,1-dioxide (4.5 g) in ethanol (120 mL) was treated with palladium (900 mg, 8.46 mmol) (10% palladium on carbon) and placed on a par hydrogenator under a 50 psi atmosphere of hydrogen for 24 h. The reaction was filtered though celite. After concentration, the crude material was purified by silica gel chromatography (3–10% ethyl acetate:hexanes) to afford product as a white solid (3.6 g, 79%). 1H NMR (400 MHz, CDCl3): δ7.21–7.17 (m, 1H), 7.02–6.96 (m, 2H), 5.04 (dd, J=9.0, 7.0 Hz, 1H), 3.26 (dd, J=17.2, 9.0 Hz, 1H), 3.08 (dd, J=17.2, 7.0 Hz, 1H), 2.37 (s, 3H), 1.66 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.O.NN.[OH-].[K+].Cl>C(O)C>[F:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: O=C1COc2cc(O)c(F)cc21
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Oc1cc2c(cc1F)CCO2
Temperature: 1500 °C
Yield: 37.7 %

Procedure:
To a stirred solution of 5-fluoro-6-hydroxy-benzofuran-3-one (551 mg, 3.28 mmol) in ethanol (10 mL) was added hydrazine hydrate (3.75 mL, 76.93 mmol), and the reaction was heated to reflux for 30 minutes. The reaction was subsequently concentrated in vacuo. The residue was then dissolved in ethylene glycol (10 mL), and then treated with potassium hydroxide (551.64 mg, 9.83 mmol). The reaction was then heated to 1500° C. for 3 hours. The reaction was poured into 2M aq. HCl (100 mL), and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was suspended in DCM (50 mL), and the reaction was filtered. The filtrate was concentrated in vacuo and loaded onto a silica column (25 g, SNAP cartridge), which was eluted with EtOAc:isohexane 0% to 50%. Fractions containing desired product were combined and concentrated in vacuo to give 5-fluoro-2,3-dihydrobenzofuran-6-ol (D95) (190.4 mg, 1.2352 mmol, 37.7% yield) as a colourless oil which crystallised on standing;
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[H-].[Na+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CN(C=O)C>[C:17]([O:20][CH2:21][CH2:22][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 20 mL pressure vial was charged pyrazole-4-boronic acid pinacol ester (5.15 mmol, 1.00 g) and DMF (10 mL). NaH (60% w/w in mineral oil, 5.67 mmol, 227 mg) was then added portion-wise. The resulting solution was stirred at room temperature for 10 minutes. 2-bromoethyl acetate (5.67 mmol, 623 μL) was then added dropwise. The vial was flushed with argon, sealed, and the reaction was stirred at 60° C. for 18 hours. At 18 hours, the DMF was removed in vacuo, and the residue taken up in DCM. This suspension was filtered through celite and then purified via flash chromatography to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[O:18][CH3:19])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:24]([NH2:42])=[CH:25][C:26]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:29][CH2:28][C:27]=2[CH:41]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[O:18][CH3:19])=[N:7][C:2]([NH:42][C:24]2[C:23]([O:22][CH3:21])=[CH:41][C:27]3[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N(C)C)cc3OC)n1)CCN(CCN1CCOCC1)CC2
Yield: 22 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product was isolated as a light yellow foam (40 mg, 22%). mp: 115° C. (glass @ 75) MS (ESI+): 582 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 6.35 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.74 (t, J=5 Hz, 4H), 2.99 (s, 6H), 2.87 (m, 2H), 2.82 (m, 2H), 2.70 (t, J=7 Hz, 6H), 2.56 (m, 2H), 2.51 (m, 4H).
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].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[Br:48][C:49]1[N:50]=[C:51]([C:58]([F:61])([F:60])[F:59])[N:52]2[CH2:57][CH2:56][NH:55][CH2:54][C:53]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Br:48][C:49]1[N:50]=[C:51]([C:58]([F:60])([F:59])[F:61])[N:52]2[CH2:57][CH2:56][N:55]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:5])[CH2:54][C:53]=12
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FC(F)(F)c1nc(Br)c2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Reaction time: 12 h
Yield: 48 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (210 mg, 0.70 mmol) was dissolved in 30 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.95 mmol), 1-bromo-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride 11c (214 mg, 0.70 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.10 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H2O, extracted with dichloromethane (80 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with saturated sodium carbonate solution (40 mL), H2O (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 11 (185 mg, yield 48.0%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:20]([O-])=O>CCO.[Fe]>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH2:1])=[C:3]([NH2:20])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Product: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1N
Yield: 64.9 %

