Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=1)[C:6]([CH:21]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a mixture of 1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptan-1-one (709 mg) synthesized above, methyl 4-aminobenzoate (263 mg), triethylamine (1.94 mL) and methylene chloride (10 mL) was added titanium (IV) chloride (229 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (10 mL) of the obtained oil in tetrahydrofuran were added acetic acid (498 μL) and sodium cyanoborohydride (219 mg), and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title object compound (645 mg, 68%) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:27][C:26]([F:28])([F:29])[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:20][CH:21]=1)([OH:34])[C:30]([F:31])([F:33])[F:32]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1

Procedure:
4-(4-Nitrophenoxy)piperidine (2.70 mmol, 600 mg), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.70 mmol, 910 mg) and potassium carbonate (5.40 mmol, 746 mg) were combined and stirred at 70° C. in acetonitrile (20 mL) overnight. The reaction mixture was filtered and the filtrate concentrated under vacuum to afford the title compound. MS (ESI) m/z 490.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].[OH-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>O.C(O)CC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:9]1[C:10]2[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=2[N:7]=[CH:8]1
Reactant: BrCCCCCCBr
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O

Procedure:
1,3-dimethylxanthine is dissolved in a mixture of 250 ml of water and 750 ml of n-propanol by adding an equimolar quantity of sodium hydroxide and heating. An equivalent amount of 1,6-dibromohexane is quickly added to the solution and the mixture is boiled under reflux for 1 hour. After evaporation of the n-propanol, 7-(6-bromohexyl)-1,3-dimethylxanthine is isolated.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][CH:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (25 mg, 0.057 mmol, 1 eq), DIPEA (20 μL, 0.11 mmol, 2 eq) and TBTU (20 mg, 0.063 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 15 min before the addition of 3-aminoquinuclidine dihydrochloride (11 mg, 0.055 mmol, 1.1 eq) and DIPEA (40 μL). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide (±)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:7]=1)C.[OH-].[Li+]>O1CCOCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2CCCC2=O)c1

Procedure:
{3-[4-Bromo-2-(2-oxo-pyrrolidin-1-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.35 mmol) in 1,4-dioxane and H2O was treated with lithium hydroxide at 50° C. for 30 minutes. The crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:18])=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[Cl:18][C:5]1[N:4]=[N:3][C:2]([NH:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][CH:21]=2)=[N:7][C:6]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[F:17]
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: Fc1cccc(CNc2nc(Cl)nnc2Cl)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1ccc(Nc2nnc(Cl)c(NCc3cccc(F)c3F)n2)cc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
3,6-Dichloro-N-(2,3-difluorobenzyl)-1,2,4-triazin-5-amine (75 mg, 0.26 mmol) was dissolved in 5 mL NMP. To it was added 4-amino-N,N-dimethylbenzamide (86 mg, 0.52 mmol) and pTSA (49 mg, 0.26 mmol). The mixture was stirred at 105° C. for overnight and subjected to reverse phase preparative HPLC to isolate 4-(6-chloro-5-(2,3-difluorobenzylamino)-1,2,4-triazin-3-ylamino)-N,N-dimethylbenzamide (58 mg). MS found for C19H17ClF2N6O as (M+H)+ 419.3. UV: λ=273 nm.
Reaction SMILES: Br.[Br-].[NH2:3][CH2:4][CH2:5][CH2:6][N+:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][NH2:3])[CH2:8][CH:9]=1
Reactant: NCCC[n+]1ccc(-c2ccccn2)cc1
Agent: Br
Agent: [BH4-]
Agent: [Br-]
Solvent: CO
Product: NCCCN1CC=C(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 1-(3-aminopropyl)-4-[2-pyridyl]pyridinium bromide hydrobromide (6 g, 16 mmol) in MeOH (150 mL) at 0-5° C. was added NaBH4 (2 g, 53 mmol) in small portions over a period of 2 h. The reaction mixture was stirred overnight at room temperature and the solvent was evaporated. The residue was suspended in ether (200 mL) and treated with 50% NaOH solution (100 mL). The ether layer was separated and the aqueous layer was extracted with more ether (2×50 mL). The combined ether extracts were dried over potassium carbonate and the solvent was removed to give 3-(3′,6′-dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propylamine (3.48 g) as an oil. It was used in the next step immediately without purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=O.C(OC(=O)[N:19]([CH2:34][CH2:35][NH2:36])[CH:20]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[N:23]=1)[CH3:21])(C)(C)C.O>O1CCOCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOC(C)=O>[O:10]1[C:7]2[CH:8]=[CH:9][C:4]([CH:2]([NH:36][CH2:35][CH2:34][NH:19][CH:20]([C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[N:23]=3)[CH3:21])[CH3:1])=[CH:5][C:6]=2[O:12][CH2:11]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: Cc1cc(C(C)N(CCN)C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)NCCNC(C)c2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 87 %

