Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](OC)(=[O:26])[CH:24]=[CH2:25].[K].C(O)(=O)C>C(O)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[CH2:25][CH2:24][C:23]([OH:26])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: C=CC(=O)OC
Agent: [K]
Solvent: O
Solvent: CCCCO
Solvent: CC(=O)O
Product: OC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)CC1
Reaction time: 2 h

Procedure:
To a mixture of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (7.82 g, 0.025 mol) and Methyl acrylate (2.58 g, 0.030 mol) in tert BuOH (80 ml) is added Potassium tert-butoxyde (5.6 g, 0.05 mol) in portions at 25° C. After stirring for two hours the resulting brown solution is poured in water (500 ml), acidified with acetic acid and partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by crystallizing from acetone. The resulting precipitate is filtered with suction to yield the title compound. (1.55 g, 16.9%) m.p. 222–226° C.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH:16]1[C:33]2=[C:34]3[C:23]([C:24]4[C:35]5[C:28](=[CH:29][CH:30]=[CH:31][C:32]2=5)[CH:27]=[CH:26][CH:25]=4)=[CH:22][CH:21]=[CH:20][C:19]3=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl.O>[CH:31]1[C:32]2=[C:35]3[C:24]([C:23]4[C:34]5[C:19](=[CH:18][CH:17]=[CH:16][C:33]2=5)[CH:20]=[CH:21][CH:22]=4)=[CH:25][CH:26]=[CH:27][C:28]3=[C:29]([CH:9]=[O:10])[CH:30]=1
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c3cccc4cccc(c5cccc1c52)c43

Procedure:
About 22 grams N-methylformanilide is initially dissolved in 40 milliliters o-dichlorobenzene, the vessel containing the above solution partially immersed in a water bath (bath temperature less than 25° C) and 22 grams phosphorous oxychloride introduced into the flask by dropewise addition. About 20 grams of perylene is stirred into the above solution and the resulting mixture heated on a steam bath for twelve hours (temperature of contents of vessel 90°-95° C). The contents of the flask are thereafter poured into a second vessel containing 100 grams sodium acetate dissolved in 250 milliliters water. The organic liquid phase of the mixture is separated from the aqueous phase by steam distillation. Crude aldehyde is thereafter precipitated from aqueous solution and the solids recystalized from acetic acid and from benzene. The solids thus obtained are further extracted in a soxhlet extractor with 30-60 pet ether. The material remaining in the extraction thimble is 3-perylenecarboxaldehyde, mp 230° C; yield 9.5 grams.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([C:12](=O)[CH2:13][CH2:14][CH2:15]Br)[CH:8]=[CH:9][C:10]=1[Cl:11])C(C)=O.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]2[C:19]3[N:18]([CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: c1c[nH]cn1
Reactant: CC(=O)Nc1cc(C(=O)CCCBr)ccc1Cl
Product: Nc1cc(C2=CCCn3ccnc32)ccc1Cl
Temperature: 25 °C

Procedure:
Combine 5 g (15.7 mmol) of 3'-acetamino-4-bromo-4'-chlorobutyrophenone with 15 g (0.22 mol) of imidazole, and heat to 175° C. for 18 hr. Isolate the crude product by crystallization from ether, and add to a solution of 5 g of potassium hydroxide in 20 ml of 1:1 solution of methanol/water. Heat to reflux for 2 hr. Cool to room temperature, and pour the reaction mixture into 100 ml of water with rapid stirring. The resulting precipitate is recrystallized from ether to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.CO[C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1.C(Cl)(Cl)Cl.[CH3:36][OH:37]>>[CH3:36][O:37][C:31]1[CH:30]=[C:27]([N:28]([CH3:29])[C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CO
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: CNc1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Product: COc1cccc(N(C)c2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)c1
Reaction time: 72 h
Yield: 45 %

