Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[C:5]([CH3:19])=[C:6]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:7]([O:9]CC)=[O:8]>O.C(O)C>[I:3][C:4]1[C:5]([CH3:19])=[C:6]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)c(I)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1I
Reaction time: 1 h

Procedure:
A solution of 18.2 g (276 mmol) of 85 percent potassium hydroxide in 100 mL of water was added to a mixture of 67.8 g (184 mmol) of ethyl 3-iodo-2-methyl-4-methylsulfonylbenzoate in 300 mL of ethanol with stirring. After about 1 hour, all of the solids had dissolved and after 2 hours the mixture was concentrated by evaporation under reduced pressure. The residue obtained was diluted with water and the solution obtained was extracted with ether and then diluted with ethyl acetate. Aqueous hydrochloric acid (3N) was then added until the mixture was acidic. The organic phase was separated and the aqueous phase was twice extracted with ethyl acetate. The organic phase and extracts were combined and washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The 62.1 g (99 percent of theory) of colorless solid residue was the title compound. The purified compound melts at 193° C.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:3]1[C:4](=[O:6])[CH2:5][S:1][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CSC(=O)N1
Product: CCCc1c(OCCCN2C(=O)CSC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione was prepared as for Example 10 from thiazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl) amide (62.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (82 mg, 63%).
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N+:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17].[OH-].[K+].C(O)C>O>[N+:16]([CH:19]([CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: OC1c2ccccc2Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C1c2ccccc2Oc2ccccc21)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
9-Hydroxyxanthene (9.9 g, 50 mmol) and ethyl nitroacetate (6.1 mL, 55 mol) are mixed and heated at 100° C. (oil bath) for 1.5 hours. After cooling, a waxy mixture is suspended in 40 mL of absolute alcohol and 40 mL of 1.25 M of ethanolic potassium hydroxide solution is added. The solution is stirred for 45 minutes at room temperature and ethanol is stripped off. The remaining solid is suspended in water and extracted with diethyl ether. The aqueous portion is acidified with 85% phosphoric acid to pH 2 to 3 to give a white suspension which is cooled overnight. The precipitate is collected by filtration and dried in a vacuum oven at 50° C. This gives 9.18 g of the title compound as a white solid; mp 89°-91° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([N:10]([CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([CH3:32])[C:26]([CH3:34])([CH3:33])[CH2:25]2)[C:11](=[O:23])[CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[CH2:4][C:3]1([CH3:36])[CH3:35].[H-].[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:32][N:27]1[C:26]([CH3:34])([CH3:33])[CH2:25][CH:24]([N:10]([CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:36])([CH3:35])[CH2:4]2)[C:11](=[O:23])[C:12]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([OH:15])=[O:14])[CH2:29][C:28]1([CH3:31])[CH3:30]
Reactant: CN1C(C)(C)CC(N(C(=O)C(Cc2ccccc2)C(=O)O)C2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1C(C)(C)CC(N(C(=O)C(Cc2ccccc2)(Cc2ccccc2)C(=O)O)C2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
With stirring, a solution of 20 g of benzylmalonic bis-(1,2,2,6,6-pentamethyl-4-piperidinyl)-amide in 50 ml of toluene and 100 ml of dimethylformamide is added dropwise in the course of about 1/2 hour to a suspension of oil-free sodium hydride (0.97 g) in toluene (20 ml). After the addition of the amide, the reaction mixture is stirred for a further 20 hours at 60° C. until all the sodium hydride is reacted. A solution of 7.7 g of benzyl bromide in 10 ml of toluene is then added dropwise to the reaction mixture at room temperature in the course of 40 minutes, the temperature is raised to 70° C. and stirring is continued for 12 hours at this temperature. For working up, the reaction solution is filtered warm to remove precipitated sodium bromide, the residue is washed well with chloroform and the combined filtrates are freed as completely as possible from all solvents by rotary evaporation. The residue is dissolved in 400 ml of chloroform, the solution is extracted repeatedly with water, dried over sodium sulphate and the solvent removed in vacuo. The crystalline residue is recrystallised once in toluene and once in benzene, affording dibenzylmalonic bis-(1,2,2,6,6-pentamethyl-4-piperidinyl)-amide with a melting point of 275°-277° C. (Stabiliser 4).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:15]O>>[O:1]=[C:2]1[NH:7][C@H:6]([C:8]([O:10][CH3:15])=[O:9])[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCC[C@@H](C(=O)O)N1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-6-oxopiperidine-2-carboxylic acid (17 g, 120 mmol) in methanol (200 mL) was added thionyl chloride (87 mL, 1.2 mol) and the reaction mixture was stirred at RT overnight, concentrated, combined with the product of a similar preparation, washed with saturated aqueous NaHCO3, and extracted with EtOAc (4×200 mL). The organic layers were combined, dried over sodium sulfate and evaporated to provide crude (S)-methyl 6-oxopiperidine-2-carboxylate (36.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:10]([N:23]1[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: OC1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC(O)CC1

