Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.[OH2:18]>C1COCC1.CO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:15][CH2:16][CH3:17])(=[O:1])=[O:18])=[CH:12][CH:13]=1
Reactant: O=S([O-])OO
Reactant: CCCSc1ccc(Br)cc1
Reactant: O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Add oxone (potassium mono persulfate, 15.03 g, 24.4 mmol) in one portion to a cold (0° C.) stirred solution of 1-bromo-4-propylsulfanyl-benzene (1.881 g, 8.14 mmol) in THF (20 mL), methanol (10 mL), and water (10 mL) and slowly warm to room temperature overnight. Remove the solvents under reduced pressure and add dichloromethane and water to the residue. Separate the layers, extract the aqueous layer twice with dichloromethane, wash the organic layer with saturated aqueous sodium bicarbonate, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. Purify the residue by flash chromatography (SiO2, elute 0% to 30% EtOAc/hexanes) to yield 1.96 g of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=9.2 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 3.06-3.11 (m, 2H), 1.72-1.83 (m, 2H), 1.04 (dd, J=7.2, 7.2 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[O:20][CH:21]=[CH:22][C:16]=3[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:21]1[O:20][C:17]2[CH2:18][CH2:19][N:14]([C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:13])[CH2:15][C:16]=2[CH:22]=1)[CH3:25]
Reactant: C=O
Reactant: O=C(OCCCCc1ccccc1)N1CCc2occc2C1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)OCCCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.218 g (about 0.728 mmol) of the above 5-(4-phenylbutoxycarbonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.08 g (0.9 mmol) of 50% aqueous dimethylamine and 0.07 g (0.9 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 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 (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].O[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:20][CH2:21]1
Reactant: OC(c1ccccc1)c1nc2ccccc2s1
Reactant: CN1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of benzothiazol-2-ylphenylmethanol (0.36 g), 4-hydroxy-1-methylpiperidine (0.17 g) and para-toluenesulfonic acid (0.57 g) in toluene (22 mL) is heated overnight in a Dean-Stark apparatus. The mixture is cooled back to room temperature and poured into water, alcalinised with 1N sodium hydroxide and extracted twice with ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 90/10) to give 2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole melting at 115° C.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]=2[CH:13]=1.C([Li])CCC.[CH2:39]([O:46][C:47]1[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH:51]=[CH:14][C:5]2[C:6]3[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=3[CH:13]=[C:3]([F:2])[CH:4]=2)=[CH:53][CH:54]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)Cc2cc(F)cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2O1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(F)cc(C=Cc3ccc(OCc4ccccc4)cc3)c2O1
Reaction time: 3 h

Procedure:
To a solution of ((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl) triphenyl phosphonium chloride (648) (500 mg, 1.09 mmol) in anhydrous tetrahydrofuran at room temperature (10 mL) was added n-butyllithium (0.67 mL, 1.31 mmol, 2 M in hexane). After stirring for 10 min 4-(benzyloxy)benzaldehyde (231 mg, 1.09 mmol) was added and stirred for an additional 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to give 7-(4-(benzyloxy)styryl)-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran as a cis/trans mixture (649).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([OH:30])=[C:24]([CH:29]=1)[C:25]([NH:27][NH2:28])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[CH2:37]([O:45][C:46](Cl)=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>CC(N(C)C)=O>[CH2:37]([O:45][C:46]([N:27]([C:25](=[O:26])[C:24]1[CH:29]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=[CH:22][C:23]=1[OH:30])[NH2:28])=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)NN)c1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)N(N)C(=O)OCCCCCCCC)c1
Temperature: 80 °C

Procedure:
42 g of 5-octadecoxy-2-hydroxybenzoic acid hydrazide are suspended in 200 ml of dimethylacetamide and 8 g of pyridine and 19.3 g of chloroformic acid n-octyl ester are added simultaneously over the course of 30 minutes. The reaction mixture is subsequently heated to 80° C for 5 hours whilst stirring, cooled and poured into 1 litre of water. This produces a white precipitate of the N-(5-octadecoxy-2-hydroxybenzoyl)-hydrazinecarboxylic acid n-octyl ester which has been formed (Stabiliser No. 9). The substance is isolated, washed with water, dried at 60° C and recrystallised from acetonitrile. Melting point 85° C.
Reaction SMILES: [CH:1]1([N:7]([CH3:32])[C:8](=[O:31])[CH2:9][CH2:10][CH:11]([C:29]#[N:30])[CH2:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[N+:26]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Zn].CO>[CH:1]1([N:7]([CH3:32])[C:8](=[O:31])[CH2:9][CH2:10][CH:11]([C:29]#[N:30])[CH2:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:16]=[CH:15][C:14]=2[NH2:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1N)C1CCCCC1

