Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:33](O)[CH2:34][CH2:35][OH:36].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:33][CH2:34][CH2:35][OH:36]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C)c2)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 5-methyl-3-(3-methylphenylsulfonyloxy)phenol (560 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a colorless oil (605 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.41 (s, 1H), 6.36 (s, 1H), 4.13 (t, J=7.2 Hz, 2H), 3.81 (m, 2H), 2.43 (s, 3H), 2.24 (s, 3H), 1.96 (m, 2H), 1.61 (br s, 1H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:18][O:17][C:8]2[CH:9]=[CH:10][C:11]3[NH:12][C:13](=[O:16])[O:14][C:15]=3[C:7]=2[O:6]1)=[N+]=[N-].[H][H].Cl>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[O:6][C:7]2[C:8](=[CH:9][CH:10]=[C:11]3[NH:12][C:13](=[O:16])[O:14][C:15]3=2)[O:17][CH2:18]1
Reactant: [N-]=[N+]=NC[C@H]1COc2ccc3[nH]c(=O)oc3c2O1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1COc2ccc3[nH]c(=O)oc3c2O1

Procedure:
(8S)-8-(Azidomethyl)-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-2(3H)-one (2.86 g, 11.5 mmole) in methanol (60 mL) was treated for 24 hours on a Parr shaker with 60 psi of hydrogen in the presence of 0.43 g of 10% Pd/C and 3.0 mL of 4 N isopropanolic HCl. The catalyst was removed by filtration through celite and was washed with additional methanol. The filtrate was evaporated in vacuum to give 2.12 g (68%) of the (S)-enantiomer of the title compound as a beige solid, m.p.>250° C.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([CH3:10])[CH:9]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:10][C:8]1[CH:9]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
The reaction apparatus consisted of a 50-mL single-necked round-bottom flask equipped with a water-jacketed condensor, magnetic stirrer, and an argon-filled balloon. A solution of 5-methoxy-2-nitrotoluene (0.25 g, 1.50 mmol), carbon tetrachloride (25 mL), a catalytic amount of benzoyl peroxide (25 mg, 0.83 mmol), and N-bromosuccinimide (0.32 g, 1.8 mmol) were added to the reaction flask. The mixture was refluxed and irradiated under a 90-watt lamp (GE watt-miser light bulb, 130 V, 1000 hrs) for 5 h and then cooled to room temperature. The precipitated succinimide was removed by gravity filtration and the filtrate was extracted with sodium metabisulfite (28 M, 1×50 mL) and water (1×50 mL). The organic layer was separated, dried over sodium sulfate, filtered and then evaporated to afford a crude oil (382 mg, 105%). The crude product was chromatographed on silica gel (hexane/EtOAc=9:1) to give the product as yellow crystals (172 mg, 47%): m.p. 64–65° C.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][CH2:7][O+](CC)CC.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>ClCCl>[CH2:6]([O:23][C:19](=[N:18][C:17]1[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=1)[CH:20]([CH3:22])[CH3:21])[CH3:7]
Reactant: CC(C)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=Nc1cccc(C(F)(F)F)c1)C(C)C

Procedure:
Add a solution of 5.0 g. (0.03 moles) of triethyloxonium fluoborate in 13 ml. of dichloromethane to a solution of 7.3 g. (0.03 moles) of 3'-trifluoromethylisobutyranilide in 60 ml. of dichloromethane and reflux for 20 hours. Remove 50 ml. of dichloromethane and add 150 ml. of dry ether to precipitate out the product of this example as its fluoborate salt, m.p.=95°-100°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[N:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2].ClN1C(=O)CCC1=O.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[K+]>C(OC(=O)C)C.O>[CH2:8]([N:7]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[N:6]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCNN=CC(=O)OCC
Reactant: C=Cc1ccccc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCN1N=C(C(=O)OCC)CC1c1ccccc1
Temperature: 60 °C
Yield: 22 %