Procedure:
(R)-2-(N-t-butoxycarbonylamino)-3-phenyl-propan-1-one (14 mmol) and 4-hydroxypiperidine (21.5 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first then base) and the product used without further purification. Yield 4.7 g, 94%; HPLC (60/40) 3.52 minutes (98%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[C:14]1[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([C:15]1[CH:16]=[C:17]([CH:19]=[O:20])[S:18][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=Cc1ccc(Br)s1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1csc(C=O)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 1-dodecyne (23.9 g), 5-bromo-2-thiophenecarboxaldhyde (25.0 g) and triethylamine (39.7 g) in dry tetrahydrofuran (75 ml) was degasseal and stirred at room temperature under a nitrogen atmosphere. Two mole percent of bis(triphenylphosphine)palladium(II)chloride (1.8 g) followed by one mole percent of copper(I)iodide (0.25 g) was added. The mixture was degassed and stirred at room temperature under nitrogen for three days. The precipitate was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated, and the residue was flash chromatographed (silica, 7:3-Hexane:dichloromethane). The appropriate fractions were collected and evaporated. The residue was dried at 50° C. under vacuum for three hrs to give 35.5 g (98%) of product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])[C:9]2[CH:13]=[C:12]([C:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH:15]=3)[S:11][C:10]=2[C:21]([OH:23])=[O:22])[CH2:4][CH2:3]1.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[CH2:34]([O:41][N:42]=[C:17]1[CH2:18][CH2:19][C:14]([C:12]2[S:11][C:10]([C:21]([OH:23])=[O:22])=[C:9]([N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)[C:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]3)=[O:25])[CH:13]=2)=[CH:15][CH2:16]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=O)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=NOCc4ccccc4)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-oxo-cyclohex-1-enyl)-thiophene-2-carboxylic acid (30 mg, 0.065 mmol) in a 2:1 H2O-ethanol mixture (3 mL) were added O-benzylhydroxylamine hydrochloride (21 mg, 0.13 mmol) and sodium acetate (18 mg, 0.13 mmol), and the mixture was stirred at room temperature overnight. Then the mixture was extracted with CH2Cl2, organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel eluting with 2-15% MeOH in CH2Cl2 to give 20 mg (54%) of 5-{4-benzyloxyimino-cyclohex-1-enyl}-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:13][CH2:14][CH2:15][NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=1>C(OCC)(=O)C>[CH3:1][S:2]([NH:13][CH2:14][CH2:15][NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=1)(=[O:4])=[O:3]
Reactant: Cc1cccc(Nc2nc(NCCN)ncc2C(N)=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nc(NCCNS(C)(=O)=O)ncc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 114 μl portion of methanesulfonyl chloride and 205 μl of triethylamine were added to a mixture of 382 mg of 2-(2-aminoethylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide with 10 ml of ethyl acetate, followed by stirring at room temperature for 3.5 hours. The reaction mixture was washed with water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. This was concentrated under a reduced pressure and the resulting residue was recrystallized from a mixed solvent of methanol and ethyl acetate to obtain 210 mg of 2-{[2-(methanesulfonylamino)ethyl]amino}-4-(3-methylanilino)pyrimidine-5-carboxamide (colorless crystals).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[H-].[Na+].Br[C:22]1[N:23]=[CH:24][C:25]([C:28]#[N:29])=[N:26][CH:27]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1cnc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C#N)cn3)cc(C)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.68 g, 20.0 mmol) in THF (60 mL) was treated with NaH (1.20 g, 30.0 mmol) at 0° C. The resulting suspension was stirred at room temperature 15 min and 5-bromo-pyrazine-2-carbonitrile was added. The reaction was stirred at room temperature for 3 h. The suspension was quenched with 1N HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=1:1) to afford the title compound (1.63 g). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 8.55 (s, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 5.73-5.69 (m, 1H), 4.16 (q, 2H), 3.27-3.18 (m, 1H), 2.56-2.48 (m, 1H), 2.41 (s, 3H), 1.23 (t, 3H). MS found: (M+H)+=354.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12]Cl)[CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)[CH:2]=[CH2:3].CCCCCC.C([Li])CCC.