Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[O:18][CH2:17][CH2:16][CH:15]3[NH2:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31]([NH:34][CH:35]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:36][C:37](O)=[O:38])(=[O:33])=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31]([NH:34][CH:35]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:36][C:37]([NH:20][CH:15]1[C:14]2[C:19](=[C:10]([CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH:11]=[CH:12][CH:13]=2)[O:18][CH2:17][CH2:16]1)=[O:38])(=[O:33])=[O:32]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: NC1CCOc2c(CN3CCCCC3)cccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCOc2c(CN3CCCCC3)cccc21
Reaction time: 8 h

Procedure:
8-Piperidin-1-ylmethylchroman-4-ylamine dihydrochloride (Step E) (28 mg, 0.11 mmol), 3-(naphthalen-2-yl-sulfonylamino)-3-phenylpropionic acid (40 mg, 0.11 mmol), HOBt (17 mg, 0.12 mmol), and DIEA (21 mg, 0.16 mmol) were dissolved in CH2Cl2 (5 mL). EDC (25 mg, 0.13 mmol) was added and the reaction was kept at 22-25° C. overnight until completed. The reaction solution was washed with dilute (˜5%) NaHCO3—H2O and H2O, then dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (silica gel, 0.5% Et3N in EtOAc). The compound was converted to the HCl salt in Et2O to provide the title compound as a mixture of diastereomers, as a white solid (ca. 1:1 by 1H NMR). MS (ESI) 584 (M+H)+.
Reaction SMILES: CC1C=C(C2(CC(O)=O)C(=O)NC(=O)N2)C=CC=1.COC1C=C(C2(CC(O)=O)C(=O)NC(=O)N2)C=CC=1.C[C:39]1[CH:48]=[C:47]2[C:42]([CH2:43][C:44](=[O:55])[CH2:45][C:46]32[C:52](=[O:53])[NH:51][C:50](=[O:54])[NH:49]3)=[CH:41][CH:40]=1.COC1C=C2C(CC(=O)CC32C(=O)NC(=O)N3)=CC=1>>[C:46]12([C:52](=[O:53])[NH:51][C:50](=[O:54])[NH:49]1)[C:47]1[C:42](=[CH:41][CH:40]=[CH:39][CH:48]=1)[CH2:43][C:44](=[O:55])[CH2:45]2
Reactant: Cc1ccc2c(c1)C1(CC(=O)C2)NC(=O)NC1=O
Agent: COc1ccc2c(c1)C1(CC(=O)C2)NC(=O)NC1=O
Agent: COc1cccc(C2(CC(=O)O)NC(=O)NC2=O)c1
Agent: Cc1cccc(C2(CC(=O)O)NC(=O)NC2=O)c1
Product: O=C1Cc2ccccc2C2(C1)NC(=O)NC2=O

Procedure:
Starting with 4-(m-methylphenyl)-4-(carboxymethyl)imidazolidine 2,5-dione and 4-(m-methoxyphenyl)-4-(carboxymethyl) imidazolidine 2,5-dione and following the procedures of Example 2H-2E, 3',4'-dihydro-7'-methylspiro[imidazolidine-4,1'(2'H)-naphthalene]2,3',5-trione and 3',4'-dihydro-7'-methoxyspiro[imidazolidine-4,1'(2'H)-naphthalene]2,3',5-trione are prepared, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[CH3:32].[OH-].[NH4+:34]>CO>[NH2:34][CH2:13][CH:12]([OH:25])[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH3:32])=[CH:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1
Agent: [OH-]
Solvent: CO
Product: Cc1cn(C(c2ccccc2)C(O)CN)c2ccc(F)cc12
Reaction time: 12 h

