Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][C:34](=[O:36])[NH:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:35][C:34](=[O:36])[N:33]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=4)[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CNC(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CN(C(=O)OC(C)(C)C)CC4=O)cc3)CC2)c(C)c1
Yield: 87.7 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (211 mg) described in Preparation Example 113 and 4-oxoimidazolidine-1-carboxylic acid tert-butyl ester (93 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:20])[C:15]4[CH2:21][CH:22]5[NH:26][CH:25]([C:14]=4[C:13]=3[C:12]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:34]>C(OCC)C>[ClH:34].[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[CH2:21][CH:22]4[NH:26][CH:25]([C:14]3=2)[CH2:24][CH2:23]4)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Agent: Cl
Solvent: CCOCC
Product: Cc1cccc(S(=O)(=O)c2ccc3c(c2)c2c(n3C)CC3CCC2N3)c1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide). The free base was treated with 1.25 M HCl in methanol (0.5 mL). The solution was concentrated in vacuo and the residue lyophilized to give 2-(3-methylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (52 mg, 46%, AUC HPLC >99%) as a white solid: mp 194-196° C.; 1H NMR (D2O, 300 MHz) δ 8.18 (s, 1H), 7.61-7.73 (m, 2H), 7.58 (d, J=9.3 Hz, 1H), 7.30-7.49 (m, 3H), 5.20 (d, J=4.5 Hz, 1H), 4.54 (br s, 1H), 3.55 (s, 3H), 3.42 (dd, J=17.4, 4.2 Hz, 1H), 2.94 (d, J=17.7 Hz, 1H), 2.29-2.45 (m, 2H), 2.24 (s, 3H), 2.05-2.19 (m, 1H), 1.72-1.90 (m, 1H); APCI MS m/z 367 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:6]1)=[N+:2]=[N-:3].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>C(O)CCC>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:36][CH2:35][C:28]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 80 °C

Procedure:
A solution of 9-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-9H-purine (1.29 g, 3.69 mmol) and (2,4-dimethoxyphenyl)methanamine (0.71 mL, 4.7 mmol) in 1-butanol (10 mL) was treated with N,N-diisopropylethylamine (0.93 mL, 5.3 mmol) and heated at 80° C. for 16.5 h; HPLC/LC MS indicated conversion to the desired product. The reaction mixture was allowed to cool to rt and the volatiles were removed under the flow of air to afford a brown-orange paste. Purification by column chromatography (2×8 cm silica; 0-10% acetone/CH2Cl2) afforded the title compound (1.72 g, 97%) as a yellow-orange foam/oil: MS (ESI+) for C23H28N8O4 m/z 481.2 (M+H)+; HPLC purity >95 area %.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([OH:21])=[C:16]([Br:22])[CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][S:24]([CH3:23])(=[O:26])=[O:25])=[C:16]([Br:22])[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Yield: 80 %

Procedure:
Add sodium hydride (24 g, 0.6 mmol) portionwise to a solution of 6-benzyloxy-2-bromo-naphthalen-1-ol (179 g, 0.54 mol) in THF (3.0 L) at 0° C. Add methanesulfonyl chloride (47 mL, 0.61 mol) over 45 minutes and stir the reaction for 1.5 hours at 10° C. Add sodium bicarbonate solution (500 mL) and water (500 ml). Separate the layers and extract the aqueous layer with ethyl acetate (500 mL×2). Combine the organic layers and wash with brine (200 mL). Dry with magnesium sulfate, filter and concentrate in vacuo. Triturate the residue by adding 20% ethyl acetate in hexane (1 L) to obtain a solid. Filter, wash the solid with toluene (200 mL×2) and dry the solid to get 176 g (80%) of methanesulfonic acid 6-benzyloxy-2-bromo-naphthalen-1-yl ester.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([CH3:15])([N+:12]([O-:14])=[O:13])[CH2:10][CH:11]=1.C(N)(N)=[O:17].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[CH3:5][C:6]1[N+:7]([O-:17])=[CH:8][C:9]([CH3:15])([N+:12]([O-:14])=[O:13])[CH2:10][CH:11]=1
Reactant: NC(N)=O
Reactant: CC1=CCC(C)([N+](=O)[O-])C=N1
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1=CCC(C)([N+](=O)[O-])C=[N+]1[O-]
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a chloroform (10 mL) solution of 2,5-dimethyl-5-nitropyridine (1.2 g), under ice cooling in a nitrogen atmosphere, carbamide peroxide (1.9 g) and trifluoroacetic anhydride (2.3 mL) were added dropwise, and the resultant was stirred for 30 minutes under ice cooling and then stirred at room temperature for 13 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The obtained organic layer was washed with a 10% aqueous sodium thiosulfate solution and then dried over sodium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; chloroform/ethyl acetate-gradient elution=100/0→0/100) to obtain the title compound (1.0 g) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[CH2:4][N:3]1[CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.Cl.[NH2:24][CH2:25][C@H:26]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[C@@H:26]([NH:34][S:35]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:37])=[O:36])[CH2:25][NH:24][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][N:3]([CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:2]2=[O:1])=[O:12])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2)NS(=O)(=O)c1ccccc1

