Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(COC)OC>[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C:12]1[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:23]=[CH:22]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1ccc2cc(-c3cc4ccccc4c4ccccc34)ccc2c1
Temperature: 78 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
Under an argon gas atmosphere, 19.41 g (87.4 mmol) of 9-phenanthreneboronic acid, 25.00 g (87.4 mmol) of 2,6-dibromonaphthalene, 2.02 g (1.75 mmol) of tetrakis(triphenylphosphine) palladium(0), 400 mL of dimethoxyethane and 132 mL of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 78 degrees C. The reaction mixture experienced filtration, filtrate thereof was cleansed with water and the reaction mixture was dried with magnesium sulfate. Then, toluene was distilled away under reduced pressure. By refining residue thereof by silica-gel column chromatography and by recrystallizing the residue by acetic ether, 9.80 g of 6-bromo-2-(9-phenanthrenyl)naphthalene was obtained with an yield of 29%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1OC
Yield: 48 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in toluene (3 ml) with heat, 4-fluorophenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 70 minutes. The separated crystals were filtered and washed with toluene to obtain 38 mg of the title compound (yield: 48%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH:7]=[O:8]>CO.C(OCC)(=O)C.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cc(Br)cc(Br)c1
Reaction time: 0.5 h

Procedure:
1.14 G(30 mM) of sodium borohydride was added slowly to a suspension of 3,5-dibromobenzaldehyde (7.92 G;30 mM), from step (a), in 50 mL of methanol at 0° under nitrogen. After stirring 30 mins., the reaction mixture was diluted with 150 mL of ethyl acetate and washed with 5×50 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate. Solvent removal afforded a crude product, which was dissolved in minimum amount of CH2Cl2 and applied on silica gel. Elution with 1:2 mixture of EtOAc:hexane gave 7.2 G of the desired alcohol as white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[C:18]2=[N:19][N:20]([CH2:30][CH3:31])[C:21]([CH2:22][C:23]3([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:17]2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>C(Cl)(Cl)Cl>[C:1]([N:26]1[CH2:27][CH2:28][C:23]([CH2:22][C:21]2[N:20]([CH2:30][CH3:31])[N:19]=[C:18]3[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=[C:9]3[NH2:8])([OH:29])[CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCNCC1
Solvent: ClC(Cl)Cl
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCN(C(C)=O)CC1
Reaction time: 16 h
Yield: 61.7 %

Procedure:
Acetic anhydride (88 μL, 0.922 mmol) was added to a slurry of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-4-ol (0.300 g, 0.922 mmol) in chloroform (10 mL). After 16 hours, the solution was purified via automated flash chromatography eluting with a linear gradient of 2-25% CMA in chloroform. The residue was triturated in acetonitrile and isolated by filtration to provide 0.209 g of 1-acetyl-4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-4-ol as a white solid, mp 231-232.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1ccc(Br)cc1

Procedure:
Quantities: anhydrous potassium carbonate (34.8 g, 0.25 mol), 1-bromoheptane (19.6 g, 0.11 mol) and 4-bromophenol (17.3 g, 0.1 mol). The experimental procedure was as described in Example 119.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([CH3:41])[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[O:29])[N:33]([CH3:41])[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Temperature: 85 °C
Yield: 39 %

Procedure:
5-Fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzylamine, (6v) (50 mg, 0.15 mmol), (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (a), (68 mg, 0.21 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) were combined in DMF (1.5 mL) and heated at 85° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 4% MeOH/CH2Cl2/0.5% Et3N) to provide 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzyl]-urea (7v) (30 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.03-6.80 (m, 4H), 6.11 (s, 1H), 5.93 (s, 1H), 5.25 (t, J=8.6 Hz, 1H), 4.38 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 3.67 (s, 3H), 2.61 (s, 4H), 1.81 (s, 4H), 1.26 (s, 9H); MS (APCI+) m/z 521 (M+H) detected; HPLC (5 to 95%) 2.61 min.
Reaction SMILES: O.Br[C:3]1[S:13][C:6]2[NH:7][C:8](=[O:12])[C:9](=[O:11])[NH:10][C:5]=2[C:4]=1[Br:14]>C(O)(=O)C.[Zn]>[Br:14][C:4]1[C:5]2[NH:10][C:9](=[O:11])[C:8](=[O:12])[NH:7][C:6]=2[S:13][CH:3]=1
Reactant: O=c1[nH]c2sc(Br)c(Br)c2[nH]c1=O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2scc(Br)c2[nH]c1=O
Reaction time: 24 h
Yield: 29 %

