Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:54]>CN1C(=O)CCC1>[ClH:54].[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[N:15]=4)=[O:13])[C:4]=23)[CH2:24]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cn1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: Cl
Product: Cn1nc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (0.223 g, 0.61 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.366 g, 1.83 mmol) and DIEA (0.21 mL, 1.22 mmol) in NMP (2 mL) were stirred at 156° C. (bath) for 18 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 30-70% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide hydrochloride (0.022 g, 6% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.87 (d, 1H), 7.56 (s, 1H), 7.01 (d, 1H), 3.74 (s, 3H), 3.54 (m, 1H), 3.41 (m, 1H), 3.36 (m, 2H), 3.15 (m, 1H), 2.01 (m, 1H), 1.75 (m, 1H), 1.67 (m, 1H), 1.41-1.49 (m, 1H); LCMS (APCI+) m/z 446 (M+H)+.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH2:13])=[O:12])=[O:8].[CH:14](=O)[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].[O:25]1[CH2:35][CH:26]1[CH2:27][C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29]>CO.O>[C:11]([CH2:10][N:9]1[C:7](=[O:8])[CH2:6][N:5]([CH2:35][CH:26]([OH:25])[CH2:27][C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])[CH:14]1[CH:15]([CH3:17])[CH3:16])(=[O:12])[NH2:13]
Reactant: CC(C)C=O
Reactant: CC(C)COC(=O)CC1CO1
Reactant: NCC(=O)NCC(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C

Procedure:
A solution of 1.91 g (0.01 mol) of glycylglycinamide acetate and 0.72 g (0.01 mol) of isobutyraldehyde in 40 ml of methanol was stirred for 24 hours at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in 30 ml of isopropanol and treated with 0.106 g of sodium carbonate, 1.8 g (0.0115 mol) of 2-methylpropyl 3,4-epoxybutanoate and 2 drops of water. The mixture was refluxed for 36 hours. After evaporation of the solvent the residue was chromatographed on a silica gel column, eluting with dichloromethane/methanol 9:1. The title compound (0.48 g) was constituted by two diastereoisomers.
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][C:17]([C:19]2[C:20]([F:32])=[C:21]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH:29]=[CH2:30])[CH:22]=[CH:23][CH:24]=2)=O)[CH:13]=[CH:12][N:11]=1.[NH2:33][C:34](=[S:46])[C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:37])[CH3:36]>ClCCl.CCOC(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[S:46][C:34]([C:35]([NH:38][C:39]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:45])([CH3:37])[CH3:36])=[N:33][C:17]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH:29]=[CH2:30])[CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:12][N:11]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
N-Bromosuccinimide (0.763 g, 4.29 mmol) was added to a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (1.5 g, 4.29 mmol) in dichloromethane (DCM) (50 mL). After 1 h of stirring, 1,1-dimethylethyl (2-amino-1,1-dimethyl-2-thioxoethyl)carbamate (0.936 g, 4.29 mmol) was added to the reaction mixture and heated to 80° C. for 2 h. The reaction mixture was diluted with 150 cc of EtOAc and washed with water (5×100 cc). The EtOAc layer was dried over MgSO4 and filtered and concentrated in vacuo. The residue was purified via chromatography on silica gel using Hex to 25% EtOAc in Hex to obtain the title compound (1.28 g, 54% yield). MS (ESI): 548.3 [M+H]+
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([CH2:23][CH3:24])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH2:23]([C@H:10]1[C@H:11]([NH:14][C@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:24]
Reactant: CC[C@@H]1CN(Cc2ccccc2)CC[C@H]1N[C@@H](C)c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC[C@@H]1CNCC[C@H]1N[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
