Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3][CH:2]1[N:9]1[C:13]([CH3:14])=[C:12](I)[CH:11]=[N:10]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>>[CH2:1]1[C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3][CH:2]1[N:9]1[C:13]([CH3:14])=[C:12]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)[CH:11]=[N:10]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1C1CC2(C1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5,8-dioxaspiro[3.4]oct-2-yl)-4-iodo-5-methyl-1H-pyrazole (50.0 mg, 0.156 mmol) in THF (3 mL, 40 mmol) at was added 2 M isopropylmagnesium chloride in THF (0.23 mL, 0.46 mmol), and the mixture was stirred at rt for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.10 mL, 0.62 mmol) and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][Si](C)(C)C)[S:22][C:13]=12.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[CH:24])[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(C#C[Si](C)(C)C)sc23)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To the suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile (97 mg, 0.22 mmol) in 10 mL of methanol is added potassium carbonate (46 mg, 0.33 mmol) The mixture is stirred at room temperature for 30 minutes, concentrated in vacuo and then partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 38 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 198–200° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 5.01 (s, 1H), 7.38 (s, 1H), 7.72 (s, 1H), 7.79 (s, 1H), 8.63 (s, 1H), 9.85 (s, 1H); MS 372.0 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([F:1])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)c(F)c1
Reactant: Nc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Yield: 95.1 %

Procedure:
A mixture of 1-[3-fluoro-4-(methylsulfonyl)phenyl]pentane-1,4-dione (2.8 g, 10.3 mmol), 4-bromoaniline (2.12 g, 12.3 mmol), and p-toluenesulfonic acid (150 mg) in toluene (250 mL) was heated at reflux temperature using Dean-Stark apparatus. After cooling down, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/5) to give the subtitle compound (4 g, 95% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)C>[N:22]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[O:10][C:11]4[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Reactant: C1CNCCN1
Solvent: CCO
Product: COC(=O)c1cccc2nc(-c3cccc(CN4CCNCC4)c3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and piperazine (68.8 mg, 0.8 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated under reduced pressure to obtain methyl 2-(3-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (79 mg, yield 91%). LC-MS (ESI) m/z 354 [M+1]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][N:22]([CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:23]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][N:22]([CH3:23])[CH3:21])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN(C)CC1CNCCO1
Product: CN(C)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(dimethylaminomethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-cyclopropyl-7-[2-(dimethylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 182°-183° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:31][CH2:30]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[N:2]1[NH:32][N:33]=[N:34][C:1]=1[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2cccc(-c3ccc(OCc4ccc(-c5nn[nH]n5)nc4)cc3)n2n1)C1CC1
Reaction time: 16 h
Yield: 5.7 %

Procedure:
A solution of cyclopropanecarboxylic acid{5-[4-(6-cyano-pyridin-3-ylmethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide (143 mg, 0.35 mmol, 1 equiv), sodium azide (46 mg, 0.7 mmol, 2 equiv), ammonium chloride (38 mg, 0.7 mmol, 2 equiv) was stirred at 0° C. under nitrogen for 30 minutes. Afterwards the mixture was subjected for 100° C. for 16 hours. The crude of the reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4, filtered, and dried under vacuum. The crude was diluted with DMSO and submitted for preparative HPLC purification: HPLC system (XBridge™ Prep C18, 5 μm, 19×100 mm column); 8 min LC; flow: 20 mL/min; gradient: from 30% to 70% acetonitrile in water 0.1% TFA; to afford the final pure product (9 mg, 6% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19]>CO>[CH3:17][S:18]([CH2:21][CH2:22][N:13]1[CH2:14][CH2:15][CH2:16][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Reactant: C=CS(C)(=O)=O
Solvent: CO
Product: CS(=O)(=O)CCN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-Nitro-phenyl)-[1,4]diazepane (4.90 g), Methansulfonyl-ethene (2.35 g) and Methanol (50 mL) was stirred for 2 h at room temperature. The volatiles were removed in vacuo. The product with the molecular weight of 327.40 (C14H21N3O4S) was obtained in this way; MS (ESI): 328 (M+H+).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[S:7][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1)=[O:10]>O.C1COCC1>[CH3:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=2)[S:7][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[O:10]
Reactant: COC(=O)c1ccccc1COc1ccc(CCNC(=O)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)NCCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 84.7 %

