Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[O:12])=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[OH:12])=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(O)CCC(O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Temperature: 70 °C
Yield: 82.8 %

Procedure:
The product of Example 28A (5.75 g, 14.48 mmol) was dissolved in ethanol (150 mL) at room temperature and treated with sodium borohydride (1.21 g, 31.9 mmol) portionwise over 5 minutes. The solution was heated at 70° C. for 1 h and then cooled to room temperature, quenched with water, extracted into ethyl acetate, dried over sodium sulfate, and concentrated to dryness to give 4.81 g (83%) of an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[N:21]=[C:22]4[C:28]([CH:29]=[O:30])=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]4=[N:24][CH:25]=3)=[N:7][N:8]2[CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)([OH:41])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>C1COCC1.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[N:21]=[C:22]4[C:28]([C:29]([OH:41])=[O:30])=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]4=[N:24][CH:25]=3)=[N:7][N:8]2[CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)cnc21
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)cnc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
In a 50 ml round-bottomed flask, 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (265 mg, 0.49 mmol) was dissolved in THF (10 ml) and water (2 ml). The yellow solution was cooled to 0° C. and sulfamic acid (287 mg, 2.95 mmol) was added. Then, a solution of sodium chlorite (80%, 76 mg, 0.67 mmol) and potassium dihydrogen phosphate (803 mg, 5.9 mmol) in water (6 ml) was added dropwise via pipette. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with hexanes/ethyl acetate to afford 259 mg (95%) of 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][NH2:21].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>ClCCl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[NH:21][CH2:20][CH2:19][C:18]([O:17][CH3:16])=[O:22])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 50 h
Yield: 97.2 %

Procedure:
A solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 1.98 mmol) and 3-amino-propionic acid methyl ester hydrochloride (0.277 g, 1.98 mmol) in dichloromethane (16 mL) and THF (6 mL) was treated with diisopropylethylamine (0.256 g, 1.98 mmol); it was then added EDCI (0.42 g, 2.18 mmol) and dimethylaminopyridine (0.073 g, 0.59 mmol). The reaction mixture was stirred at room temperature for 50 hours and rotavapored to dryness. The residue was dissolved in dichloromethane. The dichloromethane layer was then successively washed with aqueous 5% citric acid, aqueous saturated hydrogencarbonate solution, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield the title compound as a gum (551 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH2:10][C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-methoxyacetophenone (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-di(4-methoxyphenyl)propane-1,3-dione.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:43])[C:9]1[S:10][C:11]([S:41][CH3:42])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[NH:30][C:31]([NH:33][CH2:34][CH2:35][C:36]3[N:37]=[N:38][NH:39][N:40]=3)=[O:32])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C(Cl)Cl>>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH3:42][S:41][C:11]1[S:10][C:9]([C:8]([NH2:43])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[NH:30][C:31]([NH:33][CH2:34][CH2:35][C:36]2[N:40]=[N:39][NH:38][N:37]=2)=[O:32])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCc2nn[nH]n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCc2nn[nH]n2)c1
Yield: 46 %

Procedure:
A solution of {imino-[5-methylsulfanyl-4-(6′-methyl-2′-{3-[2-(2H-tetrazol-5-yl)-ethyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (10 mg, 15.3 μmol) in TFA/DCM (2.0 mL, 1:1) was stirred at ambient temperature for 1.5 h. The reaction mixture was concentrated to dryness, and flash chromatographed on silica gel column, eluting with 10% MeOH/DCM containing 0.1% TFA to give the title compound (4.7 mg, 46% yield) as a white solid.
Reaction SMILES: Cl.Cl.[C:3]1([C:9]2[N:14]=[N:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:28][C:29](O)=O)[CH:24]=2)[N:19]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:28][C:29]3[N:13]4[N:14]=[C:9]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH:10]=[CH:11][C:12]4=[N:15][N:16]=3)[CH:24]=2)[N:19]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: Cc1ccc2cc(CC(=O)O)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cc(Cc3nnc4ccc(-c5ccccc5)nn34)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31.2 %