Procedure:
Using the general procedure described above, the reaction of 6 (180 mg, 0.59 mmol) and 4-methoxy-N-methylaniline (612 mg, 4.46 mmol) was run for 72 hours, to provide 109 mg of 9 as brown crystals in 45% yield, TLC Rf 0.62 (chloroform-methanol 15:1); mp 248.2-249° C.; 1H NMR (DMSO-d6) δ 1.26 (s, 9H, C(CH3)3), 3.61 (s, 3H, OCH3), 3.74 (s, 3H, NCH3), 5.76-7.29 (m, 8H, Ar—H), 9.49 (s, 1H, 2-NH, exch), 11.81 (s, 1H, 9-NH, exch). Anal. Calculated (C23H25N5O2. 0.55 CH3OH): C, 67.16; H, 6.51; N, 16.63. Found: C, 67.33; H, 6.49; N, 16.28.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:13][C:14](=[CH:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22]O)[CH3:20])[CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:22][CH2:21][CH:19]([CH3:20])[CH2:18][CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)=CCCC(C)CCO
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=O)OCCC(C)CCC=C(C)C
Reaction time: 75 h
Yield: 81.9 %

Procedure:
A solution of 6.49 g (30.0 mmol) 2-acetylbenzoic acid, 3.81 g (31.2 mmol) DMAP and 12.48 g (80.0 mmol) citronellol in 60 ml dichloromethane was cooled in an ice bath before adding a solution of 8.84 g (42.9 mmol) DCC in 40 ml dichloromethane over 5 min. The reaction mixture was maintained with stirring at 40° for 75 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×). The organic phase was dried (Na2SO4), and the solvent-evaporated. The excess citronellol was distilled (1 Torr, 60-80°), and the residue chromatographed (SiO2, 9:1 toluene/ethyl acetate) and distilled (0.6 Torr, 150-155°), to give 7.43 g (63%) of 3,7-dimethyl-6-octenyl 2-acetylbenzoate in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]Br.[CH2:14](O)[CH3:15]>O>[Br:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:14][CH3:15])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCO
Reactant: BrBr
Solvent: O
Product: CCOC(=O)C(Br)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 4-chlorophenylacetic acid (34 g) and red phosphorus (1.5 g) was stirred under an atmosphere of nitrogen and dry bromine (20 g) was carefully added over a period of 30 minutes. The reaction mixture was heated to a temperature of 100° C. and dry bromine (32 g) was carefully added over a period of 45 minutes. The mixture was then heated under reflux for 3 hours and cooled. Ethyl alcohol (100 ml) was added to the reaction mixture and the mixture allowed to stand overnight. The ethanolic mixture was diluted with water and extracted with ethylene dichloride. The extract was washed with aqueous sodium carbonate, dried over anhydrous sodium sulfate and the solvent removed by distillation under reduced pressure. The product was distilled through a Fenske ring column to give ethyl α-bromo-4-chlorophenylacetate (33.4 g; 65%) b.p. 119° C. at 0.9 mm of Hg.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18][C:17](=O)[O:16][C:14]2=[O:15].[CH3:25]S(C)=O>O>[C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][N:9]([C:14]([C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:18][C:17](=[O:16])[CH3:25])=[O:15])[CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccccc1C(=O)N1CC2CC2(c2ccccc2)C1

Procedure:
A mixture of 7 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane and 6.5 g. of isatoic anhydride in 10 ml. of dimethyl sulfoxide is warmed on a steam bath for 10 minutes. The mixture is cooled and water is added producing a gummy solid which is separated by extraction with chloroform, dried, filtered and evaporated to a dark oil. This oil is dissolved in 30 ml. of acetic anhydride, refluxed for 5 minutes, evaporated to an oil and water is added and decanted from the mixture several times. The thick oil is mixed with ethanol and a solid separates. This solid is dissolved in hot ethanol filtered and cooled giving a white solid which is recrystallized once from aqueous ethanol and once from ether to give the product as a white solid, mp 124.5°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[N+:31]([O-:33])=[O:32])[C:5]2=[CH:4][CH:3]=1.C[Si]([C:39]#[CH:40])(C)C.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:39]#[CH:40])[CH:27]=[CH:26][C:25]=3[N+:31]([O-:33])=[O:32])[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2[N+](=O)[O-])N1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc([N+](=O)[O-])c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 83.7 %

