Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][CH:27]=2)O1>>[CH:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:26]3[CH:25]=[C:24]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=[CH:22][CH:27]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)c1ccn2c(Br)cnc2n1
Product: CC(C)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-isopropylimidazo[1,2-a]pyrimidine was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-isopropylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white powder: Found C, 76.71; H, 5.17; N 16.24. C22H18N4.0.3(H2O) requires C, 76.59; H, 5.43; N, 16.24; δH (400 MHz, CDCl3) 1.38 (6H, d, J 7), 3.16 (1H, septet, J 7), 6.88 (1H, d, J 7), 7.48-7.76 (7H, m), 7.82 (1H, dd, J 8 and 1), 7.85 (1H, s), 8.85 (1H, d, J 7); m/z (ES+) 339 (M++H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][C:12]1([C:23]([NH:25][CH3:26])=[O:24])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[Cl:27][C:28]1[C:29]([F:49])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH2:45]Cl)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>CN(C=O)C>[Cl:27][C:28]1[C:29]([F:49])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH2:45][N:11]([CH3:10])[C:12]4([C:23]([NH:25][CH3:26])=[O:24])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CNC(=O)C1(NC)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 40.8 %

Procedure:
Diisopropylethylamine (0.55 ml, 3.10 mmol) was added to a solution of tert-butyl 3-(methylamino)-3-[(methylamino)carbonyl]azetidine-1-carboxylate (301 mg, 1.24 mmol) in DMF (0.5 ml). After 5 minutes of stirring, the reaction mixture became homogeneous and was warmed up to 85° C. N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (400 mg, 1.03 mmol) was added portionwise over 2 hours. The reaction mixture was cooled to room temperature, diluted with DMF (2 ml) and purified by preparative HPLC (standard basic condition) to afford tert-butyl 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-3[(methylamino)carbonyl]azetidine-1-carboxylate (235 mg, 41%) as a white solid. 1H NMR Spectrum: (CDCl3) 1.45 (s, 9H), 2.34 (s, 3H), 2.90 (d, 3H), 3.78 (brs, 2H), 4.01 (s, 3H), 4.10 (d, 2H), 4.25 (brs, 2H), 6.84 (brs, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.60 (brs, 1H), 7.78 (brs, 1H), 8.53 (brs, 1H), 8.75 (s, 1H); Mass Spectrum: (M+H)+ 559.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-])=[O:4].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C)C=O>[Cl:18][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of commercially available mono-benzyl malonate (Aldrich Chemical Co., Milwaukee, Wis.) (7.76 g, 40 mmol) in methylene chloride (100 mL) was added oxalyl chloride (14 mL, 160 mmol) followed by 3 drops of dimethylformamide. The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH:2][CH3:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N+:18]=[N-:19])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:1]([N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:2]([CH3:3])[N:19]=[N:18]2)=[CH:13][CH:12]=1
Reactant: CC=CN1CCCCC1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Product: CC1N=NN(c2ccc(F)cc2)C1N1CCCCC1
Yield: 30.5 %

Procedure:
1-(1-propenyl)-piperidine (9.4 g; 75.07 mmol) and 4-fluorophenylazide (10.3 g; 75.07 mmol), prepared as described in example 1, were admixed at 0° C. and the resultant mixture was kept at room temperature for 54 hours in the absence of light. The obtained solid mass was collected with petroleum ether and filtered obtaining the title compound (6 g). The mother liquor was evaporated and the resultant crude compound was purified by chromatography on silica gel (230-400 mesh), eluent petroleum ether:ethyl acetate=9:1, obtaining further title compound (m.p. 75° 76° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([F:39])=[C:34]([F:40])[C:33]=1[CH2:41][CH:42]([NH2:44])[CH3:43]>C(O)CCC>[CH3:20][C:19]1[C:18]2[C:17](=[O:21])[N:16]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:15](=[O:29])[C:14]=2[CH:13]=[C:12]2[NH:30][C:9]([C:3]3[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=3[NH:44][CH:42]([CH3:43])[CH2:41][C:33]3[C:34]([F:40])=[C:35]([F:39])[CH:36]=[C:37]([F:38])[C:32]=3[F:31])=[N:10][C:11]=12
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Solvent: CCCCO
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Yield: 78.5 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.54 g, 2.58 mmol), Hunig,s base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.10 g of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 13.35 (s, 1H, NH), 11.35 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.93 (s, 1H, ArH), 7.81-7.77 (m, 1H, ArH), 7.42 (t, J=7.0 Hz, 1H, ArH), 6.22 (d, J=8.0 Hz, 1H, ArH), 4.34-4.29 (m, 1H, CH), 4.12 (m, 1H, CH), 3.17 (m, 2H, CH2), 3.08 (d, J=5.5 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.48 (s, 3H, CH3), 1.77-1.76 (m, 2H, CH2), 1.37 (d, J=6.5 Hz, 3H, CH3), 1.29-1.24 (m, 6H, 2×CH2); Mass (ESI, positive) m/z 597.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Na]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:11]([NH:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:9])[C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Agent: Cl[Ni]Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1cccc(F)c1