Procedure:
A vial was charged with (6-phenyl-pyridazin-3-yl)-hydrazine dihydrochloride (20 mg, 0.077 mmol), (2-methyl-quinolin-6-yl)-acetic acid (17 mg, 0.085 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (22 mg, 0.115 mmol), 1-hydroxybenzotriazole hydrate (11 mg, 0.077 mmol), potassium carbonate (32 mg, 0.231 mmol), and N,N-dimethyl formamide (0.7 mL). The reaction mixture was stirred at room temperature for 14 h. After such time the mixture was concentrated in vacuo. Acetic acid (1 mL) was added to the residue and the resulting reaction mixture was stirred at 55° C. for 5 h. After such time the mixture was concentrated in vacuo and partitioned between 1 M aqueous potassium carbonate and ethyl acetate. The organic layer was washed with 1 M aqueous potassium carbonate, then brine, and directly adsorbed on silica gel. Purification on silica gel with 0-8% gradient of methanol in ethyl acetate afforded the title compound (8.7 mg, 0.024 mmol, 32% yield) as a light yellow solid. Analytical data presented in Table 1.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[CH3:30].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[C:13]([O:12][C:10]([NH:1][C@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7](=[O:9])[CH2:30][C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)OCc1ccccc1
Reactant: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of Boc-D-alloIle-OH (15.26 g, 65.9 mmol) in dry THF (200 ml) at 0° C. under argon, was added CDI (16.04 g, 98.96 mmol). After 15 min, the mixture was allowed to warm to room temperature, and stirred over a period of 16 h. The resulting solution was cooled to −78° C., and added via cannula to a well stirred solution of benzyl lithium enolate cooled at −78° C. (625 ml, 0.37 M), [prepared by adding dropwise a solution of benzyl acetate (33.34 ml), in THF (165 ml) to a solution of lithium diisopropylamide (0.36M) in THF/hex 3:1 (642 ml) at −78° C.]. The temperature should be kept <−75° C. The reaction mixture was stirred at −78° C. for 60 min. Then, it was allowed to come to −10° C. (30 min), recooled to −78° C. and quenched with saturated aq. ammonium chloride (200 ml), then extracted with DCM (3×500 ml) at room temperature. The combined extracts were washed successively with aq sat. NaHCO3 (500 ml) and brine (200 ml). Drying (Na2SO4) followed by removal of solvent gave an oil, which was coated on silica C18 and loaded to the top of a LC-RPC18 [Lichroprep RPC-18 (40-60 microns) column. Elution using a gradient ACN-H2O (60 to 100% ACN)] yielded the product C4 as a colourless oil (16.7 g, 70%). [α]20D−20.0 (c 1, CHCl3), TLC: Rf=0.32 (Merck, RP-C18, ACN-H2O7:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Oc1ccccc1)c1cnn(CCN2CCOCC2)c1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnn(CCN4CCOCC4)c3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1-(2-morpholin-4-yl-ethyl)-1H-pyrazole-4-carboxylic acid phenyl ester, the title compound was obtained as white crystals 42% yield). MS: m/e=473(M+H+), mp 204-207° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:10]([CH3:18])[CH:11]=[CH:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:10]([CH3:18])[CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCC(=O)OC(NC(=O)OC(C)(C)C)[C@H](C)C=Cc1cccs1
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(=O)OC(NC(=O)OC(C)(C)C)[C@H](C)CCc1cccs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.6 %

Procedure:
(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)-3-butene (27.6 g, 72.4 mmol) obtained in Example 66(c) was dissolved in ethanol (450 ml), and 10% palladium-charcoal (14.0 g) was added thereto followed by stirring for 4 days at room temperature under a hydrogen atmosphere. After the palladium-charcoal in the reaction solution was filtered out through Celite, the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=20:1-10:1) to give the title compound (22.1 g, 80% yield) as a colorless oil.
Reaction SMILES: ClCCl.C(O)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[C:25]3[Br:33])[CH2:16]1)=O)(C)(C)C>CO>[Br:33][C:25]1[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([O:21][C@H:17]3[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]3)[CH:23]=2)[C:28](=[O:32])[NH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(=O)[nH]cc(Br)c3c2)C1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]cc(Br)c2cc(O[C@H]3CCCNC3)ccc12
Reaction time: 2 h

Procedure:
A solution of (S)-3-(oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.9 mmol) and N-bromosuccinamide (516 mg, 2.9 mmol) in acetonitrile was stirred overnight at ambient temperature. The mixture was absorbed onto silica and flash chromatography (eluent: ethyl acetate) to give (S)-3-(4-bromo-1-oxo-1,2-dihydroisoquinblin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (700 mg). Dichloromethane and trifluoroacetic acetic acid (3:1, 20 ml) were added to (S)-3-(4-bromo-1-oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester and the mixture stirred for 2 h, then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford crude (S)-4-bromo-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (530 mg), which was purified by prep-HPLC, El-MS: m/z=325.5 [M+H]+.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>O>[C:6]1([CH3:12])[C:7]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccccc1S(=O)(=O)O
Temperature: 65 °C
Reaction time: 5 h

Procedure:
560 g of 98% sulfuric acid was dropped into 560 g of toluene while stirring. Then, while the stirring was continued, the temperature was raised at 60 to 70° C., reacting for 5 hours. After the reaction, 500 g of distillation water was added. Then, 200 g of ether was added. The lower phase (water phase) of the two separated phases was taken, into which a step of distillation for condensation and addition of water was repeated twice, so as to obtain toluenesulfonic acid. As a result of analysis, the toluenesulfonic acid included the para compound thereof at a concentration of 85 mole % in the total of the toluenesulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:17][CH:18]=1.C(N(CC)CC)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][C:14]2[C:13]([NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:18][CH:17]=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[N:15]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Oc3ccc(C#N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.1 %

