Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:10][CH:11]([CH3:22])[CH2:12][CH2:13][C:14]1[S:18][C:17]([C:19]([NH2:21])=[O:20])=[CH:16][CH:15]=1>CS(C)=O.O>[OH:1][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[CH2:3][NH:10][CH:11]([CH3:22])[CH2:12][CH2:13][C:14]1[S:18][C:17]([C:19]([NH2:21])=[O:20])=[CH:16][CH:15]=1
Reactant: CC(N)CCc1ccc(C(N)=O)s1
Reactant: c1cncc(C2CO2)c1
Solvent: O
Solvent: CS(C)=O
Product: CC(CCc1ccc(C(N)=O)s1)NCC(O)c1cccnc1
Yield: 9.3 %

Procedure:
606 mg of 3-[(RS)-2-oxiranyl]pyridine and 991 mg of (RS)-5-(3-aminobutyl)-2-thiophenecarboxamide were heated to 100° for 25 hours in 5 ml of DMSO. The reaction mixture was diluted with water and extracted three times with methylene chloride. The methylene chloride solutions were washed with water, dried and evaporated in a vacuum. Chromatography of the residue on silica gel with ether/methanol gave 149 mg of 5-[(RS)-3-[[(RS)-2-hydroxy-2-(3-pyridyl)ethyl]amino]butyl]-2-thiophenecarboxamide, ε201 =14420; ε268 =11310.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[C:23]#[N:24])=[C:5]([CH3:25])[O:4][N:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[C:23]#[N:24])=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C#N
Temperature: 25 °C
Yield: 46.5 %

Procedure:
(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (12 mg, 0.036 mmol) was dissolved in CH2Cl2 (3 mL) and BBr3 (1 M solution in DCM, 0.3 mL, 0.28 mmol) was added. The mixture was stirred at room temperature over night. Water and DCM were added and the phases were separated. The organic phase was purified on a silica plug to give 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (5.4 mg, 47%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][C:22]=2[CH3:23])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A mixture of 4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde (114 mg, 0.41 mmol) and sodium borohydride (63 mg, 1.6 mmol) in 3 ml of methanol was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give yellow oil. The oil was purified through silica gel using chloroform as eluent to give 70 mg of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.04 (s, 2H), 6.32 (s, 1H), 4.55 (s, 2H), 4.21 (m, 1H), 2.30 (brs, 1H), 2.22 (s, 3H), 2.21 (s, 3H), 2.12 (s, 6H), 1.73 (m, 4H), 0.91 (t, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33]>C(O)(C)C>[OH:36][C:31]1([C:32]([F:35])([F:34])[F:33])[CH2:30][N:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=2)=[N:21]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C(F)(F)F)cc2)cc1

Procedure:
To a mixture of 4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70–75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by chromatography (silica gel, toluene/ethyl acetate, 7/3) to give 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:19][CH:20]([OH:23])[CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[O:23][CH:20]([CH2:21][OH:22])[CH2:19][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: OCC(O)CCl
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCC1COC(c2nc3cc(Cl)c(Cl)cc3[nH]2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (503 mg), 3-chloro-1,2-propan-diol (393 mg) and potassium carbonate (491 mg) were dissolved in DMF (5 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (2×20 mL). The extracts were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2; 40% ethyl acetate/hexanes), followed by washing solid with CH2Cl2/hexanes to yield the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]([C:4]([CH2:11][CH3:12])([CH2:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6])=[O:3].C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][NH:25][CH3:26]>CCOCC>[CH2:9]([C:4]([CH2:11][CH3:12])([C:2](=[O:3])[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:27])[C:5]([O:7][CH3:8])=[O:6])[CH3:10]
Reactant: CCC(CC)(C(=O)Cl)C(=O)OC
