Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:15]O.N1C=CC=CC=1>CCOCC>[Cl:3][CH2:15][C:8]1[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)c(OC)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(CCl)c(OC)c1
Temperature: 0 °C

Procedure:
Thionyl chloride (116 mL, 1586 mmol) was added dropwise over 1 hour to a turbid solution of (2,4-dimethoxyphenyl)methanol (97.00 g, 577 mmol) and pyridine (93 mL, 1153 mmol) in anhydrous Et2O (1153 mL) at 0° C. under nitrogen with mechanical stirring. After 1 hour the reaction mixture was poured into 2 L of ice water and the layers were separated. The aqueous layer was extracted with Et2O (2×1 L) and the organics were pooled, washed with ice water (1.2 L), cold 5:1 sat. aq. NaCl solution/sat. aq. NaHCO3 (1.2 L), dried (MgSO4), filtered and most of the ether was removed in vacuo at 12° C. Benzene (300 mL) was added and the mixture was concentrated at 12° C. until 100 mL of benzene remained to provide a solution of 1-(chloromethyl)-2,4-dimethoxybenzene.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:20][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCOc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Succinic anhydride (62.4 g) mashed by a mortar and pestle was placed in a 1 l three-necked flask, followed by adding heptyloxybenzene (100 g) and nitrobenzene (300 ml), portion-wise adding anhydrous aluminum chloride (150 g) under ice cooling, heating the mixture up to 50° C., agitating for 2 hours, allowing to stand overnight, after which the resulting reaction solution was poured in water, and subjected to steam distillation to distil off excess nitrobenzene, followed by ice-cooling, filtering off the resulting solids, heating under reflux together with toluene to remove water by means of Dien-Stark type drain tube, filtering off the solution while hot, recrystallizing from the filtrate, and further filtering off the resulting crystals, to obtain 3-(4-heptyloxybenzoyl)propionic acid (114.5 g). m.p.: 103.5°-105.7° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:13][C:14]1[CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=[C:18]([F:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:21][O:22][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OCc1cc(F)cc(F)c1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 5-fluoro-2-nitrobenzonitrile (60 g, 354 mmol), (3,5-difluorophenyl)methanol (52.14 mL, 460 mmol) and cesium carbonate (155 g, 460 mmol) in dry DMF (720 mL) was stirred at 70° C. for 6 hours. The reaction mixture was cooled at room temperature and poured into water (7 L) under stirring. The so obtained precipitated was filtered, washed with water and dried under vacuum at 50° C., affording 95 g (yield 92%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:21]CC3C=CC=CC=3)[C:9]=2[O:13]CC2C=CC=CC=2)[C:4]1=[O:29].C(O[C:38]1[C:47](OCC2C=CC=CC=2)=[CH:46][CH:45]=[C:44]2[C:39]=1[CH2:40][CH2:41][CH:42](NC(=O)C(F)(F)F)C2=O)C1C=CC=CC=1.[BrH:64]>>[BrH:64].[OH:13][C:9]1[C:8]([OH:21])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][CH:3]([NH:2][CH2:42][CH2:41][CH2:40][C:39]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:38]=1)[C:4]2=[O:29]
Reactant: O=C1c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2CCC1NC(=O)C(F)(F)F
Reactant: NC1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1=O
Agent: Br
Agent: Cl
Product: O=C1c2ccc(O)c(O)c2CCC1NCCCc1ccccc1

Procedure:
20 Parts of 2-amino-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is subjected to a procedure similar to that described in Reference Example 11 and the resultant 5,6-dibenzyloxy-2-trifluoroacetamido-3,4-dihydro-1(2H)-naphthalenone is reacted with 60 parts of 3-phenylpropanol p-toluenesulfonic acid ester under the same conditions as set forth in Reference Example 11. The reaction product is then hydrolyzed in a 47% aqueous solution of hydrogen bromide to obtain 3 parts of 5,6-dihydroxy-2-(3-phenylpropylamino)-3,4-dihydro-1(2H)-naphthalenone hydrobromide melting at 215°-217° C (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11]#[N:12].[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH:21]=O)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:11]([NH2:12])=[N:20][C:18]2[N:19]=[C:14]([NH2:13])[N:15]=[CH:16][C:17]=2[CH:21]=1
Reactant: N#CCc1c(Cl)ccc(Cl)c1Cl
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3c(Cl)ccc(Cl)c3Cl)c(N)nc2n1

