Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[N:2]1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1

Procedure:
prepared by reaction of 1H-indazol-6-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][N:27]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccc(Cl)cc5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccc(Cl)cc5)n4)n[nH]c3n2)CC1

Procedure:
To a solution of (4-{3-[2-(4-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (19 mg, 0.034 mmol) in methanol (30 mL) was bubbled in HCl (gas) for 3 hours at room temperature. The mixture was then concentrated by evaporation to afford N-{3-[2-(4-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 15 mg, 78.9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15]Br)[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CCN(C)C(C)=O)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CCN(C)C(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
16.0 g (45.8 mmol) of 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 50.3 ml (183.3 mmol) of triisopropyl phosphite (90%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2). 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32](=O)[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:32](=[O:31])[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4nnc[nH]4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 27 %

Procedure:
Prepared using the same procedure described in Example 275 from 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 5 days to afford the title compound as a colorless solid (72 mg, 27%). LC/MS (Method B) 3.52 min, [M+1]+ 484.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>CCO>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:13]
Reactant: NCc1ccco1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccco1
Temperature: 25 °C

Procedure:
Furfurylamine (5.70 mL, 61.8 mmol) and phthalic anhydride (10.0 g, 90.9 mmol) were heated to 120° C. for approximately 45 min. The reaction mixture was cooled to rt and then suspended in EtOH. The resulting suspension was filtered to afford the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 7.88 (dd, 2H, J=3.2, 5.3 Hz), 7.73 (dd, 2H, J=3.0, 5.5 Hz), 6.38 (d, 1H, J=3.2 Hz), 6.32 (m, 1H), 4.88 (s, 2H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:15][CH2:14][CH2:13]C(O[Si](C)(C)C)(C#N)[C:11]=2[CH:23]=1.[C:24]([OH:27])(=[O:26])[CH3:25]>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:15][CH2:14][CH2:13][CH:25]([C:24]([OH:27])=[O:26])[C:11]=2[CH:23]=1
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCSc2ccc(Cl)cc21
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1CCSc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
A mixture of tin(II) chloride dihydrate (115.42 g, 0.51 mol) and 6-chloro-3,4-dihydro-4-(trimethylsiloxy)-2H-1-benzothiopyran-4-carbonitrile (37.53 g, 0.126 mol) in 1:1 acetic acid/concentrated hydrochloric acid is heated at reflux under nitrogen for 3 days, cooled to room temperature and diluted with chloroform. The aqueous phase is separated and extracted with chloroform. The organic phase and organic extracts are combined and extracted with 2N sodium hydroxide solution. The combined aqueous extracts are washed with chloroform and acidified to pH 3. The acidic aqueous mixture is extracted with chloroform and the combined organic extracts are dried and concentrated in vacuo to obtain a residue. The residue is triturated with an ether/petroleum ether mixture and filtered to give the title product as an off-white solid (12.56 g, mp 139°-150° C.).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:12](=[O:13])[CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cccc(N)c1C
Product: Cc1cccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1C
Yield: 12.6 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.2 g) and 2,3-dimethylaniline (0.11 g) to give the title compound as a white solid (0.034 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:14](=O)[CH3:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH3:14][CH:15]=[N:8][CH:7]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC=NC(CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of leucine tert-butyl ester (2.0 g, 8.9 mmol) and acetaldehyde (999 ul, 17.9 mmol) was stirred at room temperature for 5 minutes. Anhydrous sodium sulphate was added and the mixture stirred at room temperature for 18 hours. The solid was removed by filtration and the solvent evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][CH2:27][O:26][CH3:25])[CH3:31])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCCCOC
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.84 (m, 2 H) 2.36 (s, 3 H) 2.91 (s, 3 H) 3.04 (br. s., 1 H) 3.14-3.21 (m, 3 H) 7.59 (dd, J=8.1, 1.5 Hz, 1 H) 7.65 (s, 1 H) 7.72 (d, J=8.1 Hz, 1 H) 7.95-8.04 (m, 1 H) 8.05-8.09 (m, 1 H) 8.30 (d, J=8.3 Hz, 1 H) 8.46 (d, J=9.9 Hz, 1 H). MS m/z [M+H]+ 406.4.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[CH3:14][C:15]([O-:17])=[O:16].[Na+].O>CC(CC)=O>[C:15]([O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4])(=[O:16])[CH3:14]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)OCC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 48 h
Yield: 87.5 %

