Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.C(OCC)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:8][C@H:9]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1ncoc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1ncoc1[C@@H](N)Cc1ccccc1
Reaction time: 1 h

Procedure:
Methyl (S)-5-[1-(tert-butoxycarbonylamino)2-phenylethyl]oxazole-4-carboxylate, (Tett. Lett., 1982, 23, 235; 417 mg) was dissolved in trifluoroacetic acid (3 ml) and stood at ambient temperature for 1 hour and concentrated to give an oil. Trituration with diethyl ether gave the title compound as a white solid. (281 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:17]([O:20][CH3:21])[O:18][CH3:19])[CH:9]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1>CC(N(C)C)=O>[CH3:19][O:18][CH:17]([O:20][CH3:21])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[O:29][C:25]1[CH:24]=[C:23]([NH2:22])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 8 h

Procedure:
K2CO3 (0.34 mol), followed by 4-chloro-2-dimethoxymethyl-1-nitro-benzene (0.2 mol) was added to a solution of 3-amino-phenol (0.3 mol) in DMA (400 mLI) and the reaction mixture was stirred overnight at 130° C. The mixture was cooled to room temperature and the solvent was evaporated. The residue was taken up in H2O and the mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH2Cl2 100%). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]([CH3:21])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonylpyroglutamate (11.5 g, 40 mmol) in THF (200 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in THF (42 mL, 42 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (3.11 mL, 50 mmol) was added. After an additional 2 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (200 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed with 1:1 ethylacetate/hexanes to give Boc-PyroGlu(4-methyl)-OtBu (10.6 grams, 35.4 mmol, 88%) as a mixture of isomers (2:1 cis to trans).
Reaction SMILES: II.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]1[C:45]([NH:47][NH:48][C:49](=O)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]1[C:45]1[O:46][C:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[N:48][N:47]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cc1ccccc1)NNC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nnc(Cc2ccccc2)o1
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
At 25° C., iodine (3.21, 12.64 mmol) was added to the PPh3 solution in CH2Cl2 (40 mL). After 10 minutes, triethylamine (1.5 mL) was added, followed by compound 71 (2.5 g, 6.32 mmol). After 20 hours, the solution was concentrated and passed through a pad of silica gel (100 mL). The crude oil was purified by column chromatography (25-30% EtOAc in hexanes), affording 600 mg (25%) of the desired product as a solid. 1.6 g of compound 71 was recovered.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[N:3]=1.[S:24]1[C:28]([NH2:29])=[N:27][CH:26]=[N:25]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:24]1[C:28]([NH:29][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=3)[N:3]=2)=[N:27][CH:26]=[N:25]1
Reactant: Nc1ncns1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1
Yield: 31.6 %

