Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:8]=[O:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCOCC>[CH2:10]1[CH2:11][O:12][CH:8]([CH:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9]1
Reactant: OCCO
Reactant: COC(=O)CC(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)CC(C)C1OCCO1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-methyl-4-oxo-butanoate (86.3 g), ethylene glycol (61.75 l g, 0.996 m), p-toluenesulfonic acid (1 g) and benzene (700 ml) is refluxed under nitrogen for 16 hr. The resulting mixture is allowed to cool to room temperature and treated with ether (300 ml). The organic phase is washed with 5% sodium bicarbonate solution (100 ml), dried (Na2SO4) and evaporated in vacuo to give methyl 4,4-ethylenedioxy-3-methylbutanoate as a crude product (63.2 g). This material is used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:17][CH2:16][C:15]3[CH:21]=[CH:22][C:12]([O:11][C:8]4[N:7]=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=4)=[CH:13][C:14]=3[CH2:20][CH2:19]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: O=C1CCCC1
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)nc1
Reaction time: 0.5 h

Procedure:
N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (150 mg, 0.5 mmol) was dissolved in 2.5% acetic acid in methanol (5 ml) and treated dropwise with cyclopentanone (0.09 ml, 1 mmol). The mixture was stirred for 30 minutes and then (polystyrylmethyl)trimethylammonium cyanoborohydride (2.04 mmol/g, 490 mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, applied to a SCX cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.25:2.25:97.5) to afford the title compound (E223). MS (ES+) m/e 366 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12]2[N:18]([CH3:31])[C:19](=[O:30])[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])=[CH:21][C:11]3=2)[N:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[C:19](=[O:30])[N:18]([CH3:31])[C:12]2[N:13]([CH3:17])[C:14]3[C:10]([C:11]=2[CH:21]=1)=[CH:9][C:8]([C:6]1[N:7]=[C:3]([CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:4][CH:5]=1)=[CH:16][CH:15]=3
Reactant: C1COCCN1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CCl)n4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CN5CCOCC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 122 above, with the compound from Example 128A 6-(2-chloromethylthiazol-4-yl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and morpholine.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:7])=[O:5])#[N:2].[H][H]>[Ni].N.CO>[NH2:2][CH2:1][CH2:3][C:4]([N:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:7])=[O:5]
Reactant: CN(C(=O)CC#N)C1CCCCC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN(C(=O)CCN)C1CCCCC1

Procedure:
A mixture of 2-cyano-N-cyclohexyl-N-methyl-acetamide (3.96 g, 0.022 mol), a known compound, (which may be prepared as disclosed in Osdene, Thomas S. et al. Journal of Medicinal Chemistry (1967), 10(2), 165-7; Osdene, Thomas S.; Santilli, Arthur A. U.S. Pat. No. 3,138,595) and Raney nickel (3 g) in NH3/MeOH (300 mL) was hydrogenated at normal pressure. After 2 equivalents of hydrogen were consumed, the catalyst was removed by filtration. The filtrate was evaporated, and toluene was added to the residue and then evaporated to yield a residue.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C@H:24]1[CH:23]=[CH:22][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:19])=[O:20])[C:2](=[O:1])[C@H:3]1[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccco2)cc1
Reactant: CCOC(=O)/C=C/C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H]1C(=O)N(S(=O)(=O)c2ccc(OC)cc2)C=C[C@@H]1c1ccco1
Yield: 71 %

