Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[N:30]1([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1>>[N:30]1([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40][C:2]3[N:7]=[CH:6][C:5]4[CH:8]=[C:9]([C:18]5[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:22]=5)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]=4[CH:3]=3)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: Nc1ccc(Cn2cccn2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(Cn5cccn5)cc4)cc3n2C(=O)OC(C)(C)C)cn1

Procedure:
The title compound was prepared from tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (70 mg, 0.15 mmol) and 4-((1H-pyrazol-1-yl)methyl)aniline (31.3 mg, 0.181 mmol, 1.2 eq), using the method described in Preparation 35 and using silica gel column chromatography eluting with EtOAc:hexane:triethylamine 10:10:1 (12 mg, 14.3%). 1H-NMR (500 MHz, CDCl3) 1.49 (s, 9H), 1.69 (s, 9H), 5.2 (s, 2H), 6.32 (s, 1H), 6.58 (s, 1H), 6.66 (d, J=8.3 Hz, 2H), 7 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.33 (m, 1H), 7.62 (s, 1H), 7.82 (s, 1H), 8.21 (s, 1H), 8.45 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:13](=[O:14])[CH:12]([N:8]3[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]4[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=4[F:26])[CH:6]=[N:7]3)[CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[N:35]2)[CH2:30][O:29]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCC(CC)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CCC(CC)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid (Intermediate 31) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a viscous oil as a mixture of diastereomers. 1H NMR (300 MHz, CDCl3) δ ppm 0.79-0.93 (m, 6H), 1.12 (br s, 1H), 1.20-1.54 (m, 4H), 1.34 (s, 3H), 1.38 (s, 3H), 2.02-2.19 (m, 1H), 2.19-2.34 (m, 1H), 3.68-3.77 (m, 1H), 4.04 (dd, J=8.6, 6.5 Hz, 1H), 4.10 (d, J=5.4 Hz, 2H), 4.32-4.47 (m, 1H), 5.66 (dd, J=9.1, 6.0 Hz, 1H), 6.00 (br s, 1H), 6.68 (s, 1H), 7.01-7.14 (m, 2H), 7.28-7.37 (m, 2H), 8.01 (d, J=2.7 Hz, 1H), 8.59 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[N:15]=[C:14]([F:16])[N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][NH:11]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:29])[CH3:28].C(Cl)Cl.CCOCC.CO>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[N:15]=[C:14]([F:16])[N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:27]([CH3:29])[CH3:28]
Reactant: Fc1cccc(CNc2nc(F)nc3[nH]cnc23)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1cnc2c(NCc3cccc(F)c3)nc(F)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (3-fluoro-benzyl)-(2-fluoro-9H-purin-6-yl)-amine (0.6 g, 2.24 mmol) in dimethylformamide (10 ml) at room temperature under an argon atmosphere, was added powdered, anhydrous potassium carbonate (1.52 g, 5 eq, 11.2 mmol), followed by 2-bromopropane (2.3 ml, 10 eq, 22.4 mmol). The reaction mixture was stirred at room temperature for 24 h, when DCM:ether:MeOH (55:40:5), indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was extracted with more ethyl acetate (2×50 ml) and the combined organic phase washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel column chromatography, eluted with chloroform to afford the title compound as a slightly yellow gum; Yield: 0.37 g (54%). δH (250 MHz, CDCl3) 1.55 (6 H, d, J 7.5, CH[CH3]2), 4.85-4.65 (3 H, m, NHCH2Ar and CHMe2), 5.96 (1 H, s, br, NH), 7.31-6.94 (4 H, m, ArH), 7.59 (1 H, s, br, ArH); δC (250 MHz, CDCl3) 164.93 (C), 161.01 (C), 156.04 (C), 139.77 (C), 137.76 (CH), 130.13 (CH), 129.92 (C), 123.19 (CH), 114.59 (CH), 114.26 (CH), 47.22 (CH), 43.93 (CH2), 22.56 (2×CH3); m/z 304.2 (M+H)
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C(Cl)(Cl)Cl.C1COCC1.