Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[C:5]([OH:7])=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]>>[OH:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:19][C:18]=1[NH:17][C:5](=[O:7])[C:4]1[C:8]([CH3:16])=[C:9]([O:14][CH3:15])[C:10]([CH3:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c(C)c(OC)c(C(=O)O)c1C
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Product: COC(=O)Cc1ccc(O)c(NC(=O)c2c(C)c(OC)c(C)c(C)c2OC)c1

Procedure:
2,5-Dimethoxy-3,4,6-trimethylbenzoic acid (m.p. 98°-100° C.) was reacted with methyl 3-amino-4-hydroxyphenylacetate to give methyl 4-hydroxy-3-(2,5-dimethoxy-3,4,6,-trimethylbenzoylamino)phenylacetate [m.p. 159°-160° C., δ 2.14 (3H), 2.20 (3H), 2.32 (3H), 3.48 (2H), 3.65 (6H), 3.70 (3H), 7.02 (3H), 8.30 (1H), 8.87 (1H)] (11.0 g, 28.4 mmol), which was dehydrated with phosphorus oxychloride (13.1 g) to give methyl 2-[6-(2,5-dimethoxy-3,4,6-trimethylphenyl)benzoxazol-6-yl]acetate m.p. 68°-69° C., δ 2.22 (3H), 2.27 (3H), 3.58 (3H), 3.70 (3H), 3.72 (3H), 3.76 (2H), 7.32 (1H), 7.55 (1H), 7.76 (1H)] .
Reaction SMILES: [C:1]([CH:5]1[CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1)([O:3][CH3:4])=[O:2]>CO.[Pd]>[C:1]([CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 4.6 g of benzyl 3-carbomethoxypyrrolidine-1-carboxylate in 150 mL of anhydrous methanol was added 0.92 g of 10% Pd/C. The reaction mixture was placed under an atmosphere of hydrogen and stirred overnight at room temperature. The reaction mixture was then filtered through a Celite® pad, and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel with 2-16% CH3OH/CHCl3 to give 1.40 g (62% yield) of 3-carbomethoxypyrrolidine as a clear oil, 1H NMR (300 MHz, CDCl3) δ1.90-2.10 (m, 2 H); 2.97-3.11 (m, 4H); 3.18-3.29 (m, 2H); 3.44 (s, 3H).
Reaction SMILES: [Na+].C1(S([O-])=O)C=CC=CC=1.BrCCCCCCCCCO.[C:22]1([S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(S(CCCCCCCCC(O)=O)(=O)=O)C=CC=CC=1.Cl.Cl.[CH2:63]([O:70][C:71](=[O:79])[CH2:72][C@@H:73]([NH2:78])[CH2:74][N:75]([CH3:77])[CH3:76])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[CH2:63]([O:70][C:71](=[O:79])[CH2:72][C@@H:73]([NH:78][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][S:28]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:29])=[O:30])[CH2:74][N:75]([CH3:76])[CH3:77])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: O=S(=O)(CCCCCCCCCO)c1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCS(=O)(=O)c1ccccc1
Agent: O=S([O-])c1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCS(=O)(=O)c1ccccc1

Procedure:
The title compound, m/e=427.5 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, benzenesulfinic acid sodium salt was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-benzenesulfonyl-nonan-1-ol, which was oxidized in step 2 to 9-benzenesulfonyl-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-(9-benzenesulfonyl-nonanoylamino)-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:21][C:22]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH:43]=[CH:42][C:23]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[C:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:31]=1)=O)[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>CN(C)C=O.O>[CH2:17]([O:21][C:22]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]([CH3:49])[CH3:50])[CH:43]=[CH:42][C:23]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[C:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:31]=1)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccc(OCC(C)C)c(CCC(=O)O)c1)c1ccc(OCC(C)C)cc1OCC(C)C
Temperature: 25 °C