Procedure:
To a magnetically stirred solution of (pentylhydrazono)acetic acid ethyl ester (Intermediate II-1) (35.16 g, 179 mmol) in ethylacetate (450 ml) was added N-chlorosuccinimide (NCS) (26.34 g, 197 mmol) and the resulting mixture was heated at 60° C. for 1 hour in a nitrogen atmosphere. To the reaction mixture was added styrene (41.1 ml, 359 mmol) and potassium bicarbonate (89.8 g, 897 mmol) and water (8 ml). The resulting mixture was heated at 70° C. for 16 hours. The resulting mixture was allowed to attain room temperature, concentrated in vacuo and the resulting residue was chromatographically separated using Sepacore equipment (eluant: dichloromethane/methanol=98/2 v/v) to give ethyl 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (Intermediate (V-1) (12.1 g, 22% yield) as an oil. 1H-NMR (400 MHz, CDCl3) δ 0.83 (t, J=7, 3H), 1.13-1.28 (m, 4H), 1.35 (t, J=7, 3H), 1.53-1.67 (m, 2H), 2.89 (dd, J=16 and 13, 1H), 3.01-3.09 (m, 1H), 3.14-3.22 (m, 1H), 3.41 (dd, J=16 and 12, 1H), 4.31 (double (diastereotopic) quartet, J˜7, 2H), 4.63 (dd, J=13 and 12, 1H), 7.27-7.39 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][C:3]=1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(OCCN)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCCNS(C)(=O)=O)cc(C)c1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-(4-bromo-3,5-dimethylphenoxy)ethanamine (100 mg) and triethylamine (63 μL) in dichloromethane (2 mL) is added methanesulfonyl chloride (32 μL). The mixture is stirred for 2 hours at 0° C. Then the mixture is partitioned between dichloromethane and water. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 90 mg; LC (method 7): tR=1.01 min; Mass spectrum (ESI+): m/z=322 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)[CH:18]=[CH:19][N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 14.2 %

Procedure:
To a solution of 1-[3-(difluoromethoxy)phenyl]-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude, 993 mg, 2.96 mmol) in 20 mL of methanol was added phenylhydrazine (480 mg, 4.44 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-[3-(difluoromethoxy)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (160 mg, 14% for two steps) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[N:5]=[C:4]([C:12](OC)=[O:13])[CH:3]=1.[BH4-].[Na+].CC(C)=O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: OCc1cc(Cl)cc(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dimethyl 4-chloro-2,6-pyridine dicarboxylate, prepared as in Example 4, (85.0 g, 370 mmol) was dissolved in MeOH (2.3 L). The solution was cooled to 0° C. To the cooled solution was added NaBH4 (63.0 g, 167 mmol) in small portions. The reaction mixture stirred at 0° C. for 1 hour, then at room temperature for 2-3 hours. After about 3 hours, the mixture was allowed to reflux overnight. Acetone (425 mL) was added to the reaction mixture. The solution was heated to reflux for 1 hour, then was concentrated in vacuo. Saturated Na2CO3 solution (650 mL) was added to the concentrate and refluxed for 45 minutes. The flask was allowed to reach room temperature and left at room temperature for 16 h. The flask contained a white precipitate which was filtered and washed with chloroform (30 mL). The white solid was dissolved in hot THF (300 mL), dried over magnesium sulfate and filtered, then concentrated in vacuo to afford 32.1 g 4-chloro-2,6-dihydroxymethyl pyridine as a white solid. The filtrate was concentrated. The resulting white solid was heated in THF (500 mL), dried over magnesium sulfate and filtered. This process was repeated then the solid was stirred in 200 mL of CHCl3 and filtered to afford an additional 23.6 g (87% overall yield) of pure 4-chloro-2,6-dihydroxymethyl pyridine as a white solid: 1H NMR (CD3OD, 400 MHz) δ 7.62 (s, 2H), 5.02 (s, 2H), 4.83 (s, 4H). 13C NMR (CD3OD, 100 MHz) δ 162.57, 145.75, 118.76, 63.74.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]([CH3:21])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH:19]([CH3:21])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CC(C)N(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 27.6 %

Procedure:
6.0 g of 1-(2-chloroethyl)-3-isopropyl-3-D-galactopyranosylurea are dissolved in 20 ml of formic acid, and 4.2 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.8 g of 1-(2-chloroethyl)-1-nitroso-3-isopropyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=O)[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1F)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1F)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a mixture of 6-(2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.21 g) and aminoguanidine hydrochloride (95 mg) were added ethanol (17 ml) and 6N hydrochloric acid (0.074 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-fluorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 40) (0.19 g).
Reaction SMILES: C([O:4][CH:5]([CH3:20])[C:6]([C:8]1[C:9]([CH:17]([CH3:19])[CH3:18])=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)=[O:7])(=O)C.[OH-].[Na+].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[OH:4][CH:5]([CH3:20])[C:6]([C:8]1[C:9]([CH:17]([CH3:19])[CH3:18])=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)=[O:7]
Reactant: CC(=O)OC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)C(=O)c1c(C(C)C)nn2ccccc12
Yield: 96.6 %