[Os](=O)(=O)(=O)=O.O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:35])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 1.06 g, 2.60 mmol) in chloroform (1 mL) and THF (15 mL) were sequentially added N-methylmorpholine-N-oxide in water (0.807 mL, 3.89 mmol) and osmium tetroxide in water (0.317 mL, 0.052 mmol) at room temperature. The solution was stirred at room temperature overnight. More N-methylmorpholine-N-oxide in water (0.40 mL) was added. The mixture was stirred at room temperature for 2 hr before sodium periodate (0.666 g, 3.11 mmol) in water (4 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hr. Water (30 mL) was added and the mixture was concentrated to remove THF. The solid was filtered, washed with water (1 mL), and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde as a yellow solid. The filtrate was extracted with dichloromethane (3×6 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give a yellow liquid. This liquid was combined with the yellow solid obtained above with dichloromethane (5 mL), THF (5 mL), and methanol (7 mL). The suspension obtained was treated with sodium borohydride (0.147 g, 3.89 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 1 hr before water (10 mL) and saturated aqueous ammonium chloride solution (5 mL) were added. The mixture was concentrated to remove organic solvents. The solid was filtered, washed with water (2×2 mL), and crystallized in methanol to give (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (500 mg, 1.213 mmol, 46.7% yield) as a yellow solid. The filtrate was extracted with dichloromethane (3×10 mL). The dichloromethane extracts were dried over sodium sulfate and combined with the mother liquor from the crystallization. Purification using silica gel chromatography (20 to 100% dichloromethane in heptane and then 20→100% ethyl acetate in heptane) afforded an additional crop of (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (205 mg, 0.497 mmol, 19.15% yield) as a yellow solid. LC/MS M+1=413.1.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([F:35])[CH:20]=[C:21]([CH:33]=[O:34])[CH:22]=2)[N:17]=1>C(Cl)Cl.O=[Mn]=O>[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([F:35])[CH:20]=[C:21]([C:33]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=3)=[O:34])[CH:22]=2)[N:17]=1
Reactant: Cn1cncc1Br
Reactant: O=Cc1cc(F)c2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: O=[Mn]=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1cc(F)c2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-bromo-1-methyl-1H-imidazole (95.7 mg, 0.594 mmol) in DCM (0.6 mL) was stirred on an ice bath while iPrMgCl—LiCl (0.495 mL, 1.2 M in THF, 0.593 mmol) was added dropwise over 2.5 min under argon. After 15 min stirring at room temperature, the Grignard solution was added dropwise over 2.5 min to a slurry of 2,4-dichloro-8-fluoro-3-phenylquinoline-6-carbaldehyde (140 mg, 0.436 mmol, Intermediate 46, step b) in LaCl3-2LiCl (0.779 mL, 0.56 M in THF, 0.436 mmol) on an ice bath. The red-colored reaction was removed from the ice bath immediately following Grignard addition, and after 15 min stirring under ambient conditions, the reaction was partitioned with DCM (5 mL) and 1M NaHCO3 (0.6 mL). The mixture was filtered and the filter cake washed with 3 mL DCM. The combined clear yellow filtrates were dried (Na2SO4), filtered, and concentrated, and the crude secondary alcohol was dissolved in DCM (2 mL), treated with MnO2 (379 mg, 4.36 mmol), and stirred at 40° C. for 2 hours. The reaction was then diluted with DCM (4 mL) and filtered, and the clear yellow filtrate was concentrated and flash chromatographed with a 5% acetone/heptane to 100% acetone gradient to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1F
Yield: 64 %

Procedure:
The title compound is prepared from 4-amino-3-fluoro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 64% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=325 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][CH2:32][C@@H:3]12.[Li+].[OH-]>O1CCOCC1>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=4)[CH2:17][CH2:18]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][CH2:32][C@@H:3]12
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
(S)-ethyl 6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinate (0.355 mg, 0.813 mmol) was suspended in dioxane (4 mL) and treated with LiOH (1N, 4.00 mL, 4.00 mmol). The resulting solution was stirred at room temperature for 3 h and concentrated in vacuo until most of the organic solvent was removed. The solution was acidified with HCl (4.5N) to pH=3 and the resulting precipitate was filtered off, washed with ethyl ether (5 mL) and dried in vacuum to afford the title compound as a brown solid (0.260 g, 78%). [M+H] calc'd for C21H24N6O3, 409; found, 409.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:6][C:7](=[O:19])[C:8]([NH:11][C:12]([O:14]C(C)(C)C)=O)([CH3:10])[CH3:9])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][S:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:6][C:7](=[O:19])[C:8]([NH:11][C:12](=[O:14])[C@@H:22]([SH:21])[CH:23]([CH3:28])[CH3:24])([CH3:9])[CH3:10])[CH3:2]