Reactant: CNCCC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(CC)(C(=O)OC)C(=O)N(C)CCC(=O)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 19.2 g of methyl 2-chloroformyl-2-ethyl-butyrate and 20 g of triethylamine in 100 ml of dry ether, which is mechanically stirred and cooled at -10° C, there is added dropwise 12.8 g of N-methyl-β-alanine methyl ester dissolved in 50 ml of dry ether. After the addition, which takes 30 minutes, the mixture is stirred during 18 hours at room temperature. After filtration of the separated triethylamine hydrochloride, the solvent is evaporated leaving the desired product as an oil, boiling at 118° C (0.2 mm). Yield 93%. nD19 1.4646.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Se](=O)=[O:10]>O1CCOCC1>[CH3:7][C:6]1[O:5][C:4](=[O:8])[O:3][C:2]=1[CH2:1][OH:10]
Reactant: Cc1oc(=O)oc1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: Cc1oc(=O)oc1CO

Procedure:
A mixture of 4,5-dimethyl-2-oxo-1,3-dioxolene (1 mmol) and selenium dioxide (2.5 mmol) in dioxane was heated at reflux for 1 h. Evaporation, extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: Rf=0.5, 5% MeOH-dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(OC2CCNCC2)c2cc(F)ccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC2CCN(S(C)(=O)=O)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of [6-fluoro-4-(piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (80 mg, 0.25 mmol) and methanesulfonyl chloride (58 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added triethylamine (63.6 mg, 0.63 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 10-50% ethyl acetate in petroleum ether) to afford [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (82 mg, 83%) as a white solid.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][OH:25])=[CH:18][CH:17]=3)[N:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl>C1COCC1.[Pd]>[N:1]1([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=3)[N:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C#CCO)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(CCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a magnetically stirred suspension of 14 mg of palladium (10 wt % on carbon) taken in 8 ml of THF was added compound 2-1 (80 mg, 0.165 mmol) dissolved in 3 ml of THF. The resulting mixture was stirred at room temperature for 2 h under an atmosphere of hydrogen. Then to the mixture was added 10 ml of DCM and the catalyst was filtered and the residue was concentrated and purified by flash column chromatography (petroleum ether-ethyl acetate, 6:4) to afford 61 mg (76%) of 4-1 as a white solid.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>[Cu]I>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:46][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(Sc5ccccc5)n4n3)cc2)CC1
Temperature: 120 °C
Yield: 27.1 %

Procedure:
Into a sealed tube was added (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.120 g, 0.310 mmol), Sodium tert-butoxide (89.5 mg, 0.931 mmol), Copper(I) iodide (4 mg, 0.02 mmol), 1,2-Ethanediol (34.7 uL, 0.623 mmol), N,N-Dimethylformamide (4.4 mL, 56 mmol), and finally Benzenethiol (32.1 uL, 0.313 mmol). The reaction was heated at 120° C. overnight. An HPLC showed 40% starting material remaining The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The Solvent was removed under vacuum. The desired product was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 8% methanol). The collected fractions afforded [4-(4-Methyl-piperazin-1-yl)-phenyl]-(7-phenylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a yellow solid (35 mg, 27%). MP 155-157° C. LCMS (E/I+) 417.13 (M+H). NMR 1H (DSMO-d6)-9.33 (s, 1H), 8.97 (s, 1H), 7.43 (d, 2H, J=9.04 Hz), 7.30 (t, 2H, J=7.57 Hz), 7.18 (t, 1H, J=7.33 Hz), 7.13 (d, 2H, J=8.33 Hz), 7.01 (d, 1H, J=4.60 Hz), 6.92 (d, 1H, J=4.60 Hz), 6.74 (d, 2H, J=9.09 Hz), 3.03 (t, 4H, J=5.96 Hz), 2.44 (t, 4H, J=5.21 Hz), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].O.[OH-].[K+].[CH3:18][N:19]=[C:20](SC)[S:21][CH3:22]>ClCCl>[CH3:18][NH:19][C:20](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:21][CH3:22]
Reactant: CN=C(SC)SC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask fitted with a condenser, stirrer and thermometer were added 20 g. of the dioxalate salt of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole, and 50 ml. of water. The pH of the solution was adjusted to 6.1 by the addition of 52 ml. of 2N aqueous potassium hydroxide, and 7.5 g. of methylcarbonimidodithioic acid, dimethyl ester, was added. The mixture was stirred at 75° for 3 hours, and was then cooled to ambient temperature. Its pH was adjusted to 6.5 by addition of 3.2 ml. of 2N aqueous potassium hydroxide, and 100 ml. of dichloromethane was added with vigorous mixing. The pH was adjusted to 6.5 again with 1 ml. of 2N aqueous potassium hydroxide, and the organic layer was separated and discarded. The aqueous layer was mixed with 100 ml. of additional dichloromethane, and its pH was adjusted to 13 by addition of 55 ml. of 2N aqueous potassium hydroxide. The organic layer was separated, dried over potassium carbonate and evaporated under vacuum to obtain 13.1 g. of product, which was found by NMR analysis to be substantially identical to that of Example 1. Its purity was 94.6% by high performance liquid chromatographic analysis.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccc(C#N)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.267 g, 1.00 mmol), 4-bromomethyl-2-fluoro-benzonitrile (0.321 g, 0.1.50 mmol), DIPEA (0.259 g, 2.00 mmol) and KI (0.017 g, 0.10 mmol) in dry CH3CN (10 mL) was stirred at 60° C. for 16 h. After that period of time the CH3CN was removed by evaporation under vacuum, and saturated aqueous NaHCO3 (20 mL) was added. The aqueous mixture was extracted with CH2Cl2 (3×30 mL, and the extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on a silica gel column (1000:30:1, CH2Cl2/CH3OH/NH4OH), affording 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-fluoro-benzonitrile as a white foam (0.400 g, 100%). 1H NMR (CDCl3) δ 1.65-1.80 (m, 3H), 2.09-2.14 (m, 1H), 2.20-2.38 (m, 2H), 2.44 (s, 6H), 3.58 (s, 2H), 4.16 (s, 1H), 4.20 (s, 1H), 6.37-6.43 (m, 2H), 6.93-7.03 (m, 3H), 7.23 (d, 2H, J=7.5 Hz), 8.35 (dd, 2H, J=0.9, 4.5 Hz).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(O)=O.[NH2:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]2[N:16]=[C:15]([N:32]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35][CH2:34][CH2:33]2)[CH:14]=1>CC#N>[NH2:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]2[N:16]=[C:15]([N:32]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35][CH2:34][CH2:33]2)[C:14]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: O=CO
Solvent: CC#N
Product: Nc1c(Br)c(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
A solution of NBS (14.6 mg, 0.082 mmoL) in CH3CN (0.5 mL) was added to a mixture of 1-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,4-diazepan-5-one formic acid salt (32.3 mg, 0.077 mmoL) in CH3CN (3 mL). After stirring at room temperature for 10 min, the solvent was evaporated and the residue was purified by prep-LC to afford titled compound (22.6 mg, 59%). LCMS tR=2.78 Min. Mass calculated for, M+ 451.0, observed LC/MS m/z 452.0 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[N:50]=[CH:49][C:48](O)=[CH:47][N:46]=1>O1CCCC1.C(OCC)(=O)C>[Cl:44][C:45]1[N:50]=[CH:49][C:48]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:47][N:46]=1
Reactant: CN1CCC(O)CC1
Reactant: Oc1cnc(Cl)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(Oc2cnc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 100 mg (0.766 mmol) of 4-hydroxy-1-methyl piperidine in 1.5 ml of tetrahydrofuran, 155 mg (1.53 mmol) of di-tert-butyl azocarboxylic acid, 402 mg (1.53 mmol) of triphenylphosphine and 0.170 ml (1.53 mmol) of 2-chloro-5-hydroxypyrimidine were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution and the reaction solution was extracted with 1 N hydrochloric acid. 1 N sodium hydroxide aqueous solution was added to the aqueous layer to make its pH 10 and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to provide 152 mg of the title compound as a white solid (yield: 87%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)[CH:22]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[O:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]3)[CH:22]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)[CH:12]=3)[O:8][C:7]=12
Reactant: BrCc1ccccn1
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc(O)c5)cc34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc(OCc6ccccn6)c5)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
