Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[S:53](=[O:57])(=[O:56])CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][S:53](=[O:57])(=[O:56])[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCS(=O)(=O)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and thiomorpholine 1,1-dioxide and isolated as white solid (13.5 mg, 66%). MS(m/e): 435.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15](OCC)=[O:16])[C:12]([N+:20]([O-])=O)=[C:11]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C([C:39](OCC)=[O:40])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[NH2:56]C1C=C(O)C=CC=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[C:11]3[C:12]([NH:20][C:39](=[O:40])[N:23]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:13]([C:15]([NH2:56])=[O:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3cccc(O)c3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Ethyl 2-(3-hydroxyphenylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. To a solution of ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (200 mg, 0.567 mmol) in DMF (3 mL) was added 3-aminophenol (74.3 mg, 0.680 mmol) and N,N-diisopropylethylamine (0.149 mL, 0.851 mmol). The reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography on a normal phase silica gel column (25-43% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (227 mg, 0.534 mmol, 94% yield) as an orange solid. MS (ESI) m/z 426.2 [M+1]+.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:27]([NH2:35])(=[NH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CN(C=O)C>[C:11]1([CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:34]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:35][C:1]=2[CH3:2])=[O:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)C(=O)NCCCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCc2ccccc2)C(c2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
100 mg (0.266 mmol) of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenylpropyl)acrylamide was dissolved in 2 ml of DMF. 63.0 mg (0.400 mmol) of benzamidine hydrochloride and 26.0 mg (0.317 mmol) of sodium acetate were added to the obtained solution, and they were stirred at 60° C. overnight. Ethyl acetate was added to the reaction mixture and then the obtained mixture was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/3) to obtain the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[CH3:25]I>O1CCCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[C@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:25]
Reactant: COc1ccccc1CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Reactant: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Reaction time: 0.75 h

Procedure:
19.1 g of sodium 1,1,1,3,3,3-hexamethyldisilazanate are added to a solution, cooled to −50° C., of 10 g of (4S,5S)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]oxazolidin-2-one in 150 cm3 of tetrahydrofuran, the mixture is stirred for 45 minutes at this temperature and then 7.72 cm3 of methyl iodide are added. The reaction mixture is then stirred for 15 hours at room temperature, then diluted with ethyl acetate, washed with 50 cm3 of water and then with 50 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized from isopropyl ether, filtered off and dried. There are obtained 4.2 g of (4S,5S)-4-methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)propionyl]oxazolidin-2-one in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].C1COCC1>CO>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C#N)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Temperature: 25 °C

