Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=[O:3].C([O:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:47])[F:46])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1)(=O)C1C=CC=CC=1.[OH-].[K+:50].O>CO>[OH-:3].[K+:50].[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:46])[F:47])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1
Reactant: O=C(O)C(=O)O
Reactant: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCOC(=O)c1ccccc1)NCCOc1ccccc1OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCO)NCCOc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
3-{7-Cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate monooxalate(10.0 g) was dissolved. in methanol (40 mL), then an aqueous potassium hydroxide solution, which was prepared from potassium hydroxide (2.93 g) and water (10 mL) was added little by little, and the mixture was stirred at room temperature for overnight. To the reaction mixture, water (150 mL) was added and extracted with ethyl acetate (150 mL and 50 mL) successively. The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (7.86 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:12]3[N:17]=[CH:16][C:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: C1CN(CC2CC2)CCN1
Product: N#Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Temperature: 140 °C
Yield: 36.9 %

Procedure:
1-Cyclopropylmethyl-piperazine (13 g, 94 mmol) was mixed with 4-(6-cloro-pyridin-3-yl)benzonitrile (5 g, 23 mmol). The mixture was heated at 140° C. for 1.5 hours. The mixture was cooled to rt and purified by column chromatography (EtOAc:petrolether=1:1) on silica gel to give 2.7 g (43%) of 4-[6-(4-cylopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzonitrile.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:24])[C:17]([C:25]([O-])=O)=[CH:16]1.CN1C2C(=CC=CC=2)C(C)=C1C([O-])=O>>[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:24])[C:17]([CH2:25][NH:6][CH3:5])=[CH:16]1
Reactant: Cc1cccc2c(C(=O)[O-])cn(C)c12
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C(=O)[O-])n(C)c2ccccc12
Product: CNCc1cn(C)c2c(C)cccc12
Yield: 98 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 1,7-dimethyl-1H-indole-3-carboxylate for the 1,3-dimethyl-1H-indole-2-carboxylate, the title compound (0.74 g, 98%) was obtained as an amber oil: MS (ES) m/e 189.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a stirring solution of 1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinol (4.00 g, 15.0 mmol) in DCM (150 mL) was sequentially added solid NaHCO3 (6.31 g, 75.1 mmol), Dess-Martin Periodane (7.65 g, 18.0 mmol) and H2O (0.27 mL, 15.0 mmol). The reaction was then vigorously stirred at rt for 1 h. The reaction was quenched with equal volumes of saturated sodium thiosulfate (aq) and saturated NaHCO3 (aq) and allowed to stir for an additional 0.5 h. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were then dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinone (2.15 g, 54%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (d, J=9.3 Hz, 1H), 6.61 (dd, J=9.4, 2.6 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 4.21 (q, J=7.0 Hz, 2H), 3.81 (t, J=6.1 Hz, 4H), 2.46-2.53 (m, 4H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)=[O:11])=[C:7]([NH:20][C:21]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[O:22])[C:6]=2[CH:32]=1.[CH3:33][O:34][CH2:35][C:36](O)=[O:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:33][O:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=3)=[O:11])=[C:7]([NH:20][C:21]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:30])[CH3:31])[CH2:25][CH2:24]3)=[O:22])[C:6]=2[CH:32]=1)=[O:37]
Reactant: COCC(=O)O
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(N)cc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COCC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 180 is suspended in N,N-dimethylformamide (6 ml), and thereto are added successively methoxyacetic acid (23 mg), 1-hydroxybenzotriazole (39 mg) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (55 mg) under ice-cooling, and the mixture is stirred at room temperature for 17 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform, then chloroform/methanol=30/1) to give trans-5-methoxyacetylamino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide. Subsequently, this product is dissolved in ethanol, and treated with 4N hydrogen chloride in ethyl acetate to give the title compound (84 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[S:14][C:13]=1[NH:21][C:22]([NH2:24])=[NH:23].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:17]1[CH2:18][CH2:19][C:20]2[N:12]=[C:13]([NH:21][C:22]([NH2:24])=[NH:23])[S:14][C:15]=2[CH2:16]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc2c(s1)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzyl chloroformate is added to a stirred suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine (0.1 mmol) and diisopropylethylamine (0.22 mmol) in dimethylformamide (0.7 ml) and the mixture is stirred for another 3 hours at room temperature. After the addition of saturated aqueous sodium carbonate solution extraction is carried out with ethyl acetate; the combined organic phases produce the pure title compound after drying over sodium sulphate and complete evaporation of the solvent.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[C@H:14]([N:16]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:17]([C@@H:19]1[C@@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21](=[O:27])[O:20]1)=[O:18])[CH3:15].C(O)=O.[CH2:51](O)[CH3:52].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[C@H:14]([N:16]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:17]([C@@H:19]1[C@@H:23]([C:24]([O:26][CH2:51][CH3:52])=[O:25])[CH2:22][C:21](=[O:27])[O:20]1)=[O:18])[CH3:15]
Reactant: CCO
Reactant: C[C@H]([C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)[C@H]1OC(=O)C[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: O
Product: CCOC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
155 mg of (2S,3S)-2-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylic acid prepared by deprotecting the ester of the compound of Example 67(1) with formic acid, 13.5 mg of ethanol and 36.0 mg of 4-dimethylaminopyridine, were dissolved in 2 ml of chloroform, and 57.0 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was poured into water and extracted with chloroform. The extract solution was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 123 mg (yield: 76%) of the above-identified compound as slightly yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13](S(C)(=O)=O)=[N:12][CH:11]=1)[CH3:9])=[O:6].[CH2:23]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33])(=[O:27])=[O:26])[CH3:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:33][C:32]2[CH:34]=[C:28]([S:25]([CH2:23][CH3:24])(=[O:26])=[O:27])[CH:29]=[CH:30][C:31]=2[O:35][CH3:36])=[N:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: CC(NC(=O)c1cccc(Br)c1)c1cnc(S(C)(=O)=O)nn1
Reactant: CCS(=O)(=O)c1ccc(OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Reaction time: 24 h
Yield: 34.1 %