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:4]1[CH2:11][CH2:12][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN(CCCl)Cc1ccoc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCN1CCc2occc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 9.03 g of the above crude N-allyl-N-(3-furylmethyl)-2-chloroethylamine in 200 ml of tetrahydrofuran, 63.8 ml (102 mmol) of 1.6 M n-butyl lithium hexane was added under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield 5-allyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH2:11][CH2:10][NH:9][C:8]2[CH:12]=[N:13][CH:14]=[CH:15][C:7]1=2.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27])[C:20](O)=[O:21].[OH-].[Na+]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:20]([N:9]2[CH2:10][CH2:11][O:6][C:7]3[CH:15]=[CH:14][N:13]=[CH:12][C:8]2=3)=[O:21])[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27]
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1c(Cl)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CCOc3ccncc32)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To phosphorus oxychloride (3.00 ml), 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (177 mg, 1.30 mmol) and 3-chloro-4-methoxy-5-nitro benzoic acid (200 mg, 0.87 mmol) were added and then stirred at 95□ for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and neutralized with saturated solution of sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate
Reaction SMILES: [Cl:1][C:2]1([C:5]2OC(=O)[S:7][N:6]=2)[CH2:4][CH2:3]1.[S:11]([C:21]#[N:22])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1([C:5]2[N:22]=[C:21]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[S:7][N:6]=2)[CH2:4][CH2:3]1
Reactant: O=c1oc(C2(Cl)CC2)ns1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: CCCCC
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(S(=O)(=O)c2nc(C3(Cl)CC3)ns2)cc1
Yield: 85.4 %

Procedure:
66.2 g (372 mmol) of 5-(1-chlorocyclopropyl)-1,3,4-oxathiazol-2-one and 70.9 g (391 mmol) of tosyl cyanide are stirred in 125 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled and treated with pentane, and the precipitate is filtered off and dried under vacuum. 100.0 g of product are obtained (99.9% purity, 85.2% yield, log P (pH 2.3)=3.67).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](O)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:12][OH:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc2ccccc2cc1C(=O)O
Solvent: C1CCOC1
Product: Nc1cc2ccccc2cc1CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-amino-2-naphthoic acid (2 g, 10.7 mmol) in THF (11 mL) at 0° C. is added a 1 M solution of borane-tetrahydrofuran complex (27 mL) dropwise over 15 min. The mixture is allowed to warm to ambient temperature and stirred for 6 h. The excess borane-tetrahydrofuran complex is quenched by adding methanol at 0° C., and the solvent evaporated to obtain a yellow solid. The solid is washed with water, EtOAc and then dried under high vacuum to give (3-aminonaphthalen-2-yl)-methanol.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:24][NH:23][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NNc1cccnc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 3-hydrazinopyridine dihydrochloride 237 (0.120 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 238 (0.20 g, 60%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)=[O:21]
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C(C)(C)C)c3)nn12
Reaction time: 3 h

Procedure:
To solution of 8.0 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 4.6 ml of trimethylacetyl chloride and 6.8 ml of diisopropylethylamine. The mixture was stirred for 3 hours and then poured into 200 ml of aqueous saturated sodium bicarbonate. The organic layer was separated, dried, and the solvent was removed in vacuo. The residue was recrystallized from dichloromethane-hexane to give 9.2 g of white crystals, mp 256°-258° C.
Reaction SMILES: [C:1](#N)C.[F:4][C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C(=O)([O-])[O-].[K+].[K+].CI>O>[F:4][C:5]1[C:6]([O:13][CH3:1])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9]
Reactant: O=Cc1cccc(F)c1O
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1c(F)cccc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To an acetonitrile (50 mL) solution containing 3.01 g (21.5 mmol) of commercially available 3-fluoro-2-hydroxybenzaldehyde were added 5.92 g (42.8 mmol) of potassium carbonate and 6.66 mL (107 mmol) of methyl iodide, and the mixture was stirred at 90° C. for 3 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 3.22 g of a crude product of 3-fluoro-2-methoxybenzaldehyde.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)(=O)C>[C:25]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OC(C)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate [synthesized by the method described in Tetrahedron Lett., 46(3), 447-450 (2005)] (10 g, 38.3 mmol), pyridine (100 mL) and acetic anhydride (18.1 mL, 192 mmol) was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with 1 N hydrochloric acid and brine, and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Elution solvent: hexane/ethyl acetate=4/1) to obtain 9.65 g of the title compound as a colorless oil (83%).