Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl-].[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: [Cr+6]
Agent: [Cl-]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Chromium trioxide (3.00 g.) was added to a stirred solution of pyridine (4.75 g.) in dry methalene chloride (75 ml.), and stirring was continued for a further 15 minutes. 3-Phenoxybenzyl alcohol (1 g.) in methylene chloride (5 ml.) was added, the mixture stirred for a further 15 minutes, decanted and the residue washed with diethyl ether (100 ml.). The filtrate was washed with 55 sodium hydroxide solution (3 × 50 ml), 2.5 NHCl (50 ml.) and 5% sodium carbonate solution (50 ml.) and dried over Na2SO4 to give 3-phenoxy-benzaldehyde. Alternatively the alcohol can be oxidized using Jones' reagent, a similar yield of aldehyde being obtained. Yield (0.80 g.), b.p. 126°/0.8 mm.Hg, nD = 1.5984.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Cl:1])[NH:8][C:7](=[O:11])[CH2:6]2)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccc(Cl)cc2N1
Product: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1

Procedure:
Step a) involves acylation of a composition comprising 6-chloro-1,3-dihydro-2H-indol-2-one of Formula III with chloroacetyl chloride by Friedel-Crafts acylation to obtain 5-(2-chloroacetyl)-6-chloro-2-oxindole of Formula IV.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][N:56]=1>CN(C=O)C.O>[OH:54][C:55]1[CH:63]=[CH:62][C:58]([C:59]([NH:11][CH2:12][C:13](=[O:14])[N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]2)=[O:60])=[CH:57][N:56]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 24.9 %

Procedure:
DIPEA (418 mg, 0.56 mL, 3.2 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (303.4 mg, 0.86 mmol) in DMF (4 mL). HOBT (106 mg, 0.79 mmol) and EDCI (344 mg, 1.7 mmol) were then added at room temperature. After 2 minutes, 6-hydroxy nicotinic acid (100 mg, 0.71 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by preparative HPLC to afford 77 mg (24.6% yield) of 6-hydroxy-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-nicotinamide. LCMS Purity: 95.26%. 1H NMR (DMSO-d6): δ 12 (s, 1H), 8.4 (s, 1H), 7.9-7.74 (m, 3H), 7.72-7.62 (m, 1H), 7.6-7.5 (m, 1H), 4.2-4.0 (d, 2H), 3.9-3.52 (m, 5H), 3.24-3.0 (m, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:9]1[CH2:10][CH2:11][CH2:12][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.64 ml, 8.24 mmol) was added to a solution of tert-butyl 1,4-diazepane-1-carboxylate (1.5 g, 7.49 mmol) and triethylamine (1.6 ml, 11 mmol) in dichloromethane (20 ml), and the reaction stirred at room temperature for 18 hours. The solution was washed with sodium bicarbonate solution, then brine, dried (MgSO4) and evaporated under reduced pressure to give the title compound, 2.01 g.
Reaction SMILES: CS(O[CH:6]([CH:18]1[CH2:20][CH2:19]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=O)=O.C([O-])(C)(C)C.[K+].O>CS(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]1[CH2:7][CH:6]1[CH:18]1[CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Reaction time: 1.5 h

Procedure:
1.06 g of 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate (3.54 mmol) is dissolved in 20 ml of dimethyl sulfoxide, 1.05 g of potassium tert-butanolate (97%, 10.62 mmol) are added, and stirring is carried out for 1.5 hours at ambient temperature under a nitrogen atmosphere. Water is added to the reaction mixture. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:10). After removal of the eluant, 0.68 g of 2-(2-nitrophenyl)-bicyclopropane (67% of theory) are obtained in the form of an orange-coloured liquid (trans:cis ratio: 7.7:1).
Reaction SMILES: [F:1][C:2](F)([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=CC(C#N)=CN=1.FC(F)CO>>[F:14][CH:2]([F:1])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: N#Cc1ccc(Cl)nc1
Agent: OCC(F)F
Product: CC(N)c1ccc(OCC(F)F)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and 2,2-difluoroethanol.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[O:24]C)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[OH:24])=[CH:27][CH:28]=1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC(=O)C(Cc2ccc(O)c(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)S1
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a suspension of N-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide (800 mg) in anhydrous methylene chloride (30 ml), a 1.0N boron tribromide-methylene chloride solution (2.20 ml) was slowly added dropwise in an argon atmosphere under cooling with dry ice-acetone and stirring. After stirred for 6 hours at room temperature, the reaction liquor was allowed to stand for 3 days. After water was added and the mixture was stirred for 30 minutes, this was concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with water and then dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride:methanol=40:1) to obtain 618 mg (80%) of aimed compound as crystals. These were recrystallized from ethanol-water to obtain purified aimed compound as a light brown powdery crystals. Melting point 146.0~148.0° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:24][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 20 °C

