Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CN1CCOCC1.[Cl:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>C(#N)C>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:33])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:18]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
N-Boc-cis-4-Amino-L-proline methylester hydrochlorid (5 g) was dissolved in acetonitrile (25 ml) and suspended with NMM (1.2 g) for 15 min at 25° C. (Suspension A). 5-Chlorothiophene-2-carboxylic acid (5.184 g) was dissolved in acetonitrile (25 ml), NMM (2.4 g) and IBCF (4.865 g) were added to the solution. This solution was stirred for 30 min at 25° C. and then added to the above mentioned suspension A. The whole mixture was stirred for 24 h at 25° C. The mixture was then evaporated to dryness and purified by chromatography (silica gel; gradient: CH2Cl2->methanol 2N NH3) to yield (2S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) as a light yellow gum. MH+=289.1 (Cl-isotopes, loss of Boc-group).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:9][CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH:20]1([C:5]2([CH2:9][CH2:10][C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1nccs1
Reactant: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1OC(CCC#Cc2cccc(O)c2)(C2CCCC2)CC(O)=C1Sc1nccs1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 10.6 %

Procedure:
To a solution of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione (216 mg, 0.6 mmol) from Step 5 below and 2-mercaptothiazole (141 mg, 1.2 mmol) in DMF (6 mL) was added triethylamine (0.15 mL, 1.2 mmol). The reaction was stirred at 50° C. for 2.5 hours and then quenched with 10 mL of saturated ammonium chloride. The mixture was further acidified to a pH of 1–2 with 1 N HCl. To this mixture was added 10 mL CH2Cl2 and the layers were separated. The aqueous was extracted with 2×10 mL CH2Cl2, and the organic layers were combined. After drying the organic layer over MgSO4, the solids were filtered away and the liquid was concentrated to an oil. The oil was chromatographed on silica to yield the desired product (28 mg, 11% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][C:15]1=[O:22])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:9][C@H:8]1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][C:15]1=[O:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CN1CCN(C=O)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C=O)CC1=O

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(4-formyl-2-oxopiperazin-1-yl) methyl-4-hydroxypyrrolidine (11.38 g) in ethyl acetate (110 ml) were added triethylamine (5.6 ml) and methanesulfonyl chloride (3.11 ml) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added water and the mixture was evaporated in vacuo. To the residue was added tetrahydrofuran, and the mixture was stirred at 50° C. for 20 minutes. The mixture was filtered and the filtrate was dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-(4-formyl-2-oxopiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (14.2 g).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][C:8](=[O:20])[CH2:9][CH:10](O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([CH:10]1[O:21][C:6](=[O:5])[CH2:7][C:8](=[O:20])[CH2:9]1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(=O)OC(CCc2ccccc2)C1

Procedure:
A solution of 5-hydroxy-3-oxo-7-phenyl-heptanoic acid tert-butyl ester (0.96 g, 3.3 mmol) and TFA (0.38 g, 3.3 mmol) in DCM (60 mL) was stirred at rt for 18 h. Removal of the volatile components under reduced pressure afforded the product 6-Phenethyl-dihydro-pyran-2,4-dione as an off white solid (0.56 g, 78%). 1H NMR (300 MHz, CDCl3) δ1.9-2.2 (m, 2H), 2.4-2.7 (m, 2H), 2.75-2.95 (m, 2 H), 3.5 (q, 2H), 4.55-4.65(m, 1H), 7.10-7.35 (m, 5H). ESMS calcd (C13H14O3): 218.1; found: 219.1 (M+H)+.
Reaction SMILES: [OH2:1].[O:2]=[CH:3][C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.OO>C(O)(C)C>[CH3:8][O:7][C:6]1[CH:5]=[C:4]([CH:3]=[O:2])[CH:12]=[C:11]([C:11]2[C:9]([OH:1])=[C:6]([O:7][CH3:8])[CH:5]=[C:4]([CH:3]=[O:2])[CH:12]=2)[C:9]=1[OH:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: O
Agent: OO
Solvent: CC(C)O
Product: COc1cc(C=O)cc(-c2cc(C=O)cc(OC)c2O)c1O
Reaction time: 21 h
Yield: 82 %

