Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.Cl>ClCCl>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([C:8]([OH:10])=[O:9])[CH2:3]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a suspension of (S)-piperidine-3-carboxylic acid hydrochloride (0.75 g, 4.53 mmol) in dry dichloromethane (30 mL), triethylamine (1.97 mL, 14.0 mmol) and 4-fluorobenzoyl chloride (543 mL, 4.53 mmol) were added dropwise at 0° C. The resulting solution was kept under stirring overnight at room temperature, under nitrogen atmosphere, then HCl 1N (30 mL) was added and the phases were separated. The organic layer was washed with HCl 1N (30 mL), with water (30 mL), dried over Na2SO4 and evaporated under reduced pressure to provide 1.05 g of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid as a yellow oil, used for the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:28]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 46 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 115 mg of 4-methoxyisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 138 mg of the target compound.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:30]2[CH2:31][CH2:32][N:28]([C:26]3[S:25][C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([CH3:22])[CH:27]=3)[C:29]2=[O:33])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: Fc1ccc(CBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Yield: 95 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-fluorobenzyl bromide to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 95% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.25 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.15 (s, 1H), 4.44 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.49 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 363.2 (M+1).
Reaction SMILES: [CH2:1]1[O:7][P:5]2([O:8][CH2:9][C:2]1([CH2:10][OH:11])[CH2:3][O:4]2)=[O:6].P(Cl)(Cl)([Cl:14])=O.OCC(CO)(CO)CO>>[CH2:3]1[O:4][P:5]2([O:7][CH2:1][C:2]1([CH2:10][OH:11])[CH2:9][O:8]2)=[O:6].[ClH:14]
Reactant: O=P(Cl)(Cl)Cl
Agent: O=P12OCC(CO)(CO1)CO2
Agent: OCC(CO)(CO)CO
Product: Cl

Procedure:
A process for the production of pentaerythritol phosphate alcohol (PEPA) comprising reacting in the liquid phase phosphorus oxychloride (POCl3) with pentaerythritol (PE) at a reaction temperature of at least about 100° C. in the presence of a solvent which is an alkane substituted with at least one halogen atom and having an atmospheric boiling point of about 40 to about 150° C., the reaction pressure being sufficiently high to maintain the solvent in the liquid phase, the reaction resulting in the production of PEPA and HCl by-product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(C(F)(F)F)cc4)n3c2)cc1

Procedure:
The title compound, off-white solid (87 mg, 70%), MS (ISP) m/z=423.5 [(M+H)+], mp 172° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (intermediate M) (0.1 g, 0.29 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[C:20]2[S:24][C:23]([CH3:25])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>C1C=CC=CC=1>[CH3:25][C:23]1[S:24][C:20]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:14][CH:15]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(C(=O)c2ccc(C)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)c2ccc(C(C)C(=O)O)cc2)s1
Reaction time: 0.17 h

Procedure:
A mixture of 15.5 parts of diethyl 2-methyl-2-[p-(5-methyl-2-thenoyl)phenyl]malonate and 120 parts of sodium hydroxide solution 5% is stirred and refluxed for 5 hours. The reaction mixture is cooled and shaken twice with 80 parts of benzene. The aqueous phase is acidified with concentrated hydrochloric acid solution. After standing for 10 minutes, the product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The residue is triturated in pertroleumether. The crude product is filtered off and purified by column-chromatography using a mixture of chloroform and 10% of methanol. The pure fractions are collected and the solvent is evaporated. The residue is crystallized from acetonitrile at -20 ° C, yielding p-(5-methyl-2-thenoyl)hydratropic acid; mp. 93.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[Cl:11].C(Cl)(=O)[C:18](Cl)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:16]=[C:18]=[O:19])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[Cl:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C=Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
3,5-Dichloro-4-(2,2-dichloro-1,1-difluoroethoxy)benzenamine (12 g, 0.04 mole) was added to a solution of 20 g oxalyl chloride in 100 ml CCl4 and heated under reflux with stirring for 0.5 hour. A solid precipitated. The carbon tetrachloride and excess oxalyl chloride were removed by evaporation in a rotary evaporator. The residue (16 g) was a slightly oily white solid, which was used in the next reaction without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14](=[O:16])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:18])=[O:17].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+].Cl>CN(C)C=O>[CH3:1][N:2]1[C:15]([C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])=[C:14]([OH:16])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:18])=[O:17]
Reactant: O=C=Nc1ccccc1
Reactant: CN1CC(=O)c2c(c3ccccc3n2C)S1(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of 1.0 gm (3.7 millimols) of 2,5-dihydro-2,5-dimethyl-1,2-thiazino[5,6-b]indole-4(3H)-one-1,1-dioxide and 0.44 ml (4.0 millimols) of phenyl isocyanate in 20 ml of dimethylformamide was added to a suspension of 230 mgm of a 55% sodium hydride-in-oil dispersion (5.0 millimols) in 15 ml of dimethylformamide, while cooling on ice. The reaction mixture was stirred for 30 min. on an ice bath and then for 4 hours at room temperature. Afterwards, it was stirred into 100 ml of aqueous 3 N hydrochloric acid. The precipitate formed thereby was filtered off, washed with water, dried and recrystallized from xylene, yielding 340 mgm (27% of theory) of 2,5-dihydro-2,5-dimethyl-4-hydroxy-N-phenyl-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide; M.p.: 269°-270° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.54 g), 2-(4-methanesulfonylbenzyl)-3-oxopentanoic acid ethyl ester (0.78 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was diluted with water (100 mL) and the pH of this solution adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a honey coloured solid, 1.2 g.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[NH2:25][C:26]1[N:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1>>[C:32]([C:29]1[N:30]=[CH:31][C:26]([NH:25][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[N:27][CH:28]=1)#[N:33]
Reactant: N#Cc1cnc(N)cn1
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cnc(C#N)cn1)CCC2