Procedure:
A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 250 g (1.097 mol, 140.4 mL, 1.0 eq.) of 5-bromo-2,4-dichloropyrimidine (A1h) and 1127 g, (1250 mL) of ethyl acetate. The content is stirred at 20° C. and 283.5 g (2.194 mol, 382.0 mL, 2.0 eq.) of N,N-diisopropylethylamine is added. A solution of 102.8 g (1.207 mol, 119 mL, 1.1 eq.) of cyclopentylamine (A1g) dissolved in 1127 g, (1250 mL) of ethyl acetate is added over 60 min. An 18° C. to 36° C. exotherm is observed. The solution is warmed to 40° C. This temperature is maintained for at least 6 h or until all the starting material A1h, is consumed as determined by HPLC analysis. The resulting slurry is cooled to 25° C. and 500 g (500 mL) of water is added. The content is stirred for 15 min and the phases are allowed to separate. The bottom (aqueous) layer is removed and the organic layer is washed once more with 500 g (500 mL) of water. The sample is stirred for 15 min, and the phases are allowed to separate. The bottom (aqueous) layer is removed. The organic phase is concentrated (atmospheric pressure) to a volume of 1500 mL (batch temp=82° C.). 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=85° C.). Again, 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=96° C.). The sample is cooled to 50° C. and seeded. The cooling is continued to 4° C. and the temperature is maintained at 4° C. for 1 h. The solids are filtered and the filter cake is washed once with 137 g (200 mL) of cold (4° C.) heptane. The solids are dried at 50° C. for 16 h, to afford 259.0 g (88.0%, corrected) of Compound A1f as a white, crystalline solid, mp=95-96° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH3:5][C:6]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])[CH3:7].N#N.Cl>N1C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][Si:9]([C:6]([CH3:8])([CH3:7])[CH3:5])([CH3:11])[CH3:10])[C:2]#[CH:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCO
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCO[Si](C)(C)C(C)(C)C
Reaction time: 72 h

Procedure:
To a solution of 5.82 mL of propargyl alcohol in 20 mL of pyridine and 30 mL of CH2Cl2 was added 0.122 g of DMAP and 16.88 g of TBDMSCl in a N2 atmosphere. After stirring 3 days, the reaction was poured into 100 mL of 1N HCl, and diluted with CH2Cl2. The layers were separated and the organic layer washed with 100 mL of 1N HCl (2×), 10% NaHCO3, H2O and brine and dried (MgSO4). Filtration and concentration provided 15.07 g of an oil which was used without purification.
Reaction SMILES: [F-].[Cs+].C([Sn](CCCC)(CCCC)[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)CCC.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[C:28](I)[C:27]([OH:31])=[CH:26][CH:25]=1>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.[Cu]I>[N:11]1[CH:12]=[CH:13][C:8]([C:26]2[CH:25]=[C:24]([C:23]([F:33])([F:32])[F:22])[CH:29]=[CH:28][C:27]=2[OH:31])=[CH:9][N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1ccc(C(F)(F)F)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Product: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 47.5 °C
Yield: 60 %