Procedure:
4-cyano-5-(2-nitro-5-phenoxy-phenyl)-pentanoic acid cyclohexyl-methyl-amide (0.200 g, 0.46 mmol), ammonium chloride (0.31 g, 5.75 mmol) and methanol (3.0 mL) were added to a round bottom flask followed by addition of powdered zinc (0.4 g). The vessel was equipped with a condenser and the reaction was headed to reflux for 2 h followed by filtration through a pad of Celite®. The solvent was removed and the resulting residue was dissolved in ethyl acetate, then washed 3 times with 10% sodium carbonate solution. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting residue was used in subsequent steps without further purification.
Reaction SMILES: C(N1CCC(C(O)=O)CC1)(OC(C)(C)C)=O.[Cl-].[CH3:18][N:19]([CH3:33])[CH:20]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28](NC)=[CH:27][CH:26]=2)[CH2:21]1.CN(C)C1CCN(C2C=C[C:44]([NH:47][C:48]([CH:50]3[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]3)=[O:49])=CC=2)C1>ClCCl.CN(C1C=CN=CC=1)C.C(N(CC)CC)C.N1C=CC=CC=1>[CH3:33][N:19]([CH3:18])[CH:20]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([CH2:44][NH:47][C:48]([CH:50]3[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:54][CH2:55]3)=[O:49])=[CH:29][CH:30]=2)[CH2:21]1
Reactant: CNc1ccc(N2CCC(N(C)C)C2)cc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(c2ccc(CNC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Reaction time: 16 h

Procedure:
A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine (0.47 ml) in dichloromethane (15 ml) was mixed with thinoyl chloride (0.21 ml) and, after 30 minutes, a solution of dimethyl[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine (0.5 g), triethylamine (1.17 ml), DMAP (0.44 g) and dichloromethane (10 ml) was added dropwise. After 16 hours, the mixture was diluted with dichloromethane, washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 430.60 (C24H38N4O3); MS (ESI): 431 (M+H+). tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]carbamoyl}piperidin-1-carboxylate can be prepared analogously.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=S.[CH2:22]([O:24][C:25]([NH:27][NH2:28])=[O:26])[CH3:23]>C1COCC1.C([O-])(=O)C.[Hg+]>[OH:1][CH:2]([CH2:20][CH3:21])[C:3](=[N:28][NH:27][C:25]([O:24][CH2:22][CH3:23])=[O:26])[N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1
Reactant: CCOC(=O)NN
Reactant: CCC(O)C(=S)N1CCc2nc(-c3ccccc3)oc2C1
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: C1CCOC1
Product: CCOC(=O)NN=C(C(O)CC)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
185.00 mg (612 μmol) 2-hydroxy-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-thione, 70.00 mg (672 μmol) ethylhydrazinecarboxylate and 200.00 mg (628 μmol) mercury acetate are placed in 10 mL THF and the mixture is stirred for 2 h at RT. The reaction mixture is filtered through silica gel suction and the solvent is eliminated in vacuo.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=1>C(#N)C>[Cl:9][C:10]1[C:15]([Cl:8])=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH:11]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
NCS (3.14 g. 23.5 mmol) was added to a solution of N-(4-chloropyridin-2-yl)pivalamide (1.00 g, 4.7 mmol) in dry acetonitrile (10 mL). The resulting suspension was heated for 3 h and then cooled to r.t. The solvent was removed in vacuo and the crude mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with aqueous NaOH (10%, 2×20 mL), water (20 mL) and dried (MgSO4). The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate and hexane (1/9), to give the title compound as a colourless solid (0.87 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].N1C=CC=CC=1.[CH:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([C:33]=2[S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]3[C:34]([C:33]=2[S:35]([NH:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:4]([OH:13])[C:3]([O:2][CH3:1])=[O:14])(=[O:37])=[O:36])=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1c2ccccc2cc2ccccc12
Reactant: COC(=O)C(O)[C@@H](N)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](O)[C@@H](NS(=O)(=O)c1c2ccccc2cc2ccccc12)c1ccccc1
Reaction time: 1.5 h