1-(4-{4-[7-Amino-2-(3-hydroxy-phenyl)-furo[2,3-c]pyridin-4-yl]-pyrazol-1-yl}-piperidin-1-yl)-ethanone (50 mg, 0.12 mmol) was dissolved in acetone (10 mL) and potassium carbonate (50 mg, 0.36 mmol) and 2-bromomethyl-pyridine (24 mg, 0.14 mmol) was added. The solution was stirred at RT overnight. After filtration the filtrate was concentrated and the residue was purified by preparative TLC (10% MeOH:DCM) to afford 8 mg (13%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.56-8.57 (d, J=4 Hz, 1H), 8.17 (s, 1H), 7.85-7.93 (m, 3H), 7.74 (s, 1H), 7.66-7.68 (d, J=7.2 Hz, 2H), 7.54 (s, 1H), 7.39-7.43 (m, 2H), 7.10-7.12 (d, J=8 Hz, 1H), 5.29 (s, 2H), 4.65-4.72 (m, 1H), 4.49-4.60 (m, 1H), 4.06-4.14 (m, 1H), 3.33-3.35 (m, 1H), 2.80-2.88 (m, 1H), 2.20-2.27 (m, 2H), 2.16 (s, 3H), 1.95-2.11 (m, 2H); MS (ESI): 509.11 [M+H]+; HPLC tR=2.18 min (ZQ3: polar—4 min).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:14]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[S:21](=[O:24])(=[O:23])[CH2:22][C:13]=3[C:12]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[N:11]2)[CH2:5]1.[NH3:33]>CC#N>[N:27]1([C:25]([C:12]2[C:13]3[CH2:22][S:21](=[O:24])(=[O:23])[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]=3[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH2:33])[CH2:5]3)[N:11]=2)=[O:26])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: O=C(c1nn(C2CCCN(CCCl)C2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: N
Solvent: CC#N
Product: NCCN1CCCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)C1
Temperature: 135 °C
Reaction time: 0.25 h

Procedure:
To a solution of enantiomer B of 1-[1-(2-chloroethyl)piperidin-3-yl]-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (90 mg; 0.19 mmol; 1.00 eq.) in CH3CN (0.90 ml) is added aq ammonia (181.88 μl; 2.82 mmol; 15.00 eq.) and the reaction is stirred at 135° C. for 15 min under microwave irradiation which after purification by MD-Autoprep affords the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.05 (d, J=7.8 Hz, 1H), 7.96 (t, J=7.1 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.4 Hz, 1H), 4.79 (q, J=16.2 Hz, 3H), 3.90 (s, 2H), 3.66 (s, 6H), 3.15 (d, J=9.7 Hz, 2H), 2.90 (q, J=13.0 Hz, 3H), 2.73-2.53 (m, 2H), 2.27-2.02 (m, 2H), 2.00-1.59 (m, 3H). MS (ESI+): 460.3. HPLC (max plot) 55.4%; Rt 2.09 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][SH:28]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][S:28][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCC2)CC1
Reactant: COC(=O)CCS
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCC2)C2CCC(C)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea (Example 202) and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)[CH3:2].Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C@@:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:18]2=[O:34]>C(#N)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([C@@:25]2([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:18]3=[O:34])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Product: CCc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N([C@@]2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
TEA (0.44 g, 4.4 mmol) was added to a mixture of 4-ethylbenzoyl chloride (0.34 g, 2.0 mmol) and 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) in acetonitrile (20 mL). The mixture was stirred at room temperature for 2 hours, and was evaporated under vacuum. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic phase was evaporated. The residue was chromatographed on silica gel using ethyl acetate as the mobile phase, providing 0.65 g, in 76% yield. The product was obtained as a white solid; mp 160-162° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 45/55 CH3CN/0.1% H3PO4, 4.20 (97.47%); 1H NMR (DMSO-d6) δ 1.19 (t, J=7.7 Hz, 3H), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.54-2.62 (m, 2H), 2.65-2.78 (m, 3H), 4.61 (d, J=6.0 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.76-7.84 (m, 5H), 9.14 (t, J=6.0 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 15.4, 21.1, 28.1, 28.6, 29.2, 42.6, 58.8, 121.6, 123.2, 127.4, 127.8, 129.6, 131.4, 131.5, 133.4, 147.6, 147.7, 166.4, 167.8, 167.9, 172.2, 172.3; Anal. Calcd for C24H23N3O5: C, 66.50; H, 5.35; N, 9.69. Found: C, 66.30; H, 5.26; N, 9.56.