Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:2]3[CH2:3][CH2:4][CH:5]([C:8]4[C:9](=[O:18])[NH:10][C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:17]=4)[CH2:6][CH2:7]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: O=c1[nH]c2ccccc2nc1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3nc4ccccc4[nH]c3=O)CC2)C1=O
Yield: 49 %

Procedure:
Title compound was prepared from 3-(piperidin-4-yl)quinoxalin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 49% yield. MS m/e (M−H)−=573.2. 1H NMR (500 MHz, DMSO-D6): δ=13.53 (s, 1H), 12.35 (s, 1H), 8.36 (s, 1H), 7.72 (t, J=8.70, 1H), 7.48 (t, J=7.78, 1H), 7.28 (m, 2H), 7.24 (s, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=17.09, 1H), 4.49 (m, 1H), 4.12 (m, 1H), 3.86 (m, 1H), 3.59 (t, J=12.36, 1H), 3.45 (m, 1H), 3.22 (m, 1H), 3.10 (m, 1H), 2.99 (m, 1H), 2.87 (dd, J1=15.56, J2=14.34, 1H), 2.72 (m, 1H), 2.36 (m, 1H), 1.96 (d, J=12.82, 1H), 1.89 (d, J=13.12, 1H), 1.70 (m, 1H), 1.52 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:20]([CH2:21][C:22]([NH:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[CH:11][C:10]=2[N:9]=1>ClCCl>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:20]([CH2:21][C:22]([NH:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])([CH3:23])[CH3:24])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)NC(C)C)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
Isopropyl isocyanate (190 μL, 1.93 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (0.90 g, 1.75 mmol) in dichloromethane (50 mL) at 0° C. After approximately 30 minutes, the solution was allowed to warm to room temperature. A precipitate formed and the mixture was stirred over the weekend. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica gel, gradient elution with 8-10% methanol in dichloromethane) to provide a solid that was dried under vacuum at 60° C. to yield 0.34 g of N-(2-{4-amino-2-(ethoxymethyl)-7-[(6-{[(isopropylamino)carbonyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)-N′-isopropylurea as a tan solid, mp 205-209° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1F

Procedure:
The title compound, off-white solid (72 mg, 90%), MS (ISN) m/z=320.4 [(M+H)+], mp 278.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)n1
Reactant: OB(O)c1ccccc1F
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnnc(-c3ccccc3F)n2)ccc1F
Yield: 48 %

Procedure:
4,2′-Difluoro-5′-(3-methylsulfanyl-[1,2,4]triazin-5-yl)biphenyl-2-carbonitrile (0.115 g, 0.338 mmol) was coupled to 2-fluorobenzeneboronic acid (0.104 g, 0.743 mmol) by the method of Example 2 to give the title product as a pale yellow solid (63 mg): 8H (400 MHz, CDCl3) 7.27 (1H, q, J 1.3 Hz), 7.32-7.37 (1H, m), 7.43-7.48 (2H, m), 7.53-7.60 (3H, m), 8.24-8.29 (1H, m), 8.35-8.39 (2H, m), 9.67 (1H, s); m/z(ES+) 389 (M++H).
