Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:23][C:24]([CH3:26])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:26])[CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 221.5 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(5-(piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one 188d (1.2 g, 3.3 mmol), and acetone (1.0 g, 16.5 mmol) in methanol/acetic acid (30 mL/3 mL) was stirred for 5 minutes at room temperature, followed by the addition of NaBH(OAc)3 (3.5 g, 16.5 mmol). The mixture was stirred at 50° C. for 2 h. It was cooled to room temperature and H2O (50 mL) was added. The mixture was extracted with DCM (50 mL) three times. The organic layers were concentrated under reduced pressure and the residue was purified by column chromatography eluting with 25:1 DCM/methanol to give 220a (2.97 g, 81%). MS: [M+H]+ 406. 1H NMR (500 MHz, DMSO) δ 8.58 (d, J=3.0, 1H), 8.53 (s, 1H), 7.92 (d, J=3.0, 1H), 7.44 (d, J=2.5, 1H), 7.37 (d, J=2.5, 1H), 7.25 (d, J=8, 1H), 3.51 (s, 3H), 3.06 (t, J=4.5, 4H), 2.69 (s, 1H), 2.57-2.50 (m, 4H), 1.00 (d, J=7, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([F:14])[CH2:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[F:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC(F)C1
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCC(F)C3)c2)CC1
Temperature: 80 °C
Yield: 93 %

Procedure:
A solution of 1-(5-chloro-2-nitro-phenyl)-3-fluoro-piperidine (as prepared in the previous step, 0.44 g, 1.7 mmol) in N-methylpiperazine (2 mL) was heated to 80° C. for 18.5 h. The reaction was cooled to room temperature, diluted with CH2Cl2 and washed with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.50 g, 93%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.00 (d, 1H, J=9.2 Hz), 6.44 (dd, 1H, J=9.2 Hz, J=2.8 Hz), 6.34 (d, 1H, J=2.8 Hz), 4.91-4.71 (m, 1H), 3.54-3.44 (m, 1H), 3.41-3.36 (m, 4H), 3.18-3.10 (m, 1H), 3.02-2.94 (m, 1H), 2.87-2.80 (m, 1H), 2.5-2.52 (m, 4H), 2.35 (s, 3H), 1.82-1.66 (m, 4H). LC-MS (ESI, m/z): Calcd. for C16H23FN4O2 323.2 (M+H), found 323.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][CH2:18][OH:19]>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([CH2:17][CH2:18][OH:19])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: Nc1c(CCO)cccc1C(O)c1ccc(Br)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: Nc1c(CCO)cccc1C(=O)c1ccc(Br)cc1
Yield: 93.7 %

Procedure:
A mixture of 5.3 g (0.016 mole) of 2-amino-3-[(4-bromophenyl)hydroxymethyl]benzeneethanol, 7.1 g (0.08 mole) of manganese dioxide and 250 ml of benzene was heated at reflux for 20 hr. utilizing a Dean-Stark trap for water removal. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 4.8 g of brown gum as residue. The residue was purified by column chromatography on 100 g of silica gel and the product was eluted with 15% ethyl acetate in benzene. The fractions containing the title compound were combined and concentrated under reduced pressure to give a solid residue. The solid was recrystallized from cyclohexane benzene to give 1.6 g (30%) of the titled compound as orange flakes,
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:5]=[CH:6][N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: COc1ccc(CNc2cc(Cl)ncn2)cc1OC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cc(-c3ccc(CC(N)C(=O)O)cc3)ncn2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 6 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (64 mg, 0.19 mmol), 4-borono-L-phenylalanine (40 mg, 0.19 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to above solution followed by 5 mol percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified with Prep-LC to give 5.3 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08(m, 2H), 3.65(s, 3H), 4.20(m, 1H), 4.46(d, 2H), 4.68(m, 1H), 6.82(t, 2H), 6.87(d, 2H), 7.40(d, 2H), 7.90(s, 2H), 8.25(s, 2H), 8.6(s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)O
Reactant: NCCc1ccccc1Cl
Product: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCCc1ccccc1Cl

Procedure:
The title compound was prepared using the method outlined in Example 48, coupling 2-methyl-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoic acid with 2-(ortho-chlorophenyl)ethylamine. The product was a colorless oil. MS (ES+) 385.2; (ES−) 383.2; LC retention time=2.1 min (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: C(OC(C1C(=O)NC2C=CSC=2C=1Cl)=O)C.[CH3:17][O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH2:26])=[O:20].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:26][C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:19]([O:18][CH3:17])=[O:20])=[CH:31][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1sccc1N
Agent: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Product: COC(=O)c1sccc1NCc1ccc(OC)cc1

