Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: NCCCC(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)NCCCC(=O)O)cc1
Reaction time: 2 h

Procedure:
10.2 g. of p-methoxybenzoyl chloride are added at 30° C. in one portion while stirring well to 30.9 g. of 4-amino-butyric acid, 24.0 g. of sodium hydroxide and 300 ml. of ion-free water. After 2 hours, the mixture is acidified with 75 ml. of concentrated hydrochloric acid at a temperature below 10° C. The precipitate is filtered off, washed ion-free with water, dried in a drying oven at 65° C. over phosphorus pentoxide and then recrystallized from 45 ml. of acetone/low-boiling petroleum ether (3:1). There is obtained 4-(p-methoxybenzoylamino)butyric acid having a melting point of 120.5°-122° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]O)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1.O.O.NN>CCO.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1N
Reaction time: 1 h

Procedure:
Compound 29a is dissolved in a 9:1 mixture of EtOH:H2O at 85° C., a solution of hydrazine monohydrate in a Ra—Ni solution is added and the reaction mixture is stirred for 1 hour. The obtained solution is cooled and thereafter filtered over Celite®. The filtrate is evaporated under reduced pressure to afford Compound 41a.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:26][OH:27].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[OH:27])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccccc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccccc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-1-(2-methylpyridin-4-yl)-3-phenyl-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=331.2 ([M+H]+).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1>COCCOC.C(OCC)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:23])=[CH:9][C:10]#[N:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccc(C(C)=CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethylcyanomethylphosphonate (85 g) is added dropwise to a stirred suspension of sodium hydride (19.2 g) in 1,2-dimethoxyethane (400 ml) under nitrogen. The solution is cooled in an ice bath and a solution of paramethoxyacetophenone (48 g) in 1,2-dimethoxyethane (80 ml) is added dropwise. The reaction mixture is stirred at RT for three hours and diluted with diethyl ether, washed, dried, filtered and evaporated in vacuo affording the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=O)=[CH:8][CH:9]=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CO.CN(C=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:22]([C:7]1[CH:6]=[C:5]2[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]3[C:4]2=[CH:3][C:2]([Cl:1])=[C:19]2[C:14]=3[N:15]=[CH:16][CH:17]=[CH:18]2)=[CH:9][CH:8]=1)=[O:24]
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 51.6 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), N,N dimethylethylenediamine (0.06 ml, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), TEA (0.12 ml, 0.83 mmol) and DMF (1 ml) gave the title compound (60 mg, 50%) after trituration from MeOH.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.ClCCl>C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:39][C:35]2[S:34][CH:38]=[CH:37][N:36]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=Cc1nccs1
Reactant: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CCN(Cc1nccs1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Sodium triacetoxyborohydride (0:30 g, 1.42 mmol) is added to a stirred solution of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.71 mmol), 2-thiazolecarboxaldehyde (0.12 ml, 1.42 mmol), and dichloromethane (3.5 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is diluted with ethyl acetate, washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. Water is added to the residue, and the solution loaded onto a SCX-2 (10 g) column and washed with water (20 ml) and methanol (20 ml). The product is then eluted with 2M ammonia in methanol (30 ml). The filtrate is concentrated and the crude material purified on silica gel eluting with 0-50% ethyl acetate/hexanes to yield (0.20 g) of 4-{(3-methyl-butyl)-[(thiazol-2-yl)-methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=368 (M+1); 1H NMR (CDCl3): δ=7.67 (1H, d), 7.23 (1H, d), 4.17 (2H, brs), 3.93 (2H, s), 2.72-2.54 (5H, m), 1.78 (2H, brd), 1.7-1.57 (2H, m), 1.45-1.41 (10H, m), 1.40-1.32 (2H, m), 0.87 (6H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCNC2)CC1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
4-[2-(Piperidin-3-yloxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Preparation 49A, Step 2) (340 mg, 0.94 mmol) was dissolved in CH2Cl2 (15 mL) under nitrogen and cooled to 0° C. Isobutyryl chloride (0.29 mL, 2.82 mmol) was added followed by dropwise addition of triethylamine (0.52 mL, 3.76 mmol). The mixture was warmed to r.t. and stirred for about 16 hours. Methylene chloride (20 mL) was added, and the solution was washed with saturated NaHCO3 (20 mL)and brine (20 mL), and then dried over magnesium sulfate. The solvents were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1), to afford the final compound as a white solid (322 mg, 80%). TLC (SiO2): Rf=0.42 (1:1 ethyl acetate/hexanes)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]2[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]1[CH2:4][CH2:5]2.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH:6]2[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]1[CH2:4][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1C(O)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylate (500 mg, 2.37 mmol) in methanol (4.7 mL) at 0° C. was added sodium borohydride (134 mg, 3.55 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then stirred for 16 hours at room temperature. The mixture was quenched with saturated aqueous ammonium chloride and concentrated. The resulting residue was extracted with DCM (3×) and the combined extracts were dried over sodium sulfate, filtered, and concentrated to afford tert-butyl 2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate. 1H NMR (500 MHz, CDCl3) δ 4.35 (broad, 1H), 4.13 (s, 2H), 2.28-2.19 (m, 1H), 2.18-2.12 (m, 1H), 1.83-1.75 (m, 1H), 1.71-1.68 (m, 1H), 1.66-1.56 (m, 1H), 1.56-1.48 (m, 1H), 1.44 (s, 9H), 1.05 (dd, J=3.4, 12.7, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN[C@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl N-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}glycinate (910 mg, 3.18 mmol) was taken up in dioxane (16 mL) and HCl (7.5 mL of 4 M in dioxane, 30.0 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to afford ethyl N-[(1S,2S)-2-aminocyclopentyl]glycinate (HCl salt) which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>>[CH3:9][O:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccnc1Cl
Reactant: NN
Solvent: O
Product: COc1cccnc1NN
Temperature: 25 °C
Yield: 57 %