Procedure:
Acetonitrile (9 L) was sparged with nitrogen for 2 hours. To the solvent was added cesium fluoride (335.8 g, 2.21 mol), 4-(tributylstannyl)pyridazine (408 g, 1.11 mol), 4-trifluoromethyl-6-iodophenol (318.3 g, 1.11 moles), palladium tetrakis 25 triphenylphosphine (61.31 g, 53.05 mmol) and copper (I) iodide (40 g, 210 mmol) at 20° C. The resulting orange suspension was heated to 45-50° C. for 2 hours. The reaction was cooled and partitioned between TBME (2×5 L) and aqueous hydrochloric acid solution (2 N, 2×5 L). The resulting biphasic solution was filtered and the layers separated. The aqueous phases were combined and basified with a sodium hydroxide solution (4 M, 6 L) to obtain a pH=4-5. The resulting suspension was extracted with EtOAc (10 L) and the organic layer concentrated in vacuo to afford the title compound as an orange solid (60%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:17]([O:19]C)=[O:18])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3].CO>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:17]([OH:19])=[O:18])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1-c1ccccc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 4-(methylsulfonyl)-[1,1′-biphenyl]-2-carboxylate (330 mg, 1.1 mmol) in methanol (15 ml) NaOH 2N (1.1 ml; 2.3 mmol) was added and the solution left stirring at room temperature for 72 hours.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.[Li+].[Cl-]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1cc(OCC2CC2)c(Br)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(OCC2CC2)c(Br)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of the title compound from step 1 (450 mg, 1.74 mmol) in DMF (5 mL) was added LiCl (370 mg, 8.72 mmol) and TsORH2O (1.52 g, 8.72 mmol) at room temperature. The mixture was heated to 120° C. and stirred for 1 hour. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phase was washed with saturated brine (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (380 mg, yield: 88.9%) as yellow solid which used directly for the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 1H), 5.91 (s, 1H), 3.87 (d, J=6.8 Hz, 2H), 1.36-1.22 (m, 1H), 0.71-0.67 (m, 2H), 0.46-0.42 (m, 2H). LCMS: 244.0 (M+1)+; 246.0
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1([CH2:16][N+:13]([O-:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1

Procedure:
14.8 g (0.088 mol) of the cyclohexylideneacetic acid ethyl ester produced according to 1.1 were dissolved in 50 ml of tetrahydrofuran, 7.11 ml (0.132 mol) of nitromethane and 88 ml of tetrabutylammonium fluoride (1 molar in tetrahydrofuran) were added under a nitrogen atmosphere and refluxed for 20 hours. After cooling, the mixture was diluted with 50 ml of water and extracted three times with dieethyl ether. The organic phase was washed with 10 wt. % aqueous potassium hydrogensulfate solution and then washed with water, dried over magnesium sulfate and evaporated. (1-Nitromethylcyclohexyl)acetic acid ethyl ester was obtained as an orange-yellow oily liquid. The yield amounted to 19.8 g (98% of theoretical).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]([CH3:24])[N:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.II.[PH2](=O)O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]([CH3:24])[N:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 120 °C
Yield: 85.8 %

Procedure:
A mixture of 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethanol (1.1 g, 3.18 mmol), diiodine (2.019 g, 7.95 mmol) and phosphinic acid (0.840 g, 12.73 mmol) in acetic acid (10 mL) was heated at 120° C. for 5 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was taken with water and adjusted to pH 8 with aqueous NaOH. Then the mixture was extracted with DCM, dried over Na2SO4 and concentrated. The residue was purified with column chromatography (MeOH:EtOAc) to give 900 mg (60%) of the title compound. LCMS (method B): [MH]+=330, tR=2.59 min.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[I-]>C1COCC1.O>[Cl:13][C:14]1[C:15]([CH3:1])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)NC(C)C
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 91 %

