Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C.CCOC(C)=O>[C:33]([O:32][C:30](=[O:31])[CH2:29][N:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:11]1=2)([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3CCCCC3)c2s1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution (0.2 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as described in example 13, step 4) in DMF was treated with NaH (2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min, then tert-butyl bromoacetate (3 eq.) was added. The reaction mixture was heated at 50° C. for 2 h then cooled down and diluted with AcOEt. The organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (93%).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1>CN(C=O)C>[C:11]1([C:9]2[S:10][C:6]([CH2:5][C:1]#[N:2])=[CH:7][N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1cnc(-c2ccccc2)s1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 73.2 %

Procedure:
KCN (154 mg, 2.36 mmol) was added to a solution of 5-(bromomethyl)-2-phenylthiazole (400 mg, 1.57 mmol) in dry DMF (10 mL). The resulting reaction mixture was stirred at room temperature for 10 h. The mixture was then quenched with water and the organic product was extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20% EtOAc in petroleum ether) to afford 2-(2-phenylthiazol-5-yl)acetonitrile (230 mg, yield 73%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.94-7.90 (m, 2H), 7.76 (s, 1H), 7.47-7.45 (m, 3H), 3.98 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C11H8N2S: 200.05. found: 201.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O.N1CCOCC1>COCCOCCOC.CO>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](=[O:15])[CH:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CO
Solvent: O
Solvent: COCCOCCOC
Product: O=C(C=C1Nc2ccccc2N1)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A 4.0 g portion of 2-methyl-1H-benzimidazole and 13.9 ml of TEA were dissolved in 40 ml of Diglyme, and 17.5 g of 2-chlorobenzoic acid chloride was added dropwise thereto. The reaction mixture was stirred at 100° C. for 3 hours. After cooling to room temperature, the reaction mixture was mixed with water, extracted with chloroform, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an orange oily substance. This was dissolved in 60 ml of methanol, mixed with 7.9 ml of morpholine and then heated under reflux for 3.5 hours. The reaction mixture was cooled to room temperature, mixed with water and then stirred for 1 hour. The thus formed precipitate was collected by filtration, washed with cool water and then dried to obtain 6.1 g (75%) of 1-(2-chlorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone (Reference Example 1-2) as pale yellow powdery crystals. ES+: 271
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]1[C@H:9]([NH:10][C:11](=[O:47])/[C:12](=[N:26]\[O:27][C:28]2([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:30][CH2:29]2)/[C:13]2[N:14]=[C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:16][CH:17]=2)[C:8](=[O:48])[NH:7]1.C1N=CN([C:54](N2C=NC=C2)=[O:55])C=1>C(Cl)(Cl)Cl>[C:22]([O:21][C:19]([NH:18][C:15]1[S:16][CH:17]=[C:13](/[C:12](=[N:26]/[O:27][C:28]2([C:31]([O:33][CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:32])[CH2:29][CH2:30]2)/[C:11](=[O:47])[NH:10][C@H:9]2[C@@H:6]([CH2:5][N:4]3[CH2:3][CH2:2][NH:1][C:54]3=[O:55])[NH:7][C:8]2=[O:48])[N:14]=1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCNC2=O)cs1
Reaction time: 12 h
Yield: 49.1 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(((2-aminoethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (90 mg, 0.133 mmol) in chloroform (2.7 mL) was added CDI (43.1 mg, 0.266 mmol) and TEA (111 μl, 0.797 mmol). After 12 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-100%) to afford the title compound (46 mg, 49%). LCMS: Rt=0.95 min, m/z=704.0 (M+1), Method 2m_acidic.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:36])[C@@H:14]([NH:23][C:24]([C:26]1[NH:35][C:29]2=[N:30][CH:31]=[C:32]([Cl:34])[CH:33]=[C:28]2[CH:27]=1)=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(C)(C)C>C(Cl)Cl>[Cl:34][C:32]1[CH:33]=[C:28]2[CH:27]=[C:26]([C:24]([NH:23][C@@H:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:13]([OH:36])=[O:12])=[O:25])[NH:35][C:29]2=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)c1cc2cc(Cl)cnc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (1.9 mL, 24.3 mmol) was added to a suspension of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)-propionic acid tert-butyl ester (EXAMPLE 281, 507 mg, 1.21 mmol) in DCM (25 mL) and the reaction mixture was