Procedure:
In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 201c (0.36 g, 0.59 mmol) was reacted with trimethylsilyl acetylene (120 mg, 1.18 mmol), CuI (0.23 g, 1.18 mmol), triethylamine (120 mg, 1.18 mmol), and dichlorobis(triphenylphosphine)palladium(0) (83 mg, 0.118 mmol) in anhydrous tetrahydrofuran, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-ethynyl-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 84%)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:21]=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 500-mL round-bottomed flask was added (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (2.5 g, 12.42 mmol) in DMF (80 mL) at 0° C. NaH (1.080 mL, 24.84 mmol) was added slowly and the mixture was stirred at 0° C. for 15 min. 2,6-dichloropyrazine (1.851 g, 12.42 mmol) was added and the mixture was warmed to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with water, brine, dried, filtered and concentrated to give the crude title compound. The material was used in the next step without further purification
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[OH2:28]>CN(C)C=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:3]2[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]2[S:1][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:20])=[O:28])=[CH:15][CH:14]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)c(Sc2ccc([N+](=O)[O-])cc2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
Ethyl 2-mercapto-1H-imidazole-4-carboxylate (1.00 g), 1-fluoro-4-nitrobenzene (2.05 g) and anhydrous potassium carbonate (4.00 g) were mixed in N,N-dimethylformamide (30 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue and the resulting crystals were collected by filtration to give the title compound as pale-yellow crystals (yield 2.06 g, 86%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[N+:36]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N+:48]([O-:50])=[O:49])[CH:47]=1)[C:42](Cl)=[O:43])([O-:38])=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[N+:36]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N+:48]([O-:50])=[O:49])[CH:47]=1)[C:42]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:43])([O-:38])=[O:37]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5cc([N+](=O)[O-])cc([N+](=O)[O-])c5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
20.00 g (51.7 mmol) of cholesterol, 2.88 g (25.75 mmol) of 4-dimethylaminopyridine, 6.27 g (62.04 mmol) of triethylamine are dissolved in 100 mL of dichloromethane. 11.92 g (51.7 mmol) of commercial 3,5-dinitrobenzoylchloride dissolved in 50 mL of dichloromethane are added at 0° C. The solution is stirred for 2 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Crystallization from ethyl acetate:hexane mixture yielded 16.94 g (56%) of (3-β)-cholest-5-en-3-yl 3,5-dinitrobenzoate as yellowish crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[Cl:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: NCc1ccc(Cl)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.564 g, 1.25 mmol), [(3-bromo-4-chlorophenyl)methyl]amine (0.275 g, 1.25 mmol, HBTU (0.474 g, 1.25 mmol), and TEA (0.348 mL, 2.5 mmol) were combined in CH2Cl2 (30 mL). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness. Residue taken up in EtOAc, washed with 1 N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. It was purified further using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to give the title compound as a white solid. LC-MS m/z 652.9 (M+H)+, 1.91 min (ret time); mp 115-117° C.; analytical HPLC shows 98.4% purity, (ret time 13.689 min).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:42][C@H:43]([C:47]([NH:49][C@H:50]([C:52](O)=[O:53])[CH3:51])=[O:48])[CH:44]([CH3:46])[CH3:45]>CN(C=O)C.C1COCC1>[NH2:42][C@H:43]([C:47]([NH:49][C@H:50]([C:52]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:53])[CH3:51])=[O:48])[CH:44]([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: -15 °C
Reaction time: 0.67 h

