Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[C:13]([C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][CH2:23][CH2:24][N:25]([CH2:33][CH3:34])[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:13]([C:17]1[CH:36]=[CH:35][C:20]([CH2:21][N:22]([CH2:23][CH2:24][N:25]([CH2:33][CH3:34])[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: CCN(CCNCc1ccc(C(C)(C)C)cc1)c1cccc(C)c1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12)c1cccc(C)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
81 mg (0.50 mol) of 1H-indole-7-carboxylic acid, 162 mg (0.5 mmol) of N′-(4-tert-butyl-benzyl)-N-ethyl-N-m-tolyl-ethane-1,2-diamine and 108 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 140 mg (55%) product as a colorless oil. MS (ISP) 468.4 (M+H)+.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23]([C:25]1([NH2:34])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])[CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1([NH:34][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (500 mg, 2.84 mmol) in DCM (10 mL) is added oxalyl chloride (0.50 mL, 5.68 mmol) dropwise. The resulting solution is stirred at RT for 2 h. After the removal of DCM and excess oxalyl chloride, the residue, 2-amino-indan-2-carboxylic acid ethyl ester (583 mg, 2.84 mmol) and DIPEA (1.88 mL, 11.3 mmol) are dissolved in DCM (20 mL). The resulting solution is stirred overnight. The reaction solution is diluted with DCM (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give the pure product (37) as white solid (610 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:16][CH:17]([CH2:19]O)O>>[CH:10]1([CH2:9][C:7]2[CH:6]=[C:5]3[C:3](=[C:2]([Br:1])[CH:8]=2)[N:4]=[CH:19][CH:17]=[CH:16]3)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Nc1ccc(CC2CCCC2)cc1Br
Reactant: OCC(O)CO
Product: Brc1cc(CC2CCCC2)cc2cccnc12