Procedure:
The title compound was prepared according to the general procedure from ethyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-(furan-2-yl)prop-2-en-1-imine using 10 mol % 9 as the catalyst in 71% yield as a yellow solid. [α]D20 (c 1.58, CHCl3)=+125.7; mp=98-100° C.; 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, 2H, J=7.0, 1.9 Hz), 7.12 (d, 2H, J=8.0 Hz), 7.00 (dd, 21-1, J=7.0, 1.9 Hz), 6.87 (d, 1H, J=1.8 Hz), 6.11 (dd, 1H, J=3.2, 1.8 Hz), 5.82 (d, 1H, J=3.2 Hz), 5.51 (dd, 1H, J=8.0, 6.8 Hz), 4.15-4.10 (m, 2H), 3.90 (s, 3H), 3.75 (t, 1H, J=6.7 Hz), 3.45-3.40 (m, 1H), 2.72 (dd, 1H, J=17.3, 6.0 Hz), 2.52 (s, 3H), 2.04 (dd, 1H, J=17.3, 7.7 Hz), 1.22 (t, 3H, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.7, 168.7, 164.2, 142.6, 131.4, 129.6, 125.7, 114.1, 110.4, 108.0, 61.0, 56.0, 43.2, 35.1, 31.5, 14.3; IR (thin film) ν 3114, 2982, 2843, 1724, 1595, 1498, 1363, 1263, 1167, 1133, 1092, 1025 cm−1; HRMS (ESI) calcd for C20H21NO7S [M+Na]+ 494.1243, found 494.1265; >99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=43.7 min, tr (3R,4R)=37.4 min.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[C:18]1([CH2:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3]3[NH:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[CH2:30][CH2:31]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1ccc(CCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CCC2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.5 %

Procedure:
2-(Chloromethyl)benzimidazole (448 mg, 2.64 mmol) and potassium carbonate (729 mg, 5.28 mmol) were added to a solution of 4-(2-phenylethyl)piperidine (500 mg, 2.64 mmol) in dry DMF (20 ml) under a nitrogen atmosphere and the mixture stirred at room temperature for 20 hours. The reaction was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml), the combined organic layers were washed with water (25 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a brown oil which was triturated with toluene and recrystallised from methanol to give the title compound as a sandy solid (97.3 mg, 12%), m.p. 170° C.; (Found: C, 78.38; H, 7.79; N, 12.93. C21H25N3.0.1 H2O requires C, 78.51; H, 7.91; N, 13.08%); δH (DMSO-d6) 1.22 (3H, m, piperidinyl H and CH2CH2Ph), 1.50 (2H, m, piperidinyl CH2), 1.67 (2H, m, piperidinyl CH2), 2.01 (2H, m, piperidinyl CH2), 2.56-2.60 (2H, m, piperidinyl CH2), 2.83 (2H, d, J 10.8Hz, CH2 -Ph), 3.67 (2H, s, N-CH2Ar), 7.12-7.19 (5H, m, ArH), 7.24-7.28 (2H, m, ArH), 7.42 (1H, d, J 7.3 Hz, ArH), 7.53 (1H, d, 3 7.3Hz, ArH), and 12.20 (1H, brs, NH); m/z (CI+, NH3) 320 (M+1)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22][C:23]3C=CC=CC=3C(OC)=O)[C@@H:18]([OH:33])[C@H:17]2[OH:34])[CH2:2]1.SC1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(C1C=CC=CC=1S)(OC)=O>>[O:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:34])[C@H:18]([OH:33])[C@@H:19]([CH2:21][S:22][C:23]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[O:20]2)[CH2:2]1
Reactant: Sc1ncccn1
Reactant: COC(=O)c1ccccc1SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: COC(=O)c1ccccc1S
Product: O[C@@H]1[C@H](O)[C@@H](CSc2ncccn2)O[C@H]1n1cnc2c(N[C@H]3CCOC3)ncnc21

Procedure:
Compound 27 was prepared in the manner of compound 23 substituting 2-mercaptopyrimidine for 2-carbomethoxythiophenol [MS 432.4 (M+1)].
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]([NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[NH:20]2)=[O:18])[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([OH:29])(=[S:28])[CH3:27].CC(N=NC(C#N)(C)C)(C#N)C>O1CCOCC1>[O:25]=[C:21]1[NH:20][C@@H:19]([C:17]([NH:16][C@H:10]([C:8](=[O:9])[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:28][C:26](=[O:29])[CH3:27])=[O:18])[CH2:24][CH2:23][CH2:22]1
Reactant: C=CCCC[C@H](NC(=O)[C@H]1CCCC(=O)N1)C(=O)Nc1ccccc1
Reactant: CC(O)=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Product: CC(=O)SCCCCC[C@H](NC(=O)[C@H]1CCCC(=O)N1)C(=O)Nc1ccccc1
Temperature: 0 °C
Yield: 53 %