Procedure:
A stirred solution of 2-chloro-3-methoxypyridine (4.86 g, 33.8 mmol) in hydrazine hydrate (40 mL) was heated under reflux for 1.5 hours. After cooling to RT, the reaction mixture was evaporated to dryness. The resulting residue was partitioned between 10% MeOH in CHCl3 and 40% w/v aqueous potassium carbonate. The aqueous phase was isolated and extracted twice with 10% MeOH in CHCl3. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.7 g, 57%) as a buff solid. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (dd, J=5.1 and 1.3 Hz, 1H), 6.99 (dd, J=7.7 and 1.3 Hz, 1H) overlapped with 6.98 (br s, 1H), 6.56 (dd, J=7.6 and 5.1 Hz, 1H), 4.05 (br s, 2H), 3.76 (s, 3H). LCMS (Method A): RT=0.34 min, [M+H]+=140.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[C:14]([F:22])[CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:19])=[O:20])=[C:14]([F:22])[CH:13]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Yield: 66.1 %

Procedure:
Following General Procedure B, the title compound (380 mg, 66%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (273 mg, 1.57 mmol) and 4-chloro-2-fluoro-benzenesulfonyl chloride (360 mg, 1.57 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])(CC)C.[CH2:17]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)[CH2:18][CH3:19].O>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:35]=[CH:34][CH2:33][CH2:32][C@H:29]2[CH2:30][CH2:31][C@H:26]([C@H:23]3[CH2:22][CH2:21][C@H:20]([CH2:17][CH2:18][CH3:19])[CH2:25][CH2:24]3)[CH2:27][CH2:28]2)=[C:6]([F:10])[C:5]=1[F:11])[CH3:2]
Reactant: CCOc1cccc(F)c1F
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=Cc3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
Under nitrogen gas stream, a solution of 30.7 g (194 mmol) of 1-ethoxy-2,3-difluorobenzene in 300 ml of THF was cooled down to −70° C., 194 ml of sec-butyl lithium (1.0M cyclohexane solution) was added by drops thereto while being maintained at the same temperature, and they were stirred at the same temperature for 2 hours. To this reaction mixture was added by drops a solution of 45.1 g (162 mmol) of the crude 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal obtained by the reaction in the fifth step in 450 ml of THF while being maintained at the same temperature, and stirred for 2 hours. Subsequently, they were raised up to −50° C. and stirred for 2 hours. The reaction mixture was added to 200 ml of water to terminate the reaction, the solvent was distilled off under a reduced pressure, the residue was extracted with 500 ml of toluene, and the organic layer was washed with 100 ml of water thrice, and then dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was removed by filtration, 2.83 g of p-toluenesulfonic acid monohydrate was added to the filtrate, and heated to reflux for 4 hours. The organic layer was washed with 200 ml of water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: mixed solvent of heptane/toluene=7/3) to obtain 50.2 g of a crude 1-ethoxy-2,3-difluoro-4-(4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)-1-butenyl)benzene.
Reaction SMILES: C([NH:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12])(=O)C>CO.Cl>[NH2:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1scc(Cl)c1NC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1scc(Cl)c1N
Temperature: 60 °C
Reaction time: 4 h