Procedure:
Lithium hydroxide (4 mg, 0.166 mmol) in water (1 ml) was added into methyl 2-[(4-{2-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}carbonyl)amino]ethyl}-phenoxy)methyl]benzoate (46 mg, 0.083 mmol) dissolved in THF (2 ml). The mixture was then irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 38 mg the desired product, yield 85%.
Reaction SMILES: C(O[C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:34]=[CH:33][CH:32]=[CH:31][C:11]=2[C:12]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:21]2C=N[C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[O:13])=[N:8][CH:9]=1)C.Cl.[F:36][C:37]1C(N[C@H]2CCC[C@@H]2N)=NC=C(C(F)(F)F)[CH:42]=1.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[F:36][C:37]1[C:21]([NH:20][C@H:16]2[CH2:17][CH2:18][CH2:19][C@@H:15]2[NH:14][C:12](=[O:13])[C:11]2[CH:31]=[CH:32][CH:33]=[CH:34][C:10]=2[C:7]2[N:6]=[CH:5][CH:4]=[CH:9][N:8]=2)=[N:22][CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:42]=1
Reactant: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34: 263 mg, 1.00 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 200 mg, 1.00 mmol) except after the reaction was complete it was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) and then was purified by reverse phase column chromatography (C18 silica, 0-100% water (0.05% ammonia)/methanol) and triturated with DCM/petrol. The product was further purified by reverse phase column chromatography (C18 silica, 0-100% water (0.1% ammonia)/acetonitrile to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2].[NH2:18][CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:18][CH2:19][CH:20]2[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21]2)=[O:11])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.4 %

Procedure:
To a stirred mixture of 4-acetylamino-5-chloro-2-ethoxybenzoic acid (2.0 g), 2-aminomethyl-4-(4-fluorobenzyl)morpholine (1.6 g), and dichloromethane (20 ml) is added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g), and the resulting mixture is stirred at 25° C. for 1.5 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is recrystallized from ethanol to give the title compound (2.1 g), mp 161°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH2:12][CH3:13].[Br:14][C:15]1[C:20]([NH2:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1>N1C=CC=CC=1>[Br:14][C:15]1[C:20]([NH:21][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:12][CH3:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: CCc1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Product: CCc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 1.71 g (7.15 mmol) of 4-chloro-3-ethyl-benzenesulfonyl chloride and 1.34 g (6.47 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 4 mL pyridine using procedure x. Yield: 2.35 g of a white solid. LC-MSD, m/z for C13H11BrCl2N2O2S [M+H]+=408.8, 410.8, 412.8
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([NH:20][C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Reaction time: 8 h

