Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9](O)=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:29][Si](C)(C)C>C(Cl)Cl.CN(C)C=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH2:29])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
A mixture of 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (450 mg, 1.51 mmol) in methylene chloride (4 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then slowly treated with oxalyl chloride (145 μL, 1.66 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (960 μL, 4.53 mmol) and subsequently stirred at 25° C. for 15 h. The resulting reaction mixture was diluted with methylene chloride (10 L) and methanol (10 mL). The organic layer was washed with a 5% aqueous sulfuric acid solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide (295 mg, 67%) as a yellow oil which solidified upon sitting to a yellow solid. The yellow solid was used without further purification: mp 112-114° C.; EI-HRMS m/e calcd for C14H17ClN2O3 (M+) 296.0927, found 296.0931.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH3:19])[C:9]=1[O:20][CH3:21].[C:22]1([CH2:28][O:29][C:30](=[O:42])[C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH2:38][CH2:39][CH3:40])[C:32]=2[OH:41])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C)C=O>[C:22]1([CH2:28][O:29][C:30](=[O:42])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH3:19])[C:9]=3[O:20][CH3:21])=[C:33]([CH2:38][CH2:39][CH3:40])[C:32]=2[OH:41])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Reactant: COc1c(CCCCCCBr)ccc(C(C)(C)C)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCc2ccc(C(C)(C)C)c(OC)c2OC)ccc(C(=O)OCc2ccccc2)c1O
Yield: 84 %

Procedure:
A mixture of 4.0 g (11.2 mmole) of 1-(6-bromohexyl)-2,3-dimethoxy-4-(1,1-dimethylethyl)benzene, 3.2 g (11.2 mmole) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 3.1 g (22.4 mmole) of potassium carbonate and 1.7 g (11.2 mmole) of sodium iodide in 70 mL of anhydrous acetone and 7 mL of anhydrous dimethylformamide was stirred at reflux for 31 hours. Workup as in Example 16 and purification by HPLC using 5% ethyl acetate-hexane gave 5.3 g, (84% yield) of 2-hydroxy-4-[6-[2,3-dimethoxy-4-(1,1-dimethylethyl)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:15]=O.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:13][N:14]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:31]=[CH:15]1
Reactant: N#Cc1ccccc1
Reactant: CN(C=O)Cc1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1cnc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of di-iso-propyl-amine (11.2 mL, 79.9 mmol) in 150 mL of THF at -78° C. was added n-butyllithium (31.9 mL of 2.5M solution, 79.9 mmol). To the resulting mixture was added a solution of N-methyl-N-[4-picolyl]formamide (10 g, 66.5 mmol) in THF. The resulting orange-brown solution was stirred at -78° C. for 20 min, at which time benzonitrile (13.6 mL, 133 mmol) was added. The resulting dark brown mixture was allowed to warm to rt and stirred for 1 h, heated to reflux for 4 h, and then cooled to rt and partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2 /MeOH. The title compound was obtained as a light tan solid (5.83 g, 37%): mp 158°-159° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[SH:6][C:7]1[NH:8][C:9]([CH2:12][C:13]([O-:15])=[O:14])=[N:10][N:11]=1.O.Cl.CC(O[CH2:22][C:23]1[CH2:40][S:39][C@@H:26]2[C@H:27]([NH:30][C:31]([CH2:33][C:34]3[S:38][CH:37]=[CH:36][CH:35]=3)=[O:32])[C:28](=[O:29])[N:25]2[C:24]=1[C:41]([OH:43])=[O:42])=O>[Na]>[S:38]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:33][C:31]([NH:30][CH:27]1[C:28](=[O:29])[N:25]2[C:24]([C:41]([OH:43])=[O:42])=[C:23]([CH2:22][S:6][C:7]3[NH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[N:10][N:11]=3)[CH2:40][S:39][C@H:26]12)=[O:32]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: O=C([O-])Cc1nnc(S)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)[nH]1
Temperature: 0 °C

