Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].[C:13](Cl)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:13])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)c(OC)c1
Reaction time: 36 h
Yield: 98 %

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (6.0 g) in methanol (120 ml) was treated with acetyl chloride (6 ml) and stirred for 36 hours. The solution was evaporated. The residue was dissolved in methanol (100 ml) and the solution evaporated. This procedure was repeated to give methyl 3-methoxy-4-methylbenzoate (6.34 g, 98%) as a colorless oil; NMR (80 MHz, CDCl3): 2.2(s, 3H, CH3), 3.9(2s, 6H, 2 x OCH3), 7.1(d, 1H), 7.5(m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (50 gm, 300 mmol) in acetone (1 L) was added potassium carbonate (150 gm) and benzyl bromide (37 mL, 1.1 eq). The mixture was refluxed for 6 hours and cooled to ambient temperature. The reaction was poured into ice cold aqueous 1M HCl (1 L) and the aqueous mixture was extracted with ether (3×500 mL). The combined organic extracts were dried over MgSO4 and filtered and the solvent was removed under reduced pressure. Methyl 2-hydroxy-4-benzyloxybenzoate was obtained by crystallization from EtOH in 60% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 80 °C

Procedure:
4-Methyl benzophenone (product of Aldrich) (25.1 parts), N-bromo succinimide [product of Wako Pure Chemical industries, Ltd.] (22.8 parts), benzoyl peroxide [water content: 20%, product of Wako Pure Chemical Industries, Ltd.] (0.54 parts), and acetonitrile (80 parts) were mixed, heated to 80° C., and allowed to react for 2 hours under reflux. Subsequently, the resulting mixture was cooled, and the organic solvent was evaporated under reduced pressure. The residue was recrystallized in methanol (160 parts). As a result, 26 parts of an intermediate (C123-6-1) was obtained (as white crystals).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:19]([S:21]([CH2:24][CH2:25]O)(=[O:23])=[O:22])[CH3:20].CC1C=CC(S([O-])(=O)=O)=CC=1>CN(C)C=O>[CH2:19]([S:21]([CH2:24][CH2:25][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:23])=[O:22])[CH3:20]
Reactant: CCS(=O)(=O)CCO
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCN1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 96 h
Yield: 812.7 %

