Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:9](O)[CH2:8][CH2:7][O:6][P:5]1(=[O:15])[NH:11][CH2:12][CH2:13][Cl:14].[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[SH:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27].ClC(Cl)(Cl)C(O)=O>O>[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:1][CH2:2][CH2:3][N:4]1[CH:9]([S:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])[CH2:8][CH2:7][O:6][P:5]1([NH:11][CH2:12][CH2:13][Cl:14])=[O:15]
Reactant: O=P1(NCCCl)OCCC(O)N1CCCl
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: O
Product: O=P1(NCCCl)OCCC(SCCS(=O)(=O)[O-])N1CCCl
Reaction time: 20 h

Procedure:
277 mg (1 mmol) of 3-(2-chloroethyl)-2-(2-chloroethylamino)-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 240 mg (1 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 4 ml of water, mixed with a trace of trichloroacetic acid and stored for 20 hours at 0° C. The reaction mixture which was concentrated under vacuum was dissolved twice in ethanol and re-concentrated. It was then taken up in ethanol and precipitated with ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(Cl)cc2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-trifluoromethyl-1H-pyridin-2-one (29.5 g, 108 mmol) and phosphoryl chloride (49.2 mL, 539 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a light brown solid (19.7 g, 62%). MS (ISP) 292.1 [(M+H)+], 294 [(M+2+H)+] and 296 [(M+4+H)+].
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[S:10](=[O:21])(=[O:20])[CH2:11][C:12]3[N:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18]=2[OH:19])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[Br:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[S:10](=[O:21])(=[O:20])[CH2:11][C:12]3[N:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18]=2[O:19][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=S1(=O)Cc2nccnc2C(O)=C1c1c(F)ccc(Br)c1Cl
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)OC1=C(c2c(F)ccc(Br)c2Cl)S(=O)(=O)Cc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(3-bromo-2-chloro-6-fluoro-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol (Compound C21 of Table C) (0.5 g) in dichloromethane (5 ml) at 0° C. was added pyridine (0.12 ml) followed by drop wise addition of isobutyryl chloride (0.142 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: 0-100% v/v ethyl acetate in hexane) to give isobutyric acid 7-(3-bromo-2-chloro-6-fluoro-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-yl ester (0.17 g) 1H-NMR (400 MHz, CDCl3): 1.15 (6H, d), 2.80 (1H, quin), 5.00 (2H, s), 7.10 (1H, t), 7.70 (1H, m), 8.65 (1H, d), 8.70 (1H, d).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]12S[CH:12]1[CH:13]1[S:18][C:14]1(O)[CH:15]=[CH:16]2.CC(O)=O>C(Cl)Cl.[Zn]>[SH:18][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: NC12C=CC3(O)SC3C1S2
Reactant: O=C(Cl)c1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc(S)cc1)c1ccccc1
Reaction time: 8 h