Procedure:
12 ml of a 0.5N aqueous solution of sodium bicarbonate was dissolved in a mixture of 836 mg of the sodium salt of 7-(2-thienylacetamido)cephalosporanic acid, 480 mg of 2-(2-mercapto-1,3,4-triazol-5-yl)acetate and 5 ml of water. The resulting solution was heated to a temperature of 62° to 65° C. for 5.5 hours. After completion of the reaction, 10 ml of ice-water was added to the reaction mixture, and 8 ml of 1N HCl was slowly added thereto under ice-cooling and stirring. The precipitated white mass was filtered and washed with water. Immediately thereafter, the precipitate was pulverized with a sufficient amount of diethyl ether to obtain 810 ml of 7-(2-thienylacetamido)-3-(5-carboxymethyl-1,3,4-triazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid as a white powder.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([NH:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:22]([CH2:24][C:25](OCC)=[O:26])#[N:23].C([O-])(=O)C.[NH4+].C(O)C>O>[C:22]([C:24]1[C:25](=[O:26])[N:10]([C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[CH2:11][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:23]
Reactant: CS(=O)(=O)Nc1ccc(NCC(=O)c2ccccc2)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(N2CC(c3ccccc3)=C(C#N)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Methanesulfonamidoanilino)acetophenone (5.0 g, 16.4 mmol), ethyl cyanoacetate (4.5 g, 39.4 mmol) and ammonium acetate (1.5 g, 19.5 mmol) were combined in a 100 mL round-bottomed flask equipped with a magnetic stir bar. The mixture was lowered into a pre-heated 140° C. oil bath, and became a stirrable melt within several minutes. Heating continued for 35 min during which time ethanol and water byproducts were observed boiling off, and a bright yellow solid formed amidst the dark supernatant. The reaction was removed from the heat and allowed to cool to 25° C. under vacuum. The crude material was stirred in ethanol (20 mL) for 30 min, then the product was collected by filtration, washed with more ethanol, and dried to yield 3.0 g (52%) as a bright yellow powder, m.p. 280° C. (dec). NMR and mass spectral data were consistent with the assigned structure. Elemental analysis: Calculated: C=61.18, H=4.28, N=11.89, S=9.07; Found: C=60.77, H=4.33, N=11.66, S=9.14.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH3:9])[CH3:8])=[N:4][CH:3]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].CC(N(C)C)=O.Cl[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:31][N:32]=2)[N:29]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH3:8][N:7]([CH3:9])[C:5]1[S:6][C:2]([C:24]2[CH:25]=[CH:26][C:27]3[N:28]([C:30]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[N:31][N:32]=3)[N:29]=2)=[CH:3][N:4]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Reactant: CN(C)c1ncc(Br)s1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN(C)c1ncc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)s1
Yield: 71.9 %

Procedure:
To a solution of 5-bromo-N,N-dimethylthiazol-2-amine (0.73 g, 3.53 mmol) in anhydrous THF (9 mL) was added isopropylmagnesium lithium chloride (1.0 M in THF, 4.8 mL, 4.8 mmol) at −40° C. The solution was stirred for twenty minutes followed by the dropwise addition of zinc chloride (0.5 M in THF, 10 mL, 5.2 mmol). The mixture was brought to room temperature and stirred for thirty minutes followed by the addition of dimethylacetamide (12 mL), Pd2(dba)3, (0.32 g, 0.35 mmol), Q-Phos (0.34 g, 0.56 mmol), and tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.29 g, 1.0 mmol). The mixture was stirred at 50° for two hours then was quenched with saturated ammonium chloride and purified by MPLC chromatography (eluted with a gradient of 0 to 10% (1:10:90 NH4OH:MeOH:DCM) in DCM) to yield the product as a light orange solid (0.27 g, 71%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5].Cl.C(N(C(C)C)CC)(C)C.[CH3:23][N:24]=[C:25]=[O:26]>ClCCl>[CH3:23][NH:24][C:25]([N:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7]1)=[O:26]
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)NC)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Commercially available ethyl 4-piperidone-3-carboxylate hydrochloride (203.2 mg; 0.98 mmol) was suspended in dichloromethane (7 ml), diisopropylethylamine (180 μl; 0.99 mmol) was added, followed by commercially available methyl isocyanate and (57 μl; 0.98 mmol). This mixture was stirred at ambient temperature for approximately 3 hours, and then diluted with fresh dichloromethane and washed with water. The dichloromethane solution was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure, giving ethyl 1-(N-methylaminocarbonyl)-4-oxo-3-piperidinecarboxylate (74.4 mg) as a white solid. MS m/z (positive ion) 479 (dimer+Na+; 40), 457 (dimer+; 25), 251 (M+Na+; 100), 229 (MH+; 90), 205 (25), 130 (25).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1ccc(C2CCNCC2)cc1
Reaction time: 12 h
Yield: 78.7 %