Procedure:
2-Bromo-1-(3-nitrophenyl)ethanone (25 g) was dissolved in methylethyl ketone (150 mL). NaOAc (12.5 g) was added and the mixture stirred for 48 hours. Water (100 mL) was added and the reaction mixture extracted with DCM. The DCM layer was dried over Na2SO4 and concentrated to give the title compound (20 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.N1C=CC=CC=1.[CH3:39][C:40](OC1C(=O)OC(=O)C1OC(C)=O)=[O:41]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:40]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:41])[CH3:39]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CC(=O)OC1C(=O)OC(=O)C1OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.6 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydro-3-isoxazolyl]-3-pyridinyl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 200 mg, 0.46 mmol) was suspended in 2 mL of anhydrous dimethylformamide. Anhydrous pyridine (2 mL, 24 mmol), 4-dimethylaminopyridine (DMAP) (20 mg, 0.17 mmol) and di-O-acetyl-L-tartaric anhydride (210 mg, 0.97 mmol) were added and the solution was stirred for 16 hours at room temperature during which the mixture turned black. The reaction was quenched with 1 mL of methanol, the solvents evaporated in vacuo and the product isolated by flash chromatography on silica using a gradient from 0 to 5% methanol in dichloromethane to yield 50 mg (25%) of the title compound as an off white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)[CH:10]=2)=[O:6].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH2:16][C:17]1[NH:21][CH:20]=[CH:19][N:18]=1)[CH:10]=2)=[O:6]
Reactant: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.17 g. of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester (0.90 g.) in dry N,N-dimethylformamide (50 ml.) and the mixture was stirred at room temperature for 1 hour. Benzyl bromide (0.61 g.) was added and the resulting mixture was stirred for 2 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 1-benzyl-6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester, m.p. 120°-122° C.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH3:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][O:48]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH3:52])[CH2:46][C@@H:47]2[CH2:51][CH2:50][CH2:49][O:48]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 42.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N—[(S)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH3:31]
Reactant: CCOC(=O)CNC(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 2-(tert-butylamino)acetate (CAN 37885-76-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=426.5 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC#N.O>[CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([Cl:20])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(CCc1ccc(O)c(Cl)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-hydroxy-phenyl)-propionic acid benzyl ester (13.36 g, 52.1 mmol) in MeCN (100 ml) was cooled to 0° C. Trichloroisocyanuric acid (4.00 g, 17.2 mmol) was added, and the resulting white suspension was gradually allowed to warm to RT and stirred overnight. The reaction mixture was diluted with water (200 ml) and the product was extracted into EtOAc (250 ml) and dried (MgSO4). Purification by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (1H, s), 7.32 (3H, m), 7.29 (2H, d), 7.18 (1H, d), 6.97 (1H, dd), 6.85 (1H, d), 5.07 (2H, s), 2.76 (2H, t), 2.64 (2H, t). LC-MS Rt 1.46 mins; 313.2 [M+H]+, Method 2minLC_v002.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[CH2:22]([NH:25][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[C:7]3[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=3[O:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:10][CH:11]=1)=[O:17])[CH2:23][CH3:24]
Reactant: CCCN
Reactant: O=C=Nc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1
Product: CCCNC(=O)Nc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1

Procedure:
Using the method of Example 25, 4-(2-nitro-3-benzofuranyl)phenyl isocyanate is reacted with n-propylamine to provide 1-(1-propyl)-3-[4-(2-nitro-3-benzofuranyl)phenyl]urea having the structure ##STR23##
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([C:6]1[C:10]([C:11](OCC)=[O:12])=[CH:9][N:8]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[N:7]=1)=O.[CH3:28][NH:29][NH2:30]>C(O)C>[CH3:28][N:29]1[C:11](=[O:12])[C:10]2=[CH:9][N:8]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[N:7]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:27])[CH3:1])=[N:30]1
Reactant: CNN
Reactant: CCOC(=O)c1cn(Cc2cccc3ccccc23)nc1C(=O)CC(C)C
Solvent: CCO
Product: CC(C)Cc1nn(C)c(=O)c2cn(Cc3cccc4ccccc34)nc12