Procedure:
In a mixture of 50 ml of methanol and 50 ml of concentrated hydrochloric acid, 7 g of methyl 3-acetylamino-4-chlorothiophene-2-carboxylate are stirred at 60° C. for 4 hours, under reflux for 5 hours and at room temperature for another 3 days. Any precipitate that has formed is removed by filtration, and about ⅓ of the volume of the solvent is removed by distillation under reduced pressure. Following addition of about 100 ml of water, the mixture is stirred at room temperature for another 15 minutes and the colorless crystals are filtered off and dried in a stream of air. M.p.: 62-64° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:10]#[C:11][CH2:12][Si](C)(C)C)[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].Cl>C(O)(C)(C)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:11]([CH3:12])[NH:9][C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)CC#Cc1nc(Br)c(Cl)nc1N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc2nc(Br)c(Cl)nc2[nH]1
Temperature: 60 °C

Procedure:
5-Bromo-6-chloro-3-(3-(trimethylsilyl)prop-1-ynyl)pyrazin-2-amine (step 2) (280 mg, 0.879 mmol) in tert-butanol (4 ml) at RT was treated with KOtBu (217 mg, 1.933 mmol) and heated at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and the pH adjusted to pH 1 using 2M HCl. The aqueous was extracted with DCM (×3) and the organic solvent removed under reduced pressure to afford the titled compound:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](O)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.S(Cl)([Cl:24])=O>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([Cl:24])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)O)c2nc1OC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC

Procedure:
A mixture of 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid (12) (500 mg, 1.70 mmol) in thionyl chloride (twice distilled over triphenyl phosphite) (25 mL) was heated at reflux for 20 hours. The reaction mixture was concentrated to an off-white solid which was purified by elution through a flash column (4:1 hexanes:ethyl acetate), 510 mg (96%), mp 162-164° C.; 1H NMR (CDCl3): δ 8.35 (s, 1H), 4.15 (s, 3H), 4.03 (s, 3H), 2.55 (s, 3H); MS: m/z 312 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@H:10]([CH3:25])[CH2:9]1)C1C=CC=CC=1.Cl>CCO.[Pd]>[CH3:25][C@H:10]1[C@H:11]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCOC(=O)c1cccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc([C@@H]2CCNC[C@H]2C)c1
Yield: 109 %

Procedure:
Ethyl 3-[(3S,4R)-1-benzyl-3-methylpiperidin-4-yl]benzoate (9 g, 26.7 mmol) was dissolved in EtOH:1M HCl (1:1, 160 mL) and was hydrogenated at 50 psi in the presence of a catalytic amount of palladium on carbon (1 g) for 36 hr. Palladium was filtered through a celite plug and the filtrate was evaporated to dryness to give 7.2 g of ethyl 3-[(3S,4R)-3-methylpiperidin-4-yl]benzoate as an HCl salt.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[CH2:2][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Yield: 45.6 %