Procedure:
3,4-(Methylenedioxy)acetophenone (95.0 mg, 577 μmol) and (2-amino-ethyl)-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethyl]-carbamic acid tert-butyl ester (200 mg, 577 μmol) were heated to 70° C. in 1,4-dioxane (4 mL) under a nitrogen atmosphere for 16 h. The reaction was then cooled to r.t. and NaHB(OAc)3 (367 mg, 1.73 mmol) was added. After stirring for an additional hour, water was added and the solution was extracted with ethyl acetate (2×50 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave a yellow residue which was dissolved in TFA/DCM (1:1, 5 mL) and stirred at room temperature for 30 min. The solvent was evaporated to afford an orange residue. The crude product was diluted with EtOAc (50 mL), washed with 1M NaOH (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to an oil. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 198 mg (87%) of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-N′-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethyl]-ethane-1,2-diamine as a clear glass. [M+H]+ 395.05; 1H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.09 (s, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 7.00 (d, 1H), 6.91 (dd, 1H), 6.78 (dd, 1H), 5.96 (s, 2H), 4.30 (q, 1H), 3.57 (m, 2H), 3.38 (q, 1H), 2.73 (m, 4H), 2.60 (s, 3H), 1.60 (d, 3H), 1.48 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[CH:38][CH:39]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=[C:6]([NH:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:5]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Product: Cc1c(Cl)nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preperation 17) and tert-butyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate [JP 63183560 A2], to afford the product as a colourless oil, (100%).
Reaction SMILES: [Br:1][C:2]1[C:19]2[C:20]3[C:5]([C:6]4[C:21]5[C:10]6=[C:11]([C:22](O[C:25](=[O:26])[C:9]6=[CH:8][CH:7]=4)=[O:23])[CH:12]=[CH:13][C:14]=5[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[CH2:27]([CH:34]([NH2:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN1CCCC1=O.C(O)(=O)C>[CH2:27]([CH:34]([N:42]1[C:25](=[O:26])[C:9]2[C:8]3[C:7]4[C:6](=[CH:21][CH:10]=2)[C:5]2[C:20]5[C:19]([C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=[CH:16][C:15]=5[C:14]=4[CH:13]=[CH:12][C:11]=3[C:22]1=[O:23])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCC(N)CCCCCCC
Reactant: O=C1OC(=O)c2ccc3c4ccc(Br)c5cccc(c6ccc1c2c63)c54
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CCCCCCCC(CCCCCCC)N1C(=O)c2ccc3c4cccc5c(Br)ccc(c6ccc(c2c36)C1=O)c54
Temperature: 135 °C