Procedure:
The title compound was prepared according to Example 1, starting from 1.0 g of (2,3,6-trichloro)-phenyl-acetonitrile and 0.6 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 320-322° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (450 mg, 1.71 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (342 ml, 2.56 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (553 mg, 87%).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:15]([CH3:17])[CH3:16])[C:6]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:8]=[CH:9][CH:10]=1.[Na+].[CH:19](Cl)(Cl)Cl>CN(C=O)C>[C:5]1([CH:15]([CH3:17])[CH3:16])[C:6]([S:11]([O:14][CH3:19])(=[O:13])=[O:12])=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)c1ccccc1S(=O)(=O)[O-]
Reactant: ClC(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COS(=O)(=O)c1ccccc1C(C)C
Yield: 44 %

Procedure:
594.9 g (5.0 mol) of thionyl chloride were initially introduced together with 1 g of DMF, and 222.2 g (1.0 mol) of sodium cumenesulfonate were slowly added in portions starting at room temperature. The mixture was stirred at reflux for 16 hours and 250 ml of chloroform were added after cooling. Following filtration, excess thionyl chloride was stripped off together with the chloroform under reduced pressure. 250 ml of methanol were added, and a pH of 7.0 was established using 25% strength sodium hydroxide solution at 25° C. The mixture was then stirred out with dichloromethane, the organic phase was concentrated on a rotary evaporator, and the residue obtained was subjected to fractional distillation under reduced pressure. At 102° C. and 0.03 mbar, 96.9 g (0.44 mol) of methyl cumenesulfonate were isolated in the form of a clear liquid, corresponding to a yield of 44%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CO[C:12](OC)([CH3:14])[CH3:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:13][C:12]1([CH3:14])[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: CC(CO)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(C)(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a mixture of 3-hydroxy-2-hydroxymethyl-2-methylpropionic acid (6.71 g, 50 mmol), dimethoxypropane (7.99 mL, 65 mmol) and acetone (50 mL), p-toluenesulfonic acid hydrate (0.048 g, 0.25 mmol) was added and the resulting mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, sodium bicarbonate (0.1 g) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 5 minutes and concentrated in vacuo. To the resulting residue was added water and the resulting mixture was extracted with ethyl ether. The extract was dried over anhydrous sodium sulphate and concentrated in vacuo to give 2,2,5-trimethyl-1,3-dioxane5-carboxylic acid (7.87 g, yield: 90%) as colorless oil.
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[K+].[K+].[OH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1>CC(C)=O>[C:9]([O:4][C:1]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][OH:7])[CH2:10]1)=[O:2])([CH3:14])([CH3:10])[CH3:8]
Reactant: OCC1CCCNC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CO)C1
Yield: 88 %

Procedure:
Using a procedure analogous to Example 1-C (K2CO3, acetone), 3-hydroxymethylpiperidine gave the title compound as a solid (34.2 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=O)OC(C)(C)C.[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38]C(O)=O)=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:24]([CH2:38][O:37][C:36]4[CH:35]=[CH:34][C:33]([CH2:32][CH:28]5[S:27][C:26](=[O:25])[NH:30][C:29]5=[O:31])=[CH:43][CH:42]=4)[N:16]([CH3:17])[C:3]=3[CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccc(O)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Sc3ccc(O)cc3)cc21
Yield: 21.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-hydroxyphenylthio)phenyl]-N-methylcarbamate (2.36 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.87 g), diethyl cyanophosphonate (1.67 g), triethylamine (1.03 g) and anhydrous tetrahydrofuran (60 ml) and the reaction mixture was purified. Then, in a similar manner to that described in Example (2-2a) a reaction was carried out using the above product and 4N hydrogen chloride/dioxane (20 ml) and the reaction mixture was purified to give the desired compound (0.72 g).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH2:9][NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl.O1CCCC1>[OH:3][CH:1]([C:4]1[S:8][C:7]([CH2:9][NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(CNC(=O)c2cccnc2Oc2cccnc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)c1ccc(CNC(=O)c2cccnc2Oc2cccnc2)s1
Reaction time: 2 h