Procedure:
A solution of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl acetate (0.33 g, 1 equivalent) and 1M NaOH (1.5 mL, 1.25 equivalents) in 3 mL of THF was stirred at room temperature for 24 hours. The solution was worked up with ethyl acetate and saturated NaHCO3. The crude solid obtained was recrystallized from ethyl acetate and hexane to provide 2-hydroxy-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.27 g, 96% yield) as a white solid. Compound 1068.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1)[CH2:36]Br.Cl>CC(N(C)C)=O>[CH3:42][O:41][C:39]1[CH:38]=[C:35]([CH2:36][N:9]2[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:24])[CH:34]=[C:33]([O:32][CH3:31])[CH:40]=1
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)cc(OC)c1
Reaction time: 8 h
Yield: 41.2 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (1.5 g, 11 mmoles) and 3,5-dimethoxybenzyl bromide (300 mg, 1.3 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from toluene gave the title compound (190 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (s, 1 H), 10.15 (s, 1 H), 6.40 (s, 3 H), 4.92 (s, 2 H), 4.64 (t, J=11.87 Hz, 1 H), 4.09-4.17 (m, 2 H), 3.70 (s, 6 H), 2.26 (s, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.62 (d, J=11.62 Hz, 3 H), 1.28 (q, J=13.05 Hz, 2 H), 1.06-1.17 (m, 1 H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:32](=[CH:36][CH:37]1[CH2:39][CH2:38]1)[C:33](O)=[O:34])#[N:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([C:32](=[CH:36][CH:37]3[CH2:39][CH2:38]3)[C:30]#[N:31])=[O:34])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C[C@@H]1CCCN1
Reactant: N#CC(=CC1CC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
To a mixture of (S)-5-(4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.26 mmol, 1.0 eq), 2-cyano-3-cyclopropyl-acrylic acid (45 mg, 0.32 mmol, 1.2 eq) and DIEA (102 mg, 0.78 mmol, 3.0 eq) in 10 ml DCM was added HATU (150 mg, 0.40 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-TLC to give the title compound (71 mg). LCMS: m/z 486.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH3:38][C:39]1([C:43](O)=[O:44])[CH2:42][O:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:43]([C:39]3([CH3:38])[CH2:42][O:41][CH2:40]3)=[O:44])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CC1(C(=O)O)COC1
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CC1(C(=O)NS(=O)(=O)c2cnn3c(Nc4cc(Cl)ccc4Cl)c(C(=O)N4CCC(c5ccc(F)cc5)CC4)cnc23)COC1
Yield: 79.4 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.07 g, 0.12 mmol) obtained in Example 22 step 5 and 3-methyloxetane-3-carboxylic acid (0.072 g, 0.62 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.063 g, 76%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH3:30][C:31]1[CH:32]=[C:33]([NH2:40])[CH:34]=[C:35]2[C:39]=1[NH:38][N:37]=[CH:36]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][C:31]1[CH:32]=[C:33]([NH:40][C:26]([C:22]2[CH:21]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[N:25]=[CH:24][N:23]=2)=[O:27])[CH:34]=[C:35]2[C:39]=1[NH:38][N:37]=[CH:36]2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: Cc1cc(N)cc2cn[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)Nc4cc(C)c5[nH]ncc5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 37 mg (0.25 mmol) 7-methyl-1H-indazol-5-amine in 74 μL (0.53 mmol) TEA and 1.5 mL DMF were combined with 89 mg (0.28 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1)[CH3:13])=O)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[C].[Pd]>[NH2:11][C@H:12]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[CH:16][CH:15]=1)[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a stirred solution of tert-butyl 4-((1S)-1-{[(benzyloxy)carbonyl]amino}ethyl)benzoate (step 2, 3.48 g, 9.8 mmol) in a mixture of ethanol (25 mL) and acetic acid (25 mL) was added 10% palladium-carbon (400 mg). The mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The palladium catalyst was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate aqueous solution (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic extracts were washed with brine (200 mL) and dried (sodium sulfate), and concentrated to give 2.02 g (93%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 7.95 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 4.22–4.12 (1H, dq, J=7.3, 6.6 Hz), 1.80 (2H, br.s), 1.58 (9H, s), 1.38 (3H, d, J=6.6 Hz).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+]>CO.O>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[S:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CS3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CS3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4H,6H-1,3,4-thiadiazin-5-one-2-yl)pyridinium bromide (3.84 g, 9.09 mmol) was dissolved in methanol-water (1:1 v/v %) (50 ml), gradually added with sodium borohydride (3.43 g, 90.9 mmol) under ice cooling and then stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was added with dichloromethane, then washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (2.44 g) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:28]>[C].[Pd]>[CH2:1]([O:8][C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][C:17](=[O:28])[N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
(S)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate (1.089 g, 3.00 mmol) described in Reference Example 5 was dissolved in methanol (15 mL), 10% palladium-carbon (50% water content, 200 mg) was added, followed by stirring at room temperature for 1 hour under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through Celite and the solvent was concentrated under reduced pressure to afford 595.5 mg of the title compound (yield 86.6%).