Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15](=O)[O:16]C(C)(C)C)([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:16])[NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(O)c(N)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(NC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of 2-amino-4-methyl-phenol (6.15 gm; 50 mmol) in dioxane (100 mL) was added carbonic acid di-tert-butyl ester (9.8 gm; 45 mmol) followed by sodium bicarbonate (12.6 gm; 150 mmol in 75 mL of H2O) After stirring for 8 hours, the reaction was diluted with 100 mL of ethyl acetate and washed with 1N aqueous hydrochloric acid (2×100 mL), saturated aqueous sodium bicarbonate (1×100 mL), and brine (100 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to provide the desired (2-Hydroxy-5-methyl-phenyl)-carbamic acid tert-butyl ester as a brown solid (95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
2-Chloro-4-nitroaniline (1.73 g (10.0 mmol)) was dissolved in 5.0 ml of pyridine. To this, p-toluenesulfonyl chloride (1.91 g (10.0 mmol)) was added with stirring at room temperature. After stirring for 18 hours at room temperature, water (50 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered, washed with water and then dissolved in an aqueous solution of sodium hydroxide. The resulting solution was washed with diethyl ether, and the water layer was made acidic again with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.61 g (80%) of 2′-chloro-4′-nitro-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: Cc1cnc(Br)cc1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cnc(NN)cc1C

Procedure:
3.8 g (18.4 mmol, purity 90%) of the compound from Example 20A are initially charged in 12.5 ml of ethanol. 8.9 ml (9.2 g, 183.8 mmol) of hydrazine hydrate are added, and the mixture is reacted in a single-mode microwave oven (CEM Explorer) at 170° C. (100 Watt) for 2 h. The reaction solution is then concentrated, and the residue is taken up in ethyl acetate and washed in each case once with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[NH4+:50]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[C:27]([C:28]([NH2:50])=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=4)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added ammonium hydroxide (27% aqueous) (100 mL, large excess). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide (133 mg, 0.193 mmol) as an off white solid. (ESIMS (M+H)+=691)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:13][CH2:12][CH:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(CC(CO)CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(COS(=O)(=O)c2ccc(C)cc2)Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 89 %

Procedure:
A solution of 24 (6.43 g, 30.44 mmol) in pyridine (20 mL) was added dropwise to a solution of p-toluenesulfonyl chloride (14.51 g, 76.11 mmol) in pyridine (30 mL), with temperature being kept below 0° C. After complete addition, the reaction mixture was stirred at room temperature for 10 hours, and then it was poured into ice-cold aqueous 5 M HCl (100 mL). The aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organic phase was washed with brine (2×100 mL), dried over MgSO4, and evaporated under reduced pressure to afford pale yellow oil, which was crystallized from ethanol (100 mL) to give white solid 25 (14.08 g, 89% yield).
Reaction SMILES: [K:1].[K].[OH:3][C:4]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][C:5]=1[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7].[C:29](O)(=[O:31])[CH3:30].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(OCC)C>[K:1].[C:29]([O:3][C:4]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:13][C:5]=1[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CC(C)COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)O)cc2)cc1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl 2-hydroxy-5-[2-(4-sulfophenyl)ethenyl]benzoate dipotassium salt (37.2 g, 0.09 mol) was added to a boiling solution of acetic acid (20 ml) and acetic anhydride (80ml). Sulfuric acid (8 ml) was added cautiously and the mixture refluxed until the major part of the solids had dissolved, and then more acetic anhydride (80 ml) was added. After boiling for 1 h, the mixture was cooled to room temperature. Diethyl ether (350 ml) was added and the suspension filtered and washed with diethyl ether. Yield 36.1 g (88%)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C:16]3[C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]([O:26][CH3:27])=[C:18]([O:28][CH3:29])[C:17]=3[O:30][CH3:31])[C:5]([C:12]([O:14]C)=[O:13])=[CH:6][C:7]=2[O:10][CH3:11])[O:2]1.[OH-].[K+].Cl>O1CCOCC1>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]([O:26][CH3:27])=[C:18]([O:28][CH3:29])[C:17]=3[O:30][CH3:31])[C:5]([C:12]([OH:14])=[O:13])=[CH:6][C:7]=2[O:10][CH3:11])[O:2]1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1-c1c(C(=O)OC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)c(-c2c(C(=O)O)cc(OC)c3c2OCO3)c(OC)c1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
