Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([N:19]2[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]2)(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(S(=O)(=O)Cl)c1
Reactant: CC1CNCC(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CC(C)CN(S(=O)(=O)c2cc(Cl)cc(C(=O)O)c2)C1
Reaction time: 1.5 h

Procedure:
3-Chloro-5-chlorosulfonylbenzoic acid (770 mg., 3 m moles) is added to a solution of 3,5-dimethylpiperidine hydrochloride in 30 ml. of water followed by the portionwise addition of 12 ml. of 1N sodium hydroxide solution with stirring. After 1.5 hrs. at room temperature the reaction mixture is filtered and the filtrate acidified with 12N hydrochloric acid. The product, 600 mg., m.p. 226°-231° C., is recrystallized from acetone-hexane, 390 mg., m.p. 232.5°-234° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH3:38])[OH:13])[N:9]=[CH:10][C:3]=12.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH3:38])[OH:13])[N:9]=[CH:10][C:3]=12
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ncc2c(N)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ncc2c(N)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of the compound from Step A (0.20 g, 0.33 mmol) in dichloromethane (10 mL) at −78° C. was added boron trichloride (1M in dichloromethane) (3 mL, 3 mmol) dropwise. The mixture was stirred at −78° C. for 0.5 h, then at −45° C. to −30° C. for 2 h. The reaction was quenched by addition of sodium acetate (1.0 g) and methanol (10 mL). The solution was evaporated and the residue was purified by flash chromatography over silica gel using CH2Cl2 and CH2Cl2/MeOH (95:5–90:10) gradient as the eluent to furnish the desired compound (60 mg) as a solid, which was recrystallized from methanol and acetonitrile to give the title compound as an off-white solid (40 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)C.Br[CH2:18][CH2:19][CH2:20][OH:21].[OH-].[Na+]>O>[OH:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCOc1ccc(-c2ccccc2)cc1
Yield: 42.6 %

Procedure:
Into a 200 ml flask, 7.82 g (41