Procedure:
30 g (0.09 mole) of 1-bromo-4-(2,4-dichlorophenyl)-3,3-dimethyl-2-butanone, 12.4 g (0.18 mole) of 1,2,4-triazole and 24.8 g (0.18 mole) of potassium carbonate are heated under reflux in 300 ml of acetone for 6 hours. The mixture is then allowed to cool and is filtered with suction and the mother liquor is concentrated in vacuo. The residue is taken up in methylene chloride and the mixture is washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from diethyl ether. 12.8 g (45.6% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanone of melting point 85° C. are obtained. ##STR14##
Reaction SMILES: C.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([OH:15])=[C:13]([N+:16]([O-])=O)[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=1.NN>CO.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[NH2:16][C:13]1[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[C:14]=1[OH:15]
Reactant: N#Cc1cc(-c2ccccc2F)c(O)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1cc(N)c(O)c(-c2ccccc2F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of charcoal (283 mg) in 25 ml of methanol was added iron (III) chloride hexahydrate (35 mg), and 2′-fluoro-6-hydroxy-5-nitrobiphenyl-3-carbonitrile (668 mg). The resultant green mixture was heated under nitrogen at 70° C. for 10 min. Hydrazine (403 μl) was added slowly, and the mixture was stirred for 2 h at 70° C. The mixture was then cooled to room temperature and filtered through a plug of Celite. The eluent was concentrated in vacuo to provide the title compound (543 mg, 92%). Mass spectrum (ESI) 229.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH2:14]Cl.O>CN(C)C=O>[Cl:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH2:14][C:13]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[CH:3]=1
Reactant: Oc1cc(Cl)sn1
Reactant: COc1ccc(OC)c(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(COc2cc(Cl)sn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-chloro-3-hydroxyisothiazole (4.0 g, 0.03 mole) in 15 ml of dimethyl formamide was added dropwise to a stirred suspension of 60% NaH in oil (1.4 g, 0.035 mole) in 25 ml of dimethyl formamide at 0° C. under N2. After 15 minutes, a solution of 2,5-dimethoxybenzyl chloride (5.6 g, 0.03 mole) in 10 ml of dimethyl formamide was added dropwise and the mixture was stirred at room temperature for 24 hours. The dark reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether extract was washed with water, dried (MgSO4), and concentrated. The residual white solid was purified by column chromatography on silica gel, using diethyl ether/hexane (1/1) as eluant. 5-Chloro-3-(2,5-dimethoxybenzyloxy)isothiazole was obtained as a white solid; 4.7 g; mp 52°-55° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[S:3])[NH2:2].Br[CH2:16][C:17]([C:19]1[CH:23]=[C:22]([CH3:24])[O:21][C:20]=1[CH3:25])=O>>[CH3:25][C:20]1[O:21][C:22]([CH3:24])=[CH:23][C:19]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH:16]=1
Reactant: CCOC(=O)c1cccc(C(N)=S)c1
Reactant: Cc1cc(C(=O)CBr)c(C)o1
Product: CCOC(=O)c1cccc(-c2nc(-c3cc(C)oc3C)cs2)c1
Yield: 16 %

Procedure:
In the same manner as in Example 28, ethyl 3-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dimethylfuran to obtain ethyl 3-[4-(2,5-dimethyl-3-furyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 16%, Pale yellow prisms. Melting point: 100 to 101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:12]=2[CH:13]=1)([O-])=O.C(O)CCCC>CO.[Pd]>[N:6]1[C:7]2[C:12](=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([NH2:1])[CH:5]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)CNCC2
Agent: [Pd]
Solvent: CCCCCO
Solvent: CO
Product: Nc1cnc2ccncc2c1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
3-Nitro-5,6,7,8-tetrahydro-[1,6]naphthyridine (1 g, 5.6 mmol), pentanol (2 mL) and Pd/C (300 mg) were placed in a microwave reaction vessel and stirred under microwave irradiation at 180° C. for 1 h. After cooling, the mixture was diluted with MeOH and filtered through a pad of Celite. The solvent was removed and the crude was purified by flash column chromatography to give the desired title compound as a yellow solid. MS (ES+): 146.2 (M+H)+. Calc'd for C8H7N3—145.06.
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>ClCCl>[CH3:15][S:16]([O:4][CH2:3][C@H:2]([CH3:1])[CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-methylbutane-1,4-diol (30 g, 0.29 mol) in dichloromethane (600 mL) was added triethylamine (100 mL, 0.72 mol). The solution was cooled to −20° C., and methanesulfonyl chloride (49 mL, 0.63 mol) was added dropwise over 30 min with vigorous stirring. The resulting mixture was stirred for additional 1 h while the temperature was maintained between −20 and −15° C. The mixture was allowed to warm to 0° C. and then poured into cold 1N HCl solution (100 mL). The organic layer was separated, and aqueous phase was extracted with dichloromethane (100 mL). The combined organic extracts were washed with sat'd NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting product (75.9 g, quant) was used directly for the next step. 1H NMR (400 MHz, CDCl3): δ 4.41-4.24 (m, 2H), 4.12 (dq, 2H), 3.02 (d, 6H), 2.13 (td, 1H), 1.95 (td, 1H), 1.80-1.65 (m, 1H), 1.07 (d, 3H).