Procedure:
A 2 liter, round bottom flask was charged with 261.7 milligrams (13085 units) of medium purity, soybean peroxidase, 600 mL water, 900 mL isopropanol, and 157.36 grams (1.0342 moles) vanillin. The mixture was heated to 45°-50° C. Over 18-24 hours, 120 mL of 30% hydrogen peroxide was then metered into the reaction mixture. The product precipitated out of solution during peroxide addition affording 127.63 grams (82% theory) of dehydrodivanillin (CAS Registry No. 2092-49-1) which has the following chemical formula: ##STR10##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][NH:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:26]([O:30][C:31](=[O:55])[C@@H:32]([NH:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:33][N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[C:26]([O:30][C:31](=[O:55])[C@@H:32]([NH:44][C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])[CH2:33][N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2[N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][NH:14][C:15]=3[N:16]=2)[CH2:3][CH2:2]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(Cl)ncnc21)NC(=O)OCc1ccccc1
Reactant: c1cc2c(nc1C1CCNCC1)NCCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.44 g of the compound of step c) were dissolved in 5 ml of anhydrous dimethylformamide. 0.7 ml of N,N-diisopropylethylamine were added together with 0.58 g of (S)-2-benzyloxycarbonylamino-3-(6-chloro-purin-9-yl)-propionic acid tert-butyl ester, and the mixture was stirred at ambient temperature overnight. Thin layer chromatographic control exhibited only incomplete reaction. Stirring was therefore continued for 6 hours at 40° C. until the reaction was complete. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed twice with water. The organic phase was dried with anhydrous magnesium sulfate and, after filtration, concentrated in vacuo. The raw material was chromatographed on silica gel with ethyl acetate and ethyl acetate/methanol (1:10). Yield: 224 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[CH:19]=[CH:20][CH2:21][OH:22])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[NH2:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.CN(C=O)C>CN(C)C1C=CN=CC=1.O.CCOCC>[NH2:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:22][CH2:21][CH:20]=[CH:19][CH:18]([O:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:7]3[CH:6]=[N:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=3)=[CH:25][CH:24]=2)[CH3:23])=[O:34])=[CH:31][CH:30]=1)=[O:28]
Reactant: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C=CCOC(=O)c1ccc(C(N)=O)cc1)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 1.5 g (4.2 mmol) of the pentenol obtained in Example 3 above, 1.04 g (6.3 mmol) of 4-(aminocarbonyl)benzoic acid, 1.30 g (6.3 mmol) of dicyclohexylcarbodiimide (DCC), 0.05 g of 4-(dimethylamino)pyridine and 20 ml of DMF was stirred at room temperature overnight. An additional 0.3 g of DCC and 0.25 g of 4-(aminocarbonyl)benzoic acid were added and the mixture was stirred an additional 20 hours. The mixture was then poured into ether, water added and filtered. The filtrates were separated, and the organic layer washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated to dryness. The residue was purified by preparative scale HPLC, eluting with a 3:2 hexane:acetone mixture to give 0.55 g of the desired product as a tan, glassy solid, m.p. 144°-148° C. (Compound 29).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[H-].[Na+].I[CH:12]([CH3:14])[CH3:13].O>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:3]1[C:7]([NH:8][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)I
Reactant: CCn1nccc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1nccc1NC(C)C
Yield: 50.8 %

Procedure:
1-Ethyl-1H-pyrazol-5-amine (0.7 g, 6.3 mmol) was dissolved in THF (5 ml). Sodium hydride (0.5 g, 60% dispersion in mineral oil, 12.6 mmol) was added and the mixture stirred for 10 m. 2-iodopropane (0.82 g, 8.2 mmol) was added and the mixture stirred for 16 h. Water (50 ml) and ethyl acetate (100 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×75 ml). The combined organic phases were washed with a saturated aqueous sodium chloride solution (30 ml) and then dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to give 0.49 g (50%) of 1-ethyl-N-isopropyl-1H-pyrazol-5-amine as a yellowish oil. MS (ESI) m/z 154 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](F)[CH:7]=[C:6]([F:11])[N:5]=1.[CH2:12]([OH:15])[CH:13]=[CH2:14]>>[CH2:12]([O:15][C:8]1[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([F:11])[CH:7]=1)[CH:13]=[CH2:14]
Reactant: Nc1nc(F)cc(F)n1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1cc(F)nc(N)n1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
1.14 g (0.0382 mol) of 80% sodium hydride (emulsion in linseed oil) were added at 25° C. under a nitrogen atmosphere to 70 ml of allyl alcohol. To the clear solution obtained after stirring at 40° C. for 20 minutes were added 5.0 g (0.0382 mol) of 2-amino-4,6-difluoropyrimidine, and the mixture was then stirred at 97° C. for 1.5 hours. To work up, the excess alcohol was removed by distillation under reduced pressure, the residue was taken up in methylene chloride, and the solution was washed with water, dried over magnesium sulfate and then freed of solvent. The viscous oil obtained in this way crystallized on trituration with n-pentane. 4.6 g (71.2% of theory) of the title compound of melting point 62°-66° C. were obtained after filtering off, washing with water and drying.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>C(O)C.[Pd]>[C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC=CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(=O)O
Yield: 99 %