Procedure:
From intermediate 3 and 5-aminopyrazine-2-carbonitrile, reacted in an analogous manner to the preparation of intermediate 2. (UPLC-MS 1) tR 1.08 min, ESI-MS 355.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][O:15]1>>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:23][C:22]1[NH:21][CH:20]=[C:19]2[C:14](=[O:13])[O:15][CH2:16][CH2:17][C:18]=12
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: Cc1c(Br)ccc2c1CC(=O)N2
Product: Cc1c(Br)ccc2c1C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
5-Bromo-4-methyl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH2:8][C:6]=2[N:7]=1.CC[N:16]([CH2:19][CH3:20])[CH2:17][CH3:18].CN([CH:24]=[O:25])C>>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:17][CH2:18][O:25][CH2:24][C@@H:19]2[CH3:20])[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH2:8][C:6]=2[N:7]=1
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: O=S1(=O)Cc2nc(Cl)nc(Cl)c2C1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CS(=O)(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 2,4-dichloro-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (120 mg, 0.5 mmol) and Et3N (101 mg, 1.0 mmol) in DMF (5.0 mL) at 0° C. was added a mixture of(S)-3-methylmorpholine (51 mg, 0.5 mmol) dropwise. After the addition was complete, the mixture was stirred overnight at rt. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated to give the product which was purified by preparative TLC (Eluent: petroleum ether/ethyl acetate=2/1) to provide 2-chloro-5,7-dihydro-4-((S)-3-methylmorpholino)thieno[3,4-d]pyrimidine 6,6-dioxide as a light yellow solid (100 mg, 66%).
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10].C1COCC1.Cl>C(OCC)(=O)C.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Temperature: 71 °C
Reaction time: 16 h

Procedure:
Solid LiOH (1.01 g, 42.1 mmol) was added in a single charge to a stirred solution of phenylmethyl 5-bromo-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 4, method B; 3 g, 7.55 mmol) in a 3:1 mixture of THF and water (40 ml) at 20° C. The reaction mixture was stirred at 71° C. for 16 h. After cooling to room temperature, it was diluted with ethyl acetate (200 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over Na2SO4, and concentrated to give a white solid. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (3:1) to yield the title compound as white solid. 2.1 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:32])([F:31])[C:13]2[N:18]=[CH:17][C:16]([CH:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[OH:20])=[CH:15][CH:14]=2)[CH2:11][O:10]1.[NH:33]1[CH:37]=[N:36][N:35]=[N:34]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:33]1[CH:37]=[N:36][N:35]=[N:34]1)[C:12]([F:31])([F:32])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:20])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)=[CH:17][N:18]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 178.1 %

Procedure:
To a stirred solution of (6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)methanol (AM; 600 mg, 0.32 mmol) in dry DMF (10 mL) was added 1H-tetrazole (138 mg, 1.97 mmol) followed by K2CO3 (181 mg, 1.31 mmol) at RT under inert atmosphere. The resulting reaction mixture was gradually heated up to 65° C. and stirred for 16 h; progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT, diluted with ice-cold water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 35-40% EtOAc/hexanes) afforded 72 (diastereomeric mixture; 300 mg, 0.57 mmol, 43%) as an off-white solid. 1H NMR (500 MHz, CDCl3; mixture of diastereomers): δ 8.73 (s, 2H), 8.54 (s, 1H), 8.48 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 4H), 7.62-7.58 (m, 4H), 7.50-7.44 (m, 4H), 7.42-7.39 (m, 2H), 6.81-6.74 (m, 2H), 6.72-6.64 (m, 2H), 5.99-5.93 (m, 2H), 5.48-5.40 (m, 2H), 5.20-5.12 (m, 2H), 2.78 (s, 1H), 2.70 (s, 1H). MS (ESI): m/z 528 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:2]([OH:4])=[O:3]
Reactant: COCn1ccnc1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCn1ccnc1C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
At a temperature of -10° C., 27.5 g. (0.25 mol) of ethyl chloroformate was added drop-wise to a solution of 28 g. (0.25 mol) of 1-(methoxymethyl)imidazole and 25 g. (0.25 mol) of triethylamine in 125 ml. of anhydrous chloroform. The mixture was stirred at 0° C. and then kept standing for two days at room temperature. The precipitated triethylamine hydrochloride was filtered off and washed with diethyl ether. The filtrate was concentrated by evaporating the solvents and the residue was dissolved in diethyl ether. The solution was dried over sodium sulphate, the ether was distilled off and the residue was distilled. The ethyl ester of 1-(methoxymethyl)imidazole-2-carboxylic acid was obtained. Boiling point 120°-124°/2 mm. Hg.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:36]([O:38]CC)=[O:37])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([N:18]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.CO.[OH-].[Na+]>O>[C:32]([O:31][C:29]([N:18]([CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21])[CH:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:6]([C:36]([OH:38])=[O:37])([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)N(CC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reaction time: 19 h
Yield: 99.2 %

