Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:59])[CH3:60])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 64 %

Procedure:
Condensation of BocPro-DTrp-PheOH (part B of Example 17, 0.700 g.) and HDTrp-Leu-MeNleNH2 (0.520 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DTrp-Leu-MeNleNH2 in 64% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-Leu-MeNleNH2 (0.750 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-Leu-MeNleNH2, which was isolated as the amorphous white solid phosphate (1:1) salt tetrahydrate in 30% yield.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH:24]=[CH:25][CH:26]=1)#[CH:20]>CN(C=O)C.C(OCC)(=O)C.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>[NH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:20]#[C:19][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:37])[C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=4[F:36])[CH:24]=[CH:25][CH:26]=3)=[N:7][N:6]2[CH:8]=1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)ccc2F)c1
Reactant: Nc1cn2nc(I)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(C(=O)Nc2cccc(C#Cc3ccc4nc(N)cn4n3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the nitrogen bubbled solution of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (52 mg, 0.2 mmol, 1 eq) in anhydrous DMF (2 mL) was added triethylamine (0.11 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.1 eq), copper(I) iodide (7.6 mg, 0.2 eq), and N-(3-ethynylphenyl)-2-fluoro-5-methylbenzamide (76 mg, 1.5 eq). after the mixture was stirred at room temperature for 30 minutes, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography [EtOAc-Hex 1:2 to 3:1 (with 1% v/v MeOH added)]. The product fractions were collected, concentrated, the residue was further triturated with ethyl acetate to give N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)ethynyl]phenyl}-2-fluoro-5-methylbenzamide as a yellow solid in amount of 23 mg.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12>[Pt].[I-].[Li+]>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Pt]
Agent: [I-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCC1
Temperature: 230 °C

Procedure:
A crude cyclododecanone was produced as described in Japanese laid-open patent publication No. 2000-256340, No. 2000-026441, No. 2001-302650 and No. 2001-226311. Specifically, 1,5,9-cyclododecatriene was blended with hydrogen peroxide water, and phosphotungstic acid and trioctylmethylammonium chloride as catalysts were added to initiate oxidation, giving 1,2-epoxy-5,9-cyclododecadiene. After recovering unreacted 1,5,9-cyclododecatriene by distillation, 1,2-epoxy-5,9-cyclododecadiene was purified by distillation. 1,2-Epoxy-5,9-cyclododecadiene thus obtained was hydrogenated over platinum/carbon as a catalyst, to hydrogenate a double bond. To the epoxycyclododecane thus obtained was added lithium iodide as a catalyst, and the mixture was heated to 230° C. for isomerization to give cyclododecanone. Purification of cyclododecanone and production of laurolactam were conducted as described in Example D1, and impurities were analyzed. In cyclododecanone after purification, the impurities at 24.68 min, 24.73 min and 24.87 min were contained in 2.4 ppm by weight, 2.1 ppm by weight and 4.1 ppm by weight, respectively, while the impurity at 25.12 min was not detected. In a crude laurolactam and a product laurolactam, the impurities at 31.3 min and 31.7 min were contained in 2.1 ppm by weight and 4.0 ppm by weight, and 0.3 ppm by weight and 0.6 ppm by weight, respectively.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][C:13]1[S:14][C:15](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:18])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:12][C:13]1[S:14][C:15]([C:2]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=2[CH:4]=[O:5])=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COc1ccc(Br)c(C=O)c1
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: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2sc(C)nc2C)c(C=O)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To a solution of 2-bromo-5-methoxybenzaldehyde (200 mg, 0.93 mmol) in DMF (10 mL) and H2O (2 mL) are added 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (333 mg, 1.4 mmol), Pd(PPh3)4 (107 mg, 0.09 mmol) and K2CO3 (257 mg, 1.9 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×10 mL). The combined organic layer is dried, (MgSO4), filtered and is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 2-(2,4-Dimethyl-thiazol-5-yl)-5-methoxy-benzaldehyde (150 mg, 65%) as a white foam.
Reaction SMILES: [F-:1].[K+].[F-].[Cs+].Cl[C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1.CCOCC>S1(CCCC1)(=O)=O.C1OCCOCCOCCOCCOCCOC1>[Cl:13][C:9]1[CH:10]=[C:11]([F:12])[C:6]([F:1])=[N:7][CH:8]=1
Reactant: [F-]
Reactant: Fc1cc(Cl)cnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: Fc1cc(Cl)cnc1F
Temperature: 140 °C
Reaction time: 35 h
Yield: 88 %