Procedure:
To a stirred suspension of N-(5-Acetyl-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide (0.300 grams, 0.85 mmole) in methylene chloride (25 ml) and tetrahydrofuran (25 ml) at room temperature was added sodium borohydride (0.035 grams, 0.93 mmole) and stirred for 2 hours. The mixture was quenched with saturated NH4Cl (˜1 ml) and concentrated under reduced pressure to about 15 ml. This mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 5% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave a white solid. (0.207 g). M.P. 92-94° C.; Anal. calcd. for C18H17N3O3S: C, 60.83;H, 4.82; N, 11.82. Found: C, 60.68; H, 4.77; N, 11.89.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O1CCOCC1.[OH:42][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([O:42][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:10])[CH2:3][O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)COC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reaction time: 48 h

Procedure:
A solution of Boc-Ser(tBu)-Asp(OtBu)-Ala-OH.CHA (1.205 g, 2.0 mmol) was extracted with a mixture of EtOAc: 0.5N H2SO4 (10 mL-10 mL). The organic layer was retained, washed with saturated NaCl, dried (MgSO4) and evaporated in vacuo. The resultant free acid in EtOAc:dioxane (5 mL-10 mL) was treated with HOSu (230 mg, 2.0 mmol, 1 eq) and cooled to 0°. To the cold stirring solution DCC (412 mg, 2.0 mm, 1 eq) was added portionwise and stirring proceeded at 0° for 1 hr and at 25° for 48 hr. The reaction mixture was filtered and the filtrate evaporated to dryness and crystallized from isopropanol-petroleum ether. Yield: 631 mg (52.5%); mp 129°-136°; [α]D25 -32.74° (c 1, MeOH); Rf 0.86 (CHCl3 :MeOH:AcOH; 85-10-5); Rf 0.79 (CHCl3 :MeOH:AcOH; 80-5-2). Anal. calc. for C27H44N4O11 (600.67): C, 53.99; H, 7.38; N, 9.33. Found C, 53.85; H, 7.50; N, 9.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:12](=[O:23])[CH:11]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:30][CH:31](Br)[CH3:32].CN(C=O)C>C(Cl)(Cl)Cl>[Br:30][CH2:31][CH2:32][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:11][C:12]2=[O:23])=[CH:21][CH:20]=1
Reactant: CC(Br)Br
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 14.5 h
Yield: 89 %