Procedure:
6,7-Dibromothieno[2,3-b]pyrazine-2,3(1H,4H)-dione hydrate (0.50 g, 1.45 mmol) was dissolved in 113 ml 97% acetic acid at 100° C. and 0.11 g (1.68 mmol) of zinc dust was added in one portion. After stirring 24 h another 0.11 g (1.68 mmol) of zinc dust was added and the stirring was continued at 100° C. for 24 h. The reaction mixture was filtrated and evaporated to dryness under reduced pressure and 10 ml of water was added. The precipitate was filtered off and washed with water and dried. The crude material (0.215 g) was recrystallized from acetic acid to afford 0.104 g (29%) of the title compound. M.p. 295°-296° C. 1H-NMR (DMSO-D6, δ): 7.3 (s, 1H), 11.9 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][C:11]=1[CH3:42])(=[O:3])[CH3:2].[BH4-].[Na+]>CC(O)C.O>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][C:11]=1[CH3:42])[CH3:2]
Reactant: CC(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C(C)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
To a solution of 10-[(2′-acetyl-2-methyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 29 (0.122 g, 0.220 mmol) in 2-propanol (5 mL) and water (1 mL) was added sodium borohydride (0.0092 mg, 0.242 mmol) and the reaction mixture stirred at room temperature under nitrogen for 24 hours. The reaction was quenched by the addition of 2 M hydrochloric acid (10 mL) and then washed with diethyl ether (20 mL). The aqueous phase was basified by the addition of 2 M sodium hydroxide and the resulting milky suspension extracted with ethyl acetate ( 2×30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a colorless syrup. Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a colorless glass that was recrystallized from diethyl ether/hexane to afford the title compound (0.061 g, 50%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:31]([NH2:33])#[CH:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:33][C:31]#[CH:32])=[O:29])=[C:22]([F:30])[CH:21]=3)[CH2:12][CH2:13]2)=[N:4][CH:3]=1
Reactant: C#CN
Reactant: O=C(O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: C#CNC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetic acid (80.0 mg, 0.184 mmol) and acetylenamine (11.68 mg, 0.190) in anhydrous DMF (1 mL) was added HOBt (28.2 mg, 0.184 mmol) followed by EDC (70.7 mg, 0.368 mmol) and the mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The mixture was diluted with water and ethyl acetate (5 mL). The layers were separated, the aqueous phase extracted with EtOAc (5 ml), the organic fractions combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via preparative TLC plate (1000 μM) using 40% ethyl acetate in hexane. The band containing product was removed from the plate and the silica washed with EtOAc. The filtrate was collected and the volatiles removed in vacuo to afford the title compound. HPLC/MS; 1.49 min (2 minute run), 471 (M+H)+.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[Sn:12]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cn1ccnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
n-BuLi (7.6 mL, 18.9 mmol) was added dropwise at −10° C. under nitrogen atmosphere over a period of 30 minutes to an anhydrous tetrahydrofuran solution (20 mL) of 1-methyl-1H-imidazole (1.6 mL, 18.8 mmol), and the mixture was stirred for 2.5 hours. Next, a tetrahydrofuran solution (12 mL) of Bu3SnCl (5.1 mL, 18.8 mmol) was added dropwise over a period of one hour at −78° C., and then the mixture was raised to room temperature and stirred overnight. The title compound (5.48 g, 79%) was obtained by vacuum distillation (140-142° C., 0.5 mmHg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9](N)(=[O:11])[CH3:10]>>[C:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])(=[O:11])[CH3:10]
Reactant: CC(N)=O
Reactant: NCCCCCCN
Product: CC(=O)NCCCCCCN

Procedure:
Hexamethylenediamine (90.64 g; 0.6 mol) and acetamide (11.81 g; 0.2 Mol) were stirred and refluxed for 10 hours under nitrogen. The solution was cooled overnight and then distilled under vacuum <100° C. as fast as possible. The N-acetylhexylenediamine was then separated from the resultant mixture by flash chromatography [SiO2/EtOH:25%aq.NH3 (4:1)]. The title product was obtained as a white crystalline product (18.43 g; 58% theory).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:35][C:36]([CH3:41])([CH3:40])[C:37]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:38]
Reactant: CC(C)(C)C(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 100.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 2,2-dimethylpropionic acid (34 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(2,2-dimethylpropionylamino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[O:36]1[CH2:37][CH2:38][N:33]([C:39]([O:1][C:2]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=2)=[O:5])=[O:40])[CH2:34][CH2:35]1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C=Cc2ccccc2)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C=Cc2ccccc2)ccc1OC(=O)N1CCOCC1
Yield: 99.5 %

Procedure:
Using 2-hydroxy-5-phenylethenyl-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][CH:34]=[CH:33]3)O1>C1(P([Pd-4](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)C=CC=CC=1>[CH:12]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]=[CH:33]4)[N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4[nH]ccc4c3)c12
Temperature: 80 °C

