Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.C[N:19]([CH:21]=O)[CH3:20]>CC(CC(C)=O)C>[CH3:20][N:19]([CH2:21][CH2:4][C:3]1[CH:2]=[CH:10][C:9]([OH:11])=[CH:8][CH:7]=1)[C:4]([C:3]1[CH:7]=[C:8]([OH:13])[C:9]([O:11][CH3:12])=[CH:10][C:2]=1[Br:1])=[O:6]
Reactant: COc1cc(Br)c(C(=O)O)cc1O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)CC(C)C
Product: COc1cc(Br)c(C(=O)N(C)CCc2ccc(O)cc2)cc1O
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 138 g 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13) in MIBK (690 mL) was added thionyl chloride (106 g) and DMF (13 mL) and the reaction mixture was heated to 80° C. and stirred at this temperature until TLC analysis indicated the complete disappearance of B13. The resulting mixture was subjected to distillation to remove the excess thionyl chloride. After distillation of thionyl chloride, the resulting acid chloride solution was cooled to room temperature and was added to a solution of 100 g of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine HBr (A12 HBr) and 94 g Na2CO3 in 1000 mL of MIBK and 600 mL H2O pre-cooled to 0° C. A solution of NaOH (82.5 g) in 165 mL H2O was added slowly to maintain the temperature under 5° C. The reaction mixture was stirred at this temperature until TLC analysis showed the complete disappearance of B13 acid chloride. The pH of the reaction mixture was brought to 10-11 by adding more NaOH and the resulting mixture was heated to 50° C. and stirred at this temperature for another 1 h. The reaction mixture was cooled to room temperature and the aqueous layer was separated. The organic layer was concentrated to ⅕th of its volume. 500 mL of heptane was added. The precipitate was collected by filtration to give 163 g (65% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([NH:12]C(=O)OCC)=S)[CH:3]=1.Cl.NO.CC[N:23](C(C)C)C(C)C>CO.CCO>[Cl:8][C:6]1[N:5]2[N:23]=[C:10]([NH2:12])[N:9]=[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Cl)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cc(Cl)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Ethyl [(4,6-dichloropyridin-2-yl)carbamothioyl]carbamate (2.9 g, 9.9 mmol) was added to a stirred suspension of hydroxylamine hydrochloride (1.1 g, 16 mmol) and DIEA (1.9 g, 15 mmol) in MeOH/EtOH (1:1, 40 mL) portion-wise as a solid. This mixture was stirred at rt for 2 h and then heated at 80° C. for 18 h. The reaction mixture was concentrated in vacuo and the resultant reside treated with water yielding a cream solid, which was filtered and dried in a vacuum oven at 40° C. for 18 h to give the desired product (1.2 g, 60%). 1H NMR (DMSO) δ 7.58 (d, J=2.0 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.44 (s, 2H). m/z [M+H]+=203.15.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20](C(N[C@H](C#C)CC(O)=O)=O)[CH2:19]2)=[O:17])[CH2:10][CH2:9]1.Cl.[CH2:35]([OH:37])[CH3:36]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:35]([O:37][C:3](=[O:5])[CH2:2][C@@H:9]([C:10]#[CH:11])[NH:8][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19]1)[CH3:36]
Reactant: CCO
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C#C[C@H](CC(=O)OCC)N[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine trifluoroacetate (0.57 g) and 4.9 HCl in ethanol (30 ml) was stirred at ambient temperature for 2 hours, and the mixture was evaporated in vacuo. The residue was purified by HPLc on C18 silica gel eluting with a solution of 18% CH3CN in 0.1% aqueous TFA solution, and the fractions containing object compound were combined and evaporated in vacuo and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidyl]-3(S)-ethynyl-β-alanine ethyl ester trifluoro acetate (0.52 g).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS([C:25]([F:28])([F:27])[F:26])(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.[C:51]([O-])([O-:53])=[O:52].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@H:9]([C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:45]1[CH:46]=[CH:47][C:42]([Cl:41])=[CH:43][CH:44]=1)[CH:14]=[CH:13]2)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4].[C:51]([OH:53])([C:25]([F:26])([F:27])[F:28])=[O:52]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc2nc(-c3ccc(Cl)cc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: O=C(O)C(F)(F)F