To a solution of (3R,4R)-1-benzyl-3-ethyl-N—((S)-1-phenylethyl)piperidin-4-amine (679.2 mg, 2.106 mmol) in 1,2-dichloroethane (3.50 ml) at 0° C. was added 1-chloroethyl chloroformate (0.276 ml, 2.53 mmol) dropwise. After stirring for 20 minutes, the ice-bath was removed and the reaction was heated to reflux for 1 hr. The reaction was cooled to room temperature and concentrated under reduced pressure. Methanol (10.5 ml) was added, and the reaction was heated to reflux for 2 hrs. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding (3R,4R)-3-ethyl-N—((S)-1-phenylethyl)piperidin-4-amine (443 mg, 1.906 mmol, 91.0% yield) as a yellow oil. LCMS (Method K) m/z 233.3 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.[C:36](O)([C:38]([F:41])(F)F)=O>C(Cl)Cl>[F:41][C:38]1[CH:36]=[CH:17][CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:32]#[N:33])[CH2:23][C:22](=[O:34])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K57) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (128 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2].[CH3:22][Mg]Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:8]=[C:9]([CH3:22])[C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(CC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: C[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Oc1cc(CC(=O)OC(C)(C)C)cc(C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A stirred solution of t-butyl 3-acetoxy-4-nitrophenylacetate (8.0 g, Reference Example 18) in tetrahydrofuran (350 mL) at −15° C. under argon was treated dropwise with methyl magnesium chloride solution in diethyl ether (7 mL, 3M) and after 2 hours a further aliquot of methyl magnesium chloride solution in diethyl ether (7 mL, 3M). After stirring for a further 1 hour the reaction mixture was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10.4 g), then stirred at room temperature overnight, then partially evaporated and then treated with dichloromethane. The mixture was washed with water, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with dichloromethane to give the title compound (1.66 g) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:31]([N:38]1[CH2:41][CH:40]([C:42](O)=[O:43])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C@@H:2]([NH:1][C:42]([CH:40]2[CH2:41][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39]2)=[O:43])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)c(Cl)c2)C(=O)N2CCN(c3ccccc3NS(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}azetidinecarboxylate was prepared from (2R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Example 2, Step 2) (320 mg, 0.67 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (140 mg, 0.71 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (400 mg, 1.3 mmol), HOAT (96 mg, 0.71 mmol), and DMF (5 mL) (448 mg crude). MS (ESI, pos. ion) m/z: 654 (M+H), (ESI, neg. ion) m/z: 652 (M−H). Calc'd for C29H37Cl2N5O6S: 653.18.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([N:19]2[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]2=[O:29])=[N:14][CH:13]=[CH:12]3)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][N:18]=1)[C:15]([N:19]1[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]1=[O:29])=[N:14][CH:13]=[CH:12]2
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N4C(=O)c5ccccc5C4=O)c3cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Temperature: 40 °C
Reaction time: 19 h
Yield: 96.4 %

Procedure:
A mixture of 4-6 (3.94 g, 7.43 mmol), trifluoroacetic acid (30.0 mL, 392 mmol), and dichloromethane (30.0 mL) was stirred at 40° C. for 19 hours under an atmosphere of nitrogen gas and concentrated under reduced pressure. To the resulting residue was added saturated aqueous NaHCO3 (300 mL) and hexane/dichloromethane (5:1) (150 mL) at ambient temperature. The resulting mixture was stirred vigorously at ambient temperature for 30 minutes. The precipitated solid was filtered, washed with water (60 mL) and hexane/dichloromethane (5:1) (60 mL), and dried under high vacuum to give 2.08 g (96%) of 4-7 as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 9.04 (1H, br s), 8.28 (1H, d, J=6.0 Hz), 8.05 (2H, m), 7.97 (2H, m), 7.55 (1H, br d, J=6.0 Hz), 6.78 (2H, br s), 6.63 (1H, br s); ESI-MS m/z 291 [C16H10N4O2+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cccc(CC)c1N
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cccc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Reaction time: 3 h

Procedure:
To a solution of 149.0 g (1.0 mole) of 2,6-diethylaniline in pyridine (500 ml) is added in portions at 0° C. 209.6 g (1.1 moles) of p-toluenesulfonyl chloride. The reaction mixture is allowed to come to room temperature and stir for three hours. The mixture is poured into cold aqueous 10% HCl and the crude sulfonamide solidified. The sulfonamide is filtered, washed with water and crystallized from acetic acid to give N-(2,6-diethylphenyl)-p-toluenesulfonamide m.p. 130°-131° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]#[CH:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C.CCOCC>[CH3:15][S:16]([O:1][CH2:2][CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:12][C:13]#[CH:14])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCN(CCO)C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C#CCN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 700 mg of 10d in 1 ml of triethyl amine and 15 ml of ether was treated at 0° C. with 320 μl of methanesulfonyl chloride in 3 ml of ether. The reaction mixture was stirred for ½ h and then quenched by addition of 20 ml of water and the product was extracted into ether. The organic extract was washed with 1M aq. K2CO3 and once with water, dried and concentrated, to give 900 mg of 10e as a colorless oil, essentially pure according to TLC and NMR, which was used without further purification in the next step. Rf 0.40 (heptane/ethyl acetate 1/1).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].Cl.[NH:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([O:29][CH3:30])=[O:28]>ClCCl>[N+:8]([C:11]1[CH:12]=[C:13]([S:17]([N:22]2[CH2:26][CH2:25][CH2:24][C@@H:23]2[C:27]([O:29][CH3:30])=[O:28])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: COC(=O)[C@H]1CCCN1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.38 ml of triethylamine were added dropwise, over the course of 30 minutes, to a solution of 2.56 g of 3-nitrobenzenesulfonyl chloride and 1.91 g of methyl (R)-pyrrolidine-2-carboxylate hydrochloride in 30 ml of dichloromethane (30 ml) cooled to 0° C. The reaction medium was left at ambient temperature and stirred for 1 hour. The reaction medium was diluted with 50 ml of dichloromethane, and washed with a 1 M sodium hydrogen phosphate solution (2×50 ml) and a saturated sodium hydrogen carbonate solution (50 ml). The organic phase was dried over magnesium sulfate and evaporated 3.00 g of methyl (R)-1-(3-nitrobenzenesulfonyl)pyrrolidine-2-carboxylate were obtained and used in the next step without purification.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=C(N)C=2)=[CH:4][C:3]=1C(O)=O.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Sc2cc(C(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-carboxy-4-(3'-amino-4'-sulfophenylthio)anthraquinone (9.4 parts) and cyanuric chloride (3.7 parts) were subjected to condensation reaction in an aqueous medium in a usual manner, followed by condensation reaction with 3-aminobenzenesulfonic acid (3.5 parts) at 20° to 40° C. under a weak acid condition, thereby obtaining an anthraquinone compound of the following formula (free acid form). ##STR394##
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[CH2:4]C(OC)=O.[N:12]([O-])=O.[Na+].O.O.O.C([O-])(=O)C.[Na+].[CH3:24][C:25]1([CH3:33])[CH2:30][C:29](=[O:31])[CH2:28][C:27](=O)[CH2:26]1>O.C(O)(=O)CC.[Zn].CC(O)=O>[CH3:33][C:25]1([CH3:24])[CH2:26][C:27]2[NH:12][CH:4]=[C:3]([C:2]([CH3:11])([CH3:10])[CH3:1])[C:28]=2[C:29](=[O:31])[CH2:30]1
Reactant: O=N[O-]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2c(C(C)(C)C)c[nH]c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4,4-dimethyl-3-oxopentanoate (20 g, 0.13 mol) and AcOH (48 mL) were cooled to 10° C. and a solution of NaNO2 (12.3 g, 0.19 mol) in water (48 mL) was added dropwise to the stirred mixture, maintaining the temperature below 20° C. After addition the mixture was warmed to room temperature and stirred for 2 h. The mixture was then extracted with DCM (3×100 mL). The combined organic layers were evaporated and the residue taken up in ether. The ethereal layer was washed with water (100 mL), separated and dried (Na2SO4). The resultant yellow gum (22.7 g, 96%) was used without further purification. 1H NMR (250 MHz, CDCl3) δ 1.23 (9H,s), 3.89 (3H,s), 9.00-10.00 (1H,br s). Sodium acetate trihydrate (20.6 g, 0.15 mol) and 5,5-dimethyl-1,3-cyclohexandione (16.9 g, 0.12 mol) in propionic acid (140 mL) were heated to 150° C. A solution of the oxime (22.7 g, 0.12 mol) in propionic acid (70 mL) was added via a dropping funnel, whilst simultaneously adding zinc dust (12 g) over 20 min. The solution was heated at reflux for 24 h after which time it was poured into water. The resultant solid was collected by filtration then triturated with ether. The colourless solid (3.7 g, 14%) was collected by filtration. 1H NMR (360 MHz, CDCl3) δ 1.10 (6H,s), 1.35 (9H,s), 2.35 (2H,s), 2.64 (2H,s), 6.43 (1H,d,J=2.2 Hz), 7.80-8.14 (1H,br s). MS (ES+) 220 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(Cl)Cl>[O:31]1[CH2:32][CH2:33][N:28]([CH2:2][C:3]2[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CN2CCOCC2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