Procedure:
N,N-diisopropylamine (65.6 ml) was dissolved in anhydrous THF (150 ml), to which was dropwise added n-butyl lithium (1.54 mols/liter hexane solution, 300 ml) in an argon atmosphere at −78° C., and directly stirred for 5 minutes. An anhydrous THF (600 ml) solution of 3,5-dichloropyridine (63 g) was dropwise added to this, and stirred for 1 hour, and thenmethyl iodide (29.2 ml) was dropwise added thereto, and stirred for further 1.5 hours. Water was added to this to stop the reaction, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, then dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), then suspended in hexane, and taken out through filtration to obtain 3,5-dichloropicoline (62.8 g, 91%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH:27]=[CH2:28])[C:5]1=[O:6])[CH:2]=[CH2:3].[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:20][N:19]1[NH:18][C:17]([O:21][CH2:22][C:23]([N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[O:25])=[CH:16]/[C:15]/1=[C:10]1\[N:11]=[C:12]2[C:13](=[O:14])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:6])[N:7]([CH2:26][CH:27]=[CH2:28])[C:8]2=[N:9]\1
Reactant: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c2c(n(CC=C)c1=O)=N/C(=C1/C=C(OCC(=O)N3CCN(c4ccccc4)CC3)NN1C)N=2
Yield: 27 %

Procedure:
Condensation of 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (0.5 mmol) and N-phenyl-piperazine (1.3 mmol) in the presence of EDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: Br[C:2]1[C:3]([CH2:14][P:15]([OH:18])([OH:17])=[O:16])=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[CH:7]=1.[OH-].[Na+]>[Pd].O>[P:15]([CH2:14][C:3]1[CH:2]=[CH:7][N:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=[C:5]2[N:4]=1)([OH:17])([OH:18])=[O:16]
Reactant: O=C(O)c1cn2cc(Br)c(CP(=O)(O)O)nc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cn2ccc(CP(=O)(O)O)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid 18 (15 mg) was introduced in a 250 mL Parr bottle with 0.5N NaOH (1 mL), water (15 mL) and Pd on Carbon (5%, 20 mg). The bottle was evacuated, filled with hydrogen and shaken for one hour at room temperature. The product was purified by passing through a strongly basic ion-exchange column. The product 19 was eluted with 1N HCl.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10](C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution of 3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-1α,3,8-triaza-spiro[4.5]dodecan-2,4-dione hydrochloride (40 mg, 0.1 mmol) in 1.7 mL of anhydrous DCE were added successively 28 mg (0.1 mmol) of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 17 μL (0.12 mmol) of triethylamine. The reaction mixture was agitated at room temperature for 10 minutes before adding 26 mg (0.125 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 2 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by bond elute (ethyl acetate to 5% methanol/DCM) to yield (3S,4S)-3-[3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-2,4-dioxo-1α,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (20 mg, 32.1%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)CCCCCCCCCCCCCCC.C(O)(=O)CCCCCCC/C=C\CCCCCCCC>O>[C:1]([O:20][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC
Temperature: 180 °C

Procedure:
A 2-liter round-bottom flask was charged with 142 g (0.5 mole) of rubber-maker's technical grade stearic acid, 203 g (0.75 mole) of 1-octadecanol, 11 g of p-toluenesulfonic acid and 200 ml of mixed xylenes. Rubber-maker's technical grade stearic acid typically contains approximately 56 percent by weight stearic acid, 29 percent by weight palmitic acid, 8 percent by weight oleic acid and 7 percent by weight other fatty acids. The flask was fitted with a Dean-Stark trap for water removal, a heating mantel and a thermocouple. The system was flushed with nitrogen and heated to a pot temperature of 180° C. for about 1 hour, wherein 12 ml of water were removed. Volatiles were removed under 29 inches of vacuum at 110° C. to give 342 g of a waxy solid melting at 47-55° C. and giving an infrared spectrum showing loss of hydroxyl absorption bands and formation of ester carbonyl functions.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[NH4+:13]>C(O)(C)C>[Cl:1][C:2]1[S:3][C:4]([S:8]([NH2:13])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: [NH4+]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nc(Cl)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chloro-4-methylthiazole-5-sulfonyl chloride (1.0 g) in isopropyl alcohol (10 mL) was cooled with an ice-bath. Then, ammonium hydroxide (2.89 ml) was added slowly. The resulting solution was stirred at ambient temperature overnight. The solution was concentrated, the residue was mixed with water (10 mL) and extracted with ethyl acetate (2×20 mL). The crude product was purified on a silica gel column eluting with 60% ethyl acetate-hexane.