Procedure:
2-bromo-4-(cyclopentylmethyl)aniline and glycerol can be combined to form 6-(cyclopentylmethyl)-8-bromoquinoline,
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1COCC1.O.CCOC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50 g (0.33 mol) trans-4-aminocyclohexanol-hydrochloride and 77 g (0.726 mol, 2.2 eq) Na2CO3 in 650 ml THF and 150 ml water, 51.2 ml (0.363 mol, 1.1 eq) benzyl chloroformate were added at 5° C. over a period of 20 min. The reaction mixture was stirred at RT for 2 h, diluted with EtOAc and the phases were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. Trituration from hexane yielded 162.4 g (98%) trans-4-Hydroxy-cyclohexylcarbamic acid benzyl ester as white crystals, MS: 249 (M) (in analogy to: Venuti, Michael C.; Jones, Gordon H.; Alvarez, Robert; Bruno, John J.; J. Med. Chem.; 30; 2; 1987; 303-318).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[ClH:43].CO>C1COCC1.O>[ClH:43].[S:14]([N:11]1[C:8]2=[N:9][CH:10]=[C:5]([CH2:4][NH2:1])[N:6]=[C:7]2[CH:13]=[CH:12]1)([C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN=[N+]=[N-])cnc32)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-(azidomethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (32.6 g, 99.0 mmol) in THF (100 mL) and water (50 mL) was added Ph3P (31.3 g, 119 mmol). The reaction mixture was heated to about 45° C. for about 16 h. The mixture was allowed to cool to ambient temperature followed by removal of THF under reduced pressure. The mixture was partitioned between EtOAc (500 mL) and brine (250 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was diluted with EtOAc to 1 L total volume. To the rapidly stirring solution was added drop-wise 4N HCl (4N in dioxane, 30.0 mL, 120 mmol) resulting in formation of a tan precipitate. MeOH (10 mL) was added and the mixture was filtered after about 15 min. The precipitate was triturated with Et2O (1000 mL) for about 10 min, filtered, and washed with Et2O (500 mL) to provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (32.0 g, 90%) as a tan solid: LC/MS (Table 2, Method a) Rt=1.44 min; MS m/z: 303 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][C@H:36]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:37][OH:38].OS([O-])(=O)=O.[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][C@@H:36]([CH2:37][OH:38])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CC(C)C[C@@H](N)CO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.064 mmol) and (2R)-2-amino-4-methyl-1-pentanol (75 μL, 0.64 mmol) was heated in EtOH (3 mL) at 175° C. for 45 min. in a microwave. The reaction mixture was cooled to rt and let stand overnight. Added 1N NaHSO4 (2 mL) filtered the resulting suspension, washed with EtOH:water 1:1, and Et2O then concentrated the filtrate in vacuo. Dissolved the residue in CH2Cl2, washed with 0.5N NaHSO4, water, and brine then dried the organics over Na2SO4, filtered and concentrated in vacuo. Triturated the residue with Et2O, filtered and dried in vacuo to provide the product as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.53 Hz, 6 H), 1.40-1.50 (m, 2 H), 1.53-1.67 (m, 6 H), 1.99-2.11 (m, 2 H), 3.18-3.29 (m, 2 H), 3.35-3.50 (m, 4 H), 3.53-3.59 (m, 1 H), 4.09 (dd, J=4.32, 3.26 Hz, 1 H), 4.17 (s, 2 H), 4.93 (t, J=5.16 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 8.21 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.69 Hz, 1 H), 10.31 (d, J=9.06 Hz, 1 H), 17.27 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=O>>[CH2:1]([NH:8]/[C:11](/[CH3:13])=[CH:10]\[C:9]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CC(C)=O
Product: COC(=O)/C=C(/C)NCc1ccccc1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
96.4 grams (0.9 mole) of benzylamine was added dropwise with stirring while the temperature was maintained below 45° C. to a solution of 116.1 grams (1 mole) of methyl acetoacetate and the reaction mixture allowed to stand overnight to obtain a white solid. The latter was dried and then stripped of the solvent to obtain a residue which was crystallized from hexane to obtain 115.9 grams of the methyl 3-benzylaminocrotonate, m.p. 36°-37.5° C. 4.1 grams (20 millimoles) of the product was dissolved in 5 milliliters of benzene and used in the preparation of the dihydropyridine compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:17]=2[N:18]=[C:19]([C:21]([O:23]CC)=[CH2:22])[CH:20]=1)=[O:14].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[C:21]([C:19]1[CH:20]=[C:15]([C:13]([NH:12][CH2:11][C:4]2[C:5](=[O:10])[NH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH3:2])=[O:14])[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:30])[CH3:31])[C:17]=2[N:18]=1)(=[O:23])[CH3:22]
Reactant: C=C(OCC)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
35% HCl (4 mL) was added to the N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(1-ethoxyvinyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.12 g, 0.293 mmol) at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, saturated NaHCO3 solution was added to it and extraction was carried out by using 5% MeOH/DCM, the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired compound (90% yield). LCMS: 382.10 (M+1)+; HPLC: 99.55% (@ 254 nm) (Rt;6.316); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.09 (bs, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 5.89 (s, 1H), 5.35-5.29 (m, 1H), 4.36 (d, 2H, J=4.0 Hz), 2.75 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.56 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[C:13]([CH3:20])=[CH:12][S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[N:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1cnccn1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)csc1N
Product: Cc1csc2nc(-c3cnccn3)nc(Cl)c12

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyrazine and 2-amino-4-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][CH2:26][CH:27]=[O:28].[NH4+].[Cl-]>C1COCC1>[F:23][C:24]([F:30])([F:29])[CH2:25][CH2:26][CH:27]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[OH:28]
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=CCCC(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -78 °C
Yield: 66.6 %

Procedure:
n-Butyllithium (150 uL of a 2.5M solution in hexanes, 0.38 mmol) was added dropwise to a −78° C. solution of 4-bromo-4′-(trifluoromethyl)biphenyl (113 mg, 0.375 mmol) in 3 mL THF. The resulting solution was stirred at −78° C. 15 min. 4,4,4-trifluorobutyraldehyde (98 mg, 0.78 mmol) was added neat. The resulting colorless solution was stirred at −78° C. 20 min. 1 mL sat. aqueous NH4Cl was added, and the mixture warmed to room temperature. The reaction mixture was partitioned between Et2O and water. The organic layer was dried over MgSO4 and concentrated to give a colorless oil. The crude material was purified by silica gel chromatography to provide 4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (87 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 7.64-7.71 (m, 4H), 7.57-7.62) m, 2H), 7.41-7.47 (m, 2H), 4.78-4.87 (m, 1H), 2.10-2.39 (m, 3H), 1.96-2.09 (m, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([O:20]C)(=O)[CH:17]=[CH2:18]>>[N:6]1[CH:7]=[CH:12][CH:13]=[C:14]([CH2:1][C:17]2[C:16](=[O:20])[C:4]3[CH:3]=[CH:2][CH:1]=[C:14]4[C:5]=3[N:6]([CH:18]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]4=[O:15])[CH:5]=1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: C=CC(=O)OC
Product: O=c1c(Cc2cccnc2)cn2c3ccccc3c(=O)c3cccc1c32
Yield: 13 %

