Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17]C(=O)OC(C)(C)C)=[N:14][N:15]=3)[N:12]=2)[O:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[O:4][N:3]=1
Reactant: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc3nnc(CN)n3n2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.63 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (16.9 ml, 220 mmol) and the mixture was stirred at room temperature for one hour. The mixture was concentrated, taken up in a solution of ammonia in methanol (2.0 M) and purified by MPLC chromatography (eluted with 0-10% (1:10:90 NH4OH:MeOH:DCM) in DCM) to yield the product as a brown solid. MS m/z=230.8 [M+1]+. Calc'd for C10H10N6O: 230.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][C:15]=3[O:29][CH3:30])=[O:12])[N:8]([CH3:31])[C:5]2=[N:6][CH:7]=1.Br[C:33]1[N:34]=[C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[N:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=12>>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:33]4[N:34]=[C:35]([C@H:43]5[CH2:44][CH2:45][C@H:46]([N:49]6[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]6)[CH2:47][CH2:48]5)[N:36]5[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=45)=[CH:16][C:15]=3[O:29][CH3:30])=[O:12])[N:8]([CH3:31])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2cc(Cl)cnc2n1C
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2cc(Cl)cnc2n1C

Procedure:
5-Chloro-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (34 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) were reacted according to the procedure described in example 4 step 4c and purified by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol (containing 0.1% ammonium hydroxide)) to give 5-chloro-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (27 mg).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH2:37]([O:36][C:34]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)C)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added ethyl chloroformate (0.072 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added citric acid monohydrate (3.3 g) and water, and the resulting mixture was purified by ODS solid phase extraction (washing solvent: distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=1011) and recrystalization (recrystalization solvent: ethyl acetate/hexane=1/3) afforded 3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.084 g).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH2:25]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:26]#[CH:27]>C(Cl)Cl>[C:10]1([C:9]2[CH:27]=[C:26]([CH2:25][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[O:17][N:16]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCOC1CCCCO1
Reactant: ON=Cc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(-c2cc(COC3CCCCO3)on2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
1.47 g (11 mmol) of N-chlorosuccinimide were added at -30° C. to a solution of 1.21 g of benzaldoxime in 10 ml of methylene chloride. After 2 hours a solution of 1.0 g of triethylamine and 1.4 g of (RS)-tetrahydro-2-(2-propynyloxy)-2H-pyran in 5 ml of methylene chloride was added dropwise. The reaction mixture was stirred at room temperature for 5 hours, the solvent was thereafter distilled off and, for purification, the crude product was chromatographed on silica gel using methylene chloride as the eluent. There were obtained 1.8 g of (RS)-3-phenyl-5-(tetrahydro-pyran-2-yloxymethyl)-isoxazole as a colourless liquid; MS: 259 (M)+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:39]([NH:38][CH2:36][CH3:37])=[O:40])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(NC)nc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.25 g (0.5 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochloride was dissolved in dry dichloromethane (10 ml). Triethylamine (0.28 ml, 2 mmol) was added followed by the addition of ethylisocyanate (0.06 ml, 0.753 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was triturated with water, and the precipitate was filtered to give the title compound (0.17 g, 72%) MS (EI): 459.2 (MH+). 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, □ (ppm)): 0.96 t (3H); 0.88-1.13 m (4H); 1.13-1.31 m (1H); 1.54-1.85 m (6H); 2.74 s (3H); 2.98 q (2H); 2.89-3.16 m (4H); 3.19-3.33 m (1H); 3.34-3.58 m (4H); 4.12-4.30 m (2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>ClCCl>[Cl:42][C:38]1[CH:37]=[C:36]([C:26]2([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[CH:34]3[CH:30]([CH2:31][N:32]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(C(=O)Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Triethylamine (0.45 cc) and then phenylacetyl chloride (0.49 g) are added to a solution of 7,7-bis-(3-chlorophenyl)-4-perhydroisoindolone hydrochloride (1.06 g) in dichloromethane (20 cc) cooled to +4° C. The reactio mixture is stirred for 2 hours at 25° C. and then washed with water (3×30 cc) and with saturated sodium chloride solution (3×30 cc). The organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 2.2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting 15 cc fractions. Fractions 7 to 18 are concentrated to dryness under reduced pressure (2.7 kPa) and the residue is crystallized from acetonitrile. The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-bis-(3-chlorophenyl)-2-(phenylacetyl)-4-perhydroisoindolone (0.21 g) is obtained. m.p.=160° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17](OC)=[O:18])([C:13](OC)=[O:14])[CH2:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:17][OH:18])([CH2:13][OH:14])[CH2:10][C:9]=2[C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(=O)OC)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC(CO)(CO)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
Under nitrogen, a solution of 1.01 g (2.34 mmol) of 1-[2-(4-fluorophenyl)-4,4-dicarbomethoxycyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 8) in 1.5 mL of THF at -78° C. was treated with 11.6 mL (11.6 mmol) of DIBAL (1.0M in THF). The reaction was stirred at ambient temperature for 1.5 hours, quenched with acetone and aqueous NaOH, extracted with ethyl acetate, dried (MgSO4), and concentrated in vacuo to give 840 mg of crude 1-[2-(4-fluorophenyl)-4,4-di(hydroxymethyl)cyclopenten-1-yl]-4-(methylsulfonyl) benzene as a colorless oil: NMR (CDCl3) δ2.82 (d, J=5 Hz, 4H), 3.04 (s, 3H), 3.86 (d, J=5 Hz, 4H), 6.94 (t, J=9 Hz, 2H), 7.11 (dd, J=5 and 9 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH2:32]([NH2:34])[CH3:33]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:34][CH2:32][CH3:33])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCNCCOc1ccc(C(=C(CC)c2ccc3oc(Cl)cc3c2)c2ccc(O)cc2)cc1
Yield: 54 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with ethanamine (3 mL) in MeOH (8 mL) under reflux to give the desired product (38 mg, 54%, Z/E=1/1.2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.12 & 7.03 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.8 Hz, 1H), 6.83 & 6.75 (d, J=8.8 Hz, 2H), 6.71 & 6.65 (d, J=8.6 Hz, 2H), 6.44 (s, 1H), 6.45 & 6.40 (d, J=8.4 Hz, 2H), 4.10 & 3.92 (t, J=4.8 Hz, 2H), 3.04 & 2.93 (t, J=4.8 Hz, 2H), 2.78 & 2.71 (q, J=7.2 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 1.18 & 1.13 (q, J=7.2 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H); m/z=462[M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1>CC#N>[CH3:17][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2nc3ccc(OC)cc3nc2C(F)(F)F)CC1
Temperature: 150 °C
Yield: 88.5 %