Procedure:
Benzoyl chloride (5.14 mL, 44.28 mL) was added dropwise to a mixture of 4-aminophenol disulfide (5.0 g, 20.13 mmol) and TEA (7.01 mL, 50.3 mmol) in 60 mL DCM at 0° C. The reaction was allowed to stir overnight. The resulting precipitate was collected by filtration. The solid was washed with MeOH and water and then dried. The solid was combined with 200 mL of concentrated HOAc, and 5.0 equiv of zinc powder was added. The reaction was monitored by LCMS. When the reaction was complete, the acetic acid solution was concentrated to approximately 20 mL in volume. The crude mixture was then extracted with water and EtOAc. The organic layer was dried with MgSO4 then concentrated. MS: 228 [M+H]+; 1H NMR (DMSO-d6): 10.23 (s, 1H), 7.94 (d, 2H), 7.81 (d, 2H), 7.56 (m, 3H), 7.28 (d, 2H), 5.31 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[N:13](OCCC(C)C)=[O:14]>CO>[N:13](=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11])[OH:14]
Reactant: CC(C)CCON=O
Reactant: C#Cc1ccc(CC(C)=O)cc1
Solvent: CO
Product: C#Cc1ccc(C(=NO)C(C)=O)cc1
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
8 g of Na (=0.35 mol) are dissolved at room temperature in 300 ml of methanol. 44 g (=0.28 mol) of 4-ethynylphenylacetone are added to this solution and 34.2 g (0.29 mol) of isopentyl nitrite are allowed to run in dropwise in the course of a few minutes, during which the reaction mixture warms to about 32° C. It is stirred for 1.5 hours, then evaporated. 48.5 g (=93.2% of theory) of 1-hydroximino-1-(4′-ethynylphenyl)propan-2-one are obtained; H-NMR: 2.47(s); 3.07(s); 7.20(m); 7.48(m); 8.01(s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Cl.[C@H:14]12[CH2:20][C@H:17]([NH:18][CH2:19]1)[CH2:16][O:15]2.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=[C:2]([N:18]2[CH2:19][C@@H:14]3[CH2:20][C@H:17]2[CH2:16][O:15]3)[CH:7]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H]3C[C@H]2CO3)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfonyl-pyrimidine (3.41 g, 15 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2.03 g, 15.0 mmol) in N,N-dimethylacetamide (40.5 mL), was added N,N-diisopropylethylamine (6.60 mL). The resulting mixture was stirred at room temperature. After 30 min, the reaction mixture was concentrated to a solid. The crude material was purified by column chromatography using an 80 g column, with a gradient of 0% to 100% ethyl acetate in heptane. The combined fractions containing product were concentrated under reduced pressure to provide (1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (3.03 g). 1H NMR (400 MHz, Chloroform-d) δ 6.30 (s, 1H), 3.98-3.81 (m, 3H), 3.45-3.35 (m, 2H), 3.28 (s, 3H), 2.16-1.98 (m, 2H), 1.95-1.86 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][O:8][CH3:9])[C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[Br:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1>C(#N)C>[Br:17][C:18]1[C:19]([NH:2][C@H:3]([CH2:7][O:8][CH3:9])[C@H:4]([OH:6])[CH3:5])=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COC[C@@H](N)[C@@H](C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC[C@@H](Nc1nc(Cl)ncc1Br)[C@@H](C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
311 mg (2.6 mmol) of (2R,3R)-3-amino-4-methoxy-butan-2-ol hydrochloride (production according to A. I. Meyers, D. Hoyer, Tet. Lett. 1985, 26, 4687) in 2 ml of acetonitrile is mixed with 0.28 ml of triethylamine and shaken. It is filtered, and the filter cakes are washed with 2 ml of acetonitrile. The filtrate is added in drops to a solution of 455 mg (2.0 mmol) of 5-bromo-2,4dichloro-pyrimidine in 26 ml of acetonitrile at −30° C. By removal of the cooling bath, it is slowly heated to room temperature while being stirred. After 16 hours, the solvent is drawn off in a rotary evaporator, and the remaining residue is purified by chromatography (hexane/ethyl acetate: 4:1-1:1). 509 mg (1.6 mmol, corresponding to 80% of theory) of the product is obtained.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:18][O:19][CH2:20][CH2:21][CH:22](CC)[CH2:23][CH2:24][CH3:25])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[ClH:28].OC(COC1C=CC([Cl:53])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:53].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[C:22]([Cl:1])[CH:23]=[CH:24][C:25]=1[Cl:28])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: CCCC(CC)CCOC[C@@H](O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)ccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M-15,.1), 280 (11), 279 (9), 278 (64), 276 (100), 163 (9), 161 (5), 121 (29) , 113 (8).
Reaction SMILES: [C:1](=[O:3])=O.[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.C(N=C=O)CCC.C(Cl)(Cl)=O.S(N=C=O)(N=C=O)(=O)=O>C1(C)C(C)=CC=CC=1>[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]([S:10]([N:13]=[C:1]=[O:3])(=[O:12])=[O:11])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C=O
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: CCCCN=C=O
Agent: O=C(Cl)Cl
Agent: O=C=NS(=O)(=O)N=C=O
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Into a dry, 500 ml, 3 neck round bottom flask, equipped with a dry-ice-cooled reflux condenser, stirrer, gas inlet tube and thermometer was charged 12 g of 1,1'-biphenyl-2-sulfonamide, 100 ml of xylene, 0.2 g of 1,4-diaza[2.2.2]bicyclooctane (DABCO) and 5 g of n-butyl isocyanate. The mixture was heated to 135° and then phosgene was passed into the system until the temperature dropped to 125°. Heating was continued to bring the mixture up to 135° and additional phosgene was added to lower the temperature to 120°. This cycling was repeated until the temperature of the refluxing mixture remained at 120° without further addition of phosgene. The mixture was then allowed to cool to room temperature, filtered and concentrated in vacuo. Any contact with moisture was scrupulously avoided due to the extreme reactivity of the sulfonyl isocyanate. The product thus obtained (yield 10.4 g) showed an absorption peak in the infrared spectrum at 2200 cm-1, consistent with a sulfonyl isocyanate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>O1CCOCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2cccc(Cl)c2)c1
Temperature: 90 °C