stirred at rt for 16 h. Further trifluoroacetic acid (2 mL) was added and the reaction was stirred at rt for 48 h. The solvent was removed in vacuo and the solid partitioned between 1N hydrochloric acid (50 mL) and ethyl acetate (3×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound. δH (CD3OD): 3.11 (1H, dd), 3.33 (1H, dd), 4.88 (1H, m), 6.97 (2H, m), 7.06 (1H, s), 7.28 (2H, m), 8.08 (1H, d), 8.29 (1H, d); m/z (ES+)=362 [M+H]+; RT=3.67 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].Cl>C(Cl)Cl.O>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC1CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 1-Boc-4-(aminomethyl)piperidine (18.0 g, 84.1 mmol) and DIPEA (12.9 g, 100 mmol) in anhydrous CH2Cl2 (200 mL) at 15° C. was added 3,5-bis-(trifluoromethyl)benzoyl chloride (23.4 g, 85.0 mmol) slowly. After the reaction mixture was stirred at room temperature for 30 min, water (50 mL) was added followed by adding aqueous HCl (0.5 N, 100 mL). The organic fraction was collected. The aqueous fraction was extracted with CH2Cl2 (100 mL). The combined organic solution was dried over anhydrous Na2SO4 and passed through a silica gel plug. The desired compound was eluted off with EtOAc/petroleum ether (1:3 in v/v). Solvents were removed and the product was dissolved in EtOAc (200 mL). To the solution HCl (g) bubbled for 5 min to form a white suspension. The suspension was stirred at room temperature for 30 min, and then concentrated to around 100 mL. Diethyl ether (150 mL) was added and the suspension was cooled at 7° C. for 1 h. A white HCl salt was collected by filtration. The salt was dissolved in a mixture of methanol/water (30/300 mL), and aqueous NaOH (2 N) was added until pH=˜11. The mixture was extracted with CH2Cl2 (5×200 ML) and the combined organic solution was dried over anhydrous Na2SO4. After filtration the filtrate was concentrated in vacuo to give pale yellow sticky foam (28.8 g, 97%).).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[N:18]1([C:1]([N:3]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]2=3)=[CH2:2])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C=C(n1ccnc1)n1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 1.33 mmol), 1H-imidazole (182 mg, 2.66 mmol), TBAF.3H2O (1.2 g, 3.80 mmol) and dichloro bis(triphenylphosphine) palladium (II) (47 mg, 0.06 mmol) was heated at 85° C. for 30 min. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh) eluting with 4% MeOH-DCM to yield 90 mg of 5-(1-imidazol-1-yl-vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The free base was converted into the di-HCl salt by treatment with ethanolic HCl. 1H NMR (CD3OD, Di-HCl salt) δ (ppm): 9.21 (s, 1H), 7.78 (d, 2H), 7.38 (s, 1H), 7.1 (d, 1H), 6.92 (d, 1H), 6.21 (d, 1H), 5.75 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.83 (m, 1H), 3.6 (m, 1H), 3.18 (m, 5H), 2.4 (s, 3H).
Reaction SMILES: C([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:9])C(C)C.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl>C(Cl)Cl>[OH:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
In 15 ml of methylene chloride is dissolved 1.50 g of methyl 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetate, to which is added 1.06 g of aluminum chloride at ambient temperature. The mixture is stirred at ambient temperature for 2 hours. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.62 g of methyl 2-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]acetate as a yellow-colored solid product.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:21][OH:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl>CO.[Pd]>[NH2:15][CH2:14][C:13]1[C:12]([NH:19][C@H:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:21][OH:22])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Reaction time: 6 h
Yield: 57 %

Procedure:
The mixture of (R)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile (Example 6; 0.13 g, 0.33 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.12 g) in MeOH (5 ml) was flushed with N2, evacuated, and then placed under H2 (40 psi) for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na2CO3 (100 ml) was added. The mixture was shaken vigorously for 30 min and allowed to separate. The aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was dried, filtered and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.074, 57%). 1H NMR (400 MHz, CD3OD) δ 7.45-7.42 (m, 2H), 7.17 (d, J=11.1 Hz, 1H), 7.04-7.00 (m, 2H), 5.72 (br s, 1H), 5.18-5.08 (m, 1H), 3.89-3.72 (m, 4H), 1.87-1.83 (m, 1H), 0.94-0.92 (m, 2H), 0.69-0.65 (m, 2H). MS: Calcd.: 400. Found: [M+H]+401.