Procedure:
To a solution of (2S,3S)-toluene-4 sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (Intermediate in EXAMPLE 117, step 6, 0.15 g, 0.33 mmol) in methanol (10 mL) was added concentrated ammonium hydroxide (20 mL), and the reaction was stirred for 12 hours. Upon completion, the reaction was partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 25% MeOH/dichloromethane) to give (1SR,2RS)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 4N solution of hydrochloric acid in dioxane and stirred for 1 hour s. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1SR,2RS)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ES) m/z 299.0
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][C:19](=[O:29])[NH:20][C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][CH:26]=1)([CH3:17])([CH3:16])[CH3:15].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[C:27]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:29])=[N:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNCc1ncccc1NC(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of (4-Aminobutyl)-carbamic acid tert-butyl ester and (2-formylpyridin-3-yl)carbamic acid tert-butyl ester in MeOH with NaBH4 gave {2-[(4-tert-butoxycarbonylamino-butylamino)-methyl]-pyridin-3-yl}-carbamic acid tert-butyl ester as a clear residue. 1H NMR (CDCl3): δ 1.44 (s, 9H), 1.53 (s, 9H), 1.55 (m, 4H), 2.67 (m, 2H), 3.13 (m, 2H), 4.07 (s, 2H), 4.53 (m, 1H), 7.15 (dd, 1H, J=6.3 Hz), 8.11 (dd, 1H, J=6.3 Hz), 8.33 (d, 1H, J=9 Hz), 10.09 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:18])[CH2:16][OH:17]>CN(C)C=O>[OH:17][CH2:16][CH2:15][NH:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO

Procedure:
112.8 g (0.5 mol) of 4-chloro-3-nitrobenzotrifluoride and 61.1 g (1 mol) of 2-ethanolamine were heated in 50 ml of dimethylformamide at 100° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and water was added to the residue. The precipitate was filtered off with suction and recrystallized from cyclohexane.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)NCc2ccc(Cl)cc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 4-chlorobenzylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H) 315 and 317.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:12][CH2:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH2:5]1.C(N(CC)CC)C.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.C(Cl)Cl.C(O)C>[C:20]1([NH:26][C:27]([NH:3][CH:4]2[CH2:12][CH2:11][C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH2:5]2)=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1CCc2[nH]cnc2C1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: S=C(Nc1ccccc1)NC1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
A mixture of 5-amino-4,5,6,7-tetrahydro-1H-benzimidazole, dihydrochloride (210 mg, 1.0 mmol), ethanol (1 ml), triethylamine (0.276 ml, 2.0 mmol) and phenylisothiocyanate (270 mg, 2.0 mmol) was stirred for 3 hours at ambient temperature. 1 N hydrochloric acid (20 ml), DCM (50 ml) and H2O (20 ml) were added. The phases were separated and the aqueous phase was washed with DCM (3×25 ml) and then made alkaline with 4 N sodium hydroxide. The alkaline mixture was extracted with DCM (2×20 ml) and the combined organic extracts were dried (magnesium sulphate). The solvent was evaporated in vacuo to give 140 mg (52%) of the title compound.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2][CH:3]([CH3:5])C.OC1C=CC2C(=CC=CC=2)C=1C=O.BrCC1C=C[C:37]([C:38]#[N:39])=[CH:36][CH:35]=1>>[CH:17]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:1][C:2]1[CH:3]=[CH:5][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)=[O:18]
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=Cc1c(O)ccc2ccccc12
Product: N#Cc1ccc(COc2ccc3ccccc3c2C=O)cc1

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 4-(bromomethyl)benzonitrile.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10][N:9]=N[C:7]=2[O:6][CH2:5]1.O1C2=CN=CC=C2C(=O)[CH2:14]1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:14][N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: O=C1COc2cnccc21
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2cnccc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), furo[2,3-c]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as brown solid;
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 77.3 %

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)-5-nitroindole (4 g), 2N aqueous sodium hydroxide solution (100 ml) and ethanol (100 ml) was refluxed for 7 hours. The reaction mixture was cooled and the resulting precipitate was collected by filtration. This solid was recrystallized from ethanol-water to give 3-(4-piperidyl)-5-nitroindole (2.64 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:12]([CH2:16][CH2:17]O)[CH2:13][CH2:14]O>>[F:8][C:6]1[CH:5]=[C:4]([B:9]2[O:10][CH2:17][CH2:16][NH:12][CH2:13][CH2:14][O:11]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OCCNCCO
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Fc1cc(F)cc(B2OCCNCCO2)c1
Yield: 93 %

Procedure:
The title compound (93%, crystals) was prepared from 3,5-difluorophenylboronic acid and diethanolamin.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.Cl[Cu]>[O:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: Oc1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: O=C1OCc2cc(Oc3ccccc3)ccc21
Temperature: 130 °C
Yield: 88.9 %