Procedure:
10 g of ethyl 2-aminothiazol-4-ylglyoxylate were dissolved in 100 ml of dimethylformamide, and 7.14 g of phenyl isocyanate were added dropwise to the resulting solution under ice-cooling. The mixture was left to stand overnight, and the dimethylformamide was then evaporated off under reduced pressure. The crystals thus obtained were washed with water, dried and recrystallized from ethyl acetate, giving the desired compound as yellow crystals.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[CH:18][C:16]([NH2:17])=[N:15][C:13]2=[O:14])[C@H:9]([OH:20])[C@@H:8]1[OH:21])([OH:4])([OH:3])=[O:2].C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O)(=O)C.C(O)(=O)C(C)=O.[Mg+2].[Cl-].[Cl-].O.P([O-])([O-])(OC(=O)C)=O.[OH-].[Na+:56].C([O-])(=O)C.[OH:61][C:62]([C:64]1([O:75][C@@H:74]([C@@H:76]([C@@H:78]([CH2:80][OH:81])[OH:79])[OH:77])[C@H:69]([NH:70][C:71]([CH3:73])=[O:72])[C@@H:67]([OH:68])[CH2:66]1)O)=[O:63].CC(N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)C[C@@H]1O)=O.[Na+]>C(O)C(N)(CO)CO.Cl>[CH3:73][C:71]([NH:70][C@H:69]1[C@H:74]([C@H:76]([OH:77])[C@H:78]([OH:79])[CH2:80][OH:81])[O:75][C@:64]([O:2][P:1]([O:5][CH2:6][C@H:7]2[O:11][C@@H:10]([N:12]3[C:13](=[O:14])[N:15]=[C:16]([NH2:17])[CH:18]=[CH:19]3)[CH:9]([OH:20])[C@H:8]2[OH:21])([O-:3])=[O:4])([C:62]([OH:63])=[O:61])[CH2:66][C@@H:67]1[OH:68])=[O:72].[Na+:56]
Reactant: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: CC(=O)C(=O)O
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1C([C@H](O)[C@H](O)CO)O[C@](OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Solvent: O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@](OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)C(O)[C@H]2O)(C(=O)O)C[C@@H]1O
Reaction time: 8.5 h

Procedure:
A reaction mixture of 20-100 g of 20-80 mM cytidine 5′-monophosphate (CMP, Shanghai QZU Bioscience & Biotechnology), 34.15-136.6 g of 20-80 mM N-acetyl-D-glucosamine (Shanghai Jiubang Chemical), 33.9-101.7 g of 40-120 mM pyruvic acid, 30.9 g of 20 mM MgCl2.H2O (Duksan), 3.72 g of 1 mM CTP (Sigma), 84-525 g of 80-500 mM acetyl phosphate (Sigma) and 7 liters of 50 mM Tris HCl buffer (pH 7.0), maintained at pH 6.5-8.0 using 2M NaOH at 37° C., was mixed with the polymer beads prepared in Example 4, which have each of cytidine monophosphate kinase (CMK), acetate kinase (ACK), NeuAc aldolase (NAN), CMP-NeuAc synthetase (NEU) and GlcNAc-2-epimerase immobilized thereon. Then, the mixture was stirred in a reactor for 5-12 hours.
Reaction SMILES: [C:1]([CH2:3][C:4]#[N:5])#[N:2].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>O1CCCC1>[C:1]([CH:3]([C:4]#[N:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:2]
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: N#CCC#N
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCCCC(C#N)C#N