Procedure:
(3S)-3-Phenylisoserine methyl ester (I, 0.38 g, 1.95 mmol) is dissolved in methylene chloride (5 mL) and pyridine (1 mL) and the solution treated with a suspension of 9-anthracenesulfonylchloride (0.536 g, 1.95 mmol). The reaction is stirred at 23° for 90 min. The reaction is then poured into methylene chloride and extracted with hydrochloric acid (1 N) and aqueous bicarbonate (5%) and dried over magnesium sulfate. Concentration of the organic layer under reduced pressure produces crude product. This concentrate is chromatographed (silica gel 60; ethyl acetate/toluene, 20/80) to give the title compound, TLC (silica gel GF) Rf =0.38 in (ethyl acetate/toluene, 2/8); NMR (CDCl3, TMS) 3.11, 3.57, 4.18, 4.78, 6.22, 6.59, 6.67, 7.50, 7.55-7.75, 7.92, 8.09, 8.47 and 9.15 δ
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:25])[C:12]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O-:27].[Na+]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:25])[C:12]([S:15]([C:18]2[CH:19]=[N:20][C:21]([O:27][CH3:26])=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(Cl)nc2)no1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)C)on2)cn1
Temperature: 60 °C
Yield: 31.5 %

Procedure:
To a solution of 115 mg (0.30 mmol) N-(5-tert-butyl-isoxazol-3-yl)-2-(6-chloro-pyridine-3-sulfonyl)-2-methyl-propionamide in methanol (3 mL) were added 0.14 mL (0.6 mmol, 25 wt % solution in methanol) of sodium methoxide solution. The reaction mixture was heated in a sealed tube to 60° C. for 4 h. The solution was concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent DCM, 0-20% ethyl acetate) to afford 36 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(6-methoxy-pyridine-3-sulfonyl)-2-methyl-propionamide.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[CH:15]=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:26])[CH:13]=1
Reactant: [H][H]
Reactant: COc1ccc(CCNCC(O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CCNCC(O)c2cc(O)cc(O)c2)cc1OC
Yield: 63.7 %

Procedure:
1.4 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,5-dibenzyloxybenzylalcohol hydrochloride are suspended in a mixture of 32 ml of isopropanol and 8 ml of water. 0.42 g of 10 % palladium-carbon is added to the solution. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 1 hour under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, and the residue thus obtained is recrystallized from a mixture of methanol and ether. 0.6 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,5-dihydroxybenzylalcohol hydrochloride is obtained. Yield: 63.5 % M.p. 193° - 194°C
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(C)(C)C>Cl>[NH2:18][CH2:17][C@@H:8]([CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CCCCC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCCC[C@@H](C)C[C@H](CN)CC(=O)O