In 50 ml of dioxane was dissolved 1.3 g of dimethyl 2',3'-methylenedioxy-2,3,4,4'-tetramethoxy-1,1'-biphenyl-6,6'- dicarboxylate obtained in Example 2, and 10 mg of 5% potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight. When the pH value of the mixture was adjusted to 1 by 3N hydrochloric acid, crystals were precipitated. The precipitated crystals were recovered by filtration and recrystallized from ethanol to obtain 1.12 g of 2',3'-methylenedioxy-2,3,4,4'-tetramethoxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 92%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[H-].[Na+].C(O)(=O)C>CN(C=O)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccnc(Nc2ccc(F)cc2)c1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a mixture of 2-fluoro-isonicotinic acid (Aldrich, 423 mg, 3.0 mmol) and 4-fluoroaniline (555 mg, 5.0 mmol) in DMF (18 mL) at rt was added NaH (500 mg of 60% in oil), and the mixture was heated at 85° C. for 75 min. Acetic acid (0.7 mL) was added to the reaction mixture and it was concentrated in vacuo. To the residue were added EtOAc (100 mL) and water (20 mL), stirred for 20 min and the solid was filtered, washed with EtOAc and dried to obtain the desired product (600 mg, 50%) as a tan solid. 1H NMR (DMSO-d6) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.04 (d, 1H, J=4.9 Hz), 7.69 (dd, 2H, J=8.8, 4.9 Hz), 7.24 (s, 1H), 7.05 (dd, 2H, J=8.2, 6.0 Hz); MS(ESI+) m/z 233.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:22][OH:23])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:23][CH2:22][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[F:21])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Yield: 99 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.7 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (Example 13) (0.37 g), benzene (20 ml) and pyridine (0.12 ml) to yield the title compound (0.43 g, 99%).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][NH:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[Cl:22])[N:13]=[N:12][N:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[CH3:24]>>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[C:10]([NH:9][CH2:8][C:7]2[C:2]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH2:23][CH3:24])=[CH:27][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:11][N:12]=[N:13]1
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Clc1cccc(-n2nnnc2NCc2cccnc2Br)c1Cl
Product: CCOc1ccc(-c2ncccc2CNc2nnnn2-c2cccc(Cl)c2Cl)cc1
Yield: 6 %

Procedure:
Prepared in 6% yield from (2-bromo-pyridin-3-ylmethyl)-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine from Example 142C and 4-ethoxyphenylboronic acid according to the procedure described for Example 146. MS (ESI+) m/z 441.0 (M+H)+; 1H NMR (DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 4.09 (q, J=6.9 Hz, 2H), 4.53 (d, J=5.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.34 (dd, J=7.8, 4.7 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.61 (dd, J=8.1, 8.0 Hz, 1H), 7.67-7.74 (m, 2H), 7.81 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (dd, J=8.1, 1.7 Hz, 1H), 8.53 (dd, J=4.6, 1.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27]>CN(C=O)C>[C:26]([O:29][CH2:30][C:31]([N:14]1[CH2:13][CH2:12][CH:11]([C:3]2[CH:4]=[C:5]([I:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15]1)=[O:32])(=[O:28])[CH3:27]
Reactant: COc1cc(F)c(C2CCNCC2)cc1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1I

Procedure:
A stirred solution of 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine (50 mg; 0.149 mmol) in DMF (1.2 mL) under N2 was treated with N,N-diisopropylethylamine (26 μL; 0.149 mmol), followed by acetoxyacetyl chloride (16 μL, 0.149 mmol). The resultant solution was stirred at room temperature for 5 h. The reaction was partitioned between EtOAc (25 mL) and saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic fractions were washed with water and brine (25 mL each), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with EtOAC/hexanes, to afford 2-[4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]-2-oxoethyl acetate as a colorless oil. LCMS=435.8 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.52 (d, J=8.2 Hz, 1H), 6.56 (d, J=12.2 Hz, 1H), 4.76 (s, 2H), 4.76-4.70 (m, 1H), 3.85 (s, 3H), 3.76 (br d, J=13 Hz, 1H), 3.17 (t, J=12.6 Hz, 1H), 2.98 (tt, J=12.1, 3.4 Hz, 1H), 2.68 (t, J=12.4 Hz, 1H), 2.20 (s, 3H), 1.90-1.82 (m, 2H), 1.70-1.62 (m, 2H).