Procedure:
A solution of 5(Z)-7- [2,4,5-cis]-2-methyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (500 mg.) in absolute ethanol (10 ml.) containing 5% w/w palladium on charcoal catalyst (100 mg.) was stirred under an atmospheric pressure of hydrogen for 3 hours. The catalyst was separated by filtration through kieselguhr and the filtrate was evaporated to give 5(Z) 7- [2,4,5-cis]-2-methyl -4-phenyl-1,3-dioxan-cis-5yl)heptanoic acid as a colourless oil in 99% yield; NMR: 0.8-1.8 (14H,m), 2.2 (2H,t,J=8 Hz), 3.8-4.25 (2H,m), 7.14-7.4 (5H,m) and 8.5-9.3 (1H,br)pm; m/e: 307 (M+ +H).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H-].[Na+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C)C=O.O>[NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH:5]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@H](N)C(=O)OCc3ccccc3)c3ccccc32)cc1
Reaction time: 0.33 h

Procedure:
In N,N-dimethylformamide (DMF) (10 ml) was dissolved Tr-Trp-OBzl (2.15 g, 4 mM), followed by addition of sodium hydride (50% in mineral oil, the same applies below; 240 mg, 5 mM) in a nitrogen gas stream. The reaction was conducted at room temperature for 20 minutes, after which p-toluenesulfonyl chloride (950 mg, 5 mM) was added. The reaction was further carried out at room temperature for 15 hours, at the end of which time ethyl acetate (50 ml) was added and the mixture was stirred for one hour. To the reaction mixture was added water (30 ml) with caution and the organic layer was taken and washed with 5% aqueous sodium hydrogen carbonate and water. After drying over sodium sulfate, the ethyl acetate was distilled off. The residue was purified by column chromatography on silica gel (15 g) using toluene as the solvent to give Tr-Trp(Tos)-OBzl. Yield 1.70 g (61.5%); m.p. 101°-103° C.; [α]D24 +47.6° (c=0.5, DMF).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH:3]=1.[CH2:20]([O:22][C:23](=[O:30])[CH2:24][C:25](=O)[CH:26]([CH3:28])[CH3:27])[CH3:21]>>[CH2:20]([O:22][C:23]([C:24]1[C:25]([CH:26]([CH3:28])[CH3:27])=[N:10][C:5]2[C:4]([C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[O:8][CH3:9])=[O:30])[CH3:21]
Reactant: COc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)c1c(C(C)C)nc2c(OC)cc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 10 step B from 4-chloro-2-(2-chloro-phenylethynyl)-6-methoxy-phenylamine (200 mg, 0.68 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.166 ml, 1.03 mmol). Brown solid (45 mg, 15%). LC-MS (ESI): 432 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH:18]2[CH:16]([CH:17]2[NH:20][C:21]2[N:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][N:22]=2)[CH2:15]1)(=[O:13])=[O:12].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[O:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[O:58][NH2:59]>C(Cl)Cl.C1COCC1.CCN(CC)CC>[O:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[O:58][NH:59][C:27]([C:24]1[CH:23]=[N:22][C:21]([NH:20][CH:17]2[CH:16]3[CH:18]2[CH2:19][N:14]([S:11]([C:2]2[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=2)(=[O:12])=[O:13])[CH2:15]3)=[N:26][CH:25]=1)=[O:28]
Reactant: O=C(O)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(NC2C3CN(S(=O)(=O)c4ccc5ccccc5c4)CC32)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of 2-{[3-(2-naphthylsulfonyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}pyrimidine-5-carboxylic acid (105 mg, 0.26 mmol) in DCM (5 ml) and THF (5 ml) was added EDCl (59 mg, 0.3 mmol). Et3N (0.08 ml, 0.8 mmol) was added followed by HOBt (42 mg, 0.3 mmol) and O-(tetrahydro-pyran-2-yl)-hydroxylamine (36 mg, 0.3 mmol). The suspension was stirred at r.t. for 3 days. Further EDCl (14 mg), Et3N (0.02 ml), HOBt (11 mg), and O-(tetrahydro-pyran-2-yl)-hydroxylamine (9 mg) were added and stirring at r.t. continued for a further 3 days. The reaction mixture was evaporated to dryness, re-dissolved in EtOAc (20 ml) and washed with sat. aq. NaHCO3 (10 ml) and water (10 ml). The EtOAc layer was dried (Na2SO4), filtered and concentrated to dryness to afford the title compound as a white solid (110 mg, 83%). LCMS purity 90%, m/z 511 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH2:29][C:30](O)=[O:31])[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH2:29][C:30]([N:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[C:19]5[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=5[N:13]([CH3:21])[CH:12]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:31])[CH:28]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(Cl)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(Cl)ccc2F)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl (70 mg, 0.232 mmol), (5-chloro-2-fluorophenyl)acetic acid (44.2 mg, 0.234 mmol), and HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.928 mmol). The mixture was stirred overnight. The reaction was poured into water (100 mL), and an off-white solid was formed. The solid was filtered, washed with water (10 mL), and dried to afford the title compound as an off-white solid. LC-MS (ES) m/z=436.4 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22-3.30 (m, 2H), 3.74 (s, 3H), 3.96 (s, 2H), 4.25-4.32 (m, 2H), 7.21-7.28 (m, 2H), 7.30 (s, 1H), 7.33 (s, 1H), 7.39-7.44 (m, 1H), 7.47 (dd, J=6.32, 2.78 Hz, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C([O-])(=O)C.[Na+].[I:22]Cl.S(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:22])[C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: ClI
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1)c1cc(Cl)cc(I)c1O
Reaction time: 0.08 h