Procedure:
A DMF solution (10 mL) of acid 6-4 (382 mg, 1.28 mmol) 1-4 (517 mg, 1.54 mmol), HOBT (264 mg, 1.13 mmol) NMM (563 μl, 5.1 mmol) and EDC (331 mg, 1.73 mmol) was stirred under ambient conditions for 18 h. The DMF was removed at 50° C. and the residue partitioned between EtOAc and H2O. The organic layer was washed with sat. NaHCO3 solution, brine, and dried (MgSO4). Evaporation gave a yellow foam which was purified by flash chromatography (silica, 3:1 acetone/CH2Cl2) to provide 6-5 as a colorless foam.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:15]1([C@@:20]([OH:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][C@@H:40](O)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][C@@H:40]([O:22][C:21](=[O:23])[C@:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, diisopropyl azodicarboxylate (980 μl, 5 mmol) was slowly added to a mixture of (R)-cyclopentylhydroxyphenylacetic acid (1.1 g, 5 mmol), (R)-3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5.5 mmol), and triphenylphosphine (1.3 g, 5 mmol) in 10 ml of THF. The reaction mixture was then stirred at room temperature overnight.
Reaction SMILES: C[O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[N:13][C:14]=3[C:19]([NH2:21])=[O:20])[CH2:5][CH2:4]1.CO[C@H]1CC[C@H](N2C(=O)NC3C2=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=3C(OC)=O)CC1.N>CO.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[N:13][C:14]=3[C:19]([NH2:21])=[O:20])[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(C(N)=O)nc(-c4cccc(O)c4)nc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@H](OC)CC1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
9-(trans-4-Methoxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide. Methyl 9-(trans-4-methoxycyclohexyl)-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate (0.205 g, 370 mmol) was dissolved in methanol (15 mL) reacted with ammonia gas according to General Procedure G. After 16 h, the solution was condensed under reduced pressure and the resultant crude product diluted with tetrahydrofuran (15 mL) and 1.0M tetrabutylammonium fluoride in tetrahydrofuran (0.92 mL) was added. After two h, the resulting precipitate was filtered and washed with tetrahydrofuran followed by hexanes. The product was purified using reverse-phase preparative HPLC (20 to 100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) to afford the title compound (0.093 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.55 (s, 1H), 8.33 (s, 1H), 8.01 (d, J=7.59, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.29 (t, J=7.99, 1H), 6.7 (dd, J=7.59, 1.59, 1H), 4.27 (m, 1H), 3.34 (s, 3H), 3.31 (s, 1H), 2.18 (d, J=10.79, 2H), 1.82 (d, J=11.19, 2H), 1.31 (q, J=12.39, 2H); MS (ESI) m/z 384.4 [M+1]+; mp 355-357° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH:5]1[CH2:10][OH:11].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([O:11][CH2:10][CH:5]3[CH2:6][O:7][CH2:8][CH2:9][N:4]3[CH3:3])=[O:21])[CH2:29][CH2:28]2)=[CH:35][CH:34]=1
Reactant: CN1CCOCC1CO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C
Yield: 243.2 %

Procedure:
NaH (60% in oil, prewashed with hexane; 0.91 g, 22.9 mmol) was suspended in anhydrous THF (25 mL) under nitrogen and cooled to 0° C. with stirring. A solution of (4-methyl-morpholin-3-yl)-methanol (1.00 g, 2.62 mmol) in THF (25 mL) was added dropwise. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 3.16 g, 9.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of NaHCO3 (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM to give (4-methylmorpholin-3-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (2.15 g, 83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23]
Reactant: O=[N+]([O-])c1ccc(CCl)c(Cl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc([N+](=O)[O-])cc1Cl
Yield: 44.4 %

Procedure:
Using 0.21 g of 2-chloro-4-nitrobenzyl chloride, 3 ml of N,N-di-methylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.15 g of 2-(2-chloro-4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (38)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([OH:21])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]O)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:21][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][C:17]=2[O:22][CH3:23])[N:14]=[CH:13][N:12]=[C:11]3[O:10][C:6]2[CH:5]=[C:4]3[C:9](=[N:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 53.4 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 2, 4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.133 g, 0.432 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.097, 0.51 mmol), (prepared as described for the starting material in Example 1 or Example 7), to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyquinazoline (0.11 g, 53%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.Cl[CH2:9][CH:10]=O.C([O-])(O)=O.[Na+]>C(O)CCC>[Br:1][C:2]1[S:6][C:5]2=[N:7][CH:9]=[CH:10][N:4]2[N:3]=1
Reactant: Nc1nnc(Br)s1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Brc1nn2ccnc2s1
Temperature: 120 °C