Procedure:
The preferred intermediate in the preparation of compounds of structure (I), 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester depicted by formula (4) below, was also prepared by an alternative route as shown in Scheme 34. In this method, methyl-3-amino-thiophene-2-carboxylate was reacted with 4-methoxy benzylchloride to yield methyl 3-(4-methoxybenzylamino)thiophene-2-carboxylate, depicted by formula (65). This intermediate was reacted with ethylmalonyl chloride followed by a cyclization reaction to yield 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67). Chlorination of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67) by reacting with oxalyl chloride followed by deprotection yielded the intermediate 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (4), as shown in Scheme 34.
Reaction SMILES: C(O)C.[CH3:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][C:17](/[CH:21]=[CH:22]/[C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:31])[C:12]=3[N:32]=[C:9]2[CH2:8][O:7][CH2:6]1.C(Cl)(Cl)Cl>[Pd].CO.C(O)C>[CH3:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][C:17]([CH2:21][CH2:22][C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:31])[C:12]=3[N:32]=[C:9]2[CH2:8][O:7][CH2:6]1
Reactant: C[C@H]1COCc2nc3c(N)nc4cc(/C=C/C(=O)N5CCOCC5)ccc4c3n21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: C[C@H]1COCc2nc3c(N)nc4cc(CCC(=O)N5CCOCC5)ccc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A 250-mL, glass Parr bottle was charged with palladium on carbon (10%, 0.05 g) and 2 mL of ethanol. A solution of (11S)-11-methyl-3-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (0.25 g, 0.63 mmol) dissolved in 125 mL of a 1:1 mixture of methanol/ethanol was then added. The reaction mixture was placed on Parr apparatus and shaken under H2 at 50 PSI (3.4×105 Pa) overnight at ambient temperature. The reaction mixture was treated with additional palladium on carbon (10%, 0.05 g) and shaken under H2 at 50 PSI (3.4×105 Pa) for 3 days. The reaction mixture was then filtered through a pad of CELITE filter agent. The pad rinsed with methanol and the combined filtrates were concentrated under reduced pressure to give a white solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 111 mg of the title compound as white crystals, mp 245-247° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1cccnc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccnc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-3-yl-isoquinolin-3-yl)-amine. LC-MS m/e 302(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C25H25ClN6O2, 479.0
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>ClCCl>[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[O:8])[CH2:28][CH2:27]1)[CH3:25]
Reactant: CCN1CCNCC1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2ccc(C)c([N+](=O)[O-])c2)CC1
Reaction time: 13 h
Yield: 94.8 %

Procedure:
To 4-methyl-3-nitro-benzoic acid (730 mg, 4.03 mmol), WSCI (930 mg, 4.85 mmol), HOBt (110 mg, 0.674 mmol) and N-ethylpiperazine (608 μl, 4.79 mmol), dichloromethane (8 ml) was added, followed by stirring for 13 hours. The reaction mixture was washed with aqueous ammonium chloride solution, and subsequently dried over sodium sulfate. After filtering sodium sulfate, the filtrate was concentrated under reduced pressure, to obtain (4-ethyl-piperazin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone (1.06 g, 95%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:15](Cl)([Cl:17])[Cl:16].Cl>>[Cl:16][P:15]([Cl:17])[O:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Cl)cc1-c1ccccc1
Reactant: ClP(Cl)Cl
Agent: Cl
Product: Clc1ccc(OP(Cl)Cl)c(-c2ccccc2)c1