Procedure:
To a solution of 6.6 g (0.03 mole) of 1-piperazinecarboxylic acid, phenylmethyl ester in 100 ml of N,N-dimethylformamide was added, in portions, 1.44 g (0.03 mole) of a 50% sodium hydride suspension in mineral oil. The mixture was heated at 50° for 1 hr and allowed to cool slightly. To it was added dropwise a solution of 8.8 g (0.003 mole) of 2-(ethylsulfonyl)ethanol, 4-methylbenzenesulfonate in 30 ml of N,N-dimethylformamide. The mixture was heated at 50° for 1 hr, allowed to cool, concentrated under vacuum to one-half the original volume, allowed to stand for four days and then concentrated to a paste. The paste was diluted with ether and the suspension filtered to remove insoluble salts. The filtrate was concentrated and chromatographed over 250 g of silica gel with 1 l each of the following solutions of methanol in ethyl acetate: 1.5%, 3% and 15%. That portion of the eluent containing the product, Rf(silica--10 % methanol/ethyl acetate)=0.7, was concentrated to dryness under vacuum to afford 8.3 g (81%) of the desired product as an oil. The IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].C=O.[CH:30](O)=O>O1CCOCC1>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]3[CH2:21][CH2:20][N:19]([CH3:30])[CH2:18]3)(=[O:15])=[O:16])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@@H]3CCNC3)ccc21
Reactant: O=CO
Agent: C=O
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@@H]3CCN(C)C3)ccc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of (R)—N,N-dimethyl-2-(2-neopentyl-5-(pyrrolidin-3-ylsulfonyl)-1H-benzo[d]imidazol-1-yl)ethanamine (STEP C, 453 mg, 1.15 mmol) in 1,4-dioxane (5 mL) was added 37% formalin (343 microL, 4.27 mmol) and formic acid (221 microL, 5.77 mmol) at 0° C. The mixture was stirred at 45° C. for 1 h. The mixture was concentrated in vacuo. The residue was diluted with sodium bicarbonate aqueous solution and extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with brine and dried over sodium sulfate. The resulting solution was concentrated and residue was purified by amine gel column chromatography (dichloromethane-ethyl acetate, gradient) to give the title compound (419 mg, 89%) as a clear grease.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:11]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:12]([CH2:16][CH3:17])[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2].[CH2:23]([NH2:25])[CH3:24]>>[C:1]([C:3]1[CH:4]=[C:5]([N:11]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:12]([CH2:16][CH3:17])[C:13]([NH:25][CH2:23][CH3:24])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2]
Reactant: CCN
Reactant: CCC(C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C#N)c1
Product: CCNC(=O)C(CC)N(CC(F)(F)F)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using 2-[(3,4-dicyanophenyl)(2,2,2-trifluoroethyl)amino]butanoic acid and ethylamine: MS (ES) m/z 339 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.CCN(CC)CC.Cl.[F:18][CH2:19][CH2:20][NH:21][CH3:22]>CN(C=O)C>[F:18][CH2:19][CH2:20][N:21]([CH3:22])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CNCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCF)C(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) was combined with DMF (10.0 ml) to give a colorless solution. Et3N (3.3 ml, 23.8 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, 2.8 g, 8.72 mmol) were added and the reaction mixture was stirred at RT for 1 h. 2-Fluoroethyl-methylamine hydrochloride (991 mg, 8.72 mmol) was added and stirring was continued overnight. DMF was removed under HV and the crude product (5.93 g brown oil) was purified by chromatography with a 50 g SiO2—NH2 cartridge (CH2Cl2/MeOH 95:5). The resulting product was dried under HV at RT for 48 h. Yellow oil (1.40 g, 92%); MS: m/z=186.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:2]3[N:3]=[CH:4][C:5]4[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:6]=4[N:7]=3)=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Nc3ncc4cc(C#N)n(C5CCCC5)c4n3)nc2)CC1
Yield: 49.6 %

Procedure:
Following Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (95 mg, 0.385 mmol) and 4-(6-amino-pyridin-3-yl)[1,4]diazepane-1-carboxylic acid tert-butyl ester (124 mg, 0.424 mmol) gave 4-[6-(6-cyano-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (96 mg) [following SiO2 chromatography, eluting with a 1-3% MeOH/dichloromethane and subsequent trituration with a diethyl ether]. The material is used directly in the next step.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:31])[CH2:20][CH:21]([O:23]CC1C=CC=CC=1)[CH3:22])=[CH:15][CH:14]=[C:13]([Cl:32])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:31])[CH2:20][CH:21]([OH:23])[CH3:22])=[CH:15][CH:14]=[C:13]([Cl:32])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(O)CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.9 %

Procedure:
A mixture of 2-benzoyl-3-(3-benzyloxybutyrylamino)-6-chloroindole (Step 1) (2.3 g, 5.1 mmol) and 10% Pd—C (0.2 g) in ethyl acetate (50 ml) was stirred at room temperature for 24 h under a hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (1/1) gave a yellow amorphous solid. Recrystallization from ethyl acetate/hexane afforded 290 mg (16%) of the titled compound as a pale yellow solid. m.p.: 159-162° C.
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:26])([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:9][CH2:10][S:11]([CH2:13][C:14]#[N:15])=[O:12].S([O-])([O-])=O.[Na+].[Na+]>O.CO>[F:26][C:8]([F:7])([C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[CH2:9][CH2:10][S:11]([CH2:13][C:14]#[N:15])(=[O:1])=[O:12]
Reactant: N#CCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)([O-])O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h

