Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[N:18]=2)[CH2:13][CH2:12]1.Cl.Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][CH2:32][C:31]2[CH:35]=[N:36][NH:37][C:30]1=2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:28][C:29]1([CH3:38])[CH2:34][N:33]([C:23]([C:19]2[N:18]=[C:17]([N:14]3[CH2:15][CH2:16][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:12][CH2:13]3)[CH:22]=[CH:21][N:20]=2)=[O:25])[CH2:32][C:31]2[CH:35]=[N:36][NH:37][C:30]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: O=C(O)c1nccc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(C(=O)c2nccc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)n2)Cc2cn[nH]c21

Procedure:
60 mg (0.18 mmol) 4-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylic acid, 40 mg (0.18 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 0.10 (0.72 mmol) triethylamine and 62 (0.19 mmol) TBTU in 1.5 mL DMF were stirred overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9]([S:25][CH3:26])=[N:8][C:7]=2[N:27]=1.Cl.N1C=CC=CC=1.Cl>CN(C)C=O>[CH3:26][S:25][C:9]1[N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:27][C:7]=2[N:8]=1
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(SC)nc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
7-Methoxy-2-(methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (1.55 g) and pyridine hydrochloride (3.1 g) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred at 120° C. for 2 hr, and allowed to be cooled. The reaction mixture was poured into 0.5M hydrochloric acid (22 ml), and the white precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (30 ml). The solution was diluted with ethyl acetate (60 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (1.33 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]2)[CH:3]=1.CN([CH:20]=[C:21]([C:29](=O)C)[C:22](OC(C)(C)C)=O)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][C:21]([CH3:29])([CH3:22])[CH3:20])=[O:15])[CH:10]=[N:9]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)cnn1-c1cc(Cl)ccn1
Reactant: CC(=O)C(=CN(C)C)C(=O)OC(C)(C)C
Solvent: CC#N
Product: Cc1c(C(=O)OC(C)(C)C)cnn1-c1cc(Cl)ccn1
Temperature: 85 °C
Yield: 27 %

Procedure:
1-(4-Chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.032 g, 0.148 mmol) in acetonitrile (2 mL) was added TEA (0.021 mL, 0.148 mmol) and Intermediate 42A (0.024 g, 0.133 mmol). The dark brown solution was heated to 85° C. for 1 h. The reaction mixture was concentrated, and water (1 mL) and CH2Cl2 (1 mL) were added. The organic layer was concentrated and purified by silica gel chromatography to give tert-butyl 1-(4-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate (12 mg, 27%) as yellow oil. MS(ESI) m/z: 294.2 (M+H)+. To the oil was added 4 N HCl in dioxane (2 mL). The reaction was stirred at rt for 4 h, and the clear orange solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product as sticky pink solid. MS(ESI) m/z: 238.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:21])[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[CH:9][NH:8][N:7]=1)=[O:5])C>[OH-].[Na+].CO>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[C:12]([NH:11][C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][NH:8][CH:9]=1)=[O:21]
Reactant: CCOC(=O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.7 %