Procedure:
To dimethyl 5-bromoisophthalate (880 mg, 3.22 mmol) (commercial source: Matrix scientific) in 1,4-dioxane (15 ml), 3-chlorophenyl boronic acid) (756 mg, 4.83 mmol), sodium carbonate (2M aqueous solution) (1.38 gms in 6.5 ml water) and Pd(PPh3)4 (370 mg, 0.32 mmol) was added and heated at 90° C. for 5 h. Then reaction mixture was diluted with ether, washed with water, brine and dried. Volatiles were removed under vacuum and the crude residue was column chromatographed (10% ethylacetate/90% hexanes) to yield 700 mg of dimethyl 3′-chlorobiphenyl-3,5-dicarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:21]3[N:20]=[N:19][C:18]([Cl:17])=[C:23]([CH3:24])[C:22]=3[CH3:25])[CH2:15][CH2:16]2)=[N:9][CH:10]=1)=[O:4]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: COC(=O)c1cnc(N2CCNCC2)cn1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)cn1
Temperature: 190 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To the solution of 3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (250 mg, 1.07 mmol) in NMP (5 mL) is added 3,6-dichloro-4,5-dimethyl-pyridazine (237 mg, 1.33 mmol) and TEA (446 μl, 3.21 mmol), the reaction mixture is stirred at 190° C. for 60 min. Water is added to the mixture and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by HPLC, (acetonitrile/water: 10%˜95% with 3% 1-propanol) to give white powder (165 mg, 43%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:30])[CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:31]([O:30][CH:10]([CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)COCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(C)C(COCc1ccccc1)OC(C)=O
Yield: 95.7 %

Procedure:
In chloroform, 4.33 g of 1-benzyloxy-3-hexadecyloxy-2-butanol, 26.34 g of acetic anhydride and 10.42 g of triethylamine were heated under reflux for 17 hours. The reaction mixture was treated in a conventional manner and purified by silica gel column chromatography to give 4.56 g of 2-acetyloxy-1-benzyloxy-3-hexadecyloxybutane.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH2:1]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=2)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc2cc(O)ccc2c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Decyl monobromide (7.0 g), 2,6-dihydroxynaphthalene (5.0 g) and anhydrous potassium carbonate (4.0 g) were added to 100 ml of dimethylformamide. After stirring at 130° C. for 2 hours, the reaction solution was poured into water. Dilute hydrochloric acid was added to neutralize the solution, which was extracted with diethyl ether. The extract was distilled to remove the solvent to obtain the titled compound as residue (8.0 g).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:22]=[CH:21][C:12]2[N:13]=[C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])[NH:15][C:11]=2[CH:10]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(O)(=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]=[C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])[NH:15][C:11]=3[CH:10]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: COC(=O)Nc1nc2ccc(O)cc2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.8 ml of triethylamine are added dropwise, with stirring, to 2.07 g of methyl 5-hydroxybenzimidazole-2-carbamate and 1.94 g of 4-fluorobenzenesulfonyl chloride at about 10° C. The mixture is then stirred at room temperature for 2 h, 100 ml of 2N acetic acid are added while cooling, and the resulting precipitate is filtered off with suction, washed with water and dried. Melting point 236° C., decomposition, from dimethylformamide/methanol.
Reaction SMILES: [NH2:1][C:2](=[S:25])[C@@H:3]([O:17][Si](C(C)(C)C)(C)C)[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5].Cl[CH2:27][C:28](=O)[CH3:29]>CCO>[OH:17][C@H:3]([C:2]1[S:25][CH:27]=[C:28]([CH3:29])[N:1]=1)[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:5]
Reactant: CC(=O)CCl
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)C(N)=S
Solvent: CCO
Product: Cc1csc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of benzyl ((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxopropyl)carbamate (96.8 mg, 0.253 mmol) and chloroacetone (117 mg, 101 μL, 1.27 mmol) in dry EtOH (5 mL) was heated at reflux under N2 for 20 h, then stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-100% EtOAc in hexanes gradient) to afford benzyl [(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate. Rf=0.44 (50% EtOAc in hexanes). LCMS calc.=307.1; found=307.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.31 (m, 5H), 6.80 (s, 1H), 5.49 (br s, 1H), 5.06 (m, 3H), 4.26-4.18 (m, 1H), 2.38 (s, 3H), 1.09 (d, J=6.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].Br[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH:15]1([O:8][C:7]2[C:2]([OH:1])=[C:3]([C:11](=[O:13])[CH3:12])[CH:4]=[CH:5][C:6]=2[O:9][CH3:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C(C)=O)c(O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)c(O)c1OC1CCCC1
Temperature: 110 °C