Reaction SMILES: C[O-].[Na+].C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].C([O:14][C:15](=O)[C:16]([O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH:30]([CH3:32])[CH3:31])=[CH:17]OC)C>CS(C)=O>[NH2:10][C:9]1[NH:11][C:15](=[O:14])[C:16]([O:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=2[CH:30]([CH3:32])[CH3:31])=[CH:17][N:8]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(=COC)Oc1cc(C)c(OC)cc1C(C)C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(C)C)c(Oc2cnc(N)[nH]c2=O)cc1C
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 22 %

Procedure:
To a solution of NaOMe [prepared from sodium ( 0.05 g, 2.17 mmol) in anhydrous methanol (5 ml)], was added guanidine carbonate. After 5 minutes, a solution of 2-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3-methoxy-acrylic acid ethyl ester (0.22 g, 0.713 mmol) in anhydrous DMSO (10 ml) was added. The mixture was heated at 120° C. for 3 hours and was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (5% methanol in methylene chloride/0.1% concentrated NH4OH) to yield 2-amino-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3H-pyrimidin-4-one as pale yellow solid (0.045 g, 22%). MS M+H=290.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][NH2:33]>ClCCl.[OH-].[Na+]>[NH:32]([C:15]([C:14]1[CH:18]=[CH:19][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:13]=1)=[O:16])[NH2:33]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-((tert-butoxycarbonyl)amino)ethyl)benzoic acid (3.364 g, 12.7 mmol) in anhydrous dichloromethane (60 mL) was added carbonyldiimidazole (2.264 g, 13.97 mmol). The reaction mixture was stirred at room temperature for 45 minutes before anhydrous hydrazine (1 ml) was added and the mixture stirred at room temperature for another 16 hours. Evaporation to dryness gave a white solid that was stirred in 1.5N sodium hydroxide (200 mL) for 30 minutes before being filtered off and washed with water (2×100 mL). Drying under vacuum gave tert-butyl 4-(hydrazinecarbonyl)phenethylcarbamate as a white powder (2.847 g). 400 MHz 1H NMR (DMSO-d6) δ: 9.69 (s, 1H), 7.74 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 6.9 (t, J=5.2 Hz, 1H), 4.45 (s, 2H), 3.15 (m, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.36 (s, 9H). LCMS [M+]: 279.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:21]>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][CH2:20][CH3:21])=[CH:24][CH:25]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1OC
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(OC)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with 4-ethoxyaniline gave N4-(3,4-dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (bs, 1H), 7.37 (dd, 2H, J=2.4 and 6.3 Hz), 7.21 (d, 1H, J=2.4 Hz), 7.03 (dd, 1H, J=2.4 and 8.1 Hz), 6.86-6.80 (m, 4H), 6.65 (bs, 1H), 4.00 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 3.75 (s, 3H), 1.39 (t, 3H, J=6.9 Hz); 19F NMR (CDCl3): −47501; LCMS: ret. time: 22.69 min.; purity: 98%; MS (m/e): 385 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].O>CN(C=O)C>[CH2:26]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[CH3:27]
Reactant: CCI