Reaction SMILES: [OH-].[K+].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]=[O:14])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[N+:15]([CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])#[C-:16]>CO>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([C@@H:13]3[O:14][CH:16]=[N:15][C@H:17]3[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccc2c(c1)OCCO2)N1CCCC1
Yield: 68.2 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (2.70 g, 48.1 mmol) in methanol (30 ml) was added a mixture of 1,4-benzodioxan-6-carboxaldehyde (8.20 g, 50.0 mmol) and the product from Example 1 (6.30 g, 45.6 mmol). The solution was stirred overnight with continued cooling and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was combined with additional ethyl acetate extracts, washed with aqueous sodium chloride and dried (magnesium sulfate). Concentration afforded crude product as a golden, glassy solid. Flash chromatography over silica (ethyl acetate) yielded 9.40 g (68%) of product as a colorless glassy solid. 1H NMR (CDCl3) δ 6.99 (s, 1H), 6.90–6.78 (m, 3H), 6.00 (d, J=7.3, 1H), 4.58, (d, J=7.3, 1H), 4.26 (s, 4H), 3.95–3.87 (m, 1H), 3.55–3.41 (m, 3H), 2.04–1.80 (m, 4H) ppm.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[S:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>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>[CH:1]1([NH:6][CH2:7][C:8]2[S:12][C:11]([C:17]3[CH:18]=[C:19]4[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=3)[NH:22][CH:21]=[C:20]4[CH:29]3[CH2:30][CH2:31][N:32]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH2:33][CH2:34]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(CNC2CCCC2)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC5CCCC5)s4)cc23)CC1
Yield: 85 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), cyclopentylamine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 48 mg of crude {5-[(cyclopentylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(cyclopentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 93.5 mg of the title compound (85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:18])=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH-].[K+]>C(O)(C)C>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:18])=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCS2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1cc2c(cc1C)SCCC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 380 mg (1.69 mmol) of 4,4,7-trimethy-6trimethylsilylethynylthiochroman, 4 ml of isopropanol and 2.5 ml of aqueous 1N potassium hydroxide was degassed under nitrogen and stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and extracted with 2×10 ml of ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][C:11]=1[CH3:23])(=O)=O>CN(C=O)C.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:1]#[N:2])=[C:11]([CH3:23])[CH:12]=1
Reactant: [C-]#N
Reactant: Cc1cc(-c2ccccc2Cl)ccc1COS(C)(=O)=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2Cl)ccc1CC#N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
KCN (1.1 eq.) was added to a stirred solution of (2′-chloro-3-methylbiphenyl-4-yl)methyl methanesulfonate (1 eq.) from step 2 in DMF (0.13M). The suspension was stirred 12 h. at 80° C. The final mixture was cooled down to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water (2×), brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) to afforded the desired compound as a beige solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([C:10]([O:19][CH2:20][O:21][CH3:22])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=1.O>CN(C)C=O>[F:12][C:11]([F:14])([F:13])[C:10]([C:8]1[CH:9]=[C:4](/[CH:1]=[CH:2]/[CH3:3])[C:5]([O:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([O:27][CH3:26])=[O:36])=[N:6][CH:7]=1)([O:19][CH2:20][O:21][CH3:22])[C:15]([F:18])([F:17])[F:16]
Reactant: C=CCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 3-allyl-2-chloro-5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)pyridine (80 mg, 0.220 mmol) in N,N-dimethylformamide (2 mL), sodium hydride (14.4 mg, 0.330 mmol) and 3-hydroxybenzoic acid methyl ester (50 mg, 0.330 mmol) were added under ice-cold conditions, and the resultant mixture was stirred at 80° C. for 18 hours and further stirred at 100° C. for 3 hours. The reaction solution was added with water under room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (81 mg, yield 76.5%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]([CH3:31])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23](OS(C)(=O)=O)[CH3:24])[C:17](=[O:18])[C:12]=2[C:11](=[O:32])[CH:10]=[C:9]1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CS(C)=O>[N:34]([C@H:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[C:17](=[O:18])[C:12]2[C:11](=[O:32])[CH:10]=[C:9]([CH3:33])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[N+:35]=[N-:36]