Procedure:
Following a similar procedure to that described in Example (1b), 2.82 g of isomer A of N-[(R)-1-(3-fluorophenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.64 g of nickel chloride hexahydrate, 1.16 g of sodium borolydride and 30 ml of methanol were reacted, to obtain 2.52 g of isomer A of the title compound as a colorless oil.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][C:19]([CH3:23])=[CH:20][C:21]=2Br)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C>[Cu](I)I>[CH3:23][C:19]1[S:18][C:17]2[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([OH:5])=[O:7])[CH2:9][CH2:10]3)=[N:15][O:16][C:21]=2[CH:20]=1
Reactant: Cc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: I[Cu]I
Product: Cc1cc2onc(C3CCN(C(=O)O)CC3)c2s1

Procedure:
Prepared essentially as 2211-198 except that 4-[1-(3-bromo-5-methyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester is used as the starting material. Two other differences are: 1) 0.05 equivalents of copper iodide is used, and 2) no partition between ethyl acetate and water accompanied by subsequent extraction with ethyl acetate is required. Purification of the residue via flash column chromatography uses a mixture of ethyl acetate: n-heptane (1:4) to yield a white solid. LC/MS (ESI), m/e 345 (MNa+), retention time 2.12 minutes. Condition II.
Reaction SMILES: S1C=CC=C1.C(O)C.[Cl:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[CH3:23])=[O:12].[H][H]>[Pt].CO>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[CH2:10][Cl:9])=[C:15]([CH3:23])[CH:16]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)CCl
Agent: [Pt]
Solvent: CO
Solvent: CCO
Solvent: c1ccsc1
Product: Cc1cc(N)ccc1NC(=O)CCl
Yield: 92 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 15 parts of 2-chloro-N-(2-methyl-4-nitrophenyl)acetamide and 400 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12 parts (92%)of N-(4-amino-2-methylphenyl)-2-chloroacetamide (intermediate 70).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[CH3:36][C:37]([CH3:39])=O.[BH4-].[Na+]>>[CH:37]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1)([CH3:39])[CH3:36]
Reactant: CC(Cc1cccc(CN)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCc1cccc(CC(C)Nc2nccc(N3CCCn4c3nc(-c3ccccc3)cc4=O)n2)c1
Reaction time: 0.17 h

Procedure:
A solution of 9-{2-[2-(3-Aminomethyl-phenyl) -1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (79 mg, 0.17 mmol) and acetone (0.015 mL, 0.21 mmol) was stirred for 10 min prior to adding sodium borohydride (108 mg, 3.4 mmol). After 10 min, solvent removed under vacuum and residue partitioned between dichloromethane (10 mL) and saturated sodium chloride. Product isolated as a white solid after purification on silica. M+1=509.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:18]([C:20]2[CH:25]=[C:24]([C:26]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])=[O:27])[CH:23]=[C:22]([N+:34]([O-])=O)[CH:21]=2)=[O:19])[CH:7]=[C:8]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:18]([C:20]2[CH:25]=[C:24]([C:26]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])=[O:27])[CH:23]=[C:22]([NH2:34])[CH:21]=2)[OH:19])[CH:7]=[C:8]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[CH:9]=1
Reactant: O=C(NCC(O)CO)c1cc(C(=O)c2cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)NCC(O)CO)cc(C(O)c2cc(N)cc(C(=O)NCC(O)CO)c2)c1