Procedure:
A mixture of 5-bromo-3H-isobenzofuran-1-one (75.9 g, 0.36 mol) (Sigma-Aldrich), phenol (67.1 g, 0.713 mol), CuCl (17.6 g, 0.178 mol), 2,2,6,6-tetramethyl-heptane-3,5-dione (TMHD, 7.33 mL) and cesium carbonate (232.3 g, 0.713 mol) in NMP (200 mL) was heated at 130° C. for 64 h. After cooled, reaction mixture was poured into ice/2M HCl mixture (1 L). The mixture was then refluxed for 1 h. After cooled, the solid was collected, rinsed with water and dried in vacuo to provide the title compound (72.22 g, 0.32 mol). 1H NMR in DMSO-d6, δ in ppm: 7.82 (dd, 1H, J=1.6 Hz, 7.6 Hz), 7.51-7.40 (m, 2H), 7.3-7.1 (m, 5H), 5.31 (s, 2H).
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[N:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([NH2:11])=[N:8][C:9]=1Cl>C(O)C>[Cl:3][C:4]1[N:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([NH2:11])=[N:8][C:9]=1[NH:1][NH2:2]
Reactant: NN
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Solvent: CCO
Product: NNc1nc(N)c([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To 300 ml of ethanol was added 7.4 g (0.22 mole) of a 95% hydrazine solution. This solution was cooled to 10° and with stirring 20.9 g (0.1 mole) of 5,6-dichloro-3-nitropyrazinamine (l) was added portionwise. A dark precipitate formed immediately and the suspension was stirred for 1 hour at room temperature. The mixture was filtered and the resulting solid washed with ethanol, water, ethyl acetate, ethanol and air dried to afford 18.0 g (88%) of the desired hydrazine as a brown solid, m.p. 220°; ms:m/e 205. This solid was treated with acetone to form the isopropylidene derivative, m.p. 245°-246° (dec.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:43]=[C:44]([CH:56]=[CH:57][CH:58]=1)[CH2:45][C:46]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([NH:41][C:42]2[CH:43]=[C:44]([CH:56]=[CH:57][CH:58]=2)[CH2:45][C:46]2([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[CH2:48][CH2:47]2)=[O:15])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(C(=O)O)C2CCCC2)cc1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1ccc(C(C(=O)Nc2cccc(CC3(C(=O)OC(C)(C)C)CC3)c2)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
9.50 g (34.4 mmol) of (+/−)-[4-(acetoxymethyl)phenyl](cyclopentyl)acetic acid were dissolved in 67.5 ml of DMF, and 5.58 g (41.25 mmol) of 1-hydroxy-1H-benzotriazole hydrate (HOBt) were added. The mixture was cooled to 0° C., and 15.0 ml (85.95 mmol) of N,N-diisopropylethylamine and 10.63 g (42.97 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, dissolved in a little DMF, were added. 14.38 g (37.82 mmol) of HATU were then added in several portions, and the reaction mixture was slowly warmed to RT and then stirred overnight. The mixture was then added to saturated aqueous sodium carbonate solution. After phase separation, the aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase dichloromethane/ethyl acetate 50:1→20:1). This gave 12.86 g of the target compound (69.4% of theory).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+].O>COCCOC.O>[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:31][CH:30]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N(C)C)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 47.7 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (53.3 mg, 0.32 mmol) in DME/water (3 mL:1 mL). PdCl2 (dppf)-CH2Cl2 adduct (8.7 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and the insoluble green mixture was irradiated (microwave) at 150° C. for 20 min. After cooling, 2 mL of water was added to the dark green mixture and solids that precipitated were filtered. EtOAc was added, the mixture was heated and some hexanes were added. Solids were filtered, dissolved in DCM/MeOH (1:1), and filtered through a pad of silica gel and the filtrate was evaporated. The residue was dissolved in DCM and purified by SiO2 chromatography (eluent: gradient of 0 to 90:10 DCM/MeOH) to afford a residual oil that was triturated with EtOH/EtOAc (1:1). The resultant solid was filtered and dried to afford the title compound (46 mg, 45%) as a yellow solid. LCMS E-S (M+H)=460.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1H), 9.02 (d, J=2.27 Hz, 1H), 8.87 (t, J=4.67 Hz, 1H), 8.36 (dd, J=8.84, 2.53 Hz, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 6.79 (d, J=8.84 Hz, 1H), 5.91 (s, 1H), 5.25-5.34 (m, 1H), 4.40 (d, J=4.80 Hz, 2H), 3.12 (s, 6H), 2.23 (s, 3H), 2.13 (s, 3H), 1.53 (d, J=6.57 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1.[CH3:26][O-:27].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:27][CH3:26])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1
Reactant: C[O-]
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3cccc(CO)c3)c2n1
Agent: [Na+]
Solvent: CO
Product: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(CO)c3)c2n1
Temperature: 70 °C
Yield: 76.6 %

