Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[CH2:8]=[O:9]>O>[OH:9][CH2:8][CH:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2]
Reactant: CCC1=NCCO1
Reactant: C=O
Solvent: O
Product: CC(CO)C1=NCCO1
Yield: 96 %

Procedure:
As an example, step A was conducted by reacting 2-ethyl-2-oxazoline (4 moles) having less than 1,000 ppm of water with paraformaldehyde (1 mole) at a reaction temperature of 100° C. for approximately 5.5 hours. The excess oxazoline reactant was removed along with water as "overheads" by fractional distillation of the reaction product, leaving the 2-(α-hydroxymethylethyl)-2-oxazoline in approximately 96 percent yield. Step C was then conducted by continuously adding the 2-(α-hydroxymethylethyl)-2-oxazoline to a stirred solution of sodium hydroxide in the mono-methyl ether of triethylene glycol at a temperature of from 100°-105° C. Under these conditions, the 2-isopropenyl-2-oxazoline and water were volatilized and recovered from the overheads. The product yield was approximately 98 percent of theory.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>N1C=CC=CC=1>[CH2:18]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
In 10 ml of pyridine was dissolved 2.3 g of benzyl p-hydroxybenzoate, a solution of 3 g of p-decyloxybenzoic acid chloride in 15 ml of pyridine was added to the above solution, and a reaction was carried out at room temperature overnight. The reaction liquid was put in ice-cooled dilute hydrochloric acid and the formed precipitate was recovered by filtration, dried and purified by the silica gel chromatography to obtain 4 g of benzyl 4-(4'-decyloxybenzoyloxy)benzoate. This ester was dissolved in 20 ml of ethyl acetate and 0.4 g of Pd/C was added. Catalytic reduction was carried out under a hydrogen pressure of 2 kg/cm2 overnight. The catalyst was removed by filtration, and ethyl acetate was evaporated from the reaction liquid to obtain 3.2 g of 4-(4'-decyloxybenzoyloxy)benzoic acid.
Reaction SMILES: CN(C)C=O.F[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.[H-].[Na+]>O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:8][CH:9]=1)#[N:14]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1500 ml of dry dimethylformamide (DMF) are placed in a 1000 ml four-necked flask while passing nitrogen over it and 72.67 g (0.6 mol) of 4-fluorocyanobenzene and 61.2 g (0.9 mol) of imidazole and finally 21.6 g (0.9 mol) of sodium hydride are added. The reaction mixture is heated to 100° C., stirred at this temperature for 4 hours and subsequently overnight at room temperature. The reaction mixture is then poured into water and the resulting mixture is extracted a number of times with dichloromethane. The organic phase is dried, evaporated on a rotary evaporator and finally dried further at 60° C. under reduced pressure. The yield is 94 g (93% of theory).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:25]([NH2:28])[CH:26]=[CH2:27].C(=O)([O-])O.[Na+]>>[CH2:25]([NH:28][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:26]=[CH2:27]
Reactant: CCCCCCCCCCCCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCCCCCCCCCC)c2scc(C)c2n1
Yield: 44.8 %

Procedure:
442 mg (1.2 mmol) of 2-chloro-4-dodecylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 209 mg (yield: 44.8%) of the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23].CCN(C(C)C)C(C)C>ClCCl>[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:17]2[CH2:18][CH2:19][CH:14]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:6])=[O:7])[CH2:15][CH2:16]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
143 mg (0.513 mmol) of N-cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (available from Lancaster) and 128 mg (0.513 mmol) of 4-butoxyphenylsulfonyl chloride (available from Matrix Scientific) were each dissolved in 5 mL dichloromethane (DCM) and then combined. 1.5 eq. of diisoprolylethylamine (DIEA) (0.134 mL) was added to the mixture by syringe. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The resultant product 27 was purified through a column of silica gel with a gradient of 0% to 20% EtOAc in hexanes and the pure material was concentrated (yield 24%, white solid). 1H NMR (CDCl3): δ 7.813-7.783 (m, 2H), 7.673-7.636 (m, 2H), 7.597-7.553 (m, 1H), 7.520-7.475 (m, 2H), 7.011-6.974 (m, 2H), 4.053-4.020 (t, 2H), 3.821-3.721 (m, 3H), 2.266-2.200 (t, 2H), 2.033-1.902 (m, 3H), 1.843-1.779 (m, 2H), 1.601-1.470 (m, 4H), 1.015-0.978 (t, 3H), 0.935-0.896 (m, 2H), 0.761-0.712 (m, 2H). LC: 100%. MS (e/z): 494 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].C(N(CC)CC)C.