Procedure:
64.6 g (1.11 mol) of potassium fluoride and 11.25 g (0.074 mol) of caesium fluoride are suspended in 240 ml of sulfolane and the suspension is heated to 140° C. 50 mol of sulfolane are distilled off by decreasing the pressure and then 61.4 g (0.37 mol) of 2,5-dichloro-3-fluoropyridine and 1.45 g (0.0055 mol) of 18-crown-6 in 20 ml of sulfolane are added to the suspension. This reaction mixture is stirred for 35 hours at 140° C. and then taken up in ice water. The product is isolated from the aqueous mixture either by extraction with ether or by steam distillation, affording 48.7 g (88% of theory) of 5-chloro-2,3-difluoropyridine, b.p. 65°-66° C. at 133 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.C(Cl)Cl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([NH:36][CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CN1CCC(N)CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
A mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.10 g, 0.20 mmol; prepared as in Example 7, Step B), 1-methylpiperidin-4-amine (0.070 g, 0.61 mmol), (S)-pyrrolidine-2-carboxylic acid (9.4 mg, 0.82 mmol), CuI (7.8 mg, 0.041 mmol), and K2CO3 (0.14 g, 1.0 mmol) was heated in DMSO (4 mL) with sealed tube at 100° C. for 17 hours. The reaction mixture was cooled to ambient temperature and treated with CH2Cl2, washed with water, dried over MgSO4, and concentrated to give crude material which was purified by silica gel flash column chromatography (10% MeOH in CH2Cl2) to afford 49 mg (50%) of the desired product. LRMS (ESI pos) m/e 477.1 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:13]([Cl:18])[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Br)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
14.5 mL (83.242 mmol) Hünig base was added to a solution of 7.800 g (37.222 mmol) 4-bromo-2-chlorophenol and 4.70 mL (41.537 mmol) ethyl bromoacetate in 100 mL DMF and the mixture was stirred for 4 h at 100° C. The reaction mixture was combined with water and exhaustively extracted with EtOAc. The combined org. phases were washed with saturated aqueous sodium bicarbonate, water and saturated aqueous NaCl, dried over sodium sulphate and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])(=O)C.[NH4+].[OH-]>CO>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)=[C:19]([F:25])[CH:20]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-acetoxy-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazoline (1.36 g, 3.34 mmol) (from Example 19, Step A, supra) in MeOH (30 mL) was added an aqueous solution of NH4OH (29%, 0.68 mL, 10 mmol). The reaction mixture was stirred at room temperature for 18 hours, then heated at 100° C. for 1.5 hours. The mixture was then cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give the desired 4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol as a gray solid. (Yield 0.93 g, 77%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[S-:19][C:20]1[CH:25]=[C:24]([C:26]([O-:28])=[O:27])[CH:23]=[CH:22][N:21]=1.[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl>O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=C([O-])c1ccnc([S-])c1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)O)ccn3)CS[C@H]12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (9.30 g) and disodium 2-sulfido-4-pyridinecarboxylate (6.80 g) in water (160 ml) was dropwise added sodium bicarbonate (5.73 g) at room temperature. To the resulting mixture was added a saturated aqueous solution of sodium bicarbonate so that the pH was adjusted to 6.8. The resulting mixture was warmed to 65° C. and stirred for 1.5 hours during which period the temperature was allowed to rise from 65° to 75° C. The reaction mixture was cooled and then adjusted to pH 3.6 with 10% hydrochloric acid. The precipitates were collected by filtration, washed successively with water (×2), acetone (×2) and diethyl ether and then dried to give 7-amino-3-(4-carboxypyridin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (6.61 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C[O:23][C:24]([CH2:26][CH2:27][C:28](Cl)=[O:29])=[O:25].O>C1C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:28](=[O:29])[CH2:27][CH2:26][C:24]([OH:25])=[O:23])[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccn3c2)cc1
Reactant: COC(=O)CCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCC(=O)c1c(-c2ccccc2)cc2ccccn12
Yield: 53.6 %