Procedure:
2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11, 240 mg) was suspended in MeCN (1.5 mL) with ethyl piperidine-4-carboxylate (173 mg) and TEA (205 mg) in a sealed microwave tube and heated at 150° C. with microwave for three hours. The resultant mixture was purified by silica gel column chromatography to afford 310 mg of ethyl 1-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)piperidine-4-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:33])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][O:5][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: N#N
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)COC(=O)CCCCCCCCCCCCCCCCCCCCC
Temperature: 165 °C

Procedure:
A 1000 ml round bottomed flask was charge with 648.0 g (0.15 mol) PEG 105 pentaerythritol and 99.0 g. (0.30 mol) behenic acid. The mass was heated to 100° C. with a N2 sparge, 0.75 g methane sulfonic acid and 0.1 g hypophosphorus acid were charged. The batch was heated to 165° C. while collecting the water of reaction, and maintained until an acid value of 11.5 was reached. The finished material was a white waxy solid having an acid value of 11.5, and a hydroxyl value of 27.05.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCO
Product: N#Cc1ccc(NCCO)cc1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 4-fluorobenzonitrile and ethanolamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=O)[NH:6][C:5]2=[O:15].[Sn]>CCO>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[NH2:1])[C:5](=[O:15])[NH:6][CH2:7]2
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: [Sn]
Solvent: CCO
Product: Nc1cc2c(cc1N)C(=O)NC2
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of 5-Amino-6-nitroisoindoline-1,3-dione (1.0 g, 4.83 mmol) and tin powder (5.8 g, 48.3 mmol) in EtOH (30 mL) was heated at 90° C. for 4 h. The reaction mixture was cooled to RT, filtered the precipitated solid, washed with EtOH (10 mL) and dried to afford 5,6-diaminoisoindolin-1-one (0.75 g, 95%) as a yellow solid. LCMS: 164 (M+1). 1H NMR (300 MHz, DMSO-d6): δ4.25 (s, 2H); 7.93 (s, 1H), 7.41 (s, 1H); 8.22 (s, 1H); 9.0 (br.s, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1)=O.[NH3:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH2:13][CH2:1][C:3]1[CH:4]=[C:5]([B:10]([OH:12])[OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C=O)cc(B(O)O)c1
Reactant: N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(CN)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-Formyl-5-methylphenylboronic acid (1 eq, 3.05 mmol, 0.5 g) in dry DCM (5 ml) under an inert atmosphere of argon is treated with ammonia solution 35% (1.1 eq, 3.35 mmol, 0.185 ml) followed by acetic acid (1.1 eq, 3.35 mmol, 0.192 ml) and NaBH(OAc)3 (1.2 eq, 3.66 mmol, 0.776 mg) and the resulting mixture is stirred at room temperature overnight. The reaction is quenched by addition of acetonitrile and filtered under vacuum. The filtrate is concentrated in vacuo to afford the title compound which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1=C2CC[C@H]3[C@@H]4CC[C@H](C(=O)NC(C)(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 3 h