Reaction SMILES: [N:1]([O-])=O.[Na+].[S:5]([C:9]1[S:25][C:12]2[S:13](=[O:24])(=[O:23])[CH:14]([CH2:18][C:19]([NH:21][NH2:22])=[O:20])[C:15](=[O:17])[NH:16][C:11]=2[CH:10]=1)(=[O:8])(=[O:7])[NH2:6]>O.Cl>[O:17]=[C:15]1[CH:14]([CH2:18][C:19]([N:21]=[N+:22]=[N-:1])=[O:20])[S:13](=[O:23])(=[O:24])[C:12]2[S:25][C:9]([S:5](=[O:7])(=[O:8])[NH2:6])=[CH:10][C:11]=2[NH:16]1
Reactant: NNC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of sodium nitrite (0.34 g, 5 mmol) in water (10 ml) was added slowly to a cold (0°-5° C. suspension of (2,3-dihydro-6-sulfamoyl-2,4,4-trioxo-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetic acid hydrazide (1.75 g, 5 mmol) in 1N HCl (150 ml). The reaction mixture was stirred for 0.5 hours in the cold and the resulting solid was collected, rinsed with water and air-dried to yield 1.05 g (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetyl azide.
Reaction SMILES: [CH:1]1([N:4]2[CH2:17][CH2:16][C:7]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=4[C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1>CN(C=O)C>[CH:1]1([N:4]2[CH2:17][CH2:16][C:7]3[N:8]([CH2:20][C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)([OH:22])[CH3:23])[C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=4[C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C1CC1)CC3
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CCN(C2CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2-cyclopropyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.2 mmol) in DMF (10 mL) was added sodium hydride (264 mg, 6.6 mmol). After stirring for 10 min at RT, 4-(2-methyl-oxiranyl)-pyridine (448 mg, 3.3 mmol) was added and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to afford crude material, which was re-crystallized in ether and hexane to yield 1-(2-cyclopropyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (600 mg). 1H NMR (CD3OD, TFA salt) d (ppm): 8.62 (d, 2H), 8.18 (d, 2H), 7.20 (s, 1H), 6.95 (d, 1H), 6.80 (d, 1H), 4.50 (m, 1H), 4.40 (s, 2H), 4.0 (m, 1H), 3.70 (m, 1H), 3.30 (m, 3H), 3.10 (m, 1H), 2.36 (s, 3H), 1.78 (s, 3H), 1.20 (m, 4H).
Reaction SMILES: [CH:1]([NH:4][C@@H:5]([CH2:10][CH3:11])[C:6]([O:8][CH3:9])=[O:7])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.ClCCl>C1CCCCC1>[Cl:17][C:18]1[N:23]=[C:22]([N:4]([CH:1]([CH3:3])[CH3:2])[C@@H:5]([CH2:10][CH3:11])[C:6]([O:8][CH3:9])=[O:7])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1
Reactant: CC[C@H](NC(C)C)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC[C@@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
Methyl (2S)-2-(isopropylamino)butanoate 43a (10.75 g, 67.50 mmol) was dissolved in 180 mL of cyclohexane followed by the addition of sodium bicarbonate (22.68 g, 0.27 mol) and 2,4-dichloro-5-nitro-pyrimidine (15.71 g, 0.081 mol) successively, the reaction mixture was heated to 85° C. and stirred for 2.5 hours. The resulting mixture was cooled down to room temperature, added with 200 mL of dichloromethane, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain methyl (2S)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]butanoate 43b (8.78 g, yield: 41.1%) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[N:23]([CH3:24])[C:22](=[O:25])[C:21]([F:27])([F:26])[CH2:20][N:19]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[C:18]=4[N:34]=3)=[C:9]([O:35][CH3:36])[CH:8]=2)[CH2:2]1.CO.[CH3:40][C:41]([CH3:43])=O.N1C=CC=CC=1.B>C(O)(=O)C.ClCCl>[CH:28]1([N:19]2[CH2:20][C:21]([F:27])([F:26])[C:22](=[O:25])[N:23]([CH3:24])[C:17]3[CH:16]=[N:15][C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:4][N:1]([CH:41]([CH3:43])[CH3:40])[CH2:2]5)=[O:37])=[CH:8][C:9]=4[O:35][CH3:36])=[N:34][C:18]2=3)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)=O
