Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:27]([C:37](O)=[O:38])[CH2:26]1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:40]1([CH2:46][CH2:47][CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54](C([O-])=O)[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[C@H:27]([C:37]([N:54]2[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:52][CH2:53]2)=[O:38])[CH2:26]1)=[O:23])=[O:19])([CH3:15])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])N1CCN(C(=O)CCCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCN(C(=O)CCCc3ccccc3)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.7 %

Procedure:
Triethylamine (72 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98.9 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 144.9 mg), 4-(4-phenylbutanoyl)l-piperazinecarboxylate (B, 100 mg), and 1-hydroxybenzotriazole (65 mg) in dichloromethane at room temperature. After stirring at room temperature for 20 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 20:1) to give the titled compound (220 mg) as a white powder: 1H-NMR(400 MHz, CDCl3) δ 1.46 (s, 18H), 1.99 (t, 2H), 2.33 (m, 2H), 2.69 (t, 2H), 3.39-3.85 (m, 13H), 7.18-7.31(m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS(C(F)(F)F)(=O)=O.[OH-].[Na+]>C(Cl)Cl.O.CO>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(OC)c(Br)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)c2ccccc2)c(OC)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a solution of 2-bromo-1,4-bis(methyloxy)benzene (2.0 g, 9.21 mmol) and benzoyl chloride (1.229 mL, 10.596 mmol, 1.15 eq) in DCM (9.5 mL, C=1.0M) at 0° C. was added triflic acid (0.815 mL, 9.21 mmol) over 5 min. The reaction mixture was allowed to warm to ambient temperature (40 min) and then slowly heated to gentle reflux (oil bath at 42° C.) and stirred for 48 h. The reaction mixture was cooled to r.t., and MeOH (0.3 mL) was added and stirring was continued for 30 min. The reaction mixture was poured into 80 mL of ice cooled water. The aqueous layer was neutralized with a 1 M NaOH solution. The layers were separated. The aqueous layer was extracted twice with DCM (2×20 mL). The combined organic phase was washed twice with a 1/1 water/brine mixture (2×30 mL), dried over MgSO4, filtered and concentrated in vacuo to a brown-orange oil. Then, MTBE (7 mL) was added and the mixture was stirred into an ultra-sound bath. The resulting solid was filtered, rinsed with 1:1 MTBE/hexanes mixture and air dried to afford [4-bromo-2,5-bis(methyloxy)phenyl](phenyl)methanone in 76% yield (2.258 g) as a white solid. 1H NMR (300 MHz, DMSO) δ 7.72 (d, J=8.5 Hz, 1H), 7.65 (t, J=7.4 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 3.81 (s, 2H), 3.63 (s, 2H), 13C NMR (75 MHz, DMSO) δ 194.5 (C═O), 150.7 (C), 149.7 (C), 136.7 (C), 133.5 (CH), 129.3 (2CH), 128.6 (2CH), 128.2 (C), 117.3 (CH), 113.3 (C), 112.5 (CH), 56.7 (OCH3), 56.5 (OCH3); MS (ESI) m/z: 321.1, 323.0 [M+H, 79Br, 81Br]+; 243.1, 245.0 [M-Ph, 79Br, 81Br]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=O.O.NN.[OH-].[K+].O>C(O)COCCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc2oc(CC3CCCCN3)cc2c1
Temperature: 25 °C
Yield: 5.1 %

Procedure:
To a solution of (RS)-2-(2-benzofuranylcarbonyl)-1-(tert-butyloxycarbonyl)piperidine (0.30 g, 0.91 mmol) in diethylene glycol (20 g), was added hydrazine hydrate (0.16 ml, 2.79 mmol) and the resultant mixture heated at 170° C. for 30 min. then cooled to room temperature. Potassium hydroxide (0.44 g, 7.86 mmol) was added and the mixture heated at 200° C. for 18 h. The resultant was then poured into water (100 ml) and extracted with diethyl ether (3×20 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (10 mg, 36%) as a golden oil.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([CH3:19])=[C:10]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:7]=2[C:6]([O:20]C)=[C:5]([CH3:22])[C:4]=1[CH3:23].B(Br)(Br)Br>C(Cl)Cl>[C:13]1([S:12][C:10]2[O:11][C:7]3[C:6](=[O:20])[C:5]([CH3:22])=[C:4]([CH3:23])[C:3](=[O:2])[C:8]=3[C:9]=2[CH3:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1c(C)c(C)c(OC)c2c(C)c(Sc3ccccc3)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=C(C)C(=O)c2c(oc(Sc3ccccc3)c2C)C1=O
Temperature: 25 °C