Procedure:
In 5 ml of N,N-dimethylformamide is suspended 0.85 g of 60% sodium hydride, to which is dropwise added 4.2 ml of ethyl diethylphosphonoacetate at ambient temperature over a period of 10 minutes. After stirring the mixture thus obtained for 30 minutes, 1.00 g of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoic acid is added and stirred at 110° C. for 5 hours. The reaction mixture is cooled to ambient temperature and added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.36 g of 3-{5-[1-(2,4-diisobutoxyphenyl)-3-ethoxy-3-oxo-1-propenyl]-2-isobutoxyphenyl}propanoic acid as a light yellow oily product.
Reaction SMILES: [OH-:1].[Li+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11](CC([O-])=O)=[CH:12][C:13]=2[CH3:15])[CH:8]=[N:7]1)(=O)C.[Cl-].[NH4+]>CO.O1CCCC1>[CH3:15][C:13]1[CH:12]=[C:11]([OH:1])[CH:10]=[C:9]2[C:14]=1[NH:6][N:7]=[CH:8]2
Reactant: [OH-]
Reactant: CC(=O)n1ncc2cc(CC(=O)[O-])cc(C)c21
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 2N-aqueous lithium hydroxide solution (3.7 ml, 7.4 mmol) was added to a solution of (1-acetyl-7-methyl-1H-indazol-5-yl)acetate (850 mg, 3.66 mmol) in methanol-tetrahydrofuran (1:1, 7.4 ml), and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100:3) to obtain 7-methyl-1H-indazol-5-ol (505 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:6][C:4]2=[O:5]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1nc2ccc(Cl)cc2c(=O)[nH]1
Yield: 58 %

Procedure:
2-Amino-5-chlorobenzamide (2.387 g) and diethyl oxalate were stirred at 175° C. for 6 hr. The mixture was allowed to cool, and the obtained crude crystals were washed with hot ethanol to give the title compound (2.051 g, 58%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:16]=[C:15]([Cl:17])[C:12]([CH:13]=[O:14])=[C:11]([Cl:18])[CH:10]=1)(C(C)(C)C)(C)C.C([Li])(CC)C.CN(C=O)C.Cl>C1COCC1.CO>[Cl:17][C:15]1[CH:16]=[C:9]([OH:8])[CH:10]=[C:11]([Cl:18])[C:12]=1[CH:13]=[O:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)c(C=O)c(Cl)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-(tert-butyldimethylsilanyloxy)-2,6-dichlorobenzaldehyde (15.51 g, 55.9 mmol) in THF (80 mL) at −78° C. was added sec-butyllithium (41.14 mL, 57.6 mmol) dropwise over 25 min and the mixture was allowed to stir at −78° C. for 1.5 h. To the mostly yellow suspension was added DMF (6.47 mL, 83.9 mmol) and the yellow solution was allowed to stir at −78° C. for 5 h. To the reaction mixture was added MeOH (1 mL) and 1N HCl (60 mL) and allowed to warm to ambient temperature for 18 h. The brown solution was brought to pH 4, extracted with EtOAc, washed with water, brine, and dried with Na2SO4. A solid precipitated from the organic layer and was filtered and rinsed with DCM to give 2,6-dichloro-4-hydroxybenzaldehyde as white solid. MS (m/z) 191.0 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 10.24 (s, 1H), 6.93 (s, 2H).
Reaction SMILES: C([O:4][C:5]1[C:43]([Cl:44])=[CH:42][C:8]([C:9]([NH:11][CH:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[N:14]([CH2:23][C:24](=[O:40])[NH:25][CH:26]3[CH2:30][C:29](=[O:31])[O:28][CH:27]3[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:13]2=[O:41])=[O:10])=[CH:7][C:6]=1[Cl:45])C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([O:32][CH:27]1[CH:26]([NH:25][C:24]([CH2:23][N:14]2[C:13](=[O:41])[CH:12]([NH:11][C:9](=[O:10])[C:8]3[CH:42]=[C:43]([Cl:44])[C:5]([OH:4])=[C:6]([Cl:45])[CH:7]=3)[CH2:18][CH2:17][C:16](=[O:19])[N:15]2[CH2:20][CH2:21][CH3:22])=[O:40])[CH2:30][C:29](=[O:31])[O:28]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(CCC)N(CC(=O)NC3CC(=O)OC3OCc3ccccc3)C2=O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Solvent: ClCCl
Product: CCCN1C(=O)CCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 18 %