Procedure:
To a stirred solution of 3-bromo-N-{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 6) (240 mg, 0.62 mmol) in tetrahydrofuran (10 mL) was added 5-(ethylsulfonyl)-2-methoxyaniline (270 mg, 1.2 mmol) and 4-toluenesulfonic acid monohydrate (20 mg). After stirring for 24 hours, silica gel (2.5 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (80:20) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-[1-(3-{[5-(ethylsulfonyl)-2-methoxyphenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (110 mg) as a white solid. 1H NMR (CDCl3): δ9.00 (d, J=2.2 Hz, 1H), 8.44 (s, 1H), 8.03 (s, 1H), 7.95 (dd, J=1.9, 1.4 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.57-7.52 (m, 1H), 7.22 (dd, J=8.1, 7.7 Hz, 1H) 7.00 (d, J=8.8 Hz, 1H) 5.44 (dq, J=7.2, 7.0 Hz, 1H), 3.98 (s, 3H), 3.10 (q, J=7.3 Hz, 2H), 1.68 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H). MS m/z 520, 522 (M+1, M+3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[N:2].Cl.CCOCC>CO.[Pd]>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][N:6]=1
Reactant: COc1cc(C#N)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(CN)ccn1
Reaction time: 8 h

Procedure:
4-Cyano-2-methoxypyridine (1.7 g) was dissolved in MeOH (50 mL) and conc. HCl (4.96 mL) was added. Pd/C (10%) was added and H2 was added and let stand overnight. The solids were filtered through Celite® and the cake was washed with MeOH (˜250 mL). Concentration in vacuo produced an oil which was dissolved in MeOH (˜20 mL). Et2O (200 mL) was added and stirred for 1 h. The resulting precipitate was filtered and washed with Et2O to afford (2-methoxypyridin-4-yl)methylamine (HCl salt) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1.Br[CH2:33][CH:34]1[CH2:37][CH2:36][CH2:35]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:34]1([CH2:33][N:13]2[CH:12]=[C:11]([C:10]3[N:2]([CH3:1])[C:3]4[C:8]([N:9]=3)=[C:7]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]5[C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=6[NH:24][C:23]5=[O:31])[CH2:20][CH2:21]3)[N:6]=[CH:5][N:4]=4)[CH:15]=[N:14]2)[CH2:37][CH2:36][CH2:35]1
Reactant: BrCC1CCC1
Reactant: Cn1c(-c2cn[nH]c2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cnn(CC3CCC3)c2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 100 °C
Yield: 20.7 %

Procedure:
To a solution of 1-{1-[9-methyl-8-(1H-pyrazol-4-yl)-9H-purin-6-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (30 mg, 0.07 mmol) in DMF (0.5 mL) were added (bromomethyl)cyclobutane (0.02 mL, 0.18 mmol), and sodium bicarbonate (9 mg, 0.11 mmol). The reaction mixture was heated to 100° C. for 24 hours. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 7 mg (23% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.01 (t, 1H), 7.13 (dd, 1H), 6.95-6.90 (m, 3H), 4.62-4.45 (m, 1H), 4.21 (d, 2H), 3.86-3.82 (m, 3H), 2.79 (dt, 1H), 2.40-2.25 (m, 2H), 2.01-1.92 (m, 2H), 1.87-1.70 (m, 6H); MS (EI) for C26H29N9O: 484.5 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17]([NH:16][CH3:15])=[O:18])=[CH:25][CH:24]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CCOCC3)n2)cc1
Yield: 34 %