Procedure:
A solution of 4,7-dimethoxy-2-phenylthio3,5,6-trimethylbenzofuran from Step 2 (200 mg, 0.64 mmol) in CH2Cl2 (10 mL) was cooled to -78° C. and a BBr3 solution (2.8 mL, 2.8 mmol, 1M CH2Cl2) was added dropwise. The reaction was slowly warmed to room temperature then quenched with 25% NH4OAc. Extraction with EtOAc followed by addition of powdered FeCl3 and flash chromatography on silica gel (10% EtOAc/hex) afforded the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([O:7][C:15]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=2[C:13]#[N:14])[CH2:3]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC1CCC(O)C1
Product: CC1CCC(Oc2cccc([N+](=O)[O-])c2C#N)C1
Yield: 70 %

Procedure:
Prepared as in Example 215c from 3-methylcyclopentanol and 2,6-dinitrobenzonitrile in 70% yield. MS 247 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[C:12]([Br:13])=[CH:11][N:10]=[CH:9][C:8]=1[Br:14])C.[BH4-].[Na+].C(O)(=O)C>CCO>[Br:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([Br:14])[C:7]=1[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=Cc1c(Br)cncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: OCCCc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3,5-dibromo-pyridin-4-yl)-acrylic acid ethyl ester (1 eq, 17.0 mmol, 5.7 g) in EtOH (100 ml) at −18° C. is added NaBH4 (2 eq, 34.0 mmol, 1.29 g). The cooling bath is removed and the mixture is stirred at r.t. for 1.5 h. Then additional NaBH4 (0.78 eq, 13.2 mmol, 0.5 g) is added and the mixture is heated at 50° C. for 6 h. After cooling to r.t., glacial acetic acid is added, then the mixture is concentrated under reduced pressure. The residue is taken up in EtOAc, and washed with aqueous HCl (1M), sat. aqueous NaHCO3 solution, and sat. aqueous NaCl solution. The organic layer is dried with MgSO4, filtered, and concentrated in vacuo. The crude product is purified using column chromatography (hexane/EtOAc) to give the title compound; [M+H]+=295.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH:17]([O:22][CH3:23])[C:18]([O:20]C)=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH:17]([O:22][CH3:23])[C:18]([OH:20])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(OC)c1ccc2nc(-c3ccc(Cl)cc3)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(C(=O)O)c1ccc2nc(-c3ccc(Cl)cc3)oc2c1
Reaction time: 3 h

Procedure:
Methyl 2-p-chlorophenyl-α-methoxy-6-benzoxazolyl-acetate (4.0 g.) was dissolved in dioxan (50 ml.) and a solution of sodium hydroxide (0.7g) in water was added. The solution was stirred for three hours then evaporated to dryness. The residue was stirred with dilute hydrochloric acid for thirty minutes. The solid was filtered off and recrystallised from water-ethanol to give 2-p-chlorophenyl-α-methoxy-6-benzoxazolylacetic acid, m.pt. 164°-6° C.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)CC)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][CH2:43]O)[C:37]=2[C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[CH:32][CH:31]=1>ClCCl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][CH2:43][O:10][S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:12])=[O:13])[C:37]=2[C:45]2[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCCCn1ccc(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCn2ccc(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
1.99 g (6.09 mmol) of p-toluenesulfonic anhydride and 0.85 ml (6.09 mmol) of triethylamine were added to a solution of 1.64 g (5.53 mmol) of 3-(4-fluorophenyl)-1-(3-hydroxypropyl)-2-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 22(ii) above] in 16 ml of dichloromethane. The resulting mixture was stirred at room temperature for 2 hours, after which the solvent was distilled off by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 1.33 g (yield 53%) of the title compound as a yellow powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:24]>C(O)C>[ClH:24].[ClH:24].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(CCCc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: c1ccc(CCCN2CCCNCC2)cc1
Reaction time: 2 h

