Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([NH:19][CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O.[H-].[Na+].CI.[CH2:26]1COCC1.O>C1COCC1>[CH3:1][O:3][CH2:4][CH:5]([N:19]([CH3:26])[CH:20]=[O:21])[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=CNC(CCOc1cccc2ccccc12)COC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCC(CCOc1cccc2ccccc12)N(C)C=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 2-(formylamino)-4-(1-naphthyloxy)-1-butanol formate, described in Example 3, in THF (30 ml) is added dropwise to a suspension of 51% sodium hydride (600 mg) in THF (30 ml). The mixture is heated at 40° C. for one and a half hours and then cooled to room temperature. A solution of methyl iodide (2.4 g) in THF (10 ml) is added and the mixture stirred at room temperature for 18 hours. Excess sodium hydride is decomposed by the addition of THF/water (9:1). The mixture is filtered through diatomaceous earth (Celite). The filtrate is dried and evaporated to dryness. The oily residue is subjected to chromatography on silica gel. Elution with methanol-chloroform (1:30) gives the title compound, nmr (CDCl3) δ 2.05 (m, 2H), 2.85 (s, 3H), 3.35 (s, 3H), 3.6 (m, 1H), 4.15 (m, 4H), 6.75-8.35 (7H), 8.15 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=O)[CH:8]([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH2:9][CH3:10])=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:7]1[N:29]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:11][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)C(CC)OC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CC
Yield: 48.9 %

Procedure:
4-Trifluoromethyl-benzoic acid 3-ethoxycarbonyl-1-ethyl-2-oxo-propyl ester (25 mmol) is dissolved in acetic acid (100 mL) and dry ammonium acetate (10 g, 100 mmol) is added, then the reaction is heated under nitrogen to reflux. The reaction is monitored by TLC and HPLC but complete consumption of the starting material is never observed, and then allowed to cool. The cooled reaction is concentrated and diluted with 250 mL ethyl acetate. The residue is washed with 100 mL saturated sodium bicarbonate followed by water and brine. The organic layer is dried over anhydrous sodium sulfate, then concentrated and purified by column chromatrography. The fractions that contained pure product are concentrated to yield [5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (4.0 g, 12.22 mmol) or 50% yield.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:19]([NH2:21])=[O:20])=[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:6]=1.[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:22]1([C:2]2[S:3][C:4]([C:19]([NH2:21])=[O:20])=[C:5]([O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([F:18])([F:17])[F:16])[N:6]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: NC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1sc(-n2cnc3ccccc32)nc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide (0.050 g, 0.14 mmol) and benzimidazole (0.010 g, 0.08 mmol) in DMF (4 mL) was heated at 75° C. in the presence of K2CO3 (0.011 g, 0.08 mmol) for 12 h. After the reaction mixture had cooled to rt, it was diluted with EtOAc (10 mL), washed with H2O (4×10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.54-7.40 (m, 3H), 6.80 (bs, 1H), 5.82 (s, 2H), 5.63 (bs, 1H). MS m/z 419 (m+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(OC(C)(C)C)=O)=[CH:22][CH:21]=1)[C:15]([C:34]([O:36][CH3:37])=[O:35])=[C:14]2[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:16]2[C:15]([C:34]([O:36][CH3:37])=[O:35])=[C:14]([C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=3)[C:13]3[C:18](=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=[CH:11][CH:12]=3)[C:17]2=[O:19])=[CH:25][CH:24]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cccc(OCc3ccccc3)c2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cccc(OCc3ccccc3)c2c(=O)n1-c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A solution of the compound obtained in Example 335 (53 mg) in chloroform (4 ml) is cooled to 0° C., and thereto is added a 4M solution of hydrogen chloride in ethyl acetate (2 ml). The mixture is stirred at 0° C. for two hours, and thereto is added a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The extract is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=1:2) to give 2-(4-aminophenyl)-8-benzyloxy-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (20 mg) as listed in Table 30.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CN1CCCC1=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reaction time: 67 h