Procedure:
To a stirred solution of 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (4.42 g, 7.65 mmol), MeOH (100 mL) and H2O (25 mL) was added 5 N NaOH (7.64 mL, 38.2 mmol). After 19 h, the solution was concentrated to an aqueous mixture and acidified to pH=1 with 1 N aq. HCl which turns the solution milky-white. Extraction with 3×100 mL EtOAc, washing the combined organics with 1×200 mL brine, drying over Na2SO4, filtration and concentration gave 3.96 g (99%) of product as a white solid; 1H NMR (300 MHz, DMSO-d6): δ 1.16 (d, J=6.7 Hz, 3H), 1.31 (s, 9H), 2.55-2.70 (m, 1H), 2.80-2.92 (m, 1H), 3.05-3.23 (m, 2H), 3.71-3.93 (m, 2H), 4.62-4.87 (m, 2H), 5.30-5.90 (brs, 1H), 6.59-6.99 (complexm, 4H), 7.14-7.47 (complexm, 3H), 8.60-8.80 (brs, 1H); MS (ES) m/z (relative intensity): 522. (M+ +H, 50).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:32][C@@H:33]([CH3:37])[C:34]([NH2:36])=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[NH2:36][C:34](=[O:35])[C@@H:33]([NH:32][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)=[N:15][N:16]=3)[N:19]=2)=[CH:24][CH:25]=1)[CH3:37]
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: C[C@H](N)C(N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (10 mg, 0.02 mmol), (2S)-2-aminopropanamide (3.2 mg, 0.037 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (13 mg, 0.029 mmol), and N,N-diisopropylethylamine (13 μL, 0.073 mmol) in methylene chloride (0.5 mL) was stirred at RT overnight. The solvent was evaporated. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=479.0.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.[OH-].[K+].C(OC)(C)(C)C.Cl>CO>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CO
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
In 10 ml of methanol, 222 mg of 2, 3-dihydro-7-methyl-2-(1-methylethyl)-4H, 5H-pyrano[4,3-b]pyran-4,5-dione were dissolved, and 200 mg of potassium hydroxide were added thereto and stirred at room temperature for 1 hour. After that, methyl t-butyl ether and 3% hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 130 mg of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone. 1H-NMR (CDC13, TMS) δ (ppm): 1.13 (6H, d), 2.27 (3H, s), 2.60 (1 H, m), 5.93 (1H, s), 7.23 (1H, dd), 7.58 (1H, d).
Reaction SMILES: [CH2:1]([O:9][CH2:10][C:11]([OH:13])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[CH2:1]([O:9][CH2:10][C:11]([Cl:17])=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)COCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenethyloxy-acetic acid (3.89 g, 18.9 mmol) was dissolved in a mixture of 50 ml dichloromethane and 2.6 ml DMF. Oxalyl chloride ([79-37-8], 1.76 ml, 20.8 mmol) was slowly added, and the mixture was stirred at r.t. overnight. Phenethyloxy-acetyl chloride [221019-38-1] was obtained after evaporation of the solvent, and was sufficiently pure for the next step.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[NH:9][C:8](=[O:16])[CH:7]=1.[CH:17]([OH:19])=O>O.[Pt]>[NH2:5][C:6]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[NH:9][C:8](=[O:16])[C:7]=1[NH:1][CH:17]=[O:19]
Reactant: O=CO
Reactant: O=N[O-]
Reactant: CCCn1c(N)cc(=O)[nH]c1=O
Agent: [Pt]
Agent: [Na+]
Solvent: O
Product: CCCn1c(N)c(NC=O)c(=O)[nH]c1=O

Procedure:
Sodium nitrite (127 kg) was dissolved in water and added to suspension of 6-amino-1-propyl-2,4-(1H,3H)-pyrimidinedione (300 kg) in formic acid (1 400 kg). Pt/C 5 % was added and the reaction mixture was heated to 40°-80° C. The catalyst was filtered off, formic acid was distilled off and ethanol (870 kg) was added. The product was precipitated by cooling and isolated by centrifugation, washed with ethanol/water and used directly in Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Br:11]Br.N>CC(O)=O>[Br:11][C:3]1[C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1ccc2nc[nH]c2c1
Agent: N
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 5-aminobenzimidazole (3.3 g, 2.3 mmol) in 30 ml of AcOH was added bromine (0.055 ml, 1.1 mmol) in a portion and resulting reaction mixture was stirred for 0.5 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a dark brown solid which was subjected to silica gel column chromatography (NH3 saturated 10% MeOH/EtOAc) to yield 0.22 g (0.97 mmol, 42%) of the desired product.