Procedure:
A mixture of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-hydroxyphenyl)-1H-pyridin-2-one (1.0 g, 3.1 mmols), cesium carbonate (5.0 g, 15 mmols), dibromoethane (5 mL) and DMF (10 mL) was stirred at 80° C. for 14.5 hours. Chloroform was added to the reaction liquid, followed by filtration. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil FLASH 25+ M, chloroform:methanol=1:0→100:2) to provide the title compound (1.2 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]([S:21](Cl)(=[O:23])=[O:22])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1(/[CH:14]=[CH:13]/[S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)/C=C/c2ccccc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and beta-styrenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (21.3 mg) with purity >90%. MS (pos) m/z 353.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][P:30]([Cl:32])[O:29][C@@H:28]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][P:30]([Cl:32])[O:29][C@@H:28]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OP(Cl)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OP(Cl)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-chloro-1,3-dioxaphosphorinan-4-yl)acetate.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[N:29]([CH2:30][CH2:31][O:32][C:33]4[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:34]=43)[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]>C(Cl)Cl>[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[C:34]4[CH:37]=[C:38]([S:41]([N:8]5[CH2:9][CH2:10][CH2:11][C@H:7]5[CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)(=[O:43])=[O:42])[CH:39]=[CH:40][C:33]=4[O:32][CH2:31][CH2:30][N:29]3[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCC[C@H]3CN3CCCC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-pyrrolidin-1-ylmethylpyrrolidine (36 mg, 0.23 mmol) and NEt3 (54 μL, 0.39 mmol) in DCM (5 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (64 mg, 0.08 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% 2M NH3/MeOH in DCM then C18, gradient 15-40% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 123 (22 mg, 56%). LCMS: RT 2.90 min [M+H]+ 512.3. 1H NMR (DMSO, 400 MHz): δ 9.01 (1H, d, J=2.40 Hz), 7.95 (1H, s), 7.82 (1H, s), 7.77 (1H, dd, J=8.65, 2.41 Hz), 7.26 (1H, d, J=8.65 Hz), 5.90-5.89 (1H, m), 4.61-4.60 (4H, m), 3.79-3.69 (1H, m), 3.42-3.41 (1H, m), 3.30-3.24 (1H, m), 2.76 (1H, dd, J=12.12, 4.10 Hz), 2.65-2.62 (5H, m), 1.80-1.79 (7H, m), 1.67-1.54 (1H, m). 1.59 (3H, d, J=6.62 Hz), 1.57 (3H, d, J=6.58 Hz)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][C:17]([O:1][C@@H:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(OCCC2CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)nc1

Procedure:
A mixture of (S)-3-hydroxy-pyrrolidin-2-one (0.79 g), 6-(2-cyclopropyl-ethoxy)-pyridin-3-ol (1.4 g), triphenylphosphine (2.25 g), DCM (30 mL) and THF (20 mL) was added DIAD (1.74 g). After 2 days the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI+: m/z=263 [M+H]+.
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH2:65][CH:66]1[CH2:71][CH2:70][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH2:65][CH:66]1[CH2:67][CH2:68][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73])[CH2:70][CH2:71]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCBr)CC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 4-(3-bromopropyl)-1-piperidinecarboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:26]=[C:25]([CH2:27][CH3:28])[N:24]([CH3:29])[N:23]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:26]=[C:25]([CH2:27][CH3:28])[N:24]([CH3:29])[N:23]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)nn1C
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Temperature: 78 °C
Yield: 85 %

Procedure:
5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.240 g, 0.6179 mmol) and ethyl formate (0.148 mL, 1.84 mmol) were dissolved in anhydrous ethanol (6 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.2 mL, 3.21 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.2187 g, 0.525 mmol, 85%).
Reaction SMILES: [C:1]([C:3](=[CH:5][CH2:6]Cl)[CH3:4])#[N:2].[S:8]1([C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[NH:11]1)(=[O:10])=[O:9].[Na]>CN(C)C=O>[O:10]=[S:8]1(=[O:9])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:12](=[O:13])[N:11]1[CH2:6][CH:5]=[C:3]([C:1]#[N:2])[CH3:4]
Reactant: CC(C#N)=CCCl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C#N)=CCN1C(=O)c2ccccc2S1(=O)=O
Yield: 66.3 %

Procedure:
18.2 g (150 millimoles) of 2-cyano-4-chlorobut-2-ene were slowly added dropwise to 20.0 g (100 millimoles) of sodium saccharin in 100 ml of absolute dimethylformamide, while stirring thoroughly. The reaction mixture was stirred for a further 4 hours at 40° C., after which the precipitated sodium chloride was filtered off and the filtrate was evaporated down under reduced pressure to about 30 ml. After 400 ml of water had been added, the oil initially formed slowly crystallized. The crystals were filtered off under suction, recrystallized from ethanol and dried in a drying oven under reduced pressure at 50° C. to give 17.4 g (66%) of 4-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-2-cyanobut-2-ene of melting point 107°-108° C.