Procedure:
Ethyl 3-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrazole-4-carboxylate (1.8 g) and methylhydrazine (0.6 ml) in ethanol (20 ml) were heated underreflux for 16 hours. The solution was cooled and evaporated to a solid, which was purified by chromatography on silica (ethyl acetate:isohexane 2:3) followed by crystallisation from ethyl acetate/cyclohexane to give 2,5-dihydro-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-4H-pyrazolo[3,4-d]pyridazin-4-one (0.43 g).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=1)=[C:9]([C:30]1[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][C:31]=1[CH3:38])[CH:8]=[CH:7]2.B(Br)(Br)Br>ClCCl>[CH3:38][C:31]1[CH:32]=[C:33]([S:36][CH3:37])[CH:34]=[CH:35][C:30]=1[C:9]1[C:10]([O:14][C:15]2[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([OH:3])[CH:13]=[CH:12]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(SC)cc3C)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CSc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c(C)c1
Temperature: 5 °C
Yield: 99.9 %

Procedure:
Dissolve 1-(2-{4-[6-methoxy-2-(2-methyl-4-methylsulfanyl-phenyl)-naphthalen 1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (331 mg, 0.603 mmol) in dichloromethane (15 mL) and cool to 5° C. Add BBr3 (285 μL, 3.02 mmol) to the light suspension over 5 minutes. Quench the reaction after 1 hour with saturated aqueous NaHCO3 (15 mL). Separate the layers and extract the aqueous layer with dichloromethane (2×10 mL). Pour the solution onto a SiO2 plug (20 g) and elute with methanol in dichloromethane (5 to 15%). Concentrate the fractions in vacuo to give 301 mg of the title compound (100%): mass spectrum (ion spray) m/z=500.3 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4ccc(-c5ccc(S(C)(=O)=O)cc5)cn4n3)cc2)CC1

Procedure:
[6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 6-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (54.0 mg, 0.212 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.009 g, 10%). MP=260-264° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.68-8.67 (m, 1H), 8.09-8.04 (m, 2H), 7.79-7.74 (m, 2H), 7.68 (dd, J=9.1, 1.8 Hz, 1H), 7.55 (d, J=9.3 Hz, 1H), 7.51-7.46 (m, 2H), 7.00-6.95 (m, 2H), 6.64 (s, 1H), 3.20-3.15 (m, 4H), 3.11 (s, 3H), 2.62-2.58 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:12]([O:26]CC3C=CC(OC)=CC=3)=[N:11]2)=[CH:5][CH:4]=1.O1CCOCC1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:12](=[O:26])[NH:11]2)=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)/C=C/c1cc(=O)n(Cc2ccc(OC)cc2)nc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCOC(=O)CCc1cc(=O)n(Cc2ccc(OC)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A solution of butyl (2E)-3-[1-{[4-(methyloxy)phenyl]methyl}-3-({[4-(methyloxy)phenyl]methyl}oxy)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-propenoate (580 mg) in ethanol (15 ml)/1,4-dioxane (5 ml) was treated with 10% Pd/C (400 mg) and stirred under hydrogen at atmospheric pressure and room temperature for 2 hours. The catalyst was filtered off using kieselguhr and the filtrate evaporated and redissolved in 1,4-dioxane and the solution evaporated to dryness to give the product (0.43 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:39](=[O:40])[C:33]2[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=2)[C:42]1=[O:41]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCS(=O)(=O)c1ccc(-c2ccc3oc(-c4ccc(OC)c(N)c4)nc3c2)cc1
Product: CCS(=O)(=O)c1ccc(-c2ccc3oc(-c4ccc(OC)c(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)nc3c2)cc1

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(4-ethylsulfonylphenyl)benzoxazole (63 mg, 0.15 mmol) and 1,2,4-benzenetricarboxylic anhydride (29 mg, 0.15 mmol) the title compound was obtained (34 mg, 39%). 1H NMR (DMSO) δ 8.57(dd, 1H), 8.57(m, 4H), 8.30(d, 1H) 8.10(m, 4H), 8.03(d, 1H), 7.92(dd, 1H), 7.61(d, 1H), 4.00(s, 3H), 3.45(q, 2H), 1.25(t, 3H). MS 583 m/z (M+H)+.