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@H](C)OS(C)(=O)=O)c(=O)n(C)c2n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n(C)c2n1Cc1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of the crude (S)-8-benzyl-1,7-dimethyl-3-(5-methanesulfonyloxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione, dimethylsulfoxide (6 ml) and sodium azide (116 mg, 1.79 mmol) was heated at 600 C for 18 hours. After cooling to room temperature, the mixture was partitioned between water (50 ml) and ethyl acetate (50 ml) and the aqueous layer was extracted with ethyl acetate (50 ml). The combined extracts were rinsed with water and with saturated aqueous sodium chloride solution. Concentrating under reduced pressure afforded (R)-3-(5-azidohexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (380 mg, 99% yield for 2 steps) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.22 (d, 3H), 1.36-1.60)m, 4H), 1.62-1.78 (m, 2H), 2.48 (s, 3H), 3.43 (m, 1H), 3.64 (s, 3H), 4.03 (t, 2H), 5.29 (s, 2H), 6.55 (s, 1H), 7.29
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][C:8]3[N:9]2[C:12]([CH3:15])=[N:13][N:14]=3)=[CH:4][CH:3]=1.[SH:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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]>[CH3:15][C:12]1[N:9]2[C:10]3[C:5]([C:6]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][C:8]2=[N:14][N:13]=1)=[CH:4][CH:3]=[C:2]([S:22][C:23]1[CH:24]=[C:25]([C:29]2([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1)[CH:11]=3
Reactant: Cc1nnc2cc(-c3ccccc3)c3ccc(I)cc3n12
Reactant: OC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnc2cc(-c3ccccc3)c3ccc(Sc4cccc(C5(O)CCOCC5)c4)cc3n12
Temperature: 70 °C

Procedure:
5u (100 mg, 0.26 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-ol (5v, 65 mg, 0.31 mmol), iPr2NEt (0.1 mL, 0.52 mmol), Pd2dba3 (6 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01 mmol) were dissolved in 1,4-dioxane (4 mL) and degassed with N2 for 5 minutes. The mixture was heated to 70° C. until no starting material was seen by tlc analysis. The reaction was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography to give the desired product, 5y.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1>C(N)C1C=CC=CC=1>[CH2:15]([NH:14][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: NCc1ccccc1
Product: CN1Cc2c(-c3noc(CNCc4ccccc4)n3)ncn2-c2ccccc2C1=O
Yield: 144.3 %

Procedure:
1.5 g (4.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature in 10 ml of benzylamine for 24 hours. By evaporation of the reaction mixture, chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 and crystallization from ethyl acetate and hexane there were obtained 1.3 g (71%) of 3-(5-benzylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 88°-92°, which was converted into the hydrochloride of m.p. 178°-182°.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Reactant: O=[N+]([O-])O
Product: CN1CC(=O)Nc2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
300 ml of 89 percent nitric acid are treated portionwise at room temperature over a period of 35 minutes with 94.5 g. (496.8 mmol) of 3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione. The mixture is stirred at room temperature for 18 hours and poured into 3.5 l of ice-water. The precipitated material is filtered off under suction, washed with water and dried at 70° in vacuo. There is obtained 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 252°-253°.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:47]=[CH:46][C:12]([O:13][C:14]2[CH:45]=[CH:44][C:17]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:43])([CH3:42])[C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=5)=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)([CH3:20])[CH3:19])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O.P(=O)(O)(O)O>[C:1]1(=[O:7])[N:41]([C:38]2[CH:39]=[CH:40][C:35]([O:34][C:31]3[CH:32]=[CH:33][C:28]([C:27]([C:24]4[CH:25]=[CH:26][C:21]([C:18]([CH3:20])([CH3:19])[C:17]5[CH:16]=[CH:15][C:14]([O:13][C:12]6[CH:11]=[CH:10][C:9]([N:8]7[C:1](=[O:7])[CH:2]=[CH:3][C:4]7=[O:5])=[CH:47][CH:46]=6)=[CH:45][CH:44]=5)=[CH:22][CH:23]=4)([CH3:42])[CH3:43])=[CH:29][CH:30]=3)=[CH:36][CH:37]=2)[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: CC(C)(c1ccc(Oc2ccc(N)cc2)cc1)c1ccc(C(C)(C)c2ccc(Oc3ccc(N)cc3)cc2)cc1