Procedure:
According to Example 5<steps 1 and 2>,9(10H)-acridone (10 g) was reacted with methyl acrylate (11.5 mL) to obtain the title compound (1.8 g; 13%).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][OH:7])[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].F[C:15]1[CH:20]=[CH:19][N:18]2[C:21]([C:24]([NH:26][C:27]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:28]=3[C:29]([CH:44]3[CH2:46][CH2:45]3)=[N:30][N:31]4[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=3)=[O:25])=[CH:22][N:23]=[C:17]2[CH:16]=1>C(O)(C)(C)C>[N:1]1([CH2:5][CH2:6][O:7][C:15]2[CH:20]=[CH:19][N:18]3[C:21]([C:24]([NH:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:28]=4[C:29]([CH:44]4[CH2:45][CH2:46]4)=[N:30][N:31]5[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=4)=[O:25])=[CH:22][N:23]=[C:17]3[CH:16]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1CCC1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCC6)ccn45)cccc32)n1
Temperature: 88 °C
Reaction time: 0.08 h

Procedure:
2-(Azetidin-1-yl)ethanol (52 mg, 0.51 mmol) was dissolved in tert-butanol (0.3 mL) and treated with potassium tert-butoxide (51 mg, 0.45 mmol). The mixture was stirred at 88° C. for 5 minutes before adding 7-fluoro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide in one portion. The mixture was stirred at 88° C. for 16 hours. The mixture was cooled to ambient temperature and quenched with water (2 mL) followed by vigorous stirring for 2 hours at ambient temperature. The precipitate was isolated by filtration and dried under vacuum to give a pale yellow residue which was triturated with diethyl ether 3 times to give a solid. Purification by Preparative Thin Layer Chromatography (Silica, 20×20, 0.5 mm thickness) eluting with 10% MeOH/DCM with 0.6% ammonium hydroxide gave 7-(2-(azetidin-1-yl)ethoxy)-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (18 mg). MS (APCI), positive scan, m/z=522.2 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=O)[C:8]([F:23])=[CH:7][C:6]=1[Cl:24].P(Cl)(Cl)([Cl:29])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]2[Cl:29])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24]
Reactant: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.98 g of N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, 1.5 ml of phosphorus oxychloride and 1.2 ml of pyridine in 10 ml of toluene is stirred at 80° C. for 3.5 hours. The mixture is then treated with 50 ml of ice-water and extracted three times with 80 ml of ethyl acetate each time. The combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and treated with 200 ml of n-hexane, and the mixture is filtered through 20 g of silica gel. The mixture is then concentrated and the product is left to crystallize out. In this manner there is obtained N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide, m.p. 183° C.;
Reaction SMILES: [NH2:1]N.Br[C:4]1[N:5]([C:14]2[N:15]=[C:16]([NH2:22])[NH:17][C:18](=[O:21])[C:19]=2[N:20]=1)[C@@H:6]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1.CO>O>[NH2:1][C:4]1[N:5]([C:14]2[N:15]=[C:16]([NH2:22])[NH:17][C:18](=[O:21])[C:19]=2[N:20]=1)[C@@H:6]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1
Reactant: Nc1nc2c(nc(Br)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: NN
Solvent: O
Solvent: CO
Product: Nc1nc2c(nc(N)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
Hydrazine is added to a suspension of 8-bromodeoxyguanosine in water:methanol (150 mL; 1:2) and the resulting solution is heated at reflux for 24 hours. The resulting precipitate is removed by filtration and the filtrate is evaporated to a solid. After repeated evaporations from ethanol, the product is recrystallized from methanol. The purified 8-azido-2'-deoxyguanosine (1.3 g) is dissolved in a mixture of methanol:water (160 mL, 5:3), Raney nickel (10.0 g) is added, and the mixture is heated at reflux for 18 hours. The catalyst is removed by filtration through celite and after washing with water and methanol the filtrate is evaporated to dryness. The resulting solid is recrystallized from methanol to yield 8-aminodeoxyguanosine.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CCCN(c2ccncc2)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5 g of ethyl nipecotate, 4.8 g of 4-chloropyridine hydrochloride, 6.6 g of triethylamine and 100 ml of xylene was stirred at 100° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent in an ordinary manner, and the obtained residue was purified by the silica gel chromatography (ethyl acetate/ethanol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(Cl)ccc2c1CCNCC2
Temperature: 25 °C
Reaction time: 42 h
Yield: 94 %