[Cl:26][C:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:32]([C:31]2[S:30][C:29]3[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=3[C:27]=2[Cl:26])=[O:33])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)Nc2ccccc2NC(=O)c2sc3ccccc3c2Cl)c1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-1,2-benzenediamine (500 mg, 2.1 mmol) and triethylamine (0.44 mL, 3.2 mmol) in methylene chloride (100 mL) was added 3-chlorobenzo[b]thiophene-2-carbonyl chloride (490 mg, 2.1 mmol). After stirring for 20 h, the mixture was concentrated in vacuo and chromatographed (silica gel, 25% ethyl acetate/75% hexane) to give 660 mg (73%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[CH2:16]([Mg]Cl)[CH3:17].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:16][CH3:17])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(CC)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitrophenylacetic acid ethyl ester (1.63 g) in tetrahydrofuran (100 mL) was dropwise added 2M ethyl magnesium chloride in tetrahydrofuran (3 mL) at −15° C. under argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. After further dropwise addition of 2M ethyl magnesium chloride in tetrahydrofuran (3 mL), the mixture was stirred at −15° C. for one hour, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.0 g) was added thereto at the same temperature. The mixture was stirred overnight, and water (300 mL) was added thereto, followed by extraction with chloroform (150 mL×3). The organic layers were combined, washed with saturated brine, dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=10:1 to give the title compound (1.09 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc(C2CCCCC2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-cyclohexylbenzoic acid (Aldrich; 1 molar eq.) in toluene was added diiso-butylaluminum hydride (Aldrich; 1 M in toluene; 4 molar eq.) over a 2 hour period. After addition was complete, the reaction was heated to 60° C. for 1 hour. The reaction was cooled to 5° C. and quenched with saturated aqueous ammonium chloride. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were filtered to remove salts and concentrated.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)C(C)C)(C)C.[F:15][C:16]([F:23])([F:22])[C:17](=[CH2:21])[C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:18](=[O:19])[C:17]([C:16]([F:23])([F:22])[F:15])=[CH2:21]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C(=O)N(C)OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
16.6 g (167 mmol) of N,O-dimethylhydroxylamine hydrochloride were suspended in 900 ml of CH2Cl2 and 29.1 ml (167 mmol) of N,N-diisopropylethylamine added dropwise at 0° C. The resulting solution was added dropwise to a solution of 20.0 g (143 mmol) of 2-(trifluoromethyl)propenoic acid in 500 ml of CH2Cl2 at −40° C. Afterwards, 34.5 g (167 mmol) of N,N′-dicyclohexylcarbodiimide were added and the mixture stirred at 0° C. for 16 h. The resulting suspension was then filtrated and the filtrate carefully evaporated (the desired product is volatile!). Afterwards, 100 ml of n-pentane were added and the suspension stirred for 30 minutes at ambient temperature. The precipitate was removed by filtration, the filtrate was carefully evaporated. Chromatography on silica gel using ethyl acetate/n-pentane 1:4 yielded 22.8 g of the desired product. Rt=0.56 min (Method P).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.[C:40](Cl)(=[O:42])[CH3:41].N1C=CC=CC=1>C(Cl)Cl>[C:40]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[CH:15]2[CH2:14][C:13](=[O:30])[NH:12][CH:11]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:39])[CH2:25][CH2:26]1)(=[O:42])[CH3:41]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 4 h
Yield: 8.2 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(4-piperidinyloxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (110 mg, 0.2 mmol), acetyl chloride (0.017 mL, 0.24 mmol) in DCM (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][N:25]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=1)[CH2:26]2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: Nc1cccc2c1CCNC2
Product: Nc1cccc2c1CCN(c1ncnc(Nc3cccc(CS(N)(=O)=O)c3)n1)C2

Procedure:
B41 was prepared following the general procedure reported for B10 using A1 and 5-amino-1,2,3,4-tetrahydroisoquinoline; yield: 61.5 mg (15%), pale yellow solid. MS (ES) C19H21N7O2S requires: 411. found: 412 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][CH2:16][CH:17]([CH2:19]O)[OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:8]([C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:18][CH:17]([CH2:16][OH:15])[CH2:19][O:14]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(=O)CCCCCC
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)OCC(CO)O1
Reaction time: 24 h

Procedure:
A reactor equipped with a stirrer, reflux-condenser, thermometer and nitrogen gas inlet pipe was charged with 297 g of 7-tridecanone, 166 g of glycerol and a solvent amount of toluene, and after addition of p-toluenesulfonic acid as a catalyst, the dehydrative condensation reaction was carried out at the reflux temperature for 24 hours. The resulting crude product was washed with an aqueous solution of potassium carbonate and further with 3 portions of distilled water and finally purified by distillation under reduced pressure to provide 2,2-dihexyl-4-hydroxymethyl-1,3-dioxolane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C23CCN(CC2)CC3)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 4-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1509 g, 0.823 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.2291 g, 86.6%). EI-MS m/z 322(M+H+) Rt (1.57 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][CH2:25][C:26](O)=[O:27].ClC(OCC(C)C)=O.C(N(CC)CC)C.C(O)(=O)C(O)=O.[CH2:51]([O:53][P:54]([CH2:59][NH2:60])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]>C1COCC1>[CH2:51]([O:53][P:54]([CH2:59][NH:60][C:26](=[O:27])[CH2:25][CH2:24][C:23]([CH3:29])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Reactant: CCOP(=O)(CN)OCC
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate (17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. After stirring at 0° C. for 2 hours, diethyl(aminomethyl)phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring was continued at room temperature for 20 minutes. After removal of solvent, the residue was purified by preparative reverse-phase HPLC to afford 54.8 mg (81%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.65 (dd, 2H, J=6, 12 Hz), 3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m,2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 5.86 (bs, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 23.01 ppm; MS (m/z) 568 [M−H]−, 592 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][Cl:21])=[CH:7][CH:8]=[CH:9][C:10]=1[S:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1c(CO)cccc1Sc1ccccc1C
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1c(CCl)cccc1Sc1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-methoxy-3-(o-tolylthio)benzyl alcohol (8.5 g), thionyl chloride (4.8 ml) and pyridine (3 drops) in benzene (80 ml) was stirred at room temperature and then at 80° C. for 10 minutes. The reaction mixture was treated in a similar manner to that of Example 21-(6) to give oily o-tolyl 2-methoxy-3-chloromethylphenyl thioether (8.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:12]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-Bromo-3-nitropyridin-2(1H)-one (25.0 g, 114 mmol), anhydrous DMF (500 mL) and potassium carbonate (34.7 g, 251 mmol), and the suspension stirred for 15 min at ambient temperature. After this time, methyl iodide (17.8 g, 126 mmol) was added, and the mixture stirred at room temperature for 16 h. The reaction mixture was then diluted with water (500 mL) and extracted with methylene chloride (3×500 mL). The organic extracts were combined, washed with 10% aqueous lithium chloride (300 mL) and water (300 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was flash chromatographed eluting with a gradient from 50% to 100% of ethyl acetate in hexanes, and the fractions containing 122a were collected to afford, after concentrating under reduced pressure, an 89% yield (23.6 g) of 122a as a yellow solid: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:14][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Product: CC(C)(F)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
3-Bromo-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 65 to afford 7-(1-fluoro-1-methylethyl)-3-[4-fluoro-3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidine as a white solid after crystallisation from ethyl acetate/isohexane: δH (360 MHz, CDCl3) 1.74 (6H, d, J 22), 7.26 (1H, dd, J 7 and 2), 7.53-7.60 (2H, m), 7.80 (1H, ddd, J 8, 5 and 2), 7.94 (1H, dd, J 8 and 2), 8.05 (1H, s), 8.10 (1H, ddd, J 8, 4 and 2), 8.65 (1H, dd, J 5 and 1.5), 8.89 (1H, s), 9.13 (1H, d, J 7); m/z (ES+) 351 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)=[O:14]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1c[nH]c(=O)c(N)c1
Solvent: c1ccncc1
Product: Cc1c[nH]c(=O)c(NC(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.1 g. of 3-amino-5-methyl-2-pyridone in 25 ml. of pyridine was cooled in ice and treated with 4.5 g. of 2-fluorobenzoyl chloride dropwise. After stirring for about 3 hours at room temperature, the mixture was diluted with 200 ml. of ice-water. After 0.5 hour the precipitate was collected, washed with water, dried and recrystallized from ethanol to give 3-(2-fluorobenzoylamino)-5-methyl-2-pyridone, m.p. 230°-232° C.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:21]([F:32])[C:20]=1[F:33]>>[Cl:17][C:14]1[S:13][C:12]([C:8]2[C:7]([CH2:6][O:5][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:21]([F:32])[C:20]=3[F:33])=[CH:11][S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)s1
Product: O=C(O)CCc1ccc(OCc2csnc2-c2ccc(Cl)s2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(5-chlorothiophen-2-yl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.27 (m, 1H), 6.95 (m, 1H), 6.90 (m, 1H), 6.73 (m, 1H), 5.24 (s, 2H), 2.98 (t, J=4.5 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H).