Procedure:
To a round bottom flask was added N-(4-(4,6-dichloropyrimidin-2-ylthio)phenyl)-3,3,3-trifluoropropanamide (350 mg, 0.9 mmol), 1,2,4-thiadiazole-5-amine (100 mg, 0.9 mmol), xanthphos (50 mg, 0.1 mmol), Pd2 dba3 (50 mg, 0.05 mmol), NaCO3 (150 mg, 1.5 mmol) and dioxane(10 cm). The mixture was flushed with nitrogen and then brought to reflux for 2 hours. The mixture was filtered, partitioned between ethylacetate and bicarbonate. The organic layer was dried with magnesium sulfate, and concentrated to an oil, which was purified by column chromatography to yield the product as a yellow solid (127 mg, 34%)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]C(C)(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([CH:41]=[O:42])([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([CH:41]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[OH:42])([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Reactant: CCCC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC1(C(O)c2cc3cc(F)ccc3n2S(=O)(=O)c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a −78° C. solution of 1-benzenesulfonyl-5-fluoro-1H-indole (539 mg, 1.96 mmol) in 30 mL THF, t-BuLi (1.5 mL, 2.54 mmol) was slowly added. The reaction mixture was stirred for 30 minutes, then a solution of 4-formyl-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.96 mmol) in 5 mL THF was added. The reaction was allowed to stir for 2 hours at −78° C. and was then warmed to −20° C. and quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated onto silica. The material was chromatographed over a 25 g Thomson column eluting with 20% ethyl acetate 80% hexanes to afford 4-[(1-benzenesulfonyl-5-fluoro-1H-indol-2-yl)-hydroxy-methyl]-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (319 mg, 0.6 mmol) in a 53% yield as a beige foam.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25]>ClCCCl>[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([CH2:12][C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]#[N:25])=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6]
Reactant: Cn1cccc1CC#N
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)c1ccc(Cc2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a suspension of 17.5 g. (0.131 mole) aluminum chloride in 60 ml. 1,2-dichloroethane is added 24 g (0.131 mole) p-isopropylbenzoyl chloride. The resulting mixture is added slowly and dropwise to a chilled solution (0° C.) of 15.7 g. (0.131 mole) 1-methylpyrrole-2-acetonitrile in 100 ml. of 1,2-dichloroethane. After the addition is complete, the mixture is stirred at room temperature for twenty minutes and heated at reflux for three minutes. The reaction mixture is then cooled and poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over magnesium sulfate; and the solvent evaporated. The product, 5-(p-isopropylbenzyl)-1-methylpyrrole-2-acetonitrile, is isolated from the residual oil by column chromatography. The column is packed with acid washed alumina and eluted with benzene, ether and etylacetate. The product is found in the first compound-bearing fraction which absorbs ultraviolet light at approximately 250 mμ. It is purified by recrystallization twice in ether: pentane. m.p. 59-64° C. Anal. Calcd. for C17H18 N2O: N, 10.53%. Found: N, 10.71%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:31])[NH2:30])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:32][CH3:33])=[O:10])(C)(C)C.[Cl:43]CCCl>Cl.O1CCOCC1>[ClH:43].[NH2:7][CH:8]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH2:30])=[O:31])[CH2:13][CH:12]1[CH2:32][CH3:33])=[O:10]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(N)=O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reactant: ClCCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(N)=O)CCN1C(=O)C(N)Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
[2-[4-(1-carbamoyl-2-naphthalen-2-yl-ethyl)-2-ethyl-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 37, (0.26 g, 0.5 mmol) is dissolved in 4M HCl in dioxane (7 mL). The reaction mixture is stirred for 60 minutes, then 1,2-dichloroethane (7 mL) is added. The solution is concentrated in vacuo to afford 0.24 g (quantitative yield) of the desired product.
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C@@H:7]([CH3:23])[C:6]2[S:24][CH:25]=[CH:26][C:5]=2[CH2:4]1.[Br:27]Br>>[ClH:1].[Br:27][C:25]1[S:24][C:6]2[C@H:7]([CH3:23])[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:22])[C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C@H:3]([CH3:2])[CH2:4][C:5]=2[CH:26]=1
Reactant: C[C@@H]1Cc2ccsc2[C@H](C)N1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: Cl
Product: C[C@@H]1Cc2cc(Br)sc2[C@H](C)N1CCNC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The thiophene compound from Example 28 (2.5 g, 6.96 mmol) was treated with bromine (0.71 mL, 14 mmol) as described for Example 75. The title compound was isolated (1.31 g, 43%) and treated with HCl/2-propanol (1.1 eq) to afford a brown solid; mp 265°-267° C.; IR (KBr) 3260 2480, 1665, 1600, 1550, 1525, 1340, 1290, 1105, 1110, 865, 855, 825 and 715 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:15]#[N:16])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O[CH2:18][C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[NH2:21][C@@H:19]([CH3:20])[CH2:18][N:13]1[CH:12]=[C:11]([C:15]#[N:16])[C:10]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=2)=[N:14]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2[nH]ncc2C#N)cc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)Cn1cc(C#N)c(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile (0.9 g, 3.94 mmol) dissolved in dry THF (15 ml), (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.690 g, 3.94 mmol) and triphenyl phosphine (1.549 g, 5.90 mmol) dissolved in dry THF (15 ml) were loaded into a flask and cooled to 0° C. with an ice bath. Di-tert-butyl azodicarboxylate (1.360 g, 5.90 mmol) was added slowly and stirred for 10 min while keeping the temperature at 0° C. The temperature was allowed to rise to RT and the mixture was stirred overnight. Next day the mixture was evaporated and the intermediate deprotected by adding 10% HCl/EtOH solution (40 ml) and stirring overnight at RT. The mixture was again evaporated and the residue extracted with DCM/water. The pH of aqueous phase was adjusted to 12 by adding 2 M NaOH and extracted again with DCM. The organic phase was isolated with phase separator and evaporated. The product was used in the next step without further purification. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 4.27-4.39 (m, 3H), 6.50 (s, 2H), 8.02 (dd, 1H), 8.15-8.19 (m, 2H), 8.79 (s, 1H).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10](Cl)=[O:11])[CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[CH3:20].C(N(CC)CC)C>>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[CH:15][C:14]=1[NH:13][C:10]([C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12)=[O:11]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: O=C(Cl)c1cnn2ccccc12
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cnn2ccccc12
Temperature: 25 °C

Procedure:
Pyrazolo[1,5-a]pyridine-3-carbonylchloride (100 mg, 0.55 mmol, Maybridge Lot # 291259) and N-(3-amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (163 mg, 0.55 mmol) are dissolved in 2 ml dry methylenehloride. Triethylamine (93 μl, 0.66 mmol) is added and the reaction mixture is stirred at room temperature. After complete formation of the product, the reaction mixture is quenched with water and the product is extracted with methylenehloride. The solvent is removed under reduced pressure and the crude product is absorbed to Isolute. The product is purified by automated reversed phase column chromatography (column: Interchrom Puriflash 15/35U C18, 70 g cartouche; solvents: water+0.1% trifluoroacetic acid and acetonitrile+0.1% trifluoroacetic acid) and is dried at the high vacuum pump, yielding the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(C#N)cs3)cc21
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(C#N)cs3)cc21