Procedure:
Slurry 7-chloro-6-(ethoxycarbonyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (176 g, 503 mmol) and potassium carbonate (348 g, 2516 mmol) in ethanol (1.4 L) and water (1.4 L). Stir the mixture at room temperature for 42 h. Partition the mixture between water (2.6 L) and EtOAc (2.6 L). Collect the organic layer and back extract the aqueous layer with EtOAc (1.8 L). Wash the combined organic extracts successively with water (1.8 L) and brine (1.8 L). Collect the organic layer, dry over Na2SO4 and concentrate in vacuo to obtain the desired intermediate as a green oil (120 g, 94%).
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([NH2:24])[C:17]=2[CH3:25])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[CH:26](=O)[CH2:27][CH3:28].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([NH:24][CH2:26][CH2:27][CH3:28])[C:17]=2[CH3:25])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(N)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCNn1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 34 %

Procedure:
To a mixture of 1-amino-2,4-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (415 mg, 1.21 mmol), propionaldehyde (0.52 mL, 7.3 mmol) and acetic acid (0.5 mL, 9 mmol) in methanol (10 mL) was added sodium cyanoborohydride (0.27 g, 4.2 mmol) and the mixture was stirred under argon atmosphere for 3 days at room temperature. The crude reaction mixture was concentrated in vacuo, diluted with H2O (30 mL) and extracted with dichloromethane (3×30 mL). The combined organic phases were washed with brine, dried over MgSO4 and evaporated. The crude mixture was purified by flash chromatography, yield 34%. LC-MS (m/z) 386.5 (MH+); tR=1.63 (method C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8].CO.[C:27](O)(=O)[CH3:28].[C:31]([BH3-])#N.[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH:27]([CH3:28])[CH3:31])[CH2:23][CH2:24]2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccccn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 34 %

Procedure:
A solution of 5-chloro-2-(piperidin-4-ylmethylamino)-N-(2-pyridyl)benzamide from above (1.3 g, 3.7 mmol) in acetone (28 mL) and methanol-acetic acid (95:5) (12 mL) was treated with sodium cyanoborohydride (1.0 g, 15.0 mmol). Gas evolution was observed; the reaction mixture was then stirred at room temperature for 7 h, after which it was concentrated in vacuo to a residue that was purified via silica gel chromatography. Elution with dichloromethane—2 M ammonia in methanol (9:1) provided 0.5 g (34%)of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12]C(=O)C)[N:10]=[C:6]2[N:5]=[C:4]([CH2:16][O:17]C(=O)C)[CH:3]=1.NC(N)=[S:23]>C(O)C>[OH:12][CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH2:16][OH:17])[CH:3]=[C:2]([SH:23])[N:7]2[N:8]=1
Reactant: CC(=O)OCc1cc(Cl)n2nc(COC(C)=O)nc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: OCc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
In 300 ml of ethanol was dissolved 14 g of 7-chloro-2,5-bis(acetoxymethyl)-s-triazolo[1,5-a]pyrimidine, and 10.7 g of thiourea was added thereto and the mixture was refluxed for 10 minutes. After removing ethanol from the reaction mixture, the residue was dissolved in 230 ml of a 5% potassium hydroxide. The mixture was stirred for 30 minutes, ice-cooled and adjusted to pH 2 with 2N hydrochloric acid. precipitated crystal was collected by filtration, washed with water and dried to obtain 7.16 g of the title compound.