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 moles) and potassium carbonate (83 mg, 0.6 moles) in 10 ml DMF was added dropwise iodoethane (0.06 ml, 0.75 moles) under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 21° C. The mixture was poured into 50 ml water and after stirring for one hour a white precipitate was collected and dried. Crystallization from ether/hexanes gave 117 mg (82% yield) of the desired 6-ethyl-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 127°-128° C.; TLC 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ1.42 (t, 3H, J= 7.2), 4.11 (q, 2H, J=7.2), 7.35-7.60 (m, 6H), 8.76 (dd, 1H, J=8.0, 1.9), 8.93 (dd, 1H, J=4.5, 1.8); 13C NMR (75 MHz, CDCl3) δ161.54, 154.13, 151.62, 137.15, 136.60, 134.29, 134.16, 129.96, 129.53, 128.24, 127.70, 121.95, 119.63, 108.46, 44.62, 14.67; IR (KBr) vmax 3439, 1647, 1622, 1591, 1564, 1552, 1483, 1458, 1439, 1417, 1375, 1298, 1176, 1167, 1099, 794, 729, 711, 696, 603 cm-1 ; mass spectrum (EI), m/e 284. Anal. (C16H13ClN2O .1/8 H2O) Calcd.: C, 66.96; H, 4.57; N, 9.76. Found: C, 66.82; H, 4.55; N, 9.61.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([CH2:7]Cl)[N:3]=1.[NH2:9][CH2:10][CH2:11][SH:12]>>[NH2:9][CH2:10][CH2:11][S:12][CH2:7][C:4]1[N:3]=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: NCCS
Product: NCCSCc1nsc(Cl)n1

Procedure:
Reacting 5-chloro-3-chloromethyl-1,2,4-thiadiazole with cysteamine by the procedure of Example 1(i)(c) gives 3-[(2-aminoethyl)thiomethyl]-5-chloro-1,2,4-thiadiazole.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O>[C:16]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:5][C:6](=[O:15])[CH2:7][CH2:8]2)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)c3ccccc3)ccc2N1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a stirred amount of 45.3 parts of aluminiumtrichloride were added drop wise 6.9 parts of N,N-dimethylformamide. After stirring for 5 min. at 70° C., there were added portionwise 5 parts of 3,4-dihydroquinolin-2(1H)-one and, after another 5 min., 4.7 parts of benzoylchloride. Stirring at 70° C. was continued for 2 hours and then the reaction mixture was carefully poured into ice-water. There were added 50 ml of HCl 12N and the whole was stirred for 15 min. The precipitate was filtered off and boiled in 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 6.3 parts (73.8%) of 6-benzoyl-3,4-dihydro-2(1H)-quinolinone; mp. 211.0° C. (interm. 18).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[C:13]([C:17]3[N:18]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[N:19]=[C:20]4[C:25]=3[CH:24]=[CH:23][CH:22]=[C:21]4[C:26]([F:29])([F:28])[F:27])[CH:14]=[CH:15][CH:16]=1)=[CH:5]2.[H-].[Na+].I[CH3:43]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:43])[C:6]([C:11]1[CH:12]=[C:13]([C:17]3[N:18]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[N:19]=[C:20]4[C:25]=3[CH:24]=[CH:23][CH:22]=[C:21]4[C:26]([F:27])([F:28])[F:29])[CH:14]=[CH:15][CH:16]=1)=[CH:5]2
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2cccc(-c3cc4cc(F)ccc4[nH]3)c2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)cc2cc(F)ccc21
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
A solution of 3-[3-(5-fluoro-1H-indol-2-yl)phenyl]-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (0.03 g, 0.056 mmol) in 2 mL THF was treated with sodium hydride (0.004 g, 0.1 mmol, 60% in oil). The reaction mixture was stirred for 20 minutes and treated with iodomethane (0.007 mL, 0.1 mmol). Stirring was continued for 1 hour. The reaction mixture was concentrated and purified by normal phase HPLC (silica, hexane-EtOAC, 19:1) to give 0.01 g of product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[C:22]([O:27][CH3:28])(=[O:26])[C:23]([CH3:25])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:22]([O:27][CH3:28])=[O:26])[CH3:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: COC(=O)C(C)=O
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1
Product: COC(=O)C(C)=NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-bromo-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.