Reactant: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)[C@@H](S)C(C)C

Procedure:
Under an argon atmosphere, the thioacetyl compound of Example 2 (0.48 g, 1.0 mmol) is dissolved in absolute EtOH (5 mL) and treated with 1 N NaOH of (1.0 mL, 1.0 mmol). The mixture is stirred for 4 hours at room temperature before treatment with 1 N HCl until pH 3. The mixture is evaporated to remove most of the EtOH and the aqueous residue is extracted with EtOAc (2×10 mL). The combined extracts are washed with H2O (5 mL) and then with brine solution (5 mL). The solution is dried over Na2SO4, filtered and concentrated in vacuo. The product solidifies from tert-butyl methyl ether/hexane to give product; m.p. 87-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:20][S:21][C:22]1[N:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>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]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:25]4[CH:24]=[N:23][C:22]([S:21][CH3:20])=[N:27][CH:26]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COc1ccc(-c2nn3c(-c4cnc(SC)nc4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.25 g, 0.646 mmol, 1 eq), 2-(methylthio)pyrimidine-5-boronic acid pinacol ester (0.244 g, 0.968 mmol, 1.5 eq) and K2CO3 (0.357 g, 2.584 mmol, 4 eq) in 1,2-DME/H2O (9/1, 5 mL) was stirred at RT for 10 min. Then, PdCl2(dppf) (0.053 g, 0.0646 mmol, 0.1 eq) was added and the reaction mixture was heated at 85° C. for 4 h. Solvents were evaporated and water was added to the residue. The suspension was extracted with EtOAc (×3) and the combined organics were dried, filtered and evaporated. The residue was purified in an Isolute Si II cartridge using MeOH in DCM (0% to 1%) to give the desired product (47 mg). The aqueous phase was evaporated to dryness and the residue was redissolved in DCM and filtered. The filtrate was evaporated and purified as described before to give additional desired product (136 mg). Total amount obtained: 183 mg. Overall yield: 73%. HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=5.46 min, [M+H]+ m/z 386.2; 1H NMR (300 MHz, CDCl3) δ 9.15 (d, J=5.8 Hz, 2H), 7.64 (s, 1H), 7.45 (m, 2H), 6.97 (m, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[F:29][C:30]1[CH:31]=[C:32]([C:36]#[C:37][C:38]2[CH:47]=[C:46]3[C:41]([C:42](=[O:54])[N:43]4[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48][C:44]4=[N:45]3)=[CH:40][CH:39]=2)[CH:33]=[CH:34][CH:35]=1>C1COCC1>[F:29][C:30]1[CH:31]=[C:32]([C:36]#[C:37][C:38]2[CH:47]=[C:46]3[C:41]([C:42](=[O:54])[N:43]4[CH2:52][CH2:51]/[C:50](=[CH:2]\[O:3][CH3:4])/[CH2:49][CH2:48][C:44]4=[N:45]3)=[CH:40][CH:39]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C1/CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (171 mg, 0.5 mmol, 1 equiv) in 5 mL THF at −78° C. was added n-BuLi (0.2 mL, 0.5 mmol, 1 equiv) dropwise and stirred at the same temperature for half an hour. A solution of 3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione (173 mg, 0.5 mmol, 1 equiv) in THF was then added to the mixture dropwise at the same temperature and stirred for 2 hours. Then the reaction mixture was quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 375 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:26]CC2C=CC(OC)=CC=2)[C:11]([C:24]#[N:25])=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=1.BrC1C=CC=CC=1C1N=C(C#N)C(NCC2C=CC(OC)=CC=2)=NC=1C1C=CC(=O)N(C(C)C)N=1>C(Cl)(Cl)Cl.O>[NH2:26][C:10]1[C:11]([C:24]#[N:25])=[N:12][C:13]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:9]=1
Reactant: COc1ccc(CNc2nc(-c3ccccc3Br)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Agent: COc1ccc(CNc2nc(-c3ccc(=O)n(C(C)C)n3)c(-c3ccccc3Br)nc2C#N)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2Br)ccc1=O