Procedure:
To a round bottom flash containing (E)-methyl 4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoate (606 mg, 2 mmol) was added 2 M NaOH (20 mL, 40 mmol), followed by THF (10 mL) and MeOH (10 mL). The resulting mixture was stirred O/N at rt. After removal of THF and MeOH via rotavap, the residue was cooled to 0° C. and treated with 2 M HCl (25 mL) and stirred for 2 min at that temp. The precipitates collected by suction filtration were rinsed with H2O to give crude (E)-4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoic acid as a brown red solid. It was redissolved in HOAc/pyridine/DMF (4 mL/8 mL/6 mL) and a solution of NaH2PO2 (704 mg, 8 mmol) in H2O (4 mL) was added, followed by Raney-Nickel 2400 (slurry in H2O, 0.4 mL). The resulting mixture was heated for 1 h at 55° C. (oil temp.). Usual aqueous workup, followed by trituration with H2O gave the title compound (332 mg, 54%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H), 12.90 (s, br, 1H), 10.14 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.19 (s, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.76 (d, J=16.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.64 (d, J=16.4 Hz, 1H); MS ESI 293.0 [M+H]+, calcd for [C17H12N2O3+H]+ 293.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]>C(OCC)(=O)C.C(O)C.C(O)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]
Reactant: C=C(C)Cc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)c1nc(CC(C)C)c2nc(-c3ccccc3)sc2c1O
Yield: 27.3 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-allyl)-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (128 mg, 0.36 mmole) and 10% Pd/C (100 mg) in ethyl acetate (12 ml), ethanol (3 ml) and formic acid (15 μl) was hydrogenated at 20 psi for a week before it was filtered, concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The sodium bicarbonate layer was washed with dichloromethane. The organic layer was combined and washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (35 mg). MS: (+) m/z 356.96 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:20]([C:21]#[CH:22])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:23])[CH:3]=1>C(O)C.C(OCC)(=O)C>[Cl:23][C:4]1[CH:3]=[C:2]2[C:20]([CH:21]=[CH:22][NH:1]2)=[CH:19][C:5]=1[O:6][C:7]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C#Cc1cc(Oc2cc(F)ccc2C(=O)OCC)c(Cl)cc1N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(F)cc1Oc1cc2cc[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 242D (1.0 g) in ethanol (20 mL) was added NaAuCl4.2H2O (60 mg). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[C:28](Cl)(=[O:30])[CH3:29].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:28](=[O:30])[CH3:29])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (100 mg, 0.249 mmol) (intermediate 1) was treated with acetyl chloride (22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (23 mg, 0.299 mmol) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 30 min. THF was evaporated and the residue was washed with saturated sodium bicarbonate solution and water. The solid obtained was purified by silica gel column chromatography using 30% acetone-chloroform as eluent to obtain 25 mg of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 252° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(C)[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.N1C=CC=C[CH:26]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][S:20]([C:17]1[C:18]([CH3:26])=[CH:19][CH:14]=[CH:15][CH:16]=1)(=[O:21])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OC[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (2S)-1-t-butyloxycarbonyl-2-azetidinemethanol (22.6 g, 0.121 mol) in 40 mL of pyridine was treated with p-toluenesulfonyl chloride (27.6 g, 0.145 mol). The resulting mixture was stirred at room temperature for 16 hours, diluted with CH2Cl2 and washed sequentially with 1 N aqueous HCl, H2O, saturated aqueous K2CO3, and brine. The organic phase was dried (Na2SO4) and concentrated. Purification by chromatography (silica gel; Hexane/EtOAc, 80:20) afforded 32.8 g of a white solid which was recrystallized from CH2Cl2 /hexane to afford the title compound as thin white needles: mp 59-60° C.; 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9H), 2.15-3.28 (m, 2H), 2.44 (s, 3H), 3.74-3.81 (m, 2H), 4.13 (dd, J=3.1, 10.2 Hz, 1H), 4.23-4.34 (m, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H); MS (CI/NH3) m/z: 242 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:25](I)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:25]([O:21][C:16]1[C:15]([N+:22]([O-:24])=[O:23])=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[N:19]=[C:18]([CH3:20])[N:17]=1)[CH3:26]
Reactant: CCI
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)nc(N2CCN(c3ccc(F)cc3)CC2)c1[N+](=O)[O-]

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with ethyliodide and potassium carbonate in N,N-dimethylformamide at room temperature to yield the 4-ethoxy-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidine as a light yellow solid; m.p. 116-119° C.; MS: [M+H]+=362; and the 3-ethyl-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish solid; m.p. 126-128° C.; MS: [M+H]+=362.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[CH:8]=1)[C:3]([OH:5])=O.O=S(Cl)Cl.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][CH:2]1[C:3](=[O:5])[C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[CH2:6]1)[CH:13]=[CH:12][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10]3
Reactant: CC(Cc1ccc2ccc(-c3ccccc3)cc2c1)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1Cc2ccc3ccc(-c4ccccc4)cc3c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-3-(7-phenyl-2-naphthyl)propanoic acid (6.25 g, 21.5 mmole) was suspended in CH2Cl2 (20 ml), and SOCl2 (2.9 ml, 40 mmole) and 0.05 ml of DMF were added. The resulting mixture was stirred for 2 h at room temperature, refluxed for additional 1 h, evaporated and dried in vacuo. AlCl3 (4.3 g, 33 mmol) was suspended in CH2Cl2 (40 ml), and solution of obtained chloroanhydride in CH2Cl2 (20 ml) was added at 0° C. within 0.5 h. The resulting mixture was allowed to warm to room temperature, stirred for additional 2 h, and poured into ice/HCl (˜200 g+40 ml). The resulting mixture was extracted by CH2Cl2 (4×50 ml). Combined organic phase was washed by aq. KHCO3, dried over MgSO4, evaporated and dried in vacuo giving practically pure solid product. The yield 5.45 g (92%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.[CH3:19][S:20]C.O>CCOCC>[CH3:19][S:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: CSC
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(SC)c2C1
Reaction time: 1 h