Procedure:
Asp(OtBu)OH (2.51 g) was dissolved in 40 mL of dry DMF under argon and 8.2 mL of bis(trimethylsilyl)acetamide (BSA) and the reaction was allowed to stir 40 minutes. In a separate flask, Mu-Val-Ala-OH (4.0 g) was dissolved in 200 mL of dry THF under argon and the resulting solution was cooled to -15° C. and one equivalent of N-methylmorpholine was added followed by one equivalent of isobutylchloroformate and the resulting mixture was allowed to stir 20 minutes and then the first reaction was then poured into the second reaction and both were maintained at -15° C. for one hour and then allowed to come slowly to room temperature and to stir overnight. The reaction was poured into 150 mL of 1N HCl and extracted with 2×200 mL of ethyl acetate. The combined organic fractions were washed with 15 mL 1N HCl, brine (50 mL), dried over MgSO4 (with decolorizing carbon), filtered, and the solvents were removed under reduced pressure to yield 4.89 g of Mu-Val-Ala-Asp(OtBu)OH.
Reaction SMILES: [CH2:1]([S:4]([O:7][CH3:8])(=[O:6])=[O:5])[CH:2]=C.[Cl:9]Cl.[CH:11]([Cl:14])(Cl)Cl>>[Cl:9][CH:2]([CH2:11][Cl:14])[CH2:1][S:4]([O:7][CH3:8])(=[O:6])=[O:5]
Reactant: ClCl
Reactant: C=CCS(=O)(=O)OC
Reactant: ClC(Cl)Cl
Product: COS(=O)(=O)CC(Cl)CCl
Yield: 70 %

Procedure:
To a solution of 13.6 g of methyl 2-propenesulfonate in 80 ml of chloroform was added 7.1 g of chlorine absorbed in 20 ml of chloroform dropwise with stirring below 0°C. After the addition, the mixture was stirred for two hours at room temperature. By distillation of the solvent and fractionation, 14.5 g of methyl 2,3-dichloropropanesulfonate, B.P. 89°-92°C/0.5 mmHg, was obtained in a yield of 70.0%.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+:15].O.[ClH:17]>C(O)C>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3]([OH:5])=[O:4].[Cl-:17].[Na+:15]
Reactant: Cl
Reactant: CCOC(=O)C(O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)c1ccccn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of ethyl 2-hydroxy-2-(2-pyridyl)acetate (0.5 g, 2.56 mmol) in ethanol (5 mL) was added 2.0 M NaOH in water (1.4 mL, 2.8 mmol). The resulting solution was stirred at ambient temperature for 18 h. TLC analysis indicated complete consumption of starting ester. 6.0 M HCl in water (0.46 mL, 2.8 mmol) was added and the solvents were removed under reduced pressure and the resulting solid was dried in vacuo for 18 h to give 2-hydroxy-2-(2-pyridyl)acetic acid as a mixture with sodium chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH2:28])=[N:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][N:25]=2)[N:3]=1
Reactant: Cc1ccc(CN)nc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(5-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.[Cl:14][S:15](O[Si](C)(C)C)(=[O:17])=[O:16].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:15]([Cl:14])(=[O:17])=[O:16])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Reactant: CC(C)c1cn2ccc(Br)cc2n1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
7-Bromo-2-isopropylimidazo[1,2-a]pyridine (1.00 g, 4.18 mmol) obtained in step 1 of Example 28 was dissolved in 1,2-dichloroethane (10 mL). Under ice-cooled condition, trimethylsilyl chlorosulfonate (1.20 mL, 8.36 mmol) was added, and the mixture was stirred at 90° C. for 3 hours. Under ice-cooled condition, triethylamine (1.17 mL, 8.36 mmol) and phosphoryl chloride (0.779 mL, 8.36 mmol) were added, and the mixture was stirred at 100° C. for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in acetonitrile. After adding a sodium hydrogen carbonate aqueous solution, the precipitated solid was collected by filteration to give 7-bromo-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.31 g, yield 93%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][CH3:18].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([N:17]([CH3:18])[CH3:16])=[O:15])[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-serine (2.00 g), 50% aqueous dimethylamine solution (0.987 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.36 g) in DMF (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.82 g) under ice-cooling. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.08 g).