Temperature: 27.5 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-2-pyrazinecarbonitrile (2.05 g) containing 6-(2-bromophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-2-pyrazinecarbonitrile in CHCl3 (60 ml), water (3 ml) and 2,3-dichloro-5,6-dicyano-1,4-benzoqinone (2.63 g) were added and the mixture was stirred at 25-30° C. for 24 hours. The mixture was washed with 1N aq. NaOH, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel. By elution of a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile as a solid (941 mg) and by elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained 3-amino-6-(2-bromophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile as a solid (92 mg).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([C@@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:25][CH:26]=3)=[CH:18][CH:17]=2)[CH2:13]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH:12]1[CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([C@@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:25][CH:26]=3)=[CH:18][CH:17]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(NC(=O)OCc4ccccc4)C3)cc2)c[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(N)C3)cc2)c[nH]1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(4-(3-(benzyloxycarbonylamino) cyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (A8) (449 mg, 0.87 mmol) in methanol (10 mL) was added 10% Pd/C (50 mg) and the mixture was stirred overnight under H2 atmosphere in a balloon. The mixture was filtrated and concentrated to obtain the crude product (S)-tert-butyl 2-(4-(4-(3-aminocyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (A9) (330 mg, 99% yield) without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=[C:8]2[CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][CH2:23]CCC>CCOCC>[CH2:22]([C:13]([CH3:19])([CH2:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([CH3:20])=[CH:9][CH:10]=1)[C:14]([OH:16])=[O:15])[CH3:23]
Reactant: CCCCC
Reactant: CCOC(=O)C(C)Cc1ccc(C)n1-c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCC(C)(Cc1ccc(C)n1-c1ccccc1)C(=O)O
Temperature: 92.5 °C
Yield: 84.7 %

Procedure:
A mixture of (IV) (9.4 g of crude oil, ca. 33 mmol) and Claisen's reagent (18 mL) were heated at 90-95° C. for 1 h. After cooling to room temperature, the solution was diluted with 15 g of crushed ice and acidified to pH 1-2 with 6 N HCl. The brown oily precipitate was dissolved in ether, washed with brine solution, dried over MgSO4, filtered and evaporated to waxy solids. Triteration of the solids with pentane afforded 6.6 g of V as a tan powder (84.7% yield).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:48]1([C:54]2[CH:55]=[C:56]([CH:60]=[C:61]([C:63]3[NH:67][N:66]=[N:65][N:64]=3)[N:62]=2)[C:57](O)=[O:58])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:15][CH2:16][N:17]([C:57]([C:56]4[CH:60]=[C:61]([C:63]5[NH:67][N:66]=[N:65][N:64]=5)[N:62]=[C:54]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH:55]=4)=[O:58])[CH2:18][CH2:19]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1
Reactant: O=C(O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Reactant: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(-c4ccccc4)nc(-c4nnn[nH]4)c3)CC1)O2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6-[(1-Methyl-1H-pyrazol-5-ylamino)]spiro[chroman-2,4′-piperidin]-4-one hydrochloride (117 mg), 1-hydroxybenzotriazole monohydrate (53 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68 mg), triethylamine (94 μL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 2-phenyl-6-(tetrazol-5-yl)-isonicotinic acid (75 mg), and stirred at 60° C. for 1 hour. Water was added to the reaction liquid, and the resulting precipitate was taken out through filtration, washed with hexane/ethyl acetate=2/1, and dried to obtain the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.37 (2.0H, d, J=6.8 Hz), 8.17 (1.0H, s), 8.08 (1.0H, br s), 7.93 (1.0H, s), 7.61-7.50 (3.0H, m), 7.32 (1.0H, d, J=2.0 Hz), 7.18-7.12 (2.0H, m), 6.99 (1.0H, d, J=8.4 Hz), 5.89 (1.0H, s), 4.31-4.27 (1.0H, m), 3.60 (3.0H, s), 3.50-3.20 (3.0H, m), 2.82 (2.0H, s), 2.12-2.05 (1.0H, m), 1.90-1.78 (3.0H, m). MS [M−H]+=560.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=[CH:12]2)=[CH:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[CH:12]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Cn2cnc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cn2cnc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-tert-Butyldiphenylsilyloxymethylimidazol-1-yl-methyl)benzoic acid methyl ester (1.6 g, 3.3 mmol) and tetrabutylammonium fluoride 1M in THF (3.3 ml, 3.3 mmol) in THF (10 ml) was stirred under argon at room temperature for 2 h. Water (15 ml) was added, the mixture was extracted with AcOEt, the organic phase washed with water, brine and dried over MgSO4.