tert-Butyl 4-(hydroxymethyl)thiazol-2-ylcarbamate (2.0 g, 8.7 mmol) was taken up in 25 mL of CH2Cl2 along with Et3N (1.82 mL, 13.05 mmol) and cooled to 0° C. Methanesulfonyl chloride (0.85 mL, 10.88 mmol) was added and the resulting reaction mixture was stirred at 0° C. for 60 min. Morpholine (3.0 mL, 35 mmol) was then added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc and washed with dilute aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. This material was purified by filtering through a short column of silica gel. The filtrate was concentrated to afford 1.88 g of tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate. The Boc group was removed by treating tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate with 20 mL of 25% TFA in CH2Cl2 for 18 h at room temperature. After all the solvent had been removed by concentrating and drying under high vacuum, the resulting residue was treated with a mixture of pentane/EtOAc to afford 2.17 g 4-(morpholinomethyl)thiazol-2-amine as a white solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[CH3:7][N:6]1[C:2]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 57 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 4-aminopiperidine-1-carboxylate gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)piperidine-1-carboxylate as a pale yellow solid (0.23 g, 57%). 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 6.40 (d, J=9.8 Hz, 1H), 4.06-3.95 (m, 2H), 3.81 (s, 3H), 3.70-3.59 (m, 1H), 3.05-2.93 (m, 2H), 2.00-1.92 (m, 2H), 1.60-1.50 (m, 2H), 1.49 (s, 9H)
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), N,N-dimethylcarbamoyl chloride (3.60 uL, 0.0392 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.2 mmol) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.93 (s, 6H), 4.13-4.18 (m, 2H), 7.39-7.45 (m, 1H), 7.51 (td, J=7.7, 1.3 Hz, 1H), 7.96 (d, J=7.3 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 8.14 (s, 1H). MS (ES+): m/z=352.11 (100) [MH+]. HPLC: tR=3.11 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:4]([CH3:6])=O.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.O.[NH3:25]>O1CCOCC1.C(O)C>[OH:1][N:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:6])[N:25]=[C:17]1[C:16]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:15]=1[O:14][CH3:13]
Reactant: CC(=O)C(=NO)c1cccnc1
Reactant: COc1cc(C)ccc1C=O
Reactant: N
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: COc1cc(C)ccc1-c1nc(C)c(-c2cccnc2)n1O
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a suspension of 1-hydroxyimino-1-(3-pyridyl)acetone (1.0 g) in a mixture of dioxane (20 ml) and ethanol (6 ml), were added 2-methoxy-4-methylbenzaldehyde (1.01 g) and conc. ammonia water (15 ml). The solution was stirred at ambient temperature for 8 days. After evaporation, the residue was dissolved in chloroform, and chromatographed on silicagel eluting with a mixture of chloroform and methanol. The fractions were collected, evaporated, and triturated in diisopropyl ether to give 1-hydroxy-2-(2-methoxy-4-methylphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.46 g).
Reaction SMILES: CC[Mg+].[Br-].[C:5]1([CH3:13])[CH:10]=[CH:9][CH:8]=[C:7](C#N)[CH:6]=1.[CH:14]1[CH:19]=CC=C[CH:15]=1.Cl.CC[O:23]CC>>[CH3:15][CH2:14][CH2:19][C:13]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:23]
Reactant: CCOCC
Reactant: c1ccccc1
Reactant: Cc1cccc(C#N)c1
Agent: CC[Mg+]
Agent: Cl
Agent: [Br-]
Product: CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a 0° C. solution of EtMgBr in Et2O (3.0M, 570 mL, Aldrich) was slowly added m-tolunitrile (102 mL, Aldrich). After stirring at r.t. for 19 hr., benzene (300 mL) was added and the resulting mixture was cooled to 0° C. HCl (6N, 600 mL) was then slowly added. The organic phase was separated, washed with 5% NaHCO3 and brine, dried (MgSO4) and evaporated to afford the desired ketone as a yellow liquid.