Procedure:
Iron dust reduction of 7-amino-4-(3-bromoanilino)-6-nitroquinazoline (0.5 g, 1.4 mmol) in 65% aqueous EtOH containing sufficient aqueous HCl to ensure solubility gives 4-(3-bromoanilino)-6,7-diaminoquinazoline (0.30 g, 65%). 1H NMR (DMSO) δ9.14 (1H, s), 8.27 (1H, s), 8.23 (1H, brs), 7.85 (1H, d, J=8.0 Hz), 7.31-7.14 (2H, m), 7.29 (1H, s), 6.79 (1H, s), 5.73 (2H, brs), 5.13 (2H, brs).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([N:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]2)=[CH:21][CH:22]=1
Reactant: C[C@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Reactant: Clc1ccc(I)cn1
Product: C[C@H]1CCN(c2ccc(Cl)nc2)C[C@H]1NC(=O)OC(C)(C)C
Yield: 19.9 %

Procedure:
The cis product from Example 39C (0.428 g, 2.00 mmol) and 2-chloro-5-iodopyridine (0.523 g, 2.19 mmol; Aldrich) were processed according to the procedure in Example 1A to provide the title compound (0.13 g, 20%). MS (CI/NH3) m/z 326/328 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][NH:4][C@H:5]([CH3:22])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.Cl.[C:30](OCC)(=O)[CH3:31].C(OC(C)C)(C)C>C(O)C.O1CCOCC1>[OH:1][C@H:2]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][NH:4][C@H:5]([CH3:22])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][C@@H:17]([CH3:21])[C:18]([O:20][CH2:30][CH3:31])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: C[C@H](Cc1c[nH]c2c(O[C@@H](C)C(=O)O)cccc12)NC[C@H](O)c1cccnc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](C)Oc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of (2S)-2-((3-((2R)-2-(((2R)-2-hydroxy-2-pyridin-3-ylethyl)amino)propyl)-1H-indol-7-yl)oxy)propanoic acid (6.72 g, 17.53 mmol) in ethanol (135 mL) is added a 4N solution of hydrogen chloride in dioxane (55 mL), and the mixture is stirred at room temperature for 2 hours. The reaction solution is evaporated to remove the solvent, and the residue is separated into a saturated aqueous sodium hydrogen carbonate solution and chloroform. The organic layer is washed with a saturated brine, and dried over anhydrous sodium sulfate. The mixture is evaporated to remove the solvent, and to the obtained crude product are added ethyl acetate (50 mL) and diisopropyl ether (50 mL). The product is crystallized and collected by filtration. The product on the filter is washed with diisopropyl ether, and dried to give the title compound (6.26 g, yield: 87%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]=1>>[C:19]1([S:16]([NH:15][C:10]2[CH:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([Cl:25])=[N:27][CH:28]=4)=[N:6][C:5]=3[CH3:7])[CH:13]=[N:12][C:11]=2[Cl:14])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1
Product: Cc1nc(NC(=O)c2ccc(Cl)nc2)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
Using an analogous method to that described in Example 51, N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide was reacted with 6-chloronicotinoyl chloride. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 8.5 minutes); 1H NMR Spectrum: (DMSO-d6+D2O) 8.58 (2H, dd); 8.44 (1H, d); 8.02 (3H, d); 7.86 (1H, t); 7.71 (2H, t); 7.51 (2H, d); 2.28 (3H, s); Mass Spectrum: M+H+ 520.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][C:17]([F:19])=[CH:16][CH:15]=3)[NH:1][C:21]2=[O:23])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(Br)cccc1NC(=O)c1ccc(F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65 g, 11.3 mmol) in THF (50 mL) was treated with triphosgene (3.69 g, 12.4 mmol) at room temperature. The solution was stirred at room temperature for 2 h, then was treated slowly with saturated aqueous NaHCO3 and stirred until no more gas evolution was observed. The resulting mixture was extracted twice with EtOAc. The combined organic phases were washed twice with water, then with brine, dried and concentrated to give 3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H) -dione (4.20 g), used without further purification. Mass spectrum m/z 349, 351 (M+H)+.