Procedure:
A mixture of compound 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 42.7 mmol), Pd(PPh3)4 (2.46 g, 2.1 mmol), 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (11.7 g, 42.4 mmol) and 1N Na2CO3 (168 mL, 168 mmol) in degassed 1,2-dimethoxyethane (400 mL) was heated to 65° C. for 8 hours under N2 atmosphere. The reaction mixture filtered, diluted with water, extracted with ethyl acetate and washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 20-60% ethyl acetate in pet-ether as an eluent. To give 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (5.0 g, 34% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH3:3].Br[C:13]1[CH:14]=[C:15]([O:19][CH3:20])[CH:16]=[CH:17][CH:18]=1.C([Li])CCC>C1COCC1.[Fe](Cl)(Cl)Cl>[CH3:3][N:2]([CH2:4][CH:5]1[C:6]([OH:11])([C:17]2[CH:16]=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][CH:18]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1CCCCC1=O
Agent: Cl[Fe](Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 3.53 g of (±)-2-((dimethylamino)methyl)cyclohexanone (23 mmol) dissolved in 20 mL of THF at 0° C. was added dropwise a solution of 37 mg of iron (III) chloride (0.2 mmol, 1 mol percent) in 3 mL of THF at 0° C. The resulting violet solution was cooled to −78° C. In a separate vessel, 5.10 g of 3-bromoanisole (27 mmol) was dissolved in 50 mL of THF and the resulting solution was cooled to −78° C. To the solution of 3-bromoanisole was added dropwise with stirring 2.07 g of n-butyl lithium (27 mmol, 10 M solution in hexanes). The resulting white suspension was stirred for 1 hour and then transferred dropwise over a 4 hour period to the solution of (±) 2-((dimethylamino)methyl) cyclohexanone and iron (III) chloride at −78° C. The reaction mixture was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with diethyl ether and the diethyl ether extracts were combined. The combined ether extracts were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to provide 6.92 g (14 mmol, 62% yield) of the above-titled mixture in a ratio of 97.8:2.2 as determined using HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CN(C=O)C>[CH2:24]([CH:23]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:15][CH2:14]1)[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(Br)CC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 120 °C
Yield: 18.8 %

Procedure:
To a solution of 1-(5-nitro-pyridin-2-yl)-piperazine (2.2 g, 10.5 mmol) in DMF (10 mL) were added potassium carbonate (2.9 g, 21 mmol) and 3-bromopentane (4.8 g, 31.7 mmol). The mixture was heated at 120° C. for six hours. DMF was removed in vacuo to give a residue which was partitioned between water and DCM. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give 1-(1-ethyl-propyl)-4-(5-nitro-pyridin-2-yl)-piperazine (550 mg, 19%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:26]([O-:28])=[O:27])[CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:40](O)[CH2:41][OH:42]>C1CCCCC1>[CH2:41]1[O:42][C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:14][CH2:13][CH:12]([N+:26]([O-:28])=[O:27])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:25][CH2:40]1
Reactant: COc1ccc(CC(CCC(=O)CCc2ccc(Cl)cc2)[N+](=O)[O-])cc1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: COc1ccc(CC(CCC2(CCc3ccc(Cl)cc3)OCCO2)[N+](=O)[O-])cc1OC

Procedure:
Into 1 l. r.b. flask equipped with a Dean Stark trap was placed 65 g (0.16 mole) of 1-(3',4'-dimethoxyphenyl)-7-(4'-chlorophenyl)-2-nitro-5-heptanone, 2 g p-toluenesulfonic acid, 100 ml ethylene glycol and 400 ml of cyclohexane. The mixture was allowed to reflux overnight, then concentrated in vacuo. Dil NaHCO3 solution was added to the residue and extracted with methylene chloride. The organic layer was backwashed with water, dried over anh MgSO4, filtered and concentrated under reduced pressure to obtain 45.3 g of an oil which solidified on drying at room temperature under vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]([CH:46]=O)[C:33]3[C:38]([CH3:39])=[N:37][N:36]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:34]=3[N:35]=2)=[C:26]([F:48])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:46][C:32]2[CH:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:25][C:26]=3[F:48])[N:35]=[C:34]3[N:36]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[N:37]=[C:38]([CH3:39])[C:33]=23)[CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C=O)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 106 mg 2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 5 ml of dichloromethane was added 200 mg of freshly prepared 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbaldehyde. 143 mg of sodium triacetoxyborohydride and 15 mg of acetic acid were added and the reaction was stirred at r.t. for 16 h. The reaction was then diluted with dichloromethane and shaken with sat. aqueous ammonium chloride solution. The layers were separated and the organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. 318 mg (100%) of the crude title compound were obtained which were used in the next step without further purification.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.[CH2:15](Br)[CH3:16]>>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: CCBr
Reactant: Nc1cnc2c(n1)CCNCC2
Agent: Br
Product: CCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 31 by alkylation of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide with ethyl bromide.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]2[C@H:19]([CH2:20]2)[C@H:18]1[CH2:23][NH2:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]2[C@H:19]([CH2:20]2)[C@H:18]1[CH2:23][NH:24][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At 0° C. ethyl trifluoroacetate (41.9 mmol, 1.3 eq) is added to a solution of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (32.0 mmol, 1.00 eq) in THF (80 mL). The mixture is stirred at RT for 90 min and the solvents are removed in vacuo to give the desired product which is used without further purification in the next step. LC-MS: tR=0.94 min; [M+H]+=309.1.