Procedure:
To a suspension of 9.21 g of a double salt of 2KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 50 ml of water was added dropwise a solution of 6.80 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfinyl)acetonitrile in 50 ml of methanol at room temperature over 60 minutes under a nitrogen atmosphere, and the mixture was stirred overnight. To the reaction mixture was added 25 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 25 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 5.4 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)acetonitrile represented by the formula:
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2Cl)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2Cl)CN1C(=O)Cn1cncn1
Yield: 35 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2,4-dichlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 180, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2,4-dichlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (48 mg, 35%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.03 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.68-7.35 (m, 5H), 7.19 (t, 2H), 7.07-6.88 (m, 4H), 5.24 (q, 2H), 4.57-4.48 (m, 1H), 3.91-3.78 (m, 1H), 2.97-2.70 (m, 3H), 2.11-1.88 (m, 3H). MS (EI) for C28H24FN5O3. found 569.8 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][N:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccncn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccncn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylpyrimidine-4-carboxamide
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[NH:26][C:25](=[O:27])[N:24]([C:28]2[CH:37]=[CH:36][C:31]([C:32](OC)=O)=[C:30]([O:38][CH3:39])[CH:29]=2)[N:23]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[NH:26][C:25](=[O:27])[N:24]([C:28]2[CH:37]=[CH:36][C:31]([C:32]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:7]=3)=[C:30]([O:38][CH3:39])[CH:29]=2)[N:23]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Yield: 11.6 %

Procedure:
To a solution of 4-chloro-N′-hydroxybenzimidamide (Intermediate-19, 0.069 g, 0.39 mmol) in dry toluene was added sodium hydride (0.016 g, 0.39 mmol). The reaction mixture was refluxed for 30 minutes followed by addition of methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol). The reaction mixture was refluxed for 5-6 h. The reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford crude product which was further purified by column chromatography to afford 0.015 g of desired product. 1HNMR (DMSO-d6): δ 3.98 (s, 3H), 7.45-7.48 (m, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 3H), 7.83 (d, J=8.1 Hz, 1H), 7.95 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.18 (d, J=8.7 Hz, 1H), 12.90 (br s, 1H). MS [M+H]+:499.89.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:38][C:39]1[CH:54]=[CH:53][C:42]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][C@H:46]([C@@H:50]([OH:52])[CH3:51])[CH2:45]2)=[CH:41][CH:40]=1>C1COCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:6](/[CH:12]=[CH:13]/[C:14]([N:47]2[CH2:48][CH2:49][N:44]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([F:38])=[CH:54][CH:53]=3)[CH2:45][C@H:46]2[C@@H:50]([OH:52])[CH3:51])=[O:16])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: C[C@H](O)[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1[C@H](C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.8 %

Procedure:
(E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid (2.1 g, 8.8 mmol), EDCI (3.4 g, 17.6 mmol); HOBT (2.4 g, 17.6 mmol) and 2.1 g (8.8 mmol) (S)-1-[(S)-4-(4-Fluorobenzyl)-piperazin-2-yl]-ethanol were dissolved in 180 ml THF and stirred for 20 hours at room temperature. This mixture was then extracted 3 times with water and once with saturated sodium chloride solution. The title compound was purified by chromatography (SiO2, ethyl acetate/MeOH/NH3conc. 90/10/1) and was isolated as a pale solid (2.5 g, 62%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]=[C:10]([Cl:12])[Cl:11])[N:3]=1.[CH3:13][O-:14].[Na+].[Na]>CO>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:5]=[C:6]([O:14][CH3:13])[N:7]=1
Reactant: Nc1nc(Cl)cc(C=C(Cl)Cl)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(C=C(Cl)Cl)nc(N)n1
Reaction time: 4 h