Procedure:
To a suspension of 10.2 g of 2-phenylindolizine in 150 ml of benzene were added 6 ml of pyridine and 9.6 g of β-methoxycarbonylpropionyl chloride and the mixture was refluxed overnight. After cooling, 50 ml of water was added and the whole mixture was extracted with benzene. After the extract was decolorized and concentrated, to the residue was added 30 ml of isopropyl ether and the mixture was cooled to precipitate methyl 4-(2-phenyl-3-indolizinyl)-4-oxobutyrate. The precipitate was filtered off and then this ester compound was hydrolyzed in a conventional manner to give 8.3 g of 4-(2-phenyl-3-indolizinyl)-4-oxobutyric acid, melting at 131°-133° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Cc1c(N)cccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Into a solution of 2-methyl-3-fluoroaniline (1.0 g, 8.0 mmol) in 30 mL of toluene at room temperature, thiophosgene (0.94 mL, 12 mmol) and triethylamine (1.34 mL, 12 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (1.1 g, 82%). EI-MS m/z 168.2 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([Cl:19])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)c(CC(=O)O)cc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)c(CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.1 %

Procedure:
To a solution of (2-bromo-4,5-dimethoxy-phenyl)-acetic acid (833 mg, 3.03 mmol) in dichloromethane (10 mL) were added oxalyl chloride (0.29 mL, 3.33 mmol) and dimethylformamide (1 drop) under argon atmosphere. The mixture was stirred for 3.5 hours at room temperature, then was concentrated to dryness under reduced pressure. Dichloroethane (15 mL) was added, and resulting solution was back evaporated to dryness to obtain crude (2-bromo-4,5-dimethoxy-phenyl)-acetyl chloride (917 mg).
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][C:12]1([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[CH:23][CH:24]=1.S(Cl)(Cl)=O>>[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([N:1]([CH2:8][C:9]([O:11][C:12]2([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC1(OC(=O)CNc2ccccc2)CCCC1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC2(C)CCCC2)c2ccccc2)c1
Yield: 7.2 %

Procedure:
Following a procedure analogous to that described in Example 1, but using 4.8 g of 1-methylcyclopentyl 2-anilinoacetate, 4.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 1.4 cm3 of thionyl chloride as starting materials, 0.6 g of 1-methylcyclopentyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 160° C. is obtained after recrystallization from an acetonitrile/diisopropyl ether mixture (40/60 by volume).
Reaction SMILES: O1CCCCC1[O:7][C@H:8]([CH3:11])[CH2:9][OH:10].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1.CN(C=O)C>[CH2:14]([O:10][CH2:9][C@H:8]([OH:7])[CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](CO)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.5 %