Procedure:
To a solution of 4-allyloxy-N-{2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-3,7-dioxo-1-propyl-[1,2]diazepan-4-yl}-3,5-dichloro-benzamide (10c, diastereomers) (103 mg, 0.16 mmol) in dichloromethane (15 mL) was added DMBA followed by Pd(PPh3)4 (30 mg, 0.026 mmol), stirred at room temperature for 7 hours. The reaction mixture was washed with water, dried over anhydrous Na2SO4, filtered and purified by flash chromatography using dichloromethane/methanol (99.5/0.5 to 97/3) to afford both anti diastereomer (18 mg, 18% yield, lower Rf) and syn diastereomer (48 mg, 50% yield, higher Rf) of the title compound. 1H-NMR (500 MHz, CDCl3) for the anti diastereomer: δ 0.9-1.02 (m, 3H), 1.65-185 (m, 2H), 2.01-2.18 (m, 0.5H), 2.20-2.30 (d, 0.5H), 2.37-2.47 (m, 1H), 2.58-2.70 (m, 1H), 2.90-3.00 (m, 1H), 3.00-3.10 (m, 1H), 3.25-3.50 (m, 1H), 4.0-4.15 (m, 2H), 4.15-4.25 (d, 1H), 4.40-4.55 (m, 1H), 4.55-4.67 (m, 1H), 4.72-4.82 (d, 1H), 5.05-5.17 (m, 1H), 5.27-5.38 (m, 2H), 6.90-7.00 (d, 1H), 7.25-7.40 (m, 6H), 7.60-7.70 (m, 1H), 7.80 (s, 2H; for the syn diastereomer: δ 0.9-1.00 (m, 3H), 1.50-1.70 (m, 2H), 1.8-1.92 (m, 1H), 2.38-2.42 (m, 1H), 2.48-2.58 (m, 1H), 2.74-2.87 (m, 1H), 2.88-2.98 (m, 1H), 3.00-3.13 (m, 1H), 3.17-3.30 (m, 1H), 4.00-4.12 (m, 1H), 4.14-4.30 (d, 1H), 4.22-4.32 (m, 1H), 4.62-4.46 (d, 1H), 4.75-4.80 (m, 1H), 4.90-4.95 (d, 1H), 5.10-5.20 (m, 1H), 5.53-5.57 (d, 1H), 6.24 (s, 1H), 6.49 (d, 1H), 6.70 (d, 1H), 7.25-7.40 (m, 5H), 7.71 (s, 2H). Analytical HPLC: 8.55 min for syn diastereomer and 8.57 min for the anti diastereomer. LC-MS (ES+) for the mixture of the product: m/e=621, 623 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH3:18][NH:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:19]([CH3:20])[CH3:18])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CNC
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN(C)C)CCCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 300 mg, 1.15 mmol) and dimethylamine (7.9 M in water, 1.45 ml, 11.5 mmol) in DCM (7 ml) was added sodium triacetoxyborohydride (486 mg, 2.29 mmol). The reaction mixture was stirred at room temperature overnight. Then, dimethylamine (7.9 M in water, 1.45 ml, 11.5 mmol) was added followed by sodium triacetoxyborohydride (486 mg, 2.29 mmol) and the reaction mixture was stirred room temperature for 8 h, then dimethylamine (7.9 M in water, 1.45 ml, 11.5 mmol) was added followed by sodium triacetoxyborohydride (486 mg, 2.293 mmol) and the reaction mixture was stirred room temperature overnight. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (3×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, DCM/(DCM/(7 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.37 min; ESI-MS 266.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:33]1[CH:32]=[CH:31][C:30]([C@@H:28]([CH3:29])[CH2:27][N:19]([CH3:18])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:35][CH:34]=1
Reactant: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Yield: 34.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (700 mg, 2.3 mmol) was reacted with (R)-tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate (1.3 g, 3.4 mmol) to afford the desired product (383 mg, 38%) as a yellow solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19]O)[N:10]=1.S(Cl)([Cl:34])=O>O1CCCC1>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][Cl:34])[N:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Solvent: C1CCOC1
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CCl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (600 mg, 1.29 mmol) in tetrahydrofuran (9.0 mL, 0.14 M) cooled to 0° C. was treated with thionyl chloride (0.28 mL, 3.84 mmol). The reaction mixture was allowed to slowly warm to 25° C. The reaction mixture was stirred at 25° C. overnight. At this time, the reaction mixture was concentrated in vacuo. The residue was taken up in benzene and was re-concentrated twice to afford 2-[3,5-dichloro-4-(1-chloromethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile as a yellow solid. The material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](=[O:22])[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)([OH:22])[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc([Mg]Br)cc1C
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1C
Temperature: -25 °C
Reaction time: 3 h

Procedure:
A solution of 3,4-dimethylphenyl magnesium bromide in tetrahydrofuran (0.5 M, 3.3 mL, 1.65 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.2 g, 1.1 mmol) in tetrahydrofuran (5 mL) with cooling in a −25° C. bath. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 3 hours, 15% aqueous ammonium chloride solution was added and mixture extracted with ethyl acetate. The combined organic layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(3,4-dimethyl-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as a yellow solid. This was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.NN>C(O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cn1
Agent: NN
Solvent: CCO
Product: Cc1ccc(CCCCN)cn1
Yield: 116.8 %