Procedure:
Compound 161 (1.20 g, 4.44 mmol) was heated to 50° C. in 3N HCl (30 mL) for 4 hours. The solvent was evaporated, and the oil washed with toluene, and evaporated. The crude material was passed through an ion exchange column (Dowex 50WX8-100, strongly acidic) eluting with water, then 0.5N NH4OH. Isolate (3S,5R)-3-aminomethyl-5-methyl-decanoic acid as a white solid (0.725 g, 75%): mp=174–175° C.; 1H NMR (400 MHz, CDCl3) δ 2.83 (dd, J=12.69, 4.88 Hz, 1H), 2.70 (dd, J=13.1, 7.45 Hz, 1H), 2.08 (d, J=6.59 Hz, 2H), 1.98 (m, 1H), 1.28–1.20 (m, 1H), 1.19–1.09 (m, 2H), 0.99–0.91 (m, 2H), 0.66 (m, 6H); MS (APCI) m/z 215 (M+, 10%), 174 (M+−41, 100%); [α]D=−5.7 (c1.025 in H2O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][S-:12].[Na+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH3:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C[S-]
Reactant: COc1cc(F)ccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(SC)ccc1Br
Temperature: 65 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methoxybenzene (10.0 g) in DMF (100 mL) was added sodium methanethiolate (4.44 g). The mixture was stirred at 65° C. for 2 h. The mixture was cooled to 0° C. and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h and further sodium methanethiolate (4.44 g) was added. The mixture was stirred at 65° C. for 1 h. The mixture was cooled to 0° C. and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 6.2 g of the title compound as a 2:1 mixture with the starting material. The mixture was used for the next step without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C[O-].[Na+].ClC1N=CC(C2([C:33](O)=[O:34])NC=CS2)=CC=1.Cl>CO>[CH3:33][O:34][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(-c2ccc(Cl)nc2)n1
Reactant: O=C(O)C1(c2ccc(Cl)nc2)NC=CS1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(C(=O)O)cs2)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the ethyl 2-(6-chloro-3-pyridyl)thiazole-4-carboxylate (0.61 g, 2.3 mmol) and MeOH (50 mL) was added solid NaOMe (135 mg, 2.5 mmol) and stirred at RT. After 3 h the ethyl ester transesterified to the methyl ester. NaOMe (1 eq, 135 mg) was added and the mixture was heated to reflux. After 15 h, the ester hydrolyzed to the 2-(6-chloro-3-pyridyl)thiazole carboxylic acid. NaOMe (2 eq) was added and the reaction was heated at reflux for 18 h. The mixture was acidified to pH 5 with concentrated HCl, extracted with EtOAc, washed with H2O and brine; dried (MgSO4) and concentrated in vacuo to give the desired carboxylic acid as a yellow solid. MS m/z: 237.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c(C)c1
Product: Cc1cc(C)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-2,4-dimethyl-benzene (9 g, 48.6 mmol) was added to HNO3 (100 mL, 60%) at rt. The mixture was stirred overnight at rt. The mixture was poured into ice-water and extracted with EtOAc. The organic phase was then dried over Na2SO4 and concentrated to give 1-bromo-2,4-dimethyl-5-nitro-benzene (6.5 g) which was used in the subsequent step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.O.C(O)(=[O:24])C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
7.9 g of p-cyanobenzylamine, 8.4 g of hexamethylenetetramine, 40 ml of water, 20 ml of acetic acid and 50 ml of toluene were mixed and reacted at 90° C. for 2 hours while stirring. The reaction solution was cooled to room temperature and the toluene layer was separated, washed with water and concentrated until crystals were precipitated. The concentrated toluene solvent was placed in water, the toluene was removed by azeotropic distillation, and the residue was cooled to room temperature. The crystals precipitated were collected by filtration, washed with water and dried to obtain 4.8 g (yield: 60%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)C.O.[NH2:16][NH2:17]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]2[CH2:5][C:4](=[O:3])[NH:17][N:16]=2)[CH:9]=1
Reactant: CCOC(=O)CC(=O)c1cccnc1
Reactant: NN
Solvent: O
Product: O=C1CC(c2cccnc2)=NN1
Yield: 49.5 %

Procedure:
The starting material was prepared using an analogous procedure to that described in Example 9. Ethyl-2-(3-pyridylcarbonyl)acetate (1 g, 5.18 mmol) was treated with hydrazine hydrate (251 μl, 5.2 mmol) to give 3-(3-pyridyl)-4,5-dihydro-1H-pyrazol-5-one (413 mg, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9](F)[CH:8]=2)[CH3:2].Cl.[OH:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1.C(N(CC)CC)C.C(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9]([C:28]1[NH:29][CH:30]=[C:26]([CH2:25][OH:24])[N:27]=1)[CH:8]=2)[CH3:2]
Reactant: OCc1c[nH]cn1
Reactant: CCOC(=O)c1nc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1nc2cc(-c3nc(CO)c[nH]3)c([N+](=O)[O-])cc2nc1OCC
Yield: 43 %

Procedure:
To a solution of ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate (6.90 g, 22.3 mmol) in acetonitrile (70 ml) were added dropwise 4-(hydroxymethyl)imidazole hydrochloride (15.1 g, 112 mmol) and successively triethylamine (23.4 ml, 168 mmol) under shading, and the mixture was refluxed for 16 hours. After cooling, methylene chloride was added to the reaction mixture, which was washed with water. The aqueous layer was extracted with methylene chloride, which was combined with foregoing organic layer. After dried over anhydrous sodium sulfate, solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [ethyl acetate] to obtain 3.69 g of the the title compound as brown power. Yield 43%. Moreover, 2.15 g of ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate were recovered. Yield 31%.