Procedure:
4-Fluoro benzene sulfonyl chloride (0.15 g, 0.77 mmol), dissolved in 2 ml of tetrahydrofuran (THF), was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.25 g, 0.77 mmol), triethylamine (0.155 g, 1.54 mmol) and N,N-diisopropylethylamine (0.1 g, 0.77 mmol), in 10 ml of THF, in an inert atmosphere and stirred at RT for 12 h. The reaction mixture was concentrated and dissolved in 100 ml of ethyl acetate, washed with 1 N HCl followed by saturated brine solution and dried over anhydrous sodium sulphate. The organic phase was concentrated and the crude product was purified by column chromatography to afford 0.3 g of the required compound. 1H NMR (DMSO-d6): δ 6.94 (1H, d), 7.12 (2H, m), 7.25 (1H, d), 7.35 (4H, d), 7.56 (4H, m), 7.80 (4H, m), 8.04 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:16]1([C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ccc(OC(=O)C2CCCCC2)cc1

Procedure:
The title compound was prepared from 6.0 g of 4-hydroxybenzophenone, 6.0 ml of cyclohexanecarbonyl chloride, pyridine (70 ml). Recrystallized from ethyl acetate-ethanol-water; M.P.~111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:10]([CH3:22])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([Cl:42])[CH:33]=1>C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][C:2]2[N:7]=[C:6]([N:8]3[CH2:9][C@H:10]([CH3:22])[N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@H:12]([CH3:14])[CH2:13]3)[CH:5]=[CH:4][C:3]=2[O:23][CH3:24])(=[O:39])=[O:40])=[C:34]([Cl:42])[CH:33]=1
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-amino-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D12)(1.0 g, 2.97 mmol) was dissolved in DCM (10 mL) and pyridine (10 mL) and then cooled to 0° C. 4-Bromo-2-chlorobenzenesulfonyl chloride (0.946 g, 3.27 mmol), dissolved in DCM (5 mL) was then added dropwise and the reaction then allowed to warm to rt overnight. The reaction was then evaporated to a minimum and redissolved in DCM (100 mL) and washed with water (50 mL). Aqueous layer was extracted with DCM (2×50 mL) and combined organic extracts washed with brine (100 mL). The organic layer was dried (MgSO4) and evaporated to give a dark oil which was purified by chromatography [silica gel, eluting with 0 to 50% Ethyl acetate/pentane]. Product fractions evaporated to give a yellow crunchy foam (D13) (1.29 g), MS (ES+) m/e 589/591 [M+H]+.
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:20][CH2:19]2)[C:15]([N+:31]([O-])=O)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>[Fe]>[NH2:31][C:15]1[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:22][CH2:23]2)=[CH:17][C:9]([Cl:8])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2N)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stir bar, the iron powder (5.59 g, 100.15 mmol) was suspended in clean, dry, reagent-grade ethanol (300.00 ml, 5138.06 mmol) and the mixture was stirred vigorously under nitrogen at room temperature. To this was added the acetic acid (30.00 ml, 524.05 mmol) and the reaction was allowed to stir for 5 min before the 2-chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 1d (1.51 g, 4.01 mmol) was added in one portion. The reaction was then warmed to 75° C. and allowed to stir overnight. The reaction was cooled to room temperature and was then filtered through Celite, washing heavily with methanol. The deep red product solution was then concentrated under reduced pressure and the resultant ruby red oil was taken up in 200 ml of ethyl acetate. To this solution was added 200 ml of saturated NaHCO3 (aq) solution and the layers were then separated and the product was extracted out of the aqueous using ethyl acetate (3×100 ml). The organic phases were then combined and washed with brine (1×200 ml) and dried over Na2SO4. The solution was then decanted and the solvent was removed under reduced pressure. The crude product, 5-amino-2-chloro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 14a (1.22 g, 3.53 mmol), was isolated as a brown solid and was carried on without further purification. LCMS=346 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]([CH3:17])=[N:7][NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.Br[C:20]1[S:24][CH:23]=[N:22][CH:21]=1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([C:20]2[S:24][CH:23]=[N:22][CH:21]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1
Reactant: Brc1cncs1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(-c2cncs2)c1-c1ccc(Cl)cc1

Procedure:
Methyl[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]acetate (1.0 g, 3.77 mmol), 5-bromothiazole (0.526 g, 3.21 mmol), salicylaldoxime (0.103 g, 0.75 mmol), Cu2O (0.027 g, 0.18 mmol), Cs2CO3 (1.477 g, 4.53 mmol) and acetonitrile (4.8 ml) were introduced successively into a vessel which had been dried by heating and cooled under a stream of argon.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:16]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>O.CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: COCc1ccc(C(=O)O)c(N)n1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCc1ccc(C(N)=O)c(N)n1
Yield: 58.3 %

Procedure:
2-Amino-6-methoxymethyl-nicotinic acid (0.50 g), WSC (1.1 g), HOBt (0.74 g), ammonium chloride (0.44 g), diisopropylethylamine (2.6 g), and DMSO (10 mL) were stirred for 29 hours at room temperature. Water was added thereto, and then the reaction solution was extracted with ethyl acetate. The organic layer was concentrated and purified by NH silica gel column chromatography (ethyl acetate). Ethyl acetate was added to the residue thus obtained, and the solids were filtered off to obtain the titled compound (290 mg).