Reactant: COc1cc(C(=O)NC2CNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: B
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)NC2CN(C(C)C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 3 h

Procedure:
The title compound was synthesized by solubilizing N-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide (33 mg, 0.07 mmol) in acetic acid: methanol: dichloromethane (1 mL of 1:2:2) and treatment with acetone (58 mg, 1.0 mmol), and borane-pyridine (100 μL, 0.8 mmol). The reaction was left to stir for 3 hours. The reaction solvent was removed and the final compound was purified by reverse phase HPLC and basified to give the free base (5.7 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.06 Hz, 6 H) 1.48-1.78 (m, 8 H) 1.93 (br. s., 2 H) 2.24-2.36 (m, 1 H) 2.94 (t, J=6.82 Hz, 2 H) 3.33 (s, 3 H) 3.51 (t, J=6.82 Hz, 2 H) 3.94 (s, 3 H) 4.05 (t, J=14.02 Hz, 2 H) 4.39 (q, J=6.99 Hz, 1 H) 4.70-4.83 (m, 1 H) 7.49 (d, 0 H) 7.51 (s, 1 H) 7.98 (s, 1 H) 8.26 (s, 1 H) 8.29 (d, 1 H) 8.61 (d, J=6.82 Hz, 1 H). [M+H] calculated for C28H37F2N7O3, 574; found 574.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.P(Br)(Br)([Br:12])=O>>[Br:12][C:2]1[C:7]([CH3:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Cc1nc(Br)cnc1O
Reactant: O=P(Br)(Br)Br
Product: Cc1nc(Br)cnc1Br
Temperature: 175 °C

Procedure:
A mixture of 2-hydroxy-3-methyl-5-bromopyrazine and phosphorus oxybromide is heated at about 175° C. for several hours with constant stirring. After hydrolysis of the solution on ice the crude product is extracted with ether and distilled. The distillate is refluxed with phosphorus tribromide for several hours and, after cooling, the solution is hydrolyzed on ice and the product extracted with ether, the ether removed in vacuo to give 2,5-dibromo-3-methylpyrazine.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]12([C:21]3[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>N1C=CC=CC=1>[C:11]12([C:21]3[CH:29]=[CH:28][C:24]([C:25]([S:1][C:2]4[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=4)=[O:26])=[CH:23][C:22]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:12][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:19]3)[CH2:18]1)[CH2:20]2
Reactant: O=C(O)c1ccc(S)cc1
Reactant: COCCOCOc1cc(C(=O)Cl)ccc1C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Product: COCCOCOc1cc(C(=O)Sc2ccc(C(=O)O)cc2)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
850 mg (5.5 mmol) of 4-mercaptobenzoic acid and 20 ml of pyridine were introduced into a round-bottomed flask. A solution of 2.08 g (5.5 mmol) of 4-(1-adamantyl)-3-methoxyethoxymethoxybenzoyl chloride prepared above was added dropwise and the mixture was stirred at room temperature for six hours. It was evaporated to dryness and the residue was taken up in water and ethyl acetate and acidified to pH 5, and the organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The solid obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and methanol (98/2). 1.5 g (57%) of 4-[4-(1-adamantyl)-3-methoxyethoxymethoxybenzoylthio]benzoic acid, having a melting point of 219°-21° C., was recovered.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCNC(=O)C1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of 2-piperazinone (5.0 g, 50.0 mmol) and triethylamine (11.09 g, 110.0 mmol) in DCM (15 mL) is added ethyl chloroformate (5.9 g, 55.0 mmol) at room temperature and the reaction mixture is stirred for 2 h. The reaction is quenched with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue is triturated with Et2O to give the title compound (5.0 g, 29.05 mmol) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 1.19 (t, 3H), 3.16-3.19 (m, 2H), 3.48-3.51 (m, 2H), 3.85 (s, 2H), 4.05 (q, 2H), 8.06 (s, 1H).