Procedure:
A mixture of 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid ethyl ester (10.2 g) in 2 M aqueous NaOH/MeOH (1:1, 250 ml) was stirred at ambient temperature for 14 h. Volatile materials were removed in vacuo, water (300 ml) added and the mixture taken to pH 5 using 1M aqueous HCl. The resultant precipitate was collected by filtration and dried through azeotrope with toluene to afford 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pink solid (5.70 g). (LC/MS: Rt 2.33, [M+H]+ 267.96).
Reaction SMILES: [Cl:1][C:2]1[C:7](O)=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].[CH3:15][C:16]([CH2:18]Br)=[CH2:17]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH2:17][C:16]([CH3:18])=[CH2:15])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)Cc1c(I)cc(C(C)O)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (4.49 g, 15 mmol) in 25 mL of N,N-dimethylformamide at 0° C. is treated with 600 mg (60% in oil, 15 mmol) of sodium hydride and stirred at room temperature for 1 h. The reaction is treated with 1.7 mL (16.5 mmol) of 2-methyl-3-bromopropene and stirred for 2 h. The mixture is diluted with 150 mL of ethyl acetate and washed with 4×50 mL of 1:1 50% saturated sodium chloride/sodium bicarbonate, and dried over potassium carbonate. The crude material is chromatographed over 150 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexanes to give 3.94 g (74%) of 2-chloro-3-(2-methyl-1-propen-3-yl)-4-iodo-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>[Pd].C(O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(dimethylamino)-5-nitropyridine (1 eq) and 5% palladium on carbon (0.3 eq) in ethanol was stirred at room temperature and flushed with nitrogen. The reaction vessel was evacuated and purged with hydrogen three times. The reaction mixture was left under an atmosphere of hydrogen overnight. Nitrogen was flushed through the reaction and then the reaction was filtered through a celite pad. The celite pad was washed with excess ethanol before the solvent was removed by evaporation under reduced pressure to afford 2-(dimethylamino)-5-aminopyridine.
Reaction SMILES: S(=O)(=O)(O)O.[SH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[SH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:16])=[O:10]
Reactant: O=C(O)c1ccccc1S
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1S
Reaction time: 18 h
Yield: 90 %

Procedure:
To a cooled solution of concentrated sulfuric acid (72 g) in methanol (1.5 L) at 0° C., was added 2-sulfanylbenzoic acid (300 g, 1.95 mol) in portions under argon atmosphere. After being refluxed with stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with water (800 mL), basified with a saturated aqueous solution of sodium bicarbonate to about pH 7, and extracted with dichloromethane (600 mL×3). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 g of methyl 2-sulfanylbenzoate (yield was 90%) as a light yellow oil, which was used for the next step without further purification.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC)cc21
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Temperature: -2.5 °C
Yield: 20.4 %

Procedure:
DCM (305 mL) was transferred to a 1 L 3-necked round-bottomed flask and cooled to −11° C. (internal) (ice acetone bath). BBr3 (72.0 mL, 761 mmol) was added to the DCM with stirring. A solution of ethyl 2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (41.62 g, 152 mmol) in DCM (145 mL) was added in drops maintaining the internal temperature of about −5 to 0° C. After the addition the reaction was stirred for 1 h below about 0° C. The reaction mixture was slowly poured into mixture of ice (400 mL) and saturated K2CO3 (400 mL) and stirred well (pH maintained at 9-7). The organic layer was separated, washed with brine (1×100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residual brown oil was purified by passing it through a pad of silica gel to give the title compound (8.03 g). LCMS m/z=260.2.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[CH2:44]([NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]3[CH2:65][NH:64][CH2:63][CH2:62][C:60]=3[N:61]=2)=[CH:52][CH:51]=1)=[O:48])[CH3:45]>>[C:1]([CH2:3][C:4]([N:64]1[CH2:63][CH2:62][C:60]2[N:61]=[C:56]([C:53]3[CH:52]=[CH:51][C:50]([NH:49][C:47]([NH:46][CH2:44][CH3:45])=[O:48])=[CH:55][CH:54]=3)[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]=2[CH2:65]1)=[O:6])#[N:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)CC#N)CC3)cc1
Temperature: 40 °C
Reaction time: 96 h