Temperature: 90 °C
Yield: 328.9 %

Procedure:
Pd(PPh3)4 (4.6 mg, 0.004 mmol) was added to a mixture (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (25 mg, 0.04 mmol), 4-chlorophenylboronic acid (13 mg, 0.08 mmol), Na2CO3 (0.14 mL 1 M in water, 0.14 mmol) in 1,2-dimethoxyethane (2 mL). The reaction mixture was flushed with nitrogen, heated at 90° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a TFA salt (15 mg, 55%). LCMS-ESI+ (m/z): 564.3, 566.3, 568.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:14]1[N:13]=[C:12]([N:16]2[C:20](=[O:21])[NH:19][C:18]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:17]2)[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)[CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-n2nc(CC(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-n2nc(CC(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
1-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-neopentyl-1H-1,2,4-triazol-5(4H)-one (0.15 g, 0.40 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g, 0.52 mmol), and K2CO3 (0.14 g, 1.04 mmol) were suspended in a solution of dioxane (2.0 mL) and water (0.40 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the reaction mixture was stirred at 85° C. for 12 h, allowed to cool to RT, diluted with water (5 mL), and extracted with EtOAc (5×10 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-neopentyl-1H-1,2,4-triazol-5(4H)-one (0.124 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.83 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.38 (s, 2H), 2.33 (s, 3H), 0.98 (s, 9H); MS (ESI) m/z: 420.2 (M+H+).
Reaction SMILES: O[C:2]1([OH:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)Cl.CN(C=O)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:30]1([N:34]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH:30]1([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([C:6]([CH:4]3[CH2:3][C:2](=[O:9])[CH2:5]3)=[O:8])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(O)C1CC(O)(O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a stirred solution of 3,3-dihydroxycyclobutanecarboxylic acid (80 mg, 0.61 mmol) in 4:1 DCM/DMF (2.5 ml) was added CDI (103 mg, 0.64 mmol) at RT. The mixture was stirred for 1.5 h at RT and 1-cyclobutyl-1,4-diazepane (98 mg, 0.64 mmol) was added. The resulting solution was stirred at RT for 3 H, diluted with DCM (20 ml) and washed with 1:1 H2O/brine (20 ml). The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica gel FCC (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (84 mg, 56%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:16]=1)[NH:13][N:12]=[CH:11]2)=[O:7]>O1CCOCC1.O>[S:21]1[C:17]([C:15]2[CH:16]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]1=2
Reactant: COC(=O)c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 65 °C
Yield: 100.2 %

Procedure:
Lithium hydroxide monohydrate (2.25 g, 53.5 mmol) was added to a suspension of methyl-7-benzo[b]thiophen-2-yl-1H-indazole-5-methanoate (3.37 g, 10.71 mmol) in a mixture of 1,4-dioxane (65 mL) and water (9 mL). The mixture was heated to about 65° C. for about 18 hours then cooled to about 40° C. and filtered. The filtrate was acidified with aqueous hydrochloric acid (1N, 54 mL) and the resulting precipitate was collected by filtration and dried under reduced pressure to give 7-benzo[b]thiophen-2-yl-1H-indazole-5-carboxylic acid (3.16 g, 100%); 1H NMR (DMSO-d6, 400 MHz) δ 13.56 (bs, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 8.14 (d, 1H), 8.04 (d, 1H), 7.94 (d, 1H), 7.45 (d, 2H); RP-HPLC (Table 1, Method e) Rt=1.06, m/z: (M−H)− 292.8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([F:23])[CH:14]=1.Cl([O-])=[O:25].[Na+].CC(=CC)C.P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([F:23])[CH:14]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCO)c(F)c3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCO)c(F)c3)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.7 %

Procedure:
To a solution of 6-chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodium chlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodium dihydrogen phosphate (350 mg, 2.90 mmol). The reaction solution was stirred at room temperature for 10 hrs. The reaction was diluted with water (5 mL) and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to give a crude product. The crude was purified by preparative HPLC to give the title compound (20 mg, 49% yield) as off-white solid. MS (AP−) 348.0 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.20 (m, 3H), 4.21 (t, 2H), 3.95 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:4]=1.[H-].[Na+].[CH2:24]([O:26][CH2:27]Cl)C>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([N:14]([CH2:24][O:26][CH3:27])[S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:6]=1
Reactant: COc1cc(OC)nc(C(C(=O)NS(C)(=O)=O)C(C)C)n1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN(C(=O)C(c1nc(OC)cc(OC)n1)C(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 of 2-(4,6-dimethoxypyrimidin-2-yl)-3-methyl-N-methylsulfonylbutyric acid amide was placed in a round bottom flask, and was dissolved in 50 ml of DMF. To the resultant solution, was gradually added 0.28 g of 60% sodium hydride, and the mixture was stirred at room temperature for one hour. Thereafter, 1.0 g of chloromethyl ethyl ether was added dropwise to the resultant mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water, and was extracted with 200 ml of diethyl ether, followed by drying with anhydrous sodium sulfate. After filtrating the inorganic salt, the solvent was distilled off under reduced pressure. An only product thus obtained was purified by silica gel column chromatography (developing solvent: N-hexane/ethyl acetate=10/1) to obtain 1.8 g of the aimed product of colorless transparent viscous liquid (yield=78.3%) having a refractive index (n20/D) of 1.4976.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[N-].[BrH:11]>C(Cl)Cl>[Br:11][CH2:3][C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: Br
Reactant: CC(C)(C)CC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CC(C)(C)CC(=O)CBr
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred, −10° solution of the crude product from Step A (1.233 grams) in methylene chloride (12 mL) was added 48% HBr dropwise (1.14 mL). After gas evolution ceased, the reaction was stirred for 15 minutes at room temperature. The reaction was partitioned between isopropyl acetate and water. The organic was washed once with water, dried over magnesium sulfate and filtered. Evaporation afforded an oil containing the title compound which was used without further processing.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:37]2[CH:38]=[CH:39][C:34]([C:33]([NH:32][C:28]3[S:27][CH:31]=[CH:30][N:29]=3)=[O:43])=[CH:35][CH:36]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(Nc1nccs1)c1ccc(B(O)O)cc1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nccs4)cc3)c12
Yield: 73.1 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and commercially available N-2-thiazolyl 4-boronobenzamide to afford the title compound (229 mg, 73.1%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[CH:16][CH:17]=[N:18][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-:19].[Na+]>CN(C)C1C=CC=CC=1>[NH2:19][C:16]1[CH:17]=[N:18][C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13][C:12]=2[N:15]=1
Reactant: [NH2-]
Reactant: c1ccc(CN2CCc3nccnc3CC2)cc1
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: Nc1cnc2c(n1)CCN(Cc1ccccc1)CC2
Temperature: 170 °C

Procedure:
2.4 gm (0.01 mol) of 7-benzyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine were dissolved in 20 ml of dimethylaniline, 3.9 gm (0.1 mol) of sodium amide were added, and the mixture was heated for four hours at 170° C. Thereafter, the dimethylaniline was distilled off in a high vacuum, the residue was taken up in 4N sodium hydroxide, and the solution was extracted with chloroform. The chloroform extract solution was dried and column-chromatograpically purified on silicagel with methanol/methylene chloride (3:1) as the mobile phase.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1.N([O-])=O.[Na+].OC1C(N2CCOCC2)=NC=C(OC)N=1.P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(N2CCOCC2)c(N)n1