Procedure:
To a solution of 1.0 g of methyl 4-[1-(benzyloxy-carbonyl)piperidin-4-yl]phenylacetate in ethanol (100 ml) was added 1.0 g of 10% palladium-carbon (moisture content: 50%) and a hydrogenation reaction was effected under atmospheric pressure for 12 hours. Then the palladium-carbon was filtered off and the solvent was concentrated under reduced pressure to thereby give 0.5 g of crude methyl 4-(piperidin-4-yl)phenylacetate. To a solution of 0.5 g of this crude product and 0.5 g of 8-(chloroethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine in N,N-dimethylformamide (30 ml) was added 0.87 g of anhydrous potassium carbonate and the resulting mixture was stirred under heating to 60° C. for 40 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.6 g of the title compound as a yellow oily substance.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5]2C(Cl)=C(Cl)[CH:9]=[CH:10][C:4]=2[O:3]1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[CH2:36]([C:41]1[C:46]([Cl:47])=[C:45]([Cl:48])[CH:44]=[CH:43][C:42]=1[OH:49])[CH:37]=[CH:38][CH2:39][CH3:40].C(C1C(Cl)=C(Cl)C=CC=1O)CCCC.C1(O)C=CC=CC=1.BrCCCCCC(O)=O>>[CH2:36]([C:41]1[C:46]([Cl:47])=[C:45]([Cl:48])[CH:44]=[CH:43][C:42]=1[O:49][CH2:9][CH2:10][CH2:4][CH2:5][CH2:6][C:2]([OH:3])=[O:1])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: OC1Cc2c(ccc(Cl)c2Cl)O1
Reactant: CCC=CCc1c(O)ccc(Cl)c1Cl
Agent: CCCCCc1c(O)ccc(Cl)c1Cl
Agent: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CCCCCBr
Solvent: Oc1ccccc1
Product: CCCCCc1c(OCCCCCC(=O)O)ccc(Cl)c1Cl

Procedure:
Following the general procedure of Example 6B, 2.3 g. of 2,3-dihydro-2-hydroxy-4,5-dichlorobenzofuran and 17.3 g. of propyltriphenylphosphonium bromide were reacted to provide 840 mg. of 2-(2-pentenyl)-3,4-dichlorophenol which upon hydrogenation following the procedure of Example 6C provided 300 mg. of 2-pentyl-3,4-dichlorophenol. This phenol was then reacted with 5.1 mmoles of 6-bromohexanoic acid following the procedure of Example 1C to provide 58 mg. of the desired title product. NMR.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][NH:16][C:17]([NH2:19])=[O:18].C(OC(=O)C)(=O)C>CCOCC>[C:1]([CH2:3][C:4]([N:15]([C:9]1[C:8]([CH3:7])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:14])[NH:16][C:17]([NH2:19])=[O:18])=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Cc1cccc(C)c1NNC(N)=O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C)c1N(NC(N)=O)C(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1 mole of cyanoacetic acid, 1 mole of 1-(2,6-dimethylphenyl)semicarbazide and 300 ml of acetic anhydride is heated to 80° for 2 hours. The mixture is cooled to RT, 50 ml of ether is added and it is stirred at RT overnight. The reaction mixture is filtered, washed with ether (3X) and dried to give N-(2-cyanoacetyl)-1-(2,6-dimethylphenyl)semicarbazide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:14]=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccnc(Cl)c2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(Nc2cc(OC3CCCN(C(=O)OC(C)(C)C)C3)ccn2)n1
Yield: 53.3 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (18.2 mL, 7.27 mmol), tert-butyl 3-(2-chloropyridin-4-yloxy)piperidine-1-carboxylate (2.50 g, 8.00 mmol), potassium phosphate (1.70 g, 8.00 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.166 g, 0.182 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.116 g, 0.200 mmol) were reacted in toluene (20 mL) and water (5 mL) to provide tert-butyl 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)piperidine-1-carboxylate ((1.70 g, 53.3% yield) as yellow solid. 1H NMR (CDCl3) δ 9.01 (bs, 1H), 8.15 (d, 1H), 6.46 (dd, 1H), 6.36 (s, 2H), 4.30 (m, 1H), 2.94-3.77 (m, 3H), 2.33 (d, 3H), 2.01 (bm, 1H), 1.79 (bm, 3H), 1.52 (m, 1H), 1.39 (bs, 9H); Mass spectrum (apci) m/z=391 (100) (M+H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCc1ccccc1B(O)O
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: COCc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Yield: 76.4 %

Procedure:
Analogous to Example 1499, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (85 mg, 0.22 mmol) and 2-(Methoxymethyl)phenyl-boronic acid (72.8 mg, 0.439 mmol) were reacted to afford 7-[2-(methoxymethyl)phenyl]-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine (72 mg, 76%). LCMS (HPLC): 0.88 min, m/z=429 (M+H); 1H-NMR (DMSO-d6): 9.18 (s, 1H), 8.94 (s, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.46-7.52 (m, 4H), 6.93 (d, 1H, J=4.6 Hz), 6.87 (d, 1H, J=4.6 Hz), 6.74 (d, 2H, J=9.0 Hz), 4.36 (s, 2H), 3.18 (s, 3H), 3.01 (m, 4H), 2.43 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: O[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CN(C)C=O.S(Cl)([Cl:18])=O>>[Cl:18][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(O)cn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 0 °C
Yield: 75 %