Reactant: O=C1C=CC(=O)O1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CC(C)(c1ccc(Oc2ccc(N3C(=O)C=CC3=O)cc2)cc1)c1ccc(C(C)(C)c2ccc(Oc3ccc(N4C(=O)C=CC4=O)cc3)cc2)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
In the same reactor used in Example 2A, there were placed 26.5 g (0.27 mole) of maleic anhydride, 0.7 g of phosphoric acid and 150 ml of mixed xylene. A solution was then added dropwise thereto under reflux of xylene, the solution having been prepared by thermally dissolving 52.8 g (0.1 mole) of 1,4-bis[4(4-aminophenoxy),α,α-dimethylbenzyl)benzene obtained in Example 1A in a mixture of 100 ml of mixed xylene and 50 ml of N,N-dimethylformamide. A dropping time of 5 hours and an aging time of 2 hours were used in order to carry out the reaction. The reaction solution was concentrated to about 1/2 the original amount and then cooled. When a temperature of 80° C. had been reached; 50 g of water was added thereto. Afterward, the solution was slowly cooled with stirring, so that crystals were precipitated. The crystals were then cooled to room temperature, filtered, and washed with cold methanol. 66.5 g of desired crude 1,4-bis[4-(4-maleimidophenoxy)-α, α-dimethylbenzyl]benzene was obtained. Its yield was 96.7%, and its purity according to HLC was 97.5%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1)=[O:12])=[O:4]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: COC(=O)C1CCNCC1
Agent: Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-[5-(methoxycarbonyl)-2-nitrobenzoyl]-4-piperidinecarboxylate is prepared in analogy to the process described in Example IX from 5-(methoxycarbonyl)-2-nitrobenzoic acid and methyl piperidine-4-carboxylate hydrochloride.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[C:12]([Cl:26])[CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[C:12]([Cl:26])[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NC2CCCCCC2)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)NC2CCCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Dissolve 4-tert-butoxycarbonylaminomethyl-2-chloro-N-cycloheptyl-benzamide (624 mg, 1.6 mmol) in dichloromethane (30 mL) then add trifluoroacetic acid (2 mL). Stir the solution at room temperature under a nitrogen atmosphere for 1 h. Concentrate the mixture in vacuo. Purify the crude mixture by SCX chromatography to obtain the desired intermediate (395 mg, 85%). MS (ES+) m/z: 281.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Al](C)(C)C.[C:9]([NH:12][C:13]1[C:22]2[C:17](=[N:18][C:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:21]=2)[N:16]([CH3:38])[C:15](=[O:39])[C:14]=1[C:40](OC)=[O:41])(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([NH:12][C:13]1[C:22]2[C:17](=[N:18][C:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:21]=2)[N:16]([CH3:38])[C:15](=[O:39])[C:14]=1[C:40]([N:3]([CH3:4])[CH3:2])=[O:41])(=[O:11])[CH3:10]
Reactant: CNC
Reactant: COC(=O)c1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(C(=O)N(C)C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reaction time: 0.5 h

Procedure:
To dimethylamine hydrochloride (26.1 mg) in toluene (2 mL) was added Al(CH3)3 (0.16 mL) at 0° C. The reaction stirred for about 30 minutes before adding the product of EXAMPLE 91 (85 mg) in toluene (1 mL). The reaction stirred for 3.5 hours at 50° C. and was quenched with aqueous 1 M HCl. The reaction was diluted with EtOAc washed with aqueous 1 M HCl. The solution was dried (Na2SO4) and concentrated. The concentrated residue was purified by preparative TLC on silica gel eluted with 6% methanol in CH2Cl2 affording the title compound. HPLC/MS: 543.0 (M+1), 545.0 (M+3); Rt=3.51 min.
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:41]I>C(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15]
Reactant: II
Reactant: C[C@H](CO)CN1C(=O)CCc2ccccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CI)CN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
A reaction flask was charged with (S)-1-(3-Hydroxy-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH16) (1.54 g, 7.0 mmol) dissolved in 50 mL DCM. PPh3 (4.04 g, 15.4 mmol) and imidazole (1.14 g, 16.7 mmol) were added followed by stirring at rt for 15 min. The mixture was cooled with an ice-bath followed by addition of I2 (5.00 g, 19.7 mmol). The reaction mixture was slowly warmed to rt and stirred over night. The reaction mixture was washed with a Na2S2O3 solution, dried over Na2SO4, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 1:1) to give the title compound (122LH18) (2.140 g, 93%).