Procedure:
22.0 Parts of 2-amino-4-chloro-6-(2,2-dichlorovinyl)pyrimidine was dissolved in 500 parts of dry methanol and stirred whilst a solution of sodium methoxide, prepared by dissolving 4.6 parts of sodium in 200 parts of dry methanol, was added dropwise, over 30 minutes at ambient temperature. The resulting solution was stirred for 4 hours by which time all the starting material had been consumed. The product was precipitated by the addition of water, filtered and dried. The solid obtained was purified by chromatography on silica using diethyl ether as eluent. Final purification was effected by recrystallisation from carbon tetrachloride to give 2-amino-4-(2,2-dichlorovinyl)-6-methoxypyrimidine m.p. 90°-91° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:26])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(COC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate (1.7 g, 4.53 mmol) in CH2Cl2 (15 mL, 3 mL/mmol) was added TFA (10 mL) and the mixture was stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure, taken up in chloroform, filtered and washed with diethyl ether to provide 4-(4-(trifluoromethoxy)benzyloxy) piperidine (1.2 g, 96%) as TFA salt. Observed mass (M+1): 276
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]2[CH2:16][N:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C@@H:10]1[C@H:11]([O:14]2)[O:12]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>O>[CH2:1]([O:8][C@H:9]1[C@H:15]([OH:14])[CH2:16][N:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:10]1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)CN1C(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
Methyl 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (14α) (1.015 g, 2.77 mmol) was stirred in a 1:1 mixture of trifluoroacetic acid and water (20 ml). Once all the starting material had dissolved, the solvents were evaporated (without heat) and purification by flash chromatography (ethyl acetate-hexane 1:2) gave 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-D-lyxose (901 mg, 92%) as a clear oil, [α]20 D -24.2° (c, 1.39 in chloroform); νmax (film) 3400 (OH), 1700 (2×CO), 1425, 1360, 1195 and 700 cm-1 ; δH 2.55 (1H, bs, OH); 3.65 (1H, 2×d, H-5); 3.79 (1H, 2×dd, H-5'); 4.03, 4.31 (2H, 2×bs, H-2, H-3); 4.44, 4.55 (1H, bs and dd, H-4); 4.51-4.71 (2H, m, CH2Ph); 5.09-5.20 (2H, m, CH2 -Z); 7.29-7.40 (10H, m, H-Ph); 9.49, 4.59 (1H, 2×d, H-1, J1,2 0.7 Hz). m/z: 91 (100%), 108 (68%), 230 (50%), 356 (M+H+, 20%). (Found C, 67.76; H, 6.48; N, 3.77. C20H21NO5 requires C, 67.59; H, 5.96; N, 3.94). Methyl 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-β-D-lyxofuranoside (14β) (976 mg, 2.64 mmol) reacted similarly: it afforded the title compound (15) (820 mg, 87%), spectroscopically identical to that prepared above, under the same reaction conditions.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=O)[O:9]C(=O)[C:5]=2[CH:4]=1)[CH3:2].[N-:29]=[N+]=[N-].[Na+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:9])[NH:29][C:5]=2[CH:4]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cc2c(=O)oc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-2H-thieno[2,3-d][1,3]oxazine-1(4H)-yl)methyl]biphenyl-2-carbonitrile (3.5 g), sodium azide (0.88 g) and N,N-dimethylformamide (50 mL) was stirred at 50° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in toluene (30 mL), and the mixture was stirred at 110° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.5 g, 46%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:16])[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]3[CH2:36][CH2:37][C:38](=[O:39])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C1(C)C=C(C)C=C(C)C=1S(O[NH2:52])(=O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][S:21](=[NH:52])(=[O:24])[CH2:20][CH2:19]3)=[O:16])[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)[C:11]3[CH2:36][CH2:37][C:38](=[O:39])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)CC2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=N)(=O)CC2)cc1
Temperature: 25 °C

Procedure:
4-(4-Cyanophenyl)-2,5-dioxo-N-(1-oxo-hexahydro-1λ4-thiopyran-4-yl)-1-(3-(trifluoro-methyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxamide (example 43, 40 mg, 72 μmol) is added to a solution of O-mesitylenesulfonylhydroxyl-amine (66 mg, 0.31 mmol) in dichloromethane (1.0 mL), and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 9 mg; ESI mass spectrum [M+H]+=572; Retention time HPLC: 0.90 min (Z018_S04).