Procedure:
A solution of 5,6,7 or 8-bromo-2-(di-n-propylamino)tetralin (1.4 g; 4.5 mmol) in dry ether (20 ml) was cooled to -78° C. under nitrogen atmosphere. S-BuLi (7 ml, 10 mmol) was added and the mixture was stirred for 1 hr. Methylsulphide (0.31 g; 5 mmol) was added and the mixture was stirred for 3 hr. When the temperature reached -10° C., water was added. Workup afforded the product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[CH2:13][O:12][CH2:11][CH2:10][NH:9]2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[Cl:24])[CH:20]([C:25](Cl)=[O:26])[CH2:19][C:18]2=[O:28]>C(N(CC)CC)C>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[Cl:24])[CH:20]([C:25]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH:8]1[CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:26])[CH2:19][C:18]2=[O:28]
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Reactant: C1COCC(CN2CCOCC2)N1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCOCC2CN2CCOCC2)c2cc(Cl)c(Cl)cc21
Yield: 73.9 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.25 g of 3-(morpholinomethyl)morpholine, 2.67 ml of triethylamine and 1.11 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride, to afford 0.7 g of the title compound, melting at 210°-216° C. (dec.).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2].[O:28]=[C:29]1[NH:33][CH2:32][CH2:31][N:30]1[CH2:34][C:35]#[CH:36].CCN(CC)CC.C1(C)C=CC=CC=1>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.[Cu]I.C1COCC1>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([C:36]#[C:35][CH2:34][N:30]3[CH2:31][CH2:32][NH:33][C:29]3=[O:28])[CH:13]=2)[C:8]([OH:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:7]1=[O:25])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(I)cc21
Reactant: C#CCN1CCNC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#CCN3CCNC3=O)cc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-iodooxindole (25.0 mg, 4.64×10−5 mol), 3-(2-oxo-1-imidazolidinyl)-1-propyne (8.6 mg, 1.5 eq.), Pd(PPh3)2Cl2 (4.88 mg, 15 mol %) and CuI (1.32 mg, 15 mol %) under a nitrogen atmosphere was added anhydrous Et3N (0.5 mL), anhydrous toluene (0.5 mL) and anhydrous THF (0.5 mL). The resulting yellow mixture was heated to 50° C. (bath temperature) and stirred at that temperature for 1 hour 20 minutes. The solvent was then removed in vacuo to give a yellow solid. Purification was carried out by column chromatography (silica gel, 6% MeOH in CHCl3) to yield the title compound (23.9 mg, 92%) as a light brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([NH:61][C@H:62]([C:67](O)=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]>>[C:51]([NH:61][C@H:62]([C:67]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:68])[CH2:63][CH:64]([CH3:65])[CH3:66])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-L-leucine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6]3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: O=c1n(CCCCl)nc2ccccn12
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=c1n(CCCN2CCC(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{3-[4-(1H-Indol-3-yl)-piperidin-1-yl]-propyl}-2H-[1,2,4]triazolo[4, 3-a]pyridin-3-one was prepared in a similar fashion to compound 22, using 2-(3-Chloro-propyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and 3-Piperidin-4-yl-1H-indole. Yield: 90 mg (48%); mp:111.7° C. M+: 376.1; (300 MHz, CDCl3): 8.04 (s, 1H, NH), 7.77 (d, 1H), 7.62 (d, 1H), 7.35 (d, 1H), 7.09 (m, 5H), 6.59 (m, 1H), 6.49 (m, 1H), 4.08 (m, CH2), 3.10 (d, CH2), 2.70 (t, CH) 2.55 (t, CH2), 2.04 (m, 4H), 1.82 (m, CH2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:46])[N:28]5[CH2:31][O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.FC(F)(F)C(O)=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:46])[N:28]5[CH2:31][O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CCCCCCCCCCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCCCCCCCC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.4 %

Procedure:
To a solution (5 ml) of dodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (150 mg) synthesized in the same manner as in Example 21 in THF was added trifluoroacetic acid (TFA) (0.11 ml), then to a solution (3 ml) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.27 g) in THF was added, and the mixture was stirred at room temperature for 3 days. To the reaction mixture were added water and sodium carbonate, and the mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate) to give the title compound (yield 50 mg, 33.4%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[N:7]=[CH:17][CH:15]=[CH:14]2
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c2ncccc2c1
Temperature: 45 °C
Yield: 42 %

Procedure:
4-Methoxy-2-nitroaniline (20.0 g, 119 mmol), 34.0 g (369 mmol) glycerol, 24.0 g (107 mmol) 3-nitrobenzensulfonic acid sodium salt, 25 mL H2O and 34 mL H2SO4 are refluxed for 12 h. The reaction mixture is cooled to 45° C., poured into 1 L of cold H2O and vigorously stirred with 500 mL of CH2Cl2 for 30 min. The resulting bi-phasic solution is filtered through celite, and the aqueous layer is extracted with 3×300 mL CH2Cl2. The combined organics are washed with 1×400 mL H2O, 1×400 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography of the crude product on SiO2 gel, eluting with hexanes/EtOAc (4/1), gives 10.0 g (49.0 mmol, a 42% yield) of the title compound as a tan solid. MS (ES) m/z 205 (MH)+.