Procedure:
To a stirred solution of (R)-6-oxo-piperidine-2-carboxylic acid ((S)-1-phenylcarbamoyl-hex-5-enyl)-amide (220 mg, 0.64 mmol), thioacetic acid (460 μl, 6.4 mmol) at 75° C. in degassed dioxane (7 ml) was added AIBN (105 mg, 0.64 mmol). The reaction mixture was stirred until complete conversion of the starting material as monitored by TLC analysis. The reaction mixture was cooled to 0° C. and quenched with an excess of cyclohexene under stirring, the latter being maintained for 20 minutes. Concentration under reduced pressure and purification through chromatography on silica gel using Hexane/DCM/IPA: 50/40/10 as eluent afforded the desired adduct.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:41])[C:7]=1[CH:8]([OH:40])[CH2:9][N:10]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12].Cl.[CH3:43][O:44][NH2:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:41])[C:7]=1[CH:8]([OH:40])[CH2:9][N:10]([CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28](=[O:30])[NH:45][O:44][CH3:43])[CH2:26][CH2:27]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12]
Reactant: O=C(c1cnn([C@H]2CC[C@H](C(=O)O)CC2)c1C(F)(F)F)N(Cc1cc(F)cc(F)c1)CC(O)c1c(Cl)cncc1Cl
Reactant: CON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CONC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3cc(F)cc(F)c3)CC(O)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of compound 5-3 (75 mg, 0.12 mmol) and O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol) in DMF (3 mL) were added HATU (55 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.30 mmol) and mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound 6-1 (65 mg, 82%) as a white foam. LCMS: 650 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:22])=[C:13]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:14]=2)=[N:6][CH:7]=1.[S-:23][C:24]#[N:25].[K+].BrBr>C(O)(=O)C>[NH2:25][C:24]1[S:23][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:22])=[C:13]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH:14]=1)[N:6]=2
Reactant: Nc1ccc(Oc2ccc(Cl)c(NC(=O)C(F)(F)F)c2)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
N-{5-[(5-Aminopyridin-2-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (12 g, 36.2 mmol) and potassium thiocyanate (14.1 g, 145 mmol) were suspended in acetic acid (145 mL), bromine (8.67 g, 54.3 mmol) was added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residual oily substance was dissolved in ethyl acetate (100 mL), and aqueous sodium hydrogen carbonate solution (150 mL) was gradually added to partition the solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was collected by filtration with diisopropyl ether (100 mL), and dried to give the title compound (10.1 g, 72%) as a pale-yellow solid.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)OC)c3)cs2)cc1OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
5.23 g of imidazole and 4.85 g of tert-butyldimethylchlorosilane were added, in this order, to a suspension of 4.02 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)thiazole in 60 ml of dimethylformamide at room temperature. The mixture was stirred at the same temperature for 4 hours. To the reaction mixture were added 100 ml of ice water and 200 ml of ethyl acetate. The organic layer was separated, washed with 100 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to obtain 5.14 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-tert-butyldimethylsilyloxyphenyl)thiazole.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](Cl)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>CC(O)C.CO>[NH2:2][C:3]1[N:4]=[C:5]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([Br:17])[CH:19]=2)[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[N:8]=1
Reactant: Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Reaction time: 18 h
Yield: 16 %