Procedure:
5-Hydroxypyrazine-2-carboxylic acid (1.0 g, 0.007 mol) was taken in thionyl chloride (10 mL), to this solution dimethylformamide (0.1 mL) was added which was heated to reflux for 16 h. After this period, excess thionyl chloride was distilled off to get crude compound, which was added to ice (20 g) and extracted with ethyl acetate (2×70 mL). The organic layers were combined and dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain brown solid which was triturated with diethyl ether (30 mL) to afford 600 mg (75%) of 5-chloropyrazine-2-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:20]([O-])([N+]([O-])=O)=[O:21]>>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: C=CCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Product: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 65.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([N:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=3)[C:2]2=[O:1])=[CH:18][CH:19]=1
Reactant: COc1ccc(Br)cc1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2ccn(-c3ccc(OC)cc3)c(=O)c2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (80 mg, 0.4 mmol) and p-bromoanisole (73.9 μL, 0.6 mmol) in dimethyl sulfoxide (2 mL) was added L-proline (18 mg, 0.16 mmol), potassium carbonate (0.11 g, 0.79 mmol) and copper(I) iodide (15 mg, 0.079 mmol). The reaction mixture was heated to 120° C. and stirred overnight. The mixture was then cooled to rt, water added and extracted with DCM (15 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (30 mg, 20%). LC-MS: (FA) ES+ 310.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[C:10]=1[C@@H:11]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:12]1[C:13](=O)[O:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C(C)=CC=CC=1>[Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[C:10]=1[CH:11]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:12]1[C:13](=[S:38])[O:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCc1cc2c(c(O[Si](C)(C)C(C)(C)C)c1)[C@@H]1CCCC[C@H]1C(=O)O2
Solvent: Cc1ccccc1C
Product: CCCCCc1cc2c(c(O[Si](C)(C)C(C)(C)C)c1)C1CCCCC1C(=S)O2

Procedure:
2.00 g (4.97 mmol) of (6aR*,10aR*)-1-(tert-butyldimethylsilyloxy)-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-6-one was heated under reflux at 140° C. for 17 h with 4.25 g (10.2 mmol) of Lawesson's reagent in xylene.
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.N1CC[CH2:12][C@@H:9]1[CH2:10][OH:11]>>[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:12][CH2:9][CH2:10][OH:11]
Reactant: C[C@H]1CCCN1
Reactant: OC[C@H]1CCCN1
Agent: Br
Product: C[C@H]1CCCN1CCCO

Procedure:
(2S)-2-methylpyrrolidine hydrobromide (2.70 g, 16.3 mmol), 3-bromopropanol (2.49 g, 17.9 mmol) and potassium carbonate (6.75 g, 48.9 mmol) were mixed in tetrahydrofuran (20 mL), and stirred at 60° C. for 18 hours. The precipitate was filtered off, and the filtrate was concentrated. The residue was distilled under reduced pressure, and the target compound (1.88 g, 80%) was thus obtained as a colorless oily substance. (2S)-2-methyl-pyrrolidine hydrobromide was manufactured by the method described in the literature (J. Org. Chem., 1989, Vol. 54, p. 209) using D-prolinol as starting material.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-:7].C[C:9]1[S:13][CH:12]=[CH:11][S+:10]=1>C(O)C>[I-:7].[S:10]1[CH:11]=[CH:12][S:13][C:9]1=[N+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1scc[s+]1
Reactant: C1COCCN1
Agent: [I-]
Solvent: CCO
Product: c1csc(=[N+]2CCOCC2)s1
Yield: 66.4 %

Procedure:
1.0 g of morpholine and 2.8 g of 2-methyl-1,3-dithiolium iodide were treated in the same manner as in Example 26, and the product was recrystallized from ethanol, whereby 2.4 g (yield: 79.7%) of 4-(1,3-dithiol-2-ylidene)morpholinium iodide (Compound No. 29) was obtained as crystals having a melting point of from 257° to 258° C.
Reaction SMILES: [Br:1]C1C=C(OC)C2CCN(C)CCC=2C=1.Cl.C[O:18][C:19]1[C:29]2[CH:28]=[CH:27][N:26]([CH3:30])[CH2:25][CH2:24][C:23]=2[CH:22]=[C:21]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:20]=1.Br>>[BrH:1].[OH:18][C:19]1[C:29]2[CH:28]=[CH:27][N:26]([CH3:30])[CH2:25][CH2:24][C:23]=2[CH:22]=[C:21]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:20]=1
Reactant: COc1cc(Br)cc2c1CCN(C)CC2
Reactant: COc1cc(S(C)(=O)=O)cc2c1C=CN(C)CC2
Agent: Br
Agent: Cl
Product: CN1C=Cc2c(O)cc(S(C)(=O)=O)cc2CC1

Procedure:
By the same procedure, 8-bromo-6-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is converted to 6-methoxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine hydrochloride which is treated with 48% hydrobromic acid to give 6-hydroxy-3-methyl-8-methylsulfonyl-1H-3benzazepine hydrobromide.