Procedure:
Under protective gas, a mixture of 3 g (7.48 mmol) of 9-bromoperylene-3,4-dicarboxylic anhydride and 8 g (35 mmol) of 1-heptyloctylamine in 150 ml of N-methylpyrrolidone and 3 ml of acetic acid was heated to 135° C. for 20 h.
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.[N:47]1([C:52]([C:54]2[N:55]=[C:56]([C:63]([F:66])([F:65])[F:64])[N:57]3[CH2:62][CH2:61][NH:60][CH2:59][C:58]=23)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(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:60]1[CH2:61][CH2:62][N:57]2[C:56]([C:63]([F:66])([F:64])[F:65])=[N:55][C:54]([C:52]([N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:53])=[C:58]2[CH2:59]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
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(C(=O)N3CCCC3)c2C1
Reaction time: 12 h
Yield: 18.8 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (417 mg, 1.40 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1 g, 2.80 mmol), crude pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 18a (400 mg, 1.40 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.20 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of H2O, extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (10 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-[[4-fluoro-3-[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 18 (150 mg, yield 18.0%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[K+].[Br-:13].[N+]([O-])(O)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC(Cl)C.ClCCl>[Br:13][C:4]1[CH:5]=[C:6]([CH2:9][C:10]#[N:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [Br-]
Reactant: COc1ccc(CC#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: O=[N+]([O-])O
Product: COc1ccc(CC#N)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
To a mixture of compound 4-methoxyphenyl acetonitrile (5.88 g, 40 mmol), KBr (9.52 g, 80 mmol), tetrabutylammonium chloride (332 mg, 1.2 mmol) in dichloroethane (80 mL), was added 21% w/w nitric acid (48 g, 160 mmol). The reaction mixture was stirred at rt for 20 h, diluted with dichloromethane (80 mL) and washed with sat. NaHCO3 aq. (2×50 mL), water (2×50 mL), brine and dried over Na2SO4. After removal of solvent under vacuum, the residue was triturated with Et2O (10 ml)/hexanes (40 ml) to give 6.32 g of product; Yield: 70%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: O=C(Cl)c1cccnc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1cccnc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 450 mg (2.5 mmol) of nicotinoyl chloride, and after purification, 400 mg (40%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnicotinamide are obtained in the form of a white solid with a melting point of 115° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:13]([NH:16][NH2:17])([NH2:15])=[NH:14].Cl.Cl.C(=O)([O-])O.[Na+]>CO>[NH2:15][C:13]1[N:14]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1n[nH]c(Cc2ccccc2)n1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
The synthesis method of Example 7-(2) was applied. Methyl phenylacetate (10.0 g), methanol (160 ml), metallic sodium (5.73 g) and aminoguanidine hydrochloride (27.5 g) were used as reagents. After the reaction, the reaction mixture was poured into ice water and adjusted to pH 8 with 2N hydrochloric acid and sodium hydrogencarbonate. Methanol was distilled away under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give a white solid. The solid was washed with ethyl acetate to give 7.12 g of white crystals (yield 61%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([OH:20])=O)=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[CH3:15])=[C:4]([F:21])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]1([CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O.Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([NH:44][S:41]([CH2:40][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)(=[O:42])=[O:43])=[O:20])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[CH3:15])=[C:4]([F:21])[CH:3]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)O)cn(C)c1=O
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NS(=O)(=O)Cc2ccccc2)cn(C)c1=O
Reaction time: 2 h
Yield: 68 %

Procedure:
N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-C-phenyl-methanesulfonamide was prepared from 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid as follows. To a solution of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.040 mg, 0.113 mmol) in DMF (1.5 mL) was added 1,1′-carbonyldiimidazole (0.074 mg, 0.456 mmol). After stirring for two hours, α-toluenesulfonamide (0.079 mg, 0.461 mmol) was added, followed by DBU (0.070 mL, 0.459 mmol). After stirring for 16 hours at room temperature, the reaction mixture was diluted with EtOAc and 1N HCl solution. The organic layer was separated and washed with brine. The aqueous layer was extracted with EtOAc (2×) and washed with brine. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (2% MeOH in methylene chloride) gave 0.039 g (68%) clean desired product; MS APCI (−) m/z 506, 508 (M−, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.27 (m, 3H), 7.18 (d, 1H), 7.11 (m, 3H), 6.56 (t, 1H), 4.44 (s, 2H), 3.54 (s, 3H), 1.62 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[NH2:29]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:29][N:25]3[CH2:26][CH2:27][CH2:28][C@H:24]3[CH2:23][O:22][CH3:21])=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: COC[C@@H]1CCCN1N
Product: COC[C@@H]1CCCN1NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; MS (EI) 402.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[N:6]2
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(Nc3ccc(S(N)(=O)=O)cc3)ncc12
Yield: 19.8 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 4-bromobenzenesulfonamide (0.020 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave 4-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)benzenesulfonamide (0.008 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.24 (bs, 1H), 9.21 (s, 1H), 8.93 (s, 1H), 8.80-8.75 (m, 1H), 8.05-8.00 (m, 2H), 7.95-7.90 (m, 2H), 7.88-7.82 (m, 2H), 6.53 (bs, 2H), 2.61 (s, 3H). MS m/z 449 (M+1).