Procedure:
Add 5-chloro-2-hydroxybenzophenone (23.2 g., 0.1 mole) to acetic acid (150 ml.) and sodium acetate (9.3 g., 0.11 mole). Treat the mixture with iodine monochloride (16.5 g., 0.1 mole) and warm in a bath at 70°-85° for one hour. Cool and add 20 ml. of sodium bisulfite solution and then more water. After stirring for five minutes, collect and dry the title compound; m.p. 110°-111° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:39].[K+].[K+].O1CCOCC1>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:39])[N:7]=3)=[CH:17][C:14]=2[C:15]#[N:16])=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: N#Cc1cc(CNc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: C1CN2CCN1CC2
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(CNc2cc[nH]c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of 5-{[(2-chloro-4-pyrimidinyl)amino]methyl}-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzo-nitrile (200 mg, 0.455 mmol), DABCO (25.5 mg, 0.228 mmol) and potassium carbonate (252 mg, 1.821 mmol) in a mixed solvents of 1,4-Dioxane (5 mL) and water (5.00 mL) was stirred at 80° C. overnight. Purification via MDAP, afforded the title compound (150 mg) as a white solid. LC-MS (ESI): m/z 421 [M+H]+; 2.63 min (ret time).
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]C1C=C2C(=CC=1)N(CCC)C(=O)C2=O>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=2)[N:12]([CH2:19][CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Product: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
Was prepared in a method analogous to 2-oxo-1-propylindolin-3-yl benzoate using 5-chloro-1-propylindoline-2,3-dione. 1H-NMR δ 8.11 (dd, 2H), 7.60 (dt, 1H), 7.47 (m, 3H), 7.35 (dd, 1H), 6.83 (d, 1H), 6.13 (s, 1H), 3.73 (m, 2H), 1.77 (m, 2H), 1.04 (t, 3H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C[O:14][C:15](=O)[CH:16]([CH3:21])[CH2:17][C:18]#[C:19][CH3:20].C(O)(=O)C>O1CCCC1.CCCCCC>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH:16]([CH3:21])[CH2:17][C:18]#[C:19][CH3:20])(=[O:7])[O:5][CH3:6]
Reactant: CC#CCC(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC#CCC(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78° C. and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6 M in hexane) over a 25-minute period. The mixture is stirred an additional 30 minutes at -78° C., then treated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g, 51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78° C. and then 17 hours at ambient temperature. The reaction mixture is cooled to 8° C., treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturated brine (2×75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg.