Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
A mixture of methyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate (3.34 g, 9.96 mmol) in TFA (20 mL) and CH2Cl2 (35 mL) was stirred at room temp for 15 hr. The mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, and dried over Na2CO3. The organic layer was evaporated to give 1.70 g (73%) methyl (S)-4-(2-pyrrolidinylmethoxy)benzoate as a yellow oil. 1H-NMR (CDCl3) δ 1.54–1.61 (m, 1 H), 1.77–1.86 (m, 2 H), 1.87–1.97 (m, 1 H), 2.00 (bs, 1 H), 2.93–3.06 (m, 2 H), 3.52–3.57 (m, 1 H), 3.88 (s, 3 H), 3.90–3.99 (m, 2 H), 6.92 (d, J=9.0 Hz, 2 H), 7.98 (d, J=9.0 Hz, 2 H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:33][N:34]1[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[N:35]1>O1CCCC1.O>[Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][N:5]([S:39]([C:37]2[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=2)(=[O:41])=[O:40])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(S(=O)(=O)n2cc(C=O)c(Cl)c2-c2cccnc2F)cn1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 4-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (150 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 81 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (442 mg) was added dropwise and the mixture was stirred for 5 min. 1-methyl-1H-pyrazole-4-sulfonyl chloride (242 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 160 mg, 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[O:14][CH2:13][CH2:12][O:9]2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A stirred solution of p-nitrobenzaldehyde (101.5 g, 672 mmol), ethylene glycol (112 mL) and p-toluenesulfonic acid (12.8 g, 67.2 mmol) in toluene (800 mL) was heated in flask equipped with a Dean-Stark trap at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate (800 mL) and this mixture was stirred at room temperature for 15 min. The resulting solid was isolated by filtration and dried under vacuum to give the title compound (121.8 g, 92% yield) as a yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:53]=[CH:52][C:9]([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:25]=[C:24]([N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:22][C:21]=4[NH:32][C:33]([C:35]4[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=4)[CH2:38][S:39][CH2:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])=[O:34])[CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:25]=[C:24]([N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:22][C:21]=4[NH:32][C:33]([C:35]4[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=4)[CH2:38][S:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:34])[CH:15]=3)=[O:13])=[CH:52][CH:53]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(-n4cccn4)cc3)ccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(-n4cccn4)cc3)ccn2)c1
Yield: 71.5 %

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed tert-butyl 3-(3-((2-(4-((4-(1H-pyrazol-1-yl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)-propanoate (130 mg, 0.18 mmol, 1.00 equiv), and dichloromethane (2 mL). This was followed by dropwise addition of trifluoroacetic acid (3 mL) with stirring. The resulting solution was stirred for 60 min at room temperature. The solution was adjusted to pH 7 with sodium bicarbonate (aq). The resulting solution was diluted with 30 mL of dichloromethane and washed with 2×10 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (300 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 86.9 mg (72%) of a yellow solid. 1H-NMR: (300 MHz, DMSO-d6+D2O, ppm): δ 1.63 (m, 2H), 1.82 (m, 4H), 2.58-2.62 (m, 4H), 3.47 (t, 4H), 3.87 (s, 2H), 4.56 (d, 2H), 6.53 (s, 1H), 7.44-7.54 (m, 4H), 7.72-7.79 (m, 3H), 7.87-7.89 (m, 2H), 8.36 (s, 1H), 8.42 (s, 1H), 8.99 (d, 1H), 9.53 (s, 1H), 11.97 (s, 1H). MS (ES, m/z): 675 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[N:30][CH:31]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Nc1ccc(Oc2ccc(C[C@H](N)C(=O)O)cc2)nc1
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)nc1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-amino-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:24][OH:25])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=NO)cc2)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
3.52 g (11 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate was dissolved in 150 ml ethanol. 2.29 g (33 mmole) hydroxylamine hydrochloride and 3.6 g (44 mmole) sodium acetate in 30 ml water were added. The reaction mixture was stirred at 50° C. for 1 h 45 minutes. The solvent was evaporated in vacuo and water was added to give a white precipitate, which was filtered off and washed with hexane to give 3.3 g (yield 89%) of 4-{2-[4-(hydroxyiminomethyl)phenoxy]ethyl}phenyl methanesulfonate.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(Cl)Cl.CCOCC>[Br:18][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)=[O:9]
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(Br)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a suspension of 30 g (0.12 mole) of 2-phenyl-1-(4-methylthiophenyl)ethanone in 45 ml of methylene chloride and 450 ml of ether was added dropwise a solution of 20.8 g (0.13 mole) of bromine in 65 ml of methylene chloride. The reaction mixture decolorized and became slightly exothermic. After stirring an additional 30 minutes, the reaction mixture was concentrated under vacuum. The crystalline product was collected by filtration and washed with hexane to give 36.3 g (91.5%) of 2-bromo-2-phenyl-1-(4-methylthiophenyl)ethanone as an off-white solid, m.p. 101°-103°.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=O)[CH2:3]1.Cl.[CH3:11]N(C)C=O>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C)C=CC=CC=1>[CH2:7]([CH:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1)[CH:8]=[CH2:11]
Reactant: O=CCC1CCC(O)C1
Reactant: CN(C)C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Product: C=CCC1CCC(O)C1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
A solution of 5 g of potassium tert.-butylate in 80 ml of dimethylformamide was added at -60° C. over 90 minutes to a solution of 5 g of 3-hydroxy-cyclopentyl-acetaldehyde, 15 g of triphenyl methyl phosphonium bromide and 100 ml of dimethylformamide and the resulting suspension was stirred at -60° C. for 2 hours after which the temperature was allowed to rise to 20° C. The mixture was poured into 2N hydrochloric acid solution and the mixture was extracted with isopropyl ether. The organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain 1.7 g of 3-(2-propenyl)-cyclopentanol.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:47]1([CH:53]2[CH2:57][CH2:56][NH:55][CH2:54]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:55]1[CH2:56][CH2:57][CH:53]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:54]1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1Cc1ccccc1)N1CCC(c2ccccc2)C1
Reaction time: 2 h
Yield: 18.1 %

Procedure:
A solution of 5-benzylisoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 3-phenylpyrrolidine (7 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1524.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[Sn](Cl)Cl.N>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
To 2-(2-fluoro-5-nitrophenyl)pyridine (2.11 g, 9.68 mmol) in ethanol (40 ml), stirred in a water bath at 20° C., was added dry tin(II) chloride (7.10 g, 37.3 mmol) portionwise. The mixture was then stirred at room temperature for 18 h. Aqueous ammonia (40 ml of a 25% solution) was added, and the solvent was removed in vacuo, azeotroping with ethanol to remove traces of water. The residue was sequentially boiled in ethyl acetate and filtered three times. The combined filtrates were concentrated in vacuo to yield 4-fluoro-3-(pyridin-2-yl)aniline as a yellow solid (1.54 g, 85%): 1H NMR (400 MHz, CDCl3) δ 3.65 (2H, br s), 6.68 (1H, m), 6.98 (1H, dd, J 8.6, 11.0 Hz), 7.22-7.31 (2H, m), 7.71-7.83 (2H, m), 8.70 (1H, m); MS (ES+) m/z 189 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[O:11].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COc1ccccc1N=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
2-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with hot methanol (15 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(2-methoxy-phenyl)-urea (0.7 g, 80%) as a white solid: mp 214-216° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H, OCH3), 4.73 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.3 and 12.5 Hz, 1H, CH), 6.79-6.98 (m, 3H, Ar), 7.49 (t, H=5.7 Hz, 1H, NH), 7.77-7.89 (m, 3H, Ar), 8.04-8.08 (dd, J=1.4 and 7.3 Hz, 1H, Ar), 8.19 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 48.86, 55.64, 110.59, 118.07, 120.42, 121.22, 121.88, 127.16, 129.20, 131.61, 133.65, 134.77, 140.112, 147.40, 155.24, 167.00, 167.50, 169.83, 172.76; Anal. calcd. for C22H20N4O6+0.66H2O: C, 58.94; H, 4.79; N, 12.50. Found: C, 59.24; H, 4.86; N, 12.74.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
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+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 72.4 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (168.75 mg, 0.40 mmol) in dioxane (12 mL) and water (4 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (148.85 mg, 0.60 mol), potassium carbonate (208 mg, 1.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol). The mixture was heated with microwave at 150° C. for 15 min. The mixture was concentrated. It was mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (147 mg, 72%). LC-MS m/z 508 (M+H)+.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:19]=1F.Cl>CN(C=O)C.O>[C:11]([O:10][C:8]([NH:1][C@@H:2]([CH2:3][O:4][C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])[C:5]([OH:7])=[O:6])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(F)cccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A solution of BOC-Ser-OH (2.58 g, 12.6 mmol) in DMF (10.00 mL) was added to a suspension of NaH (60% in mineral oil, 1.06 g, 26.4 mmol) in DMF (10 mL) at 0° C. over 10 min. After 1 h at 0° C. a solution of 1,2-difluoro-3-nitrobenzene (2 g, 12.6 mmol) in DMF (10 mL) was added and the mixture stirred at 0° C. for 2 h. The mixture was diluted with H2O and acidified to pH 3 with 1 N HCl, then extracted with EtOAc. The combined extracts were dried over MgSO4 and the filtrate was concentrated to give a residue that was purified by silica gel chromatography to afford (S)-2-(tert-butoxycarbonylamino)-3-(2-fluoro-6-nitrophenoxy)propanoic acid (2.94 g, 68%) as a yellow foam.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][S:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[CH3:18]
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.71 g, 42.8 mmol) in THF (40 mL), 4-methoxybenzenethiol (5.0 g, 35.7 mmol) was added dropwise at room temperature over a period of 10 min. The mixture was stirred at room temperature under N2 for 10 min and then cooled to 0° C. Ethyl bromoacetate (4.0 mL, 36 mmol) was added dropwise at 0° C. over a period of 10 min. The reaction mixture was stirred at room temperature for 30 min and then quenched with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:9 ethyl acetate/hexanes) to provide (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (7.9 g, 98%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=6.6 Hz, 2H), 6.84 (d, J=6.6 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.51 (s, 2H), 1.21 (t, J=7.1 Hz, 3H); ESI MS m/z 227 [(M+H)+, calcd for C11H15O3S, 227.0].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([Sn](CCCC)(CCCC)CCCC)[N:6]=[CH:5][N:4]=1.[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:23]1[C:28]([C:7]2[CH:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][N:6]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)ncn1
Reactant: Clc1nccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CSc1cc(-c2nccnc2Cl)ncn1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 4-methylsulfanyl-6-tributylstannanyl-pyrimidine (4) (1.80 g, 4.33 mmol), 2,3-dichloro-pyrazine (1.94 g, 13 mmol), PPh3 (0.907 g, 3.46 mmol) and palladium (II) acetate (194 mg, 0.866 mmol) in dioxane (15 mL) is degassed and sealed in a pressure tube. After stirring at 120° C. for 16 h, the reaction mixture is evaporated and purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 30% to afford the desired product 4-(3-chloro-pyrazin-2-yl)-6-methylsulfanyl-pyrimidine (37).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([N:10]3[S:18](=[O:20])(=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=13)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[C:4]3[C:9]([N:10]4[S:18](=[O:20])(=[O:19])[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11]=24)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=S1(=O)c2ccccc2-c2c(CCl)c3ccccc3n21
Product: CN1CCN(Cc2c3n(c4ccccc24)S(=O)(=O)c2ccccc2-3)CC1