Procedure:
(2R)-2-tetrahydropyranyloxy-1-hydroxypropane (60 g, 0.37 mol) was dropwise added to a suspension of sodium hydride (60%) (22 g) in THF (100 ml) under ice cooling. After completion of the dropwise addition, a solution of benzyl bromide (70 g) in DMF (300 ml) was dropwise added, followed by agitating the mixture at room temperature for 6 hours, pouring it into water (500 ml), extracting with toluene (300 ml), washing the resulting organic layer with water, concentrating it, dissolving the concentrate in ethanol (300 ml), adding 6N-hydrochloric acid (20 ml), agitating the mixture at 20° C. for 2 hours, distilling off ethanol, adding toluene (300 ml), washing the resulting organic layer with an alkali and then with water and distilling it under reduced pressure to obtain (R)-1-benzyloxy-2-propanol (b.p. 105°-107° C./5 mmHg) (28 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15]O)[CH:13]=2)[CH:8]=[N:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:43])C(=O)C1>C(Cl)Cl>[Br:43][CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: COCCCn1ncc2ccc(CO)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCCn1ncc2ccc(CBr)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To a solution of (1-(3-methoxypropyl)-1H-indazol-6-yl)methanol (660 mg, 3 mmol) in dry CH2Cl2 (15 mL) at 0° C., Ph3P (943 mg, 3.6 mmol) and NBS (640 mg, 3.6 mmol) were added in portions. After stirring for 12 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to give 6-(bromomethyl)-1-(3-methoxypropyl)-1H-indazole (420 mg, 50%). 1H NMR (400 MHz, CDCl3): 2.18 (m, 2H), 3.26 (m, 2H), 3.31 (s, 3H), 4.49 (m, 2H), 4.65 (s, 2H), 7.18 (m, 1H), 7.48 (s,1H), 7.79 (m,1H), 7.99 (m,1H)
Reaction SMILES: C(O[C:4]([N:6]1[CH2:28][CH2:27][C:9]2[N:10]([CH3:26])[C:11]3[C:12]([S:17][C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=4)=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:4][N:6]1[CH2:28][CH2:27][C:9]2[N:10]([CH3:26])[C:11]3[C:12]([S:17][C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=4)=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1
Reactant: CCOC(=O)N1CCc2c(c3cccc(Sc4ccc(SC)cc4)c3n2C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Sc2cccc3c4c(n(C)c23)CCN(C)C4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a dry THF solution (2 mL) of ethyl-5-methyl-6-{[4-(methylsulfanyl)phenyl] sulfanyl}-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (0.17 g, 0.41 mmol) was added dropwise over 15 min a THF solution of lithium aluminum hydride (1 mL, 1M in THF) at 0° C. The reaction was stirred at room temperature for 1 h. The reaction was quenched with water (0.04 mL) and stirred for 110 minutes. A 15% sodium hydroxide solution (0.04 mL) was added and stirred for 10 minutes, and water (0.12 mL) was added and stirred for 10 minutes. The resultant solids were filtered and washed with chloroform (10 mL). The filtrate was concentrated under reduced pressure. The resulted residue was purified by silica gel column chromatography, (3% methanol/chloroform) to afford 2,5-dimethyl-6-{[4-(methylsulfanyl)phenyl] sulfanyl}-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole (78 mg, 54%) as a pale-yellow colored oil. 1H NMR (CDCl3, 300 MHz) δ 7.30 (d, 1H, J=7.3 Hz), 7.09-7.02 (m, 3H), 6.92-6.88 (m, 2H), 3.87 (s, 3H), 3.66 (s, 2H), 2.86-2.79 (m, 4H), 2.56 (s, 5H), 2.41 (s, 3H) ppm.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:25]1[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26]1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:30]([C@H:27]1[CH2:28][CH2:29][O:25][CH2:26]1)=[O:31])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C1CCOC1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 362 mg, 1.90 mmol) and DMAP (202 mg, 1.90 mmol) were added to a solution of (R)-4-benzyl-oxazolidin-2-one (333 mg, 1.90 mmol) and tetrahydrofuran-3-carboxylic acid (200 mg, 1.70 mmol) in CH2Cl2 (20 mL) at ambient temperature. The reaction mixture was stirred for 3 h at ambient temperature and water (20 mL) was added. The two layers were separated and the aqueous phase was extracted with CH2Cl2 (20 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/EtOAc=100:2) to afford (R)-4-benzyl-3-((S)-tetrahydrofuran-3-carbonyl)oxazolidin-2-one (120 mg, 25% yield).