Procedure:
20 g of 5-bromo-[1,3,4]thiadiazol-2-ylamine were dissolved in 60 ml of n-butanol. 15 ml of chloroacetaldehyde (55% in water) were added to the solution. The mixture was heated for 3 h at 120° C. After cooling the reaction mixture was poured into a NaHCO3 solution. The mixture was extracted three times with ethylacetate and the organic phase dried with sodium sulphate and evaporated. The resulting material was purified via silica-gel column chromatography using a petroleum ether-ethylacetate gradient. 2.9 g yellow crystals of the desired product were obtained.
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.N([O-])=O.[Na+].O[PH2]=O.[OH-].[Na+]>CC(O)=O.O.Cl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:6]=[C:5]3[NH:4][N:3]=[CH:2][C:10]3=[CH:9][C:8]=2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:20][CH:21]=1
Reactant: CSc1nccc(-c2cc3c(N)n[nH]c3nc2-c2ccc(F)cc2)n1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)O
Product: CSc1nccc(-c2cc3cn[nH]c3nc2-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a solution of 3-amino-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine (10.00 g, 28.4 mmol, obtained in example 180) in AcOH (52 mL), water (22 mL) and HCl conc. (5.7 mL), cooled to 0° C., a solution of NaNO2 (2.30 g, 33.4 mmol) in water (7.5 mL) was added dropwise. It was stirred for 30 min at 0° C., and H3PO2 (50% aqueous solution, 56.8 mL) was added slowly. It was stirred at 0° C. for 6 h. It was allowed to cool to room temperature, basified at 0° C. by slow addition of 6 N NaOH hasta pH=8 and was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 4.00 g of the title compound (yield: 42%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Brc1cnc(NC2CCC2)nc1
Temperature: 50 °C

Procedure:
In a sealed tube 2.00 g (10.3 mmol) 5-bromo-2-chloropyrimidine, 1.15 mL (13.4 mmol) cyclobutylamin and 2.70 mL (15.5 mmol) DIPEA are added to 12 mL ACN. The reaction mixture is stirred at 50° C. over night, then diluted with EtOAc and washed with water (2×). The org. phase is dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O.C(O)C.NN>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: Cc1cccc(C)c1CCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: Cc1cccc(C)c1CCCN
Yield: 59 %

Procedure:
A 10 g (34.4 mmole) sample of the title compound of Example 33 was refluxed for 2 hours in 150 ml of ethanol containing 1.2 g (36.7 mmole) of 97% hydrazine. After concentrating the solution, the white crystalline residue was mixed with 100 ml of 10% NaOH and 100 ml of ether. The aqueous phase was separated and extracted with another 100 ml portion of ether. The combined ether extracts were than washed with water, dried over MgSO4 and stripped of all solvent under reduced pressure to yield 3.3 g (59%) of the product as an oil. This material was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=2)[CH2:7][C:6]([OH:28])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.1 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (820 mg, 2.08 mmol) in dichloromethane (10 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The mixture was stirred for 2.5 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue azeotroped with toluene (×2). The residue was then dissolved in ethyl acetate, washed sequentially with an aqueous solution of sodium dihydrogen citrate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (740 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])=[C:6]([O:12][CH3:13])[CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(Br)ccc1C(=O)CBr
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of compound 6d (43.5 g) in anhydrous DMF (150 mL) was cooled to 5° C. To this solution was added potassium phthalimide (26.1 g, 141 mmol). After 5 min the cooling bath was removed and the reaction was allowed to stir at RT for 3 hr. The solvent was evaporated under vacuum to provide a tan solid. The solid was rinsed with 4:1 DCM/methanol and then water. The filter cake was slurried in toluene and evaporated to dryness to afford 4′-bromo-2′-methoxy-2-(phthalimido)acetophenone (compound 6e, 39 g) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.Cl.[CH3:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH3:13]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: COCCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCCCNc1c(F)cccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
To a solution of 1,2-difluoro-3-nitrobenzene (5.15 g) and 4-methoxybutan-1-amine hydrochloride (5.42 g) in acetonitrile (100 ml) was added diisopropylethylamine (17 μl), and the mixture was stirred at 60° C. for 12 hr. 4-Methoxybutan-1-amine hydrochloride (1.00 g) was further added, and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with hexane-ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give the object product (7.70 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC[O:24][C:25]([CH:27]1[C:31](=O)[CH2:30][CH2:29][CH2:28]1)=O>>[O:24]=[C:25]1[N:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]2=[N:1][C:28]2[CH2:29][CH2:30][CH2:31][C:27]1=2
Reactant: Nc1ncccc1C(=O)O
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(O)c1cccn2c(=O)c3c(nc12)CCC3
Reaction time: 0.38 h

Procedure:
A mixture of 5.0 g of 2-aminonicotinic acid, 0.4 g. p-toluenesulfonic acid, and 25 ml of ethyl cyclopentanone-2-carboxylate is stirred magnetically and immersed in an oil bath preheated to 125°. The temperature of the oil bath is gradually raised and reaches 170° in 23 minutes. A clear solution occurs in 55 minutes when the oil bath temperature reaches 178° and 4.0 ml of distillate is collected in a Dean-Stark trap. The product crystallizes from the cooled reaction mixture. The filtered, air-dried product weighs 6.2 g., m.p. 187°-192°. Recrystallization from 100 ml of toluene gives 4.91 g of product, m.p. 189°-193°.