Procedure:
To a solution of Compound (6) (1.53 g, 3.74 mmol) in methanol (40 mL) was slowly added sodium methoxide (4.04 g, 74.85 mmol). The reaction mixture was heated to 70° C. for 5 hours, at which time Dowex (H+) resin was added to quench any remaining methoxide. The resin was filtered off and the solvent was evaporated. Salts were removed by partition between water and dichloromethane, and the combined organic layers were dried over magnesium sulfate and evaporated to dryness giving 1.03 g (76%) of Compound (7) as a white solid, which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.39 (s, 3H), 3.73 (t, J=4.8, 9.6 Hz, 2H), 4.12 (s, 3H), 4.45 (t, J=4.5, 9.3 Hz, 2H), 4.56 (s, 2H), 5.12 (s, 2H), 7.28 (m, 4H). LCMS: m/z for C17H21N5O4++H observed 360.1 at 1.87 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH3:17])[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8][C:7]1=[O:16]>CO>[CH3:3][CH:4]([CH3:17])[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]1=[O:16]
Reactant: COC(=O)c1ccn(CC(C)C)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cn1ccc(C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A 2M aqueous solution of sodium hydroxide (5.38 ml, 10.75 mmol) was added to a solution of methyl 1-(2-methylpropyl)-2-oxo-1,2-dihydro-4-pyridinecarboxylate (D27; 0.45 g, 2.151 mmol) in methanol (10 ml). The mixture was stirred at room temperature for 2 hrs and then the solvent was removed under vacuum. The residue was taken up with water, neutralised with 2M HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulphate and concentrated under vacuum to give the title compound as a white solid (400 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[C:17](=[O:33])[N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
3,4-Dimethylphenyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with acetone (20 mL) to give 1-(3,4-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 82%) as a white solid: mp 222-224° C.; 1H NMR (DMSO-d6) δ 2.05-2.08 (m, 1H), 2.12 (s, 3H), 2.14 (s, 3H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.70 (d, J=5.8 Hz, 2H), 5.13-5.20 (dd, J=5.3 and 12.6 Hz, 1H), 6.69 (t, J=5.9 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.17 (s, 1H), 7.75-7.88 (m, 3H), 8.57 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 18.60, 19.61, 21.99, 30.94, 38.72, 48.86, 115.33, 119.13, 121.84, 127.18, 128.75, 129.51, 131.60, 133.68, 134.71, 136.11, 137.96, 140.40, 155.29, 167.03, 167.61, 169.84, 172.78; Anal. calcd. for C23H22N4O5: C, 63.59; H, 5.10; N, 12.90. Found: C, 63.21; H, 5.09; N, 12.74.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[OH:13])[CH2:2][CH2:3][CH3:4].[CH3:14]O.[OH-].[K+].CI>O>[CH2:1]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCc1c(C)cc(C)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CCCCc1c(C)cc(C)cc1OC
Reaction time: 3 h

Procedure:
83 g. of 2-butyl-3,5-dimethyl-phenol are dissolved in 225 ml. of methanol. After the addition of 60 g. of potassium hydroxide in 25 ml. of water, the solution is treated at room temperature with 34.2 g. of methyl iodide. The mixture is heated to boiling under reflux conditions for 3 hours, then cooled, diluted with water and extracted with ether. The ether extract is washed with diluted sodium hydroxide solution, dried over sodium sulfate and evaporated. There is obtained 2-butyl-3,5-dimethyl-anisole, which is purified by absorption on silica gel, using hexane/methylene chloride 70:30 parts by volume as the eluent, before processing further.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].[OH-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([NH:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][C:11]([OH:13])=[O:12])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2CC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of o-aminomethylphenylacetic acid hydrochloride (7.50 g., 37 m.mol.) and sodium hydroxide (4.74 g., 118 m.mol.) in water (100 ml.) was added p-toluenesulfonyl chloride (7.64 g., 40 m.mol.) in portions at 60° C. The mixture was stirred for 1 hour at the same temperature and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate (4×50 ml.). The combined extracts were washed with water, treated with a small amount of carbon and dried. The solvent was evaporated under reduced pressure and the residue crystallized from ethyl acetate to afford 2 as colorless prisms. Yield, 9.84 g. (84%). M.p. 155°-156° C.