Procedure:
Di[3-nitro-5-(2,3-dihydroxypropylaminocarbonyl)phenyl]ketone (0.70 g, 1.4 mmol) was dissolved in methanol (40 ml) and was hydrogenated at 60 psi using a Pd/C catalyst (10%, 0.20 g). The catalyst was filtered off and the solvent was evaporated. Analysis by 1H NMR indicated complete conversion to the product. Yield: 0.62 g (100%).
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[NH:18][C:17](=[O:26])[C@@H:16]2[CH2:27][CH3:28])(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][CH2:38][CH3:39].[OH-].[Na+].Cl>CC(C)=O>[CH2:27]([C@@H:16]1[N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[N:18]([CH2:37][CH2:38][CH3:39])[C:17]1=[O:26])[CH3:28]
Reactant: CCCI
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3NC(=O)[C@@H]2CC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Temperature: 62 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
To a solution of ethyl 4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate (0.35 g, 0.83 mmol) in acetone (5 mL) was added cesium carbonate (0.3 g, 0.91 mmol), and 1-iodopropane (0.32 ml, 3.32 mmol). The mixture was heated at 62° C. for 2.5 hours, cooled to 25° C., and treated with a 2N aqueous solution of sodium hydroxide (3 mL). The reaction was then stirred at 25° C. for 2 hours, and was acidified to pH<2 with the addition of a 2N aqueous solution of hydrochloric acid. The resulting mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium chloride. The organic layer was separated, dried over magnesium sulfate, and concentrated. The product was purified via flash column chromatography (SiO2, 30% ethyl acetate:hexane eluted to 60% ethyl acetate:hexane) to afford 0.1 g (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one as a white solid. MS (ESI) m/z 393 ([M+H]+); MS (ESI) m/z 391 ([M−H]−); Anal. Calcd for C19H21FN2O4S: C, 58.15; H, 5.39; N, 7.14. Found: C, 57.95; H, 5.46; N, 6.66.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[C:31](=[O:40])[C:32]4[C:33](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]3=[O:35])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 70.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (17.0 g) and N-(6-bromohexyl)phthalimide (17.4 g) were reacted and treated in the same manner as in Preparation Example 150 to give 17.0 g of 4-amino-5-chloro-N-(1-(6-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)hexyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[S:5][N:4]=1.CS(C)=[O:14]>O>[S:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[C:3]([CH2:2][OH:14])=[N:4]1
Reactant: BrCc1nsc2ncccc12
Reactant: CS(C)=O
Solvent: O
Product: OCc1nsc2ncccc12
Temperature: 80 °C
Yield: 31 %

Procedure:
A solution of the crude 3-(bromomethyl)isothiazolo[5,4-b]pyridine (3.49 mmol) in dimethylsulfoxide (20 mL) was treated with water (4 mL) and the reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was diluted with water (100 mL), filtered through Celite, and was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, dried (magnesium sulfate), and concentrated to provide isothiazolo[5,4-b]pyridin-3-ylmethanol in 31% yield as yellow oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.[C:37]1([N:43]2[C:47]3[CH:48]=[CH:49][C:50](B(O)O)=[CH:51][C:46]=3[N:45]=[C:44]2[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:37]1([N:43]2[C:47]3[CH:48]=[CH:49][C:50]([C:2]4[CH:15]=[CH:14][C:13]5[C:4](=[C:5]([C:27]6[CH:36]=[CH:35][C:34]7[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=7)[CH:28]=6)[C:6]6[C:11]([C:12]=5[C:16]5[CH:25]=[CH:24][C:23]7[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=7)[CH:17]=5)=[CH:10][C:9]([C:50]5[CH:49]=[CH:48][C:47]7[N:43]([C:37]8[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=8)[C:44]([C:55]8[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=8)=[N:45][C:46]=7[CH:51]=5)=[CH:8][CH:7]=6)[CH:3]=4)=[CH:51][C:46]=3[N:45]=[C:44]2[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3cc(Br)ccc3c(-c3ccc4ccccc4c3)c2c1
Reactant: OB(O)c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
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: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nc3cc(-c4ccc5c(-c6ccc7ccccc7c6)c6cc(-c7ccc8c(c7)nc(-c7ccccc7)n8-c7ccccc7)ccc6c(-c6ccc7ccccc7c6)c5c4)ccc3n2-c2ccccc2)cc1
Yield: 73 %