Procedure:
The title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-3-carbonitrile and Lawesson's reagent. The product was obtained in the form of yellow crystals: m.p. 258-259° C. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 8.54 (d, 1H, J=0.9 Hz), 7.96 (s, 1H), 7.69-7.62 (m, 2H), 7.11-7.08 (d, 1H, J=8.3 Hz), 1.69 (s, 6H); MS (ESI) m/z 299 [M−H]−; Anal. Calcd. For C15H12N2OS2.½H2O: C, 58.0; H, 4.24; N, 9.05. Found: C, 58.33; H, 3.85; N, 8.39.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[O:23]=[CH:24][C@@H:25]([C@@H:27]([CH2:29]O)[OH:28])[OH:26].C(O)(=O)C>CO>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[NH:8][C:9](=[O:12])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([NH:1][CH2:29][C@H:27]([OH:28])[C@H:25]([OH:26])[CH2:24][OH:23])[CH:11]=2
Reactant: O=C[C@H](O)[C@H](O)CO
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@H](O)[C@H](O)CO)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 285.6 %

Procedure:
The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (2.04 g, 0.986 mmol) obtained in step C of Example 1-1 and D-(−)-erythrose (807 mg, 6.72 mmol) were dissolved in methanol (40 ml). Thereafter, acetic acid (2.31 ml, 40.3 mmol) and a 1 M sodium cyanoborohydride THF solution (20.2 ml, 20.2 mmol) were added at 0° C. to the obtained solution, and the obtained mixture was then stirred at a room temperature for 4 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and water was then added to the concentrate, followed by extraction with methylene chloride. The extract was washed with a saturated saline solution, and was then dried over sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel chromatography (methylene chloride:methanol=15:1 to 10:1), so as to obtain 3-(2-trifluoromethylphenyl)-7-((2S,3R)-2,3,4-trihydroxybutylamino)-2H-isoquinolin-1-one (1.15 g, 42%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[CH:23](O)([CH3:25])[CH3:24].O>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
CDI (2.34 g, 14.48 mmol) was added to a solution of salicylic acid (2.00 g, 14.48 mmol) in DMF (40 mL). The reaction mixture was stirred at 50° C. for 4 h and isopropyl alcohol (2.80 mL, 36.20 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×40 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 1.395 g of isopropyl 2-hydroxybenzoate (colourless oil, yield: 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[C:13](SCCC)=[N:12]3)[CH2:10][CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:30].[I-]>N.CCO>[NH2:30][C:13]1[N:14]([CH2:17][CH2:18][CH3:19])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10]2)[N:12]=1
Reactant: CCCSC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CCC
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CCCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 18.1 %

Procedure:
A solution of 6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (280 mg, 0.6 mmol) and NH4I (172 mg, 1.2 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-phenyl-1′-propylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 18%). 1H-NMR (MeOD): 0.93 (m, 3H), 1.66 (m, 2H), 2.04 (m, 1H), 2.25 (m, 1H), 3.56 (m, 2H), 5.83 (m, 1H), 6.87 (m, 1H), 7.06 (m, 1H), 7.31 (m, 2H), 7.40 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17]CC3C=CC=CC=3)[C:11]=2[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=2[NH:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c(O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-benzyl-4-benzyloxy-1,3-dihydro-benzoimidazol-2-one (0.875 g, 2.64 mmol) in 100 ml of 1:1 ethyl acetate:THF was added palladium hydroxide (0.270 mg, 1.923 mmol). The reaction mixture was purged with hydrogen gas at 1 atm., allowed to stir at room temperature for 2 hours, and then filtered through celite. The filtrate was concentrated in vacuo to give 640 mg (2.64 mmol. quantitative) of 1-benzyl-4-hydroxy-1,3-dihydro-benzoimidazol-2-one as a white solid. MS: 241 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:24]=[CH:23][N:22]=[CH:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O1CCOCC1.CC(C)=O.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:30](=[O:32])[CH3:31])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
A mixture of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine (100 mg, 0.250 mmol), acetic anhydride (0.09 mL, 1.00 mmol) and 10% Pd/C (9.0 mg) in a mixture of dioxane (2.5 mL) and acetone (1.5 mL) was stirred at room temperature for 24 h. Then, 4.0 equivalents of acetic anhydride was added and stirring was continued for 2 days. After filtration, the reaction solution was quenched with saturated NaHCO3 and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic phase was dried with anhydrous Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography using a 30% to 100% gradient of EtOAc in heptane gave the title compound (57 mg, 51%) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.23 (d, J=6.6 Hz, 3.3H), 1.24 (d, J=6.6 Hz, 2.7H), 1.93 (m, 2H), 2.11 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.71 (t, J=6.1 Hz, 0.9H), 2.80 (t, J=6.1 Hz, 1.1H), 2.95 (m, 2H), 3.34 (m, 2H), 3.79 (t, J=5.9 Hz, 1.1H), 3.84 (t, J=6.1 Hz, 0.9H), 4.15 (m, 1H), 4.44 (tt, J=7.5, 3.7 Hz, 1H), 4.53 (s, 0.9H), 4.54 (s, 1.1H), 6.86 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 446.00.