Procedure:
Alternatively, 10-Chloromethyl-5-thia-4b-aza-indeno[2,1-a]indene-5,5-dioxide (D37), may be treated with N-methylpiperazine according to the method as described under Description 1, to obtain the above said compound. Melting range (° C.): 121-125; IR spectra (cm−1): 1180, 1289, 1336, 1439; Mass (m/z): 368, 370 (M+H)+; 1H-NMR (ppm): 2.42 (s, 3H), 2.73-2.83 (bs, 8H), 3.88 (s, 2H), 7.22-8.07 (m, 8H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>C(Cl)Cl>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][CH2:3][CH:23]([C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:22]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CCCl)n1Cc1ccccc1Cl
Reactant: CCOC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CCCSc1ncc(CCC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Yield: 71 %

Procedure:
The procedure of Example 3(iv) was followed using 5-(2-chloro)ethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazole hydrochloride in place of 5-chloromethyl-1-[(2chlorophenyl)methyl]2-propylthio-1H-imidazole hydrochloride. The title compound was obtained in 71% yield after chromatography over silica gel with a gradient of ethyl acetate in methylene chloride.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[OH:23][CH2:22][C:16]1[N:15]=[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:24]=[CH:25][C:2]([C:32]5[CH:31]=[N:30][N:29]([CH2:28][C:27]([CH3:43])([OH:44])[CH3:26])[CH:33]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2

Procedure:
Following the procedures as Example 182, Suzuki reaction of (5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)methanol and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol provided 273. LCMS: Rt=2.33 min, [M+H]=464