Procedure:
To a suspension of the Wang resin-supported racemic-(trans)-2-(4-nitrophenyl)cyclopropanecarboxylic acid (XIIc) in N-methylpyrrolidin-2-one (NMP, ˜15 ml/mmol) was added tin chloride dihydrate (15 equiv.). The mixture was shaken for 67 h and then filtered. The product resin was washed with NMP (×2), DCM, dioxane, dioxane-water (1:1×2), water (×2), dioxane-water (1:1×2) dioxane (×3), DCM (×3), methanol and ether, then dried in a vacuum oven at 40° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH:5]3[CH:6]2[CH2:8][CH:3]1[CH:4]3[C:9]1[NH:17][C:16]2[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=2[N:10]=1.[NH2:26]OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CC(O)=O>[O:1]=[C:2]1[NH:26][CH:3]2[CH2:8][CH:6]3[CH:5]([CH:4]2[C:9]2[NH:17][C:16]4[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=4[N:10]=2)[CH:7]13
Reactant: NOS(=O)(=O)O
Reactant: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=O)C53)nc2n(CCC)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(C3C4CC5C(C(=O)N4)C53)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
8-(5-Oxo-tricyclo[2.2.1.02,6]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (150 mg) was taken in HOAc (5 ml) and H2NOSO3H (100 mg) was added and refluxed for 5 hrs. Cooled to room temperature, treated with ice, sat NaHCO3, extracted with ethyl acetate, washed with brine, and dried over MgSO4. After concentration, the crude product was crystallized from acetone/water. Yield (135 mg). Mass (ES+358).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[C:4]([O:17][CH3:18])[CH:3]=1.S(Cl)(Cl)=O.[C:23](=O)(O)[O-]>CO>[CH3:23][O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[O:17][CH3:18])([CH3:16])[CH3:15]
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Reactant: O=C([O-])O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=O)CC(C)(C)c1ccc(I)cc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid (WO 98/54159) is added in a solution of 1.3 ml of thionyl chloride in 12 ml of methanol at 0° C. and stirred for 10 hours at room temperature. It is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. 3.2 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester is obtained as a crude product. This ester is mixed with 4.5 ml of trifluoromethyltrimethylsilane in 70 ml of DMF and 1.63 g of cesium carbonate at 0° C. and stirred for 10 hours at room temperature. 20 mg of tetrabutylammonium fluoride is added, and it is stirred for another 30 minutes at room temperature. The batch is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 1.47 g of the title compound is obtained as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15](Cl)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15]([C:22]4[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=4)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccc2ncnc(N3CCOCC3)c2n1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2ccc3ncnc(N4CCOCC4)c3n2)cc1
Yield: 92 %

Procedure:
The reaction of 4-morpholino-6-chloro-pyrido[3,2-d]pyrimidine and 4-chlorophenylboronic acid afforded the pure title compound (yield 92%) as a white solid solid which was characterized by its mass spectrum as follows: MS (m/z): 341.2 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH2:3][OH:4].[CH2:14](I)[CH2:15][CH2:16][CH3:17].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:14]([O:4][CH2:3][CH:2]([CH3:1])[CH:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:6])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCI
Reactant: C[C@H](CO)[C@H](C)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOCC(C)C(C)OC1CCCCO1

Procedure:
1.88 g (10 retool) of the crude (2R,3S)-2-methyl-3-tetrahydropyranyloxy-l-butanol was dissolved in 30 ml of DMF. Thereto was added 18.4 g of n-BuI. Thereto was further added carefully by small portions 4 g of oily sodium hydride (about 60%), with ice cooling. To the reaction mixture was added 300 ml of ethyl acetate. The insoluble materials were removed by filtration. The filtrate was washed with two 100 ml-portions of water, dried and concentrated under reduced pressure to obtain crude 1-butoxy-2-methyl-3-tetrahydropyranyloxybutane as an oily material. This crude product was dissolved in 150 ml of methanol. 5 g of Amberlist 15 was added thereto, and the mixture was stirred for 2 days at room temperature. The Amberlist 15 was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to Kugelrohr distillation to obtain 0.90 g of the title compound as an oily material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[O:11]1CCOCC1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1ccc([N+](=O)[O-])cn1
Reactant: C1COCCO1
Product: O=Cc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirred solution of compound 2-methyl-5-nitropyridine (30) (10 g, 72.5 mmol) in 1,4-dioxane (150 mL) was added SeO2 (9.5 g, 87.0 mmol) at room temperature. The resulting reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was evaporated, the residue was diluted with water (100 mL), the resulting precipitate was separated by filtration and the filtrate was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), the organic layer was dried over Na2SO4 and concentrated to give 31 (6.4 g, 58%) as a brown solid. Rf: 0.7 (30% EtOAc/pet-ether); 1H NMR (400 MHz, CDCl3): δ 10.18 (1H, s), 9.59 (1H, d, J=2.0 Hz), 8.68-8.65 (1H, m), 8.16 (1H, d, J=8.4 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:19](Cl)[O:20][CH2:21][CH2:22][O:23][CH3:24]>C(Cl)Cl>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 4-hydroxy-benzaldehyde (3.7 g, 30 mmol) and diisopropylethylamine (7.6 mL) in CH2Cl2 (60 mL) was added MEMCl (5.0 mL) in CH2Cl2 (17 mL) dropwise at 0° C. The mixture was stirred at RT for 3 h, quenched with Hcl (60 mL, 0.5 N). The mixture was extracted with CH2Cl2. The organic phase was washed with NaOH solution (1 N) and water. The separated organic phase was dried under Na2SO4, filtered and concentrated to give 6.2 g of product (97%) which was pure enough to be used to the next reaction without further purification. 1HNMR (200 MHz, CDCl3): δ 3.36 (s, 3H), 3.54 (m, 2H), 3.83 (m, 2H), 5.41 (s, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 9.90 (s, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[C:31]([NH2:33])[N:30]=[C:29]([SH:34])[N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:34][C:29]3[N:30]=[C:31]([NH2:33])[CH:32]=[C:27]([NH2:26])[N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(N)nc(S)n1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Nc1cc(N)nc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)n1
Yield: 48 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 4,6-diamino-2-mercaptopyrimidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 48% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1)[CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Product: CN1CCC(c2cn(C(=O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1