Procedure:
79.5 g (0.389 mol) of 2-phenyl-4-chlorophenol were slowly heated to 150° C. with 65.7 g (0.478 mol) of phosphorus trichloride. Hydrogen chloride was evolved at the same time. When the reaction was complete, the mixture was distilled at 0.027 kPa. 80 g (67% of theory relative to the 2-phenyl-4-chlorophenol employed) of the abovementioned substance passed over at a temperature of 145° to 146° C. (see formula sheet, formula V where R1 =2-chloro and R2 =H)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C@H:40]3[CH2:45][CH2:44][C@H:43]([CH2:46][CH2:47][CH2:48]O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].N1C(C)=CC=CC=1C.O>ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]([C@H:40]3[CH2:45][CH2:44][C@H:43]([CH2:46][CH2:47][CH2:48][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCOS(=O)(=O)C(F)(F)F)CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3.47 g of trifluoromethanesulphonic anhydride dissolved in 10ml of dichloromethane were added dropwise at 0° C. to a solution of 4.77 g of 6-[4'-[trans-4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate and 1.32 g of lutidine in 100 ml of dichloromethane. The reaction mixture was stirred at 0° C. for 90 minutes and subsequently poured into 100 ml of water and extracted twice with 50 ml of dichloromethane. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 5.09 g of [4'-[trans-4-[3-(trifluoromethanesulphonyloxy)-propyl]-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH:16]=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C=O)c1
Reactant: CN(C)CCCCN
Product: CN(C)CCCCNCc1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde and (4-aminobutyl)dimethylamine. Purification by column chromatography (DCM/MeOH (95:5)) gave the title compound as greenish oil. 1H-NMR (300 MHz, CDCl3): δ 8.48 (d, 1H), 7.25 (s, 2H), 7.10 (d, 1H), 4.70 (s, 2H), 3.90 (s, 2H), 2.60 (m, 2H), 2.30 (m, 2H), 2.20 (s, 6H), 1.50 (m, 4H), 1.00 (s, 9H, 0.9 (s, 9H), 0.1 (s, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:13][C:14](Cl)([C:16]#[CH:17])[CH3:15].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCCCCC.CCOCC>[CH3:13][C:14]([O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)([CH3:15])[C:16]#[CH:17]
Reactant: C#CC(C)(C)Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCCCCC
Product: C#CC(C)(C)Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of p-trifluoromethoxy phenol (30.69 g), and 2-methyl-2-chloro-3-butyne (53.00 g) in dry acetonitrile (350 mL) was added potassium iodide (14.30 g) followed by potassium carbonate (92.25 g). This reaction mixture was heated at 70°-80° C. for four days then cooled to room temperature and filtered through celite. The precipitate was washed with dichloromethane and the washings were added to the acetonitrile. The organics were evaporated in vacuo and the oil was taken up in 250 mL of dichloromethane. The organics were washed with water (2×100 mL) and dilute aqueous sodium thiosulfate (2×100 mL), dried (MgSO4), filtered and evaporated in vacuo to leave a dark brown-orange oil. Flash column chromatography on SiO2 using hexane/Et2O (5/1) afforded 34.73 g of the pure product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:27]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C=O)C.C(Cl)(Cl)Cl>[N:27]1([C:32]([O:20][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH2:1])[C:11]2[N:12]=[C:13]4[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]4[C:10]3=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)N1CCCC1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1COCc2nc3c(N)nc4ccc(OC(=O)N5CCCC5)cc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol) and pyrrolidinecarbonyl chloride (275 mg, 2.03 mmol). After stirring overnight at ambient temperature, the light brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 122 mg of the title compound as an off-white solid, mp 218-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](/[C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)\[CH3:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1cccnc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.85 mmol) was dissolved in DMF (6 mL), CuI (16 mg, 0.085 mmol), L-proline (19 mg, 0.17 mmol), K3PO4 (364 mg, 1.70 mmol) were added and stirred for 10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (203 mg, 1.02 mmol) was added dropwise and the reaction mixture was heated at 90° C. for 18 h. DMF was evaporated under reduced pressure and the reaction mixture was poured into water (10 mL). The aqueous mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography to 140 mg of the desired compound. 1HNMR (CD3OD, TFA salt) δ (ppm): 9.10 (s, 1H), 8.80 (s, 1H), 8.62 (d, 1H), 7.90 (m, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.20 (m, 2H), 3.80 (m, 2H), 3.42 (m, 4H), 3.22 (m, 2H), 3.10 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[N:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:36]O.[NH4+].[Cl-]>O1CCOCC1>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12](=[O:25])[C:13]3[CH:18]=[N:17][N:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[N:15]=2)=[CH:6][CH:5]=1)(=[O:2])[CH3:36]
Reactant: COC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: CO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoic acid methyl ester (450 mg, 0.98 mmol) in dioxane (6 mL) is added NaOH (2 N, 1.5 mL, 3 mmol) and stirred at room temperature for 14 h. The mixture is then concentrated and treated with SOCl2 (4 mL) at room temperature for 1 h. The excess SOCl2 is removed under vacuum and flushed with toluene (2×2 mL). The resulted residue is dissolved in CH2Cl2 (3 mL) and slowly dropped into a solution of freshly prepared Me2CuLi (2.0 mmol) in Et20 (4 mL) at −78° C. The mixture is kept at the same temperature for 1 h. when MeOH (1 mL) is added to quench the reaction. The mixture is then allowed to warm up to room temperature and treated with saturated aqueous NH4Cl solution (20 mL). After extraction with EtOAc(3×15 mL), the organic layers are combined, washed with brine and dried (MgSO4). After filtering off the drying agent, the solvent is removed under vacuum and the residue is purified by flash column chromatography (silica gel, 0%˜50% EtOAc/hexane) to provide the titled compound 6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. HPLC-MS calculated for C25H17ClN4O2 (M+H+): 441.1. Found: 441.1.