Procedure:
A dry mixture of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine (30 mg, 0.096 mmol), cesium carbonate (38 mg, 0.117 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (26 mg, 0.107 mmol) was purged with Argon 3 times prior to the addition of tetrakistriphenylphosphino palladium (0) (6 mg, 0.005 mmol). The mixture was purged twice more and then treated with a degassed mixture of DME:water (5:1, 2 mL). The resulting solution was degassed twice more and then heated at 80° C. overnight. The resulting reaction mixture was concentrated in vacuo, the residue dissolved in 1:1 MeCN:MeOH (1.5 mL) and purified by mass directed preparative HPLC to afford 3-cyclobutyl-1-(1H-indol-5-yl)imidazo[1,5-a]pyrazin-8-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.92 (1H, m) 1.95-2.08 (1H, m) 2.32-2.41 (4H, m) 3.82-3.93 (1H, m) 5.91 (2H, br. s.) 6.45 (1H, d, J=3.03 Hz) 6.90 (1H, d, J=−5.05 Hz) 7.26 (1H, dd, J=8.34, 1.52 Hz) 7.34 (1H, d, J=5.05 Hz) 7.35-7.39 (1H, m) 7.45 (1H, d, J=8.34 Hz) 7.64-7.68 (1H, m) 11.20 (1H, br. s.); MS (ES+): m/z 304.15 [MH+]. HPLC: tR 6.18 min (XTerra C18 5 uM, 4.6×15 mm, A: MeCN & B:10 mmol NH4OAc in 0.05% HOAc/aq., method Polar15).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:6]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Yield: 87.4 %

Procedure:
In a similar manner to Step 1 of Example 16, 3,4-dichlorobenzoyl chloride (3.00 g, 14.3 mmol) was dissolved in dichloromethane (60 mL), and the solution was treated with cumylamine (2.30 mL, 15.7 mmol), triethylamine (3.00 mL, 21.5 mmol) and DMAP (175 mg, 1.43 mmol), followed by purification by slurry using chloroform to obtain 3,4-dichloro-N-(1-methyl-1-phenylethyl)benzamide (3.85 g, yield 88%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)=[O:5].[H-].[Na+].[CH3:14]I>CN(C=O)C>[CH3:14][N:8]1[CH2:7][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][N:10]=[CH:9]1
Reactant: COC(=O)C1CN=CNC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN=CN(C)C1
Reaction time: 3 h
Yield: 75.9 %

Procedure:
1,4,5,6-Tetrahydro-5-methoxycarbonylpyrimidine hydrochloride (300 mg, 1.35 mmol) and NaH (60% in mineral oil 107 mg, 1.35 mmol) were suspended in anhydrous DMF (5 ml) in an oven dried round bottom flask with stirring under nitrogen. After stirring 15 minutes CH3I 84μl, 1.35 mmol) was added via syringe and stirring continued 3 hours at room temperature. The solvents were evaporated in vacuo and the residue triturated with chloroform. The resulting suspension was filtered and evaporated in vacuo. Chromatography (silica, chloroform/methanol, 9:1) gave 160 mg (76%) crystals mp 93°-95° C. identified by 300 MHz nmr; ms m/z=156.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.[CH3:9][N:10]([C@@H:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:27][N:28]1CC[C@H:30](O)[CH2:29]1)[C:11](=[O:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[C:5]([O:4][C@H:1]1[CH2:30][CH2:29][N:28]([CH2:27][C@@H:26]([N:10]([CH3:9])[C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:2]1)(=[O:7])[CH3:6]
Reactant: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@H](CN1CC[C@H](O)C1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CCN(C[C@H](c2ccccc2)N(C)C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
30 ml of acetic anhydride and 15 ml of triethylamine are added to 5.0 grams (11.0 mmol) of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, hydrochloride, and the mixture is heated for two hours on a steam bath. The reaction mixture is subsequently evaporated to dryness, and the residue is taken up in ether and washed with bicarbonate solution. The organic phase is subsequently dried, and the solvent is distilled off. The resultant residue is purified by column chromatography on silica gel with diethyl ether/methanol (99:1) as eluent. The resultant crude product of N-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamide can be purified further by taking up in diethyl ether, precipitation by addition of ethereal HCl, filtering-off of the resultant crystals under reduced pressure, washing of the crystals with ether and drying in air (Rf=0.6 (TLC on silica gel 6 F254 with dichloromethane/methanol (8:2) as eluent)).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][CH2:8]Cl)[CH3:5].[CH3:10][N:11]1[C:17]2=[CH:18][S:19][CH:20]=[C:16]2[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[CH:23][CH:24]=[N:25][C:12]1=2.Cl([O-])(=O)(=O)=O>O.CN(C)C=O>[CH3:3][N:4]([CH3:5])[CH2:6][CH2:7][CH2:8][N:14]1[C:15](=[O:21])[C:16]2=[CH:20][S:19][CH:18]=[C:17]2[N:11]([CH3:10])[C:12]2[N:25]=[CH:24][CH:23]=[CH:22][C:13]1=2
Reactant: CN(C)CCCCl
Reactant: CN1c2cscc2C(=O)Nc2cccnc21
Agent: [H-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCN1C(=O)c2cscc2N(C)c2ncccc21
Reaction time: 18 h

Procedure:
A mixture of 0.69 g. of 55% sodium hydride-mineral oil dispersion and 0.9 ml. of dimethylaminopropylchloride in 30 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.70 g. of 5,10-dihydro-10-methyl-6H-pyrido[3,2-b]thieno[3,4-e] [1,4]diazepin-6-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an amber oil, which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent to give a semi-solid. The perchlorate salt is preparaed by standard procedures and is recyrstallized from water to give a white solid, m.p. 263°-265°C. (dec.).