Procedure:
To 5.41 g (5.41 g (16.99 mmol.) of tert-butyl 4-(3-phenylpropan-1-yl)-2,3,5,6-tetrahydro-7H-1,4-diazepine-1-carboxylate was added, at room temperature, 5 ml (60 mmol.) of 12N hydrochloric acid. The mixture was stirred for 2 hours. To the reaction system was added ethanol, then the solvent was distilled off under reduced pressure to give the object compound as a pale yellow amorphous product. The yield was 5.65 g (100%).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O>C(O)C>[CH2:14]([O:13][C:11]([C:3]1[NH:2][C:10]2[C:5]([C:4]=1[C:17](=[CH2:19])[C:16]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Product: C=C(C(=O)OCC)c1c(C(=O)OCC)[nH]c2ccccc12

Procedure:
An ethanol solution saturated with gaseous hydrochloric acid containing 39.1 g (207 mmol) of ethyl 1H-indole-2-carboxylate and 45.3 ml (410 umol) of ethyl pyruvate is brought to approximately 60° C. for 3 h. The mixture is concentrated under reduced pressure and the residue is taken up in diethyl ether. The organic phase is washed with water and dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue is crystallized from cyclohexane. 45.4 g (158 mmol) of solid product are obtained, which product is used as is in the following stage.
Reaction SMILES: [CH:1]1([CH:4]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:7]=2[O:14][CH3:15])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:34]([I:40])=[CH:33][N:32]=1>C(#N)C>[CH:1]1([CH:4]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:31]3[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][C:34]([I:40])=[CH:33][N:32]=3)=[CH:8][C:7]=2[O:14][CH3:15])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(Oc2ccc(CN)cc2OC)C2CC2)cn1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(Oc2ccc(CNc3ncc(I)cc3[N+](=O)[O-])cc2OC)C2CC2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a stirred solution of (4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine (2.50 g, 7.95 mmol) and potassium carbonate (1.41 g, 10.20 mmol) in acetonitrile (10 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.90 g, 10.20 mmol). The resulting mixture was heated to 80° C. After 2 h, the mixture was filtered, and the filtrate was concentrated. Chromatographic purification of the residue (silica gel, 20% ethyl acetate in petroleum ether elute) afforded 2.60 g (58%) of N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodo-3-nitropyridin-2-amine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[CH:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1.[Cl:36]N1C(=O)CCC1=O.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Cl:36][C:7]1[C:8]2[N:9]([CH3:17])[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[C:13]=2[N:5]([CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[Cl:1])[C:6]=1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:19]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(c(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in N,N-dimethylformamide (20 ml) was added N-chlorosuccinimide (294 mg), and the resulting mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 2 with a 10% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (917 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][CH:13]([CH3:15])[CH3:14]>>[C:1]([C:5]1[O:9][N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7](=[NH:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(C)CBr
Product: CC(C)Cn1oc(C(C)(C)C)cc1=N
Temperature: 85 °C
Reaction time: 70 h
Yield: 61.9 %

Procedure:
A mixture of 5-tert-butylisoxazol-3-amine (3.0 g, 21 mmol) and 1-bromo-2-methylpropane (3.5 mL, 32 mmol) was warmed to 85° C. and was allowed to stir for 70 h. The mixture was cooled to ambient temperature and was purified by column chromatography (silica gel, 60% hexanes/EtOAc) to give the title compound (2.5 g, 13 mmol, 60% yield). MS (DCI/NH3) m/z 197 (M+H)+.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1>O.[Os](=O)(=O)(=O)=O>[CH2:7]([C:7]1[C:11](=[O:10])[CH2:8][CH2:9][C:8]=1[CH:9]=[O:10])[CH3:11]
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CCC1=C(C=O)CCC1=O
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
15.4 g (0.113 mole) of the vinyl compound 4 in 320 ml of THF was added to a 1-liter, round-bottom flask equipped with a 250 ml addition funnel and magnetic stirring bar. 4.4. ml of a solution prepared by solution of 0.783 g of osmium tetraoxide in 50 ml water was added dropwise. The mixture was stirred for 20 minutes and then a solution of 50.7 g (0.237 mole) sodium periodate in 396 ml of water was added over a 40-minute period. After completion of the addition the mixture was stirred for one hour and then filtered through a sintered glass funnel, using CHCl3 to wash the precipitate. The filtrate was extracted with CHCl3 and the combined chloroform extracts dried over anhydrous sodium sulfate (NaSO4). The CHCl3 was removed under reduced pressure to yield 15.0 g (0.109 mole, 96.2%) of a dark green crude liquid (aldehyde 5); uv max (95% ethanol) 247 and 256 nm; ir (neat) 1710 and 1670 cm-1 (C=O); nmr (CDCl3) δ9.7 (s, 1, C--H) and 1.2 (t, 3, --CH2 --CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([OH:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([NH2:13])[C:10]([OH:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(O)c(N)cc1N