Procedure:
A solution of 4-amino-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (0.9 g, 2.34 mmole) in acetic anhydride (3mL) and pyridine (6 mL) is stirred overnight at room temperature. Water is added and the mixture is stirred for 3 hours. The solids are collected by filtration to give a brown solid which is purified by flash chromatography (hexane-50% ethyl acetate then ethyl acetate) to give 4-acetamido-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide. This compound has the following structure: ##STR6##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][NH:30][CH2:31][C:32]1[N:33]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:34]=[CH:35][N:36]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.O>[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][N:30]([CH2:31][C:32]1[N:33]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:34]=[CH:35][N:36]=1)[C:15](=[O:17])[CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: C[Si](C)(C)CCOCn1ccnc1CNCc1nccn1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
Under an argon atmosphere at room temperature, [1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid (500 mg) and the compound 2 (899 mg) were dissolved in anhydrous dimethyl formamide (12 mL), and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (590 mg), 1-hydroxybenztriazole (417 mg) and 4-dimethylaminopyridine (377 mg) were added, followed by stirring at room temperature for 16 hours. After the addition of city water and stirring, the obtained solution was extracted three times with ethyl acetate. The organic layer was collected and then washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the title compound (216 mg) having the following physical properties.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][C@@H:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][OH:15]>O1CCOCC1>[OH:15][CH2:14][C@@H:13]([N:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1[C@H](CO)Cc1ccccc1
Temperature: 150 °C

Procedure:
Isobenzofuran-1,3-dione (4.40 g, 29.76 mmol) and (S)-2-amino-3-phenylpropan-1-ol (4.50 g, 29.76 mmol) were charged into a 20 mL microwave tube along with 10 mL dioxane. The microwave tube was heated at 150° C. for 33 minutes in a Smith Synthesizer. After the reaction was complete, dioxane was evaporated off and the residue was passed through a short pad of silica gel with DCM. The resulting product (7.50 g, 89%) was used in the following step. LCMS (API-ES) m/z (%): 282.2 (100%, M++H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[NH:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:25](=[O:26])[C:24]2[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])/[NH:7][C:6]=1[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: Cc1[nH]c(=N)sc1C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1/[nH]c(C)c(C(C)(C)C)s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
A mixture of 5-tert-butyl-4-methylthiazol-2(3H)-imine (250 mg, 1.5 mmol) in tetrahydrofuran (10 mL) was treated with triethylamine (0.25 mL, 1.8 mmol) and 5-chloro-2-methoxybenzoylchloride (307 mg, 1.5 mmol). The reaction mixture was stirred at 60° C. for 18 hours then concentrated under reduced pressure. The residue was diluted with ethyl acetate and H2O. The organic extract was dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum to afford the title compound (490 mg, 96% yield). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(N(CC)CC)C.[CH2:12]([CH:17]1[C:21](O)([CH3:22])[CH:20]=[CH:19][C:18]1=[O:24])[CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:12]([C:17]1[C:18](=[O:24])[CH2:19][CH:20]([S:3][C:1](=[O:4])[CH3:2])[C:21]=1[CH3:22])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(O)=S
Reactant: CCCCCC1C(=O)C=CC1(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCC1=C(C)C(SC(C)=O)CC1=O
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Into the same flask as used in Example 1, thioacetic acid (35 g) and triethylamine (7 g) were charged, and 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (18.2 g) was dropwise added thereto at a temperature of 20° to 35° C. for 1 hour. Thereafter, the reaction mixture was stirred at a temperature of 40° to 60° C. for 3 hours. After completion of the reaction, the mixture was diluted with toluene (50 ml) and treated in the same manner as in Example 50 to obtain 2-n-pentyl-3-methyl-4-acetylthio-2-cyclopentenone (24.1 g). Yield, 94%. nD20 1.5146.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8]>C(N(CC)CC)C>[N:1]1([CH2:8][CH2:7][C:6]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=CC(=O)O
Reactant: c1cn[nH]c1
Solvent: CCN(CC)CC
Product: O=C(O)CCn1cccn1
Yield: 97.7 %

Procedure:
In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 mmol), acrylic acid (0.50 mL, 7.3 mmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oil was dried on high vacuo during 12 hours to yield quantitatively the desired acid (1.0 g) suitable for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].O[CH:14]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:14]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Product: CCCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(C(F)(F)F)ccc1Cl

Procedure:
The title compound was prepared according to the method of Example 1 step (c) but using 2-chloro-5-(trifluoromethyl)phenol and (3-hydroxyheptyl)methylcarbamic acid, 1,1-dimethylethyl ester.