Procedure:
Cyanoacetic acid (0.0300 g, 0.000353 mol) in dry N,N-Dimethylformamide (1.60 mL, 0.0207 mol) was added 1-Hydroxybenzotriazole (0.0488 g, 0.000361 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0721 g, 0.000376 mol) then followed by N,N-Diisopropylethylamine (0.161 mL, 0.000924 mol) and then (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.0002310 mol). The reaction mixture heated at 40° C. and was stirred for 4 days. The reaction mixture was concentrated, chromatographed through silica gel again (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.65 (d, J=15.7, 1H), 4.51-4.38 (m, 1H), 4.26-4.14 (m, 2H), 3.96-3.84 (m, 2H), 3.80-3.56 (m, 5H), 3.44 (dd, J=19.8, 12.6, 2H), 3.15-3.07 (m, 2H), 3.02-2.94 (m, 1H), 2.84 (s, 1H), 1.25 (t, J=5.4, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+464.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:24]=[N:23]2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:17][C:15]1([CH3:18])[O:14][C@@H:13]2[O:19][C@H:10](/[CH:9]=[CH:8]/[C:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:38]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:3][CH:4]=3)[C@H:11]([CH2:20][CH2:21][N:22]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[N:24]=[N:23]3)[C@@H:12]2[O:16]1
Reactant: OB(O)c1cncnc1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
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: [K+]
Product: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step j above (0.35 g), pyrimidin-5-ylboronic acid (0.174 g), tetrakistriphenylphosphinepalladium (0) (0.081 g), and potassium carbonate (0.291 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (5 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under the reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 40% ethyl acetate in hexane as eluant to afford the title compound (0.3 g).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].O.[OH-].[Li+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].O>CN(C=O)C>[CH2:1]([C:3]1[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1nc2c(C)ccnc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(C)ccnc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
2-Ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (1.00 g, 6.20 mmol) was dissolved in DMF (15 mL) and lithium hydroxide monohydrate (0.391 g, 9.31 mmol) was added at room temperature followed by stirring for 20 minutes. Then, 4-nitrobenzylbromide (1.34 g, 6.20 mmol) was slowly added to the mixture, and stirred at room temperature. After 30 minutes, water (20 mL) was added and precipitated crystals were collected by filtration, followed by washing with water. The crystals were dried under reduced pressure to obtain Compound P34 (0.819 g, 2.76 mmol, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1cc2nc(NC(=O)N3CCN(c4cccc(Cl)c4)CC3)c(OC)nc2cc1OC
Yield: 74 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 74%). 1H NMR (300 MHz, CDCl3) δ 3.29-3.31 (m, 4H), 3.79 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.12 (s, 3H), 6.82 (m, 1H), 6.86-6.88 (m, 1H), 6.89-6.91 (m, 1H), 7.14 (s, 1H), 7.19-7.22 (m, 3H).
Reaction SMILES: O.NN.[C:4]1([C:10]2[CH:50]=[CH:49][CH:48]=[CH:47][C:11]=2[C:12]([NH:14][C:15]2[CH:46]=[CH:45][C:18]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]4[CH2:31][C@@H:32]([N:34]5C(=O)C6=CC=CC=C6C5=O)[CH2:33][C@H:23]4[CH2:22]3)=[O:20])=[CH:17][CH:16]=2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[NH2:34][C@@H:32]1[CH2:31][N:24]2[C:25]3[C:30]([N:21]([C:19](=[O:20])[C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C:11]5[CH:47]=[CH:48][CH:49]=[CH:50][C:10]=5[C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=5)=[CH:46][CH:45]=4)[CH2:22][C@@H:23]2[CH2:33]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@H](N4C(=O)c5ccccc5C4=O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: N[C@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3N2C1
Yield: 86.1 %

Procedure:
Hydrazine monohydrate (0.41 g) was added to a solution of (2S, 3aS)-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-2-phthalimido-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline (1.0 g) prepared in Reference Example 65 in ethanol (10 ml) and the mixture was heated under reflux conditions for one and half hours. After cooling the reaction solution, the ethanol was removed through concentration. The resulting residue was dissolved in chloroform, the resulting solution was washed with a 5% aqueous solution of sodium hydroxide and water, died over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/methanol (95/5) to give 0.68 g (yield 86.0%) of the title compound as amorphous powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([S:25][CH3:26])[N:16]=1>C1COCC1>[CH3:26][S:25][C:17]1[N:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Oc2cccc(C(F)(F)F)c2)cc(C(F)(F)F)n1