Procedure:
A solution of 2,4-dinitro-5-hydroxybenzamide (4.00 g, 0.018 mmol) in MeOH/EtOAc (1:1, 50 mL) is hydrogenated over 5% Pd/C at 60 psi for 3 h to give 2,4-diamino-5-hydroxybenzamide, which is used directly. Formic acid (50 mL) is added and the solution is heated under reflux for 48 h. then the volatiles are removed under reduced pressure. The residue is triturated with EtOAc to give crude 4-oxo-3H-oxazolo[5,4-g]quinazoline(3.27 g, 97%) as a tan powder which is used directly.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][NH2:15].O>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:15][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(C(C)=O)cc1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Ex-29A: To a solution of 4-acetylbenzenesulfonyl chloride (1.1 g, 5.0 mmol) in 25 ml of THF, methylamine (0.44 ml of 40% solution in H2O, 5 mmol) was added dropwise, and the mixture was stirred for 30 min. The reaction mixture was poured into water, and the precipitate was filtered. Recrystallization from EtOAc/hexanes gave 0.67 g (62.6%) of 4-acetyl-N-methyl-benzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.09 (d, J=8 Hz, 2H), 7.96 (d, J=8 Hz, 2H), 4.48 (br, 1H), 2.70 (d, J=4 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[F:25][C:26]([F:42])([F:41])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([CH2:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:40][CH2:39][C:33]2([C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:41])[F:42])=[CH:32][CH:31]=3)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: NCC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1(c2ccc(C(F)(F)F)cc2)CCCCC1)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 1-{1-[4-(trifluoromethyl)-phenyl]cyclohexyl}methanamine (57 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is filtered. The solid is washed well with water and dried in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.09 (1H, s), 8.78 (2H, d, J 4.8), 7.65 (2H, d, J 8.4), 7.55 (2H, d, J 8.4), 7.31 (1H, t, J 4.8), 6.27 (1H, bs), 3.63 (2H, d, J 6), 2.17 (2H, m), 1.77 (2H, m), 1.66 (2H, m), 1.42 (4H, m). MS (M+1)=464.14; RT=1.37 min. *IC50.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:12][C:17]3[N:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH:10]=[C:5]2[CH:4]=1
Reactant: N#Cc1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 100 °C
Yield: 21.6 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 6-chloro-4-pyrimidinecarbonitrile (Intermediate 8, 97 mg, 0.697 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N-methyl-2-pyrrolidone (2 mL) and the resulting mixture was heated at 100° C. for 2 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as an off-white solid (32 mg);
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1>[OH-].[Na+].CO>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Yield: 33.4 %

Procedure:
A solution of 7-amino-4-(4-acetamidoanilino)pyrido[4,3-d]pyrimidine (0.30 g, 1.02 mmole) in aqueous NaOH (2 M, 10 mL) and MeOH (10 mL) is stirred at 100° C. for 7 h. The resulting product is chromatographed over alumina (3-4% EtOH/CHCl3) to give 7-amino-4-(4-aminoanilino)pyrido[4,3-d]pyrimidine (86 mg, 33%) as an orange solid. 1H NMR (DMSO) δ 9.58 (1H, brs), 9.24 (1H, s), 8.25 (1H, s), 7.31 (2H d, J=8.6 Hz), 6.58 (2H, d, J=8.6 Hz), 6.48 (2H, brs), 6.39 (1H, s), 5.00 (2H, brs)