Procedure:
100 ml of anhydrous tetrahydrofuran are introduced into a three-neck flask with stirrer, reflux condenser and dropping funnel, and 11.22 g (0.10 mol) of potassium tert.butylate are suspended with stirring. 6.61 g (0.10 mol) of 1,1-dicyanomethane dissolved in 20 ml of anhydrous tetrahydrofuran are added dropwise to this, while cooling in ice so that the temperature does not rise above 10° C. Subsequently, 28.0 g (0.10 mol) of methyl 11-bromoundecanoate are added, and the mixture is refluxed for 15 h. After cooling, the precipitated potassium bromide is filtered off, the filtrate is evaporated to dryness in a rotary evaporator, the residue is taken up in 100 ml of diethyl ether, and the solution is washed three times with 50 ml of water each time. The ethereal phase is dried over sodium sulfate and evaporated to dryness in a rotary evaporator, and the resulting crude product is distilled in a short-path distillation apparatus (boiling point 150 to 160° C./0.6 mbar).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:25]([CH:33]([CH:35]2[CH2:38][CH2:37][CH2:36]2)[OH:34])=[C:26]2[CH:32]=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1>C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:33]([CH:35]2[CH2:36][CH2:37][CH2:38]2)=[O:34])=[C:26]2[CH:32]=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1
Reactant: OC(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Dess-Martin periodinane (1.6 g, 3.8 mmol) was added to a suspension of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanol (0.3 g, 1.2 mmol) in DCM (7 mL) at about 0° C. The reaction mixture was stirred at ambient temperature for about 4 h then quenched by the addition of with saturated aqueous Na2SO3 (125 mL). The product was extracted into DCM (3×20 mL) and the combined organic extracts were washed with aqueous NaOH (2 N, 20 mL). The organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanone as an off-white solid (0.2 g, 67%) that was used directly in the next step without further purification: LC/MS (Table 2, Method a) Rt=2.27 min; m/z: 235 and 237 (M+H)+.
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH:24]=[CH:23]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[C@@H:25]1([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:22]([CH2:21][OH:20])[CH:23]=[CH:24]1
Reactant: O=c1ccn([C@H]2C=C[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5'O-trityl-2',3'-dideoxy-2',3'-didehydrouridine (0.5 gm.,1.1 mM) was dissolved in a chloroform (10 mL) and methanol (2 mL) mixture containing 2% p-toluenesulphonic acid. The reaction mixture was stirred at room temperature for 0.75 hr., and then neutralized with 2N NaOH (0.5 mL). The solvent was removed in vacuo and the residue chromatographed on silica using chloroform/acetone (2:1) as eluent. The desired product was isolated as a white crystalline solid with the same physical and spectroscopic characteristics as d4U produced by an alternative method. M.p. 155° C. 1H NMR (360 Mhz, D2O/DMSO) 7.8 (d, 1H, H6), 6.7 (m, 1H, H1'), 6.37 (m, 1H, H2'), 5.8 (m, 1H, H3'), 5.56 (d, 1H, H5), 4.7 (m, 1H, H4'), 3.6 (m, 2H, H5'). 13C NMR (70 Mhz, D2O/DMSO) 163 (C4), 151 (C2), 141 (C2'), 135 (C3'), 126 (C6), 101 (C5), 89 (C1'), 87 (C4'), 62 (C5').
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5](OCC)=[O:6].COC1C=CC=C(OC)C=1C1NC(=O)CCC1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[NH:1][C:5](=[O:6])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Agent: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1

Procedure:
5-(2,6-Dimethoxyphenyl)-3-methylpyrrolidin-2-one was prepared from ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate according to the procedure described for 6-(2,6-dimethoxyphenyl)piperidin-2-one. Subsequent purification by FC (DCM/MeOH=20/1) afforded 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one as a light orange solid. LC-MS (conditions D): tR=0.84 min.; [M+H]+: 236.43 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([O:19][CH2:20][CH:21]=[CH2:22])[CH:9]=[C:10]([OH:18])[C:11]=1[C:12]2=[O:17].[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([O:19][CH2:20][CH:21]=[CH2:22])[CH:9]=[C:10]([O:18][CH3:23])[C:11]=1[C:12]2=[O:17]
Reactant: C=CCOc1cc(O)c2c(=O)c3cccc(OC)c3oc2c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)c2c(=O)c3cccc(OC)c3oc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of xanthone 2 (150 g, 0.5 mol) in dry DMF (500 mL) was added potassium carbonate (100 g, 0.72 mol) and methyl iodide (180 g, 1.28 mol) and the mixture was heated with constant stirring under argon to 80° C. for 1 hour. The mixture was allowed to cool to room temperature and diluted with 2L ethyl acetate and the remaining potassium carbonate was dissolved in dilute sulfuric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the xanthone 3 (120 g, 0.38 mol, 77%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:40][CH2:39][CH2:38][O:37][CH3:36])[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2Cl)[C@H](c2ccccc2)C1
Reactant: COCCN
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: COCCNc1ccccc1[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1c1ccccc1

Procedure:
The title compound, MS: m/e=551.1 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(2-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, 2-methoxy-ethylamine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.