Procedure:
m-(Trifluoromethyl)phenol (1.06 g, 0.0044×1.5 mol) and NaH (0.26 g (ca.60% in mineral oil), 0.0044×1.5 mol) were dissolved in THF, and then 4-chloro-2-methylthio-6-(trifluoromethyl)pyrimidine (Compound No. VII-17) (1.0 g, 0.0044 mol) was added thereto. The resulting solution was refluxed for about 7 hours. The reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate to separate an organic phase. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. Thereafter, remaining phenol and others were distilled off in a tubular oven (under water flow, 150° C.) to obtain the intermediate compound.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Reaction time: 69 h

Procedure:
Ethyl 8-Acetyl-12-hydroxy-13-(4-fluorophenoxy)-tridecanoate (4.67 g.; 0.0113 mole) is added to a solution of sodium hydroxide (0.68 g.; 0.0170 mole) in water (6.3 ml.) and methanol (56.7 ml.). The resulting solution is allowed to stand for 69 hours at 25°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][CH:11]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:19]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[NH:14][C:13](=[O:15])[O:12][CH:11]([CH:16]([CH3:18])[CH3:17])[C:10]=3[CH:19]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC(C)C1OC(=O)Nc2ccc(OCCCCl)cc21
Product: CC(C)C1OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4-isopropyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[C:19](#[N:22])[CH:20]=[CH2:21]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][CH2:21][CH2:20][C:19]#[N:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C=CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOCCC#N
Temperature: 50 °C

Procedure:
[2-(2-Cyano-ethoxy)-ethyl]-carbamic acid tert-butyl ester (430 mg) was prepared starting from (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (320 mg) in acrylonitrile (1.5 mL). The reaction was heated to 50° C. for 1 h. The reaction was added to ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and then filtered. The solvent was evaporated and crude compound was purified by flash chromatography using hexane:ethyl actetate gradient.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5]([Cl:14])=[N:6][C:7]2[N:8]([N:11]=[CH:12][CH:13]=2)[C:9]=1Cl.[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16]>C(N(CC)CC)C>[CH:15]([N:19]1[C:9]2[N:8]3[N:11]=[CH:12][CH:13]=[C:7]3[N:6]=[C:5]([Cl:14])[C:4]=2[CH2:3][CH2:2]1)([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)N
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Solvent: CCN(CC)CC
Product: CCC(C)N1CCc2c(Cl)nc3ccnn3c21
Yield: 88.9 %

Procedure:
Synthesis was performed by the reaction of 5.26 g of 6-(2-chloroethyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine with 4.00 g of sec-butylamine and 4.82 g of triethylamine in accordance with the synthetic process in Referential Example 9 to obtain 4.68 g (yield: 89.0%) of the intended product. White crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13](=[CH2:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:18].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl.S([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]2([O:18][CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CO2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution 3-methylen-pyrrolidine-1-carboxylic acid benzyl ester (WO9624593) in 5 ml of dichloromethane was treated with 2.16 g sodium bicarbonate (MW: 84.01 26.28 mmol) and 2.47 g of 80% m-chlor-perbenzoic acid (MW: 172.57, 11.48 mmol). The reaction mixture was stirred at room temperature for three hours. The reaction mixture was diluted with 20 ml of a saturated, aqueous sodium sulfite solution and 45 ml of dichloromethane. The organic layer was successively washed with 30 ml of an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate. The residue was purified by chromatography on silica (1/1 ethyl acetate/n-hexane) to afford a off white solid. Yield: 440 mg, 57%. MS: 234.1 (M+H)+, Method ESI+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[C:32]([NH2:38])=[N:33][C:34]([CH3:37])=[N:35][CH:36]=1>>[NH2:38][C:32]1[C:31]([CH2:30][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)=[CH:36][N:35]=[C:34]([CH3:37])[N:33]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1ncc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)c(N)n1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with 5-chloromethyl-2-methyl-pyrimidin-4-ylamine (described in Pharmaceutical Chemistry Journal (Translation of Khimiko-Farmatsevticheskii Zhurnal) (1999), 33(2), 101-103) gave the title compound.