Procedure:
(22.5 mg, 61%); from 5-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5e, 25 mg, 0.10 mmol) and 4-fluorobenzoyl chloride (23.8 mg, 0.15 mmol), HRMS-FAB+ for C21H20N2OClF, calculated MH+ : 371.13263; found: 371.13063.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Cc2c(F)cccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Cc3c(F)cccc3F)cc2=O)n1
Yield: 49 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,6-difluoro-benzyl)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 65) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-benzyl)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (33.7 mg, 49%); ES+-HRMS m/e calcd for C26H31N5O3F2 [M+H+] 500.2468, found 500.2465. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 1H) 1.04 (s, 3H) 1.06 (s, 3H) 1.20-1.74 (m, 8H) 1.84-1.98 (m, 1H) 2.19-2.30 (m, 1H) 3.88 (s, 2H) 3.97 (s, 2H) 4.66 (s, 1H) 5.46 (dd, J=11.1, 4.5 Hz, 1H) 6.37 (d, J=2.1 Hz, 1H) 6.45 (br s, 1H) 7.18 (t, J=8.0 Hz, 2H) 7.39-7.50 (m, 1H) 7.51 (d, J=2.1 Hz, 1H) 7.92 (d, J=2.1 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1
Reactant: C1CCC2NCCCC2C1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(N2CCCC3CCCCC32)c(-c2ccccc2)n1
Yield: 3.2 %

Procedure:
6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 7%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.00 g, 3.96 mmol) and decahydroquinoline (0.60 g, 4.36 mmol) according to the general procedure of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCCC1
Yield: 82 %

Procedure:
A solution of 6methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (228 mg, 7.9 mmol) in thionyl chloride (5 ml) and DMF (0.2 ml) was heated at reflux for 1 hour. Toluene was added and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and cooled aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[C:12](Cl)([Cl:14])=[S:13]>>[Cl:14][C:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[S:13]
Reactant: CCOC(=O)C1CCCCN1
Reactant: S=C(Cl)Cl
Product: CCOC(=O)C1CCCCN1C(=S)Cl

Procedure:
In the same way, 3-[2-(4-chlorobenzyloxy)-5-pyridyl]-1,5-tetramethylene-4-thiohydantoin is prepared by reacting 2-ethoxycarbonylhexahydropyridine with thiophosgene to give N-chlorothiocarbonyl-2-ethoxycarbonylhexahydropyridine, which is then reacted with 2-(4-chlorobenzyloxy)-5-aminopyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[O:14])[CH2:17][CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(F)cc2c1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To a solution of 16 g of 5-fluoro-2-methylindole-3-carboxylic acid in 260 ml of tetrahydrofuran were added 16 g of 4-amino-1-benzylpiperidine and 19 g of dicyclohexylcarbodiimide, and the whole mixture was refluxed under heating for 3 hours. After cooling, the precipitated dicyclohexylurea was filtered off and the extract was concentrated. A mixture of the residue in 70 ml of tetrahydrofuran was stirred at room temperature and the insoluble dicyclohexylurea was filtered off. The filtrate was concentrated and the resulting residue was crystallized with hexane. The resultant crystals were filtered with suction and recrystallized from ethyl acetate to give 22.5 g of N-(1-benzyl-4-piperidyl)-5-fluoro-2-methylindole-3-carboxamide, melting at 166°-169° C.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].CO[CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][Si](C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:23]([N:17]1[CH2:16][CH:3]([CH3:4])[CH:2]([C:1]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C/C=C/C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(Cc2ccccc2)CC1C(=O)OCc1ccccc1
Yield: 105.9 %

Procedure:
Benzyl (2E)-but-2-enoate obtained in Example 1e (20.5 g, 116 mmol) was dissolved in dichloromethane (5 ml), and the mixture was cooled in an ice bath with stirring. Trifluoroacetic acid (257 μl, 3.47 mmol) was added, and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (33.1 g, 139 mmol) was added dropwise to the reaction liquid over 15 minutes so that the internal temperature did not exceed 62° C., while washing with dichloromethane (25 ml). The reaction liquid was left to stand until it reached mom temperature and was stirred for 15 hours. The reaction liquid was concentrated and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (38 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([NH2:42])=[C:37]([NH2:43])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1.[F:48][C:49]([F:53])([F:52])[CH:50]=O>CN(C=O)C.C(O)(C(F)(F)F)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]4[NH:42][C:50]([C:49]([F:53])([F:52])[F:48])=[N:43][C:37]=4[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N
Reactant: O=CC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2nc(C(F)(F)F)[nH]c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF was combined with 30 mg (0.26 mmol) trifluoroacetaldehyde and 3 drops of TFA and stirred for 2 h at 100° C. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.