Procedure:
A mixture of 1-(2,3-dihydroxy-4-methoxyphenyl)ethanone (10 g, 55 mmol), bromocyclopentane (6.0 mL, 56 mmol), potassium carbonate (15.5 g, 112 mmol), and anhydrous DMF (100 mL) was heated at 110° C. under N2 for 17 h and then allowed to cool to rt. The mixture was poured into 0.5N HCl (600 mL) and extracted with diethyl ether (250 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (1:0→17:3; hexanes:ethyl acetate) to give 1-[3-(cyclopentyloxy)-2-hydroxy-4-methoxyphenyl]ethanone: MS (ESI): 251.2.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=O)[CH2:5]1)(=[O:3])[CH3:2].C1(P(=[CH:35][C:36]([O:38][CH3:39])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)N(C(C)=O)CC2=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cn(C(C)=O)c2cc(OC)ccc12
Yield: 50 %

Procedure:
A mixture of 1-acetyl-6-methoxy-1,2-dihydro-3H-indol-3-one (3.96 g, 19.3 mmol) (Example 12) and methyl (triphenylphosphoranylidene)acetate (19.75 g, 57.9 mmol) in toluene (60 mL) was heated at reflux under argon for 24 h. The mixture was loaded on silica gel and eluted with EtOAc/hexane (1/5) to yield a thick oil (2.52 g, 50%). LC/MS m/z 262 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.04 (br s, 1H), 7.38 (d, 1H), 7.31 (s, 1H), 6.92 (dd, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 3.71 (d, 2H), 2.62 (s, 3H).
Reaction SMILES: [Br:1][C:2]1([C:9](Cl)=[O:10])[CH:6]([Br:7])[C:5]([Br:8])=[CH:4][S:3]1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1([C:9]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:10])[S:3][CH:4]=[C:5]([Br:8])[CH:6]1[Br:7]
Reactant: O=C(Cl)C1(Br)SC=C(Br)C1Br
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C1(Br)SC=C(Br)C1Br)C(=O)O
Yield: 60.4 %

Procedure:
15.3 g 2,3,4-tribromothiophene carboxylic acid chloride in 60 ml dioxane are reacted in a manner analogous to Example 89 with 34.56 g L-alanine and 3.20 g NaOH in 60 ml H2O. After workup, 10.5 g (60.1% of theory) N-(2',3',4'-tribromothenoyl)-L-alanine with a melting point of 175°-179° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@H:14]([N:22](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@H:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Reaction time: 0.03 h

Procedure:
Dissolve 2-(R)-(2-(R)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (610 mg, 1.2 mmol) in methanol (13 mL). Add 20% palladium hydroxide on carbon (157 mg, 0.19 mmol). Bubble hydrogen gas through the mixture and stir under 1 atmosphere of hydrogen gas overnight. Bubble nitrogen through the mixture for 2 min, filter through a filtering agent, wash with methanol and concentrate to give the title compound.
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]4[O:35][CH2:36][CH2:37][O:38][C:33]=4[CH:32]=3)[CH:24]=2)[O:6]1)(=O)C.[BrH:41]>CC(O)=O.C(Cl)Cl>[C:12]([O:11][C@H:10]1[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]4[O:35][CH2:36][CH2:37][O:38][C:33]=4[CH:32]=3)[CH:24]=2)[O:6][C@H:5]1[Br:41])(=[O:14])[CH3:13]
Reactant: CC(=O)OC1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)O[C@@H](Br)[C@H]1OC(C)=O
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Compound 137 (100 mg, 0.17 mmol) was treated with 33% HBr in AcOH (350 μL) for 30 min at room temperature. The reaction mixture was diluted with CH2Cl2 (1 mL), stirred for 30 min, diluted with more CH2Cl2 (50 mL), and washed with cold water (10 mL×2), and saturated NaHCO3 solution (40 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (100 mg, 99%) as an off-white solid. The obtained product was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:30][CH2:31]Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CC(N(C)C)=O>[C:17]([O:30][CH2:31][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCCCCCCCCCCC(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 74.1 %

Procedure:
In 100 ml of dimethylacetamide were dissolved 19.51 g (0.15 mol) of 5-fluorouracil and 75.90 g (0.75 mol) of triethylamine. To this mixture was added dropwise at room temperature 41.05 g (0.165 mol) of chloromethyl laurate and the mixture was reacted together for 20 hours. After completion of the reaction, the triethylamine and dimethylacetamide were removed by distillation and the residue was poured into 400 ml of water. The mixture was stirred, filtered and washed with water whereby crystals were obtained which were then recrystallized from 200 ml of ethanol to obtain 38.06 g of 1-lauroyloxymethyl-5-fluorouracil having a melting point of 113.7~114.2° C. in a yield of 74.2%.