Procedure:
2.0 g (3.4 mmol) of 2,6-dibromo-9,10-di(2-naphthyl)anthracene, 2.4 g (7.5 mmol) of 1,2-diphenyl-1H-benzimidazole-5-boronic acid, and 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 30 mL of 1,2-dimethoxyethane. Then, 15 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. The resultant was stood to cool. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 2.4 g of a greenish white crystal (73% yield). Mass spectral analysis confirmed that the crystal was a target product. The crystal had an m/e of 966 with respect to a molecular weight of 966.37.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CC(OC)OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(Cc1ccc(CO)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a cooled (−78° C.) solution of methyl 4-(2,2-dimethoxyethyl)benzoate (assume 7.08 mmol) in THF (30 mL) was added drop wise a solution of lithium aluminium hydride (2.0 M in THF, 3.50 mL, 7.00 mmol). The reaction mixture was allowed to warm to RT over 4 hours. The mixture was sequentially treated with water (0.266 mL), 2M aqueous sodium hydroxide (0.266 mL) and water (3×0.266 mL). The mixture was diluted with ethyl acetate and magnesium sulfate added. The mixture was stirred at RT for 1 hour and then filtered through celite. The filter cake was washed with further ethyl acetate and the filtrates combined. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-30% ethyl acetate in iso-hexane to afford the title compound (0.854 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:20](=O)(OC(Cl)(Cl)Cl)[O:21]C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([F:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cccc(F)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide (5.70 g, 17.6 mmol) in THF (100 mL) was treated with bis(trichloromethyl) carbonate (triphosgene) (6.28 g, 21.2 mmol) at room temperature and stirred for 15 min. The mixture was diluted with EtOAc, carefully treated with saturated aqueous NaHCO3 and stirred at room temperature until gas evolution stopped. The separated organic phase was washed sequentially with saturated aqueous NaHCO3, water and brine, and was dried and concentrated. The residue was triturated with ether to provide 3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as an off-white solid (6.00 g, 97% yield). Mass spectrum m/z 349, 351 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.59 (d, J=17.6 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.70 (dd, J=7.8, 1.2 Hz, 1H), 7.54-7.43 (m, 1H), 7.28-7.21 (m, 2H), 7.21-7.17 (m, 1H), 2.28 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)=O)C>C(Cl)Cl>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:14][OH:13])=[N:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CO)nc1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
Diisobutylaluminium hydride (1 M in DCM, 41.6 mL, 41.6 mmol, 1.3 equiv) was added dropwise to a cold (−78° C.) solution of 5-nitro-pyridine-2-carboxylic acid ethyl ester (Step 39.4) (6.4 g, 32 mmol) in DCM (120 mL), under an argon atmosphere. The reaction mixture was allowed to warm to rt, quenched by addition of an aqueous solution of potassium sodium tartrate, diluted with DCM and H2O, and filtered through a pad of celite. The filtrate was extracted several times with DCM. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 9:1→1:1) to provide 1.44 g of the title compound: ESI-MS: 153.1 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(OC)c1)OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester (Example 132, Step A) (0.080 g, 0.31 mmol) in acetonitrile (10 mL) was added 4-(3-bromo-propoxy)biphenyl (Example 132, Step D) (0.101 g, 0.35 mmol) and potassium carbonate (0.115 g, 0.945 mmol). The resulting suspension was stirred at 85° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (10 mL), and water (10 mL) was added. The organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO4), and concentrated. The crude product was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate, 7:3) to produce 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic acid ethyl ester (0.086 g, 59%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.26 (m, 7H), 6.98 (d, 2H, J=8.6), 6.87–6.73 (m, 3H), 4.25–4.17 (m, 6H), 3.91 (dd, 1H, J=7.0, 5.6), 3.83 (s, 3H), 3.35 (s, 3H), 2.97–2.93 (m, 2H), 2.31 (qn, 2H, J=5.9), 1.24 (t, 3H, J=7.3).