Procedure:
A mixture of 2-amino-4-chloroindolo[2,3-d]pyrimidine hydrochloride (123 mg, 0.6 mmol) and 3-bromoaniline (0.3 mL, 2.8 mmol) in 2-propanol (6 mL) is heated at reflux for 4 hr, filtered through a celite pad, and concentrated in vacuo. The residue is partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous phase is extracted with further ethyl acetate (2×20 mL), followed by washing the combined extracts with 1% aqueous sodium hydroxide (25 mL), water (2×40 mL), saturated brine (40 mL), and drying (Na2SO4). The solution is evaporated to dryness under reduced pressure to afford 105 mg crude product as a tan powder. The solid is dissolved in a minimum amount of methanol, filtered, and further purified by preparative plate chromatography (SiO2 ; 1:1, EtOAc: CH2Cl2 ; Rf =0.40 ). After extraction of the product from the silica gel with ethyl acetate, the volume of the warm solution is reduced to minimum, and it is filtered through celite, and the solvent is removed under reduced pressure. The oily solid thus obtained is dissolved in a minimum amount of 2-propanol and allowed to crystallize at 3 C. over an 18 h period. The crystals are collected by suction filtration, washed with a small amount of cold 2-propanol, and dried in vacuo to give 2-amino-4-(3-bromoanilino) indolo[2,3-d]pyrimidine (34 mg, 17%). 1 HNMR, (DMSO): δbrs), 8.57 (1H, s), 8.11 (1H, d, J =8.0 Hz), 8.01 (1H, s), 7.94 (1H, d, J=8.2 Hz), 7.34-7.12 (5H, m), 6.41 (2H, brs).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:8][N:9]1[C:13](=[O:14])[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:19])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of ethyl bromoacetate (2.05 g, 12.3 mmol) in dimethylformamide (15 ml), N-hydroxyphthalimide (3.04 g, 18.4 mmol) and Hunig base (N,N-diisopropylethylamine, 4.24 mL) were added at room temperature, and the mixture was stirred at 80° C. overnight. The reaction solution was poured into saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with saturated brine (2×30 ml), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate=2:1) to give (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetic acid ethyl ester (1.83 g, 60%) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[CH2:28](I)[CH2:29][CH2:30][CH3:31]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Reactant: CCCCI
Product: CCCCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OC

Procedure:
1-(4-Pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene and butyl iodide are treated in the same manner as in Reference Example 117-(2) to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-butoxy-7-methoxynaphthalene.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>C(OCC)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:12]=1)[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[N:9]=2)([O-:18])=[O:17]
Reactant: O=C1CCCCC1Cl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc3c(n2c1)CCCC3

Procedure:
Operations similar to Production Example 1-(2) were conducted using 2-chlorocyclohexanone and 2-amino-5-nitropyridine. The resulting solid was suspended in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to provide the title compound as yellow crystals.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([O:8]N1C(=O)CCC1=O)=O)[CH:3]([CH3:5])[CH3:4].[NH2:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl.C(N(CC)CC)C>C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:2]([C:6]([NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 17 h
Yield: 99.3 %

Procedure:
A mixture of t-Boc-Val-OSu (3.14 g, 10 mmol) and H-Lys(CBZ)-OCH3.HCl (3.31 g, 10 mmol) in THF (300 ml) was treated at room temperature with triethylamine (1.38 ml) and left stirring for 17 hr. The resulting solution was evaporated in vacuo and the residue was dissolved in EtOAc (500 ml). The organic solution was washed successively with water (2×200 ml), 5% citric acid (2×200 ml), water (2×200 ml) and dried over Na2SO4. The dried solution was filtered and evaporated in vacuo to give (VI) (4.9 g; 99%) as a foam. T.l.c. RfE4 =0.64.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:18][Li].O>O1CCCC1>[CH3:18][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:6]=1
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
The title compound of Step A (9.0 g, 38 mmol) was dissolved in 50 mL of tetrahydrofuran and treated with methyl lithium (1.4 M in ether, 34 mL, 47 mmol) at a temperature of −70° C. The reaction mixture exothermed to −35° C. The mixture was stirred at −30° C. for 1.5 h and then treated with 1 mL of water and dichlorodicyanoquinone (9.44 g, 42 mmol). The mixture was stirred at 25° C. for 30 minutes and then partitioned twice between 100 mL of water and 100 mL of dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. The residue after evaporation was subjected to silica gel chromatography using hexanes/ethyl acetate (95:5) as eluent to give 9.02 g of the title compound of Step B as a white solid melting at 128-131° C. 1H NMR (CDCl3): δ2.31 (s, 3H), 2.56 (s, 3H), 7.71 (d, 2H), 8.49 (d, 2H), 8.53 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][SH:17])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Fc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(CSc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,5-dibromopyridine (1.0 eq.) and (4-fluoro-phenyl)-methanethiol (1.2 eq.) in DMF (0.2M) at 0° C. was added portionwise NaH (1.3 eq.). The mixture was stirred for 1 h at rt, poured in water and extracted with Et2O. The organic extract was washed with water (2×), brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as a yellow solid.