Agent: COc1cnc(N2CCOCC2)c(O)n1
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methoxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][NH:24][CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][N:24]([C:33](=[O:35])[CH3:34])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Nc2nc3c(c(CCC4CCCO4)n2)CNCC3)ccc1-n1cnc(C)c1
Solvent: ClCCl
Product: COc1cc(Nc2nc(CCC3CCCO3)c3c(n2)CCN(C(C)=O)C3)ccc1-n1cnc(C)c1
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To a solution of N -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(2-(tetrahydrofuran-2-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.114 g, 0.26 mmol) in dichloromethane (2 mL) was added acetic anhydride (0.027 mL, 0.29 mmol) at rt. The reaction mixture was stirred for 45 minutes. The solvent was concentrated; the residue was suspended with methanol and purified by prepHPLC. Fractions were pooled and the solvent was evaporated. The residue was dissolved in water/acetonitrile-mixture (50:50) and freezedried giving 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(2-(tetrahydrofuran-2-yl)ethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (0.062 g, 49.6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F-].[Cs+].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(-c2ncoc2-c2ccncc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(-c4ncoc4-c4ccncc4)cc3)ccc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
To a solution of compound 4-(5-(pyridin4-yl)oxazol4-yl)phenol (90 mg, 0.38 mmol) in 1 mL of dry DMF was added CsF (115 mg, 0.76 mmol). After stirring for 0.5 h, 2-(chloromethyl)quinoline (67 mg, 0.38 mmol) was added and the reaction was heated at 80° C. for 48 h. Upon removal of DMF under vacuum, the residue was purified by PTLC (1:2 hexane/EtOAc) to give 29 mg (20%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ: 5.47 (s, 2H), 7.11 (m, 2H), 7.56 (m, 5H), 7.70 (d, 1H), 7.78 (t, 1H), 7.86 (d, 1H), 8.01 (s, 1H), 8.12 (d, 1H), 8.26 (d, 1H), 8.57 (d, (2H). MS m/z: 380 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)n1
Yield: 38.7 %

Procedure:
A suspension of 1.11 g (0.0028 mol) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 80 ml of tetrahydrofuran was treated with 7.6 ml (0.056 mol) of dipropylamine. After stirring at reflux for 24 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.50 g (39%) of 7-chloro-3-(4-dipropylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 123-125°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:19]([O:26][CH2:27][CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:19]([O:26][CH2:27][CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCOCc1ccccc1
Reactant: Clc1ncnc2ccccc12
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: c1ccc(COCCNc2ncnc3ccccc23)cc1
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 3.3 g (0.02 mol) of 4-chloroquinazoline in 50 ml of benzene were added 2.0 g (0.02 mol) of triethylamine and 3.0 g (0.02 mol) of 2-benzyloxyethylamine, and the mixture was heated, with stirring, at 60°~70° C. for 5 hours. After completion of the reaction, the benzene was evaporated under reduced pressure, and the resulting crystals were washed with water, collected by filtration, dried and recrystallized from benzene/n-hexane, affording 3.7 g of 4-[2-(benzyloxy)ethyl]aminoquinazoline in the form of colorless needles.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[N:3]=1.[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:20][CH:16]([CH2:18][CH3:19])[CH3:17])[N:7]=1
Reactant: CCC(C)N
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Solvent: CCN(CC)CC
Product: CCC(C)Nc1nc(C)nc(NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
10 ml of triethylamine are added to 8.05 g (0.035 mol) of 2-methyl-4-chloro-5-nitro-6-isopropylamino-pyrimidine. While cooling with ice, 7.3 g (0.1 mol) of sec- butylamine are slowly added dropwise and the mixture is stirred for 16 hours at room temperature. The reaction solution is evaporated, the residue suspended in 500 ml of water and extracted 3 times with ether, to yield 9.0 g of 2-methyl-4-isopropylamino-6-sec.-butylamino-5-nitro-pyrimidine (36.5%) as an oil.