Procedure:
A mixture of 2-4 (7.2 g, 24.5 mmol), hydrazine (3.8 mL), and ethanol (500 mL) was heated at reflux for 4 hours. The resulting mixture was cooled and filtered, and the filtrate concentrated to give 2-5 as a yellow solid (4.7 g) contaminated with some phthalhydrazide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH3:29])=[C:12]([NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].Cl[C:31]1[N:36]=[N:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:31]4[N:36]=[N:35][C:34]([N:37]5[CH2:38][CH2:39][O:40][CH2:41][CH2:42]5)=[CH:33][CH:32]=4)[CH:3]=3)[C:11]=2[CH3:29])=[O:28])=[CH:23][CH:22]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: Clc1ccc(N2CCOCC2)nn1
Reactant: COc1ncc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cc1Nc1ccc(N2CCOCC2)nn1
Temperature: 95 °C
Yield: 21.7 %

Procedure:
A 48-mL seal tube equipped with a magnetic stirring bar was charged with N-(3-(5-amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4-tert-butylbenzamide (6) (0.39 g, 1.0 mmol), 4-(6-chloropyridazin-3-yl)morpholine (0.30 g, 1.5 mmol), Pd2(dba)3 (0.083 g, 0.10 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.075 g, 0.13 mmol), and Cs2CO3 (0.65 g, 2.0 mmol) in dioxane (15 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-33%, MeOH in dichloromethane, to afford 0.12 g (22%) of 4-tert-butyl-N-(3-(6-methoxy-5-(6-morpholinopyridazin-3-ylamino)pyridin-3-yl)-2-methylphenyl)benzamide (7) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.[C:16](Cl)(=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>C(=O)([O-])[O-].[K+].[K+]>[C:16]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])(=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:24]
Reactant: O=C(Cl)CCCCCCC(=O)Cl
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCCCCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a stirred solution of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (6.8 g) in 1M potassium carbonate (45 ml), octanedioyl dichloride (3.2 g) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 1 hour at the same temperature and for additional 1 hour at room temperature. The solution was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residual oil was purified by silica gel column chromatography to give 7.6 g (86%) of the titled compound: mp 93°-97° C. (dec.); [α]D27 +123.6° (c=0.5, methanol). IR (nujol, cm-1): 1720 (COOH), 1620 (CON), 1600 (aromatic), 1230, 1090, 855, 765. NMR (CD3OD) δ: 0.7-1.7 (8H, m, --CH2 --CH2)4CH2 --), 1.8-2.4 (4H, m, --CH2 --CH2)4CH2), 3.25 (4H, d, J=7.5 Hz, C5 --H), 4.81 (2H, t, J=7.5 Hz, C4 --H), 6.35 (2H, s, C2 --H), 6.7-8.0 (8H, m, arom. H). TLC: Rf value* 0.34.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1([CH2:29][OH:30])[CH2:18][CH2:17][N:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)=[O:20])[CH2:15][CH2:14]1>N1C=CC=CC=1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[C:19]([N:16]1[CH2:17][CH2:18][C:13]([CH2:29][O:30][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])([F:12])[CH2:14][CH2:15]1)=[O:20]
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)c3ccc(F)c(Cl)c3)CC2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
4.87 g of para-toluenesulfonyl chloride (25.5 mmol) are slowly added to a solution of 6.70 g of (4-fluoro-4-hydroxymethylpiperidin-1-yl)-(3-chloro-4-fluorophenyl)methanone (23.12 mmol) in 40 ml of pyridine cooled to 0° C. and maintained under a nitrogen atmosphere. The mixture is stirred for 12 hours at room temperature and then it is poured into ice-cold water, extracted with chloroform and then the organic phase is washed with a 1N aqueous solution of hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and then concentrated under vacuum. The title product is purified by recrystallization from a dichloromethane/diisopropyl ether mixture. 7.73 g of a white crystalline powder are obtained.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])[CH2:24][C:23]2=[O:39]>>[N+:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:25]1[CH2:24][CH:23]([OH:39])[C:22]2[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=2)[O:26]1)([O-:38])=[O:37]
Reactant: O=C1CC(c2ccccc2[N+](=O)[O-])Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: O=[N+]([O-])c1ccccc1C1CC(O)c2cc(O)ccc2O1

Procedure:
2-(2-Nitrophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(2-nitrophenyl)-chroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.99-8.02 (m, 1H), 7.77-7.86 (m, 2H), 7.59-7.64 (m, 1H), 6.89 (d, 1H, J 2.4 Hz), 6.56-6.57 (m, 2H), 5.51-5.55 (m, 2H), 4.85-4.92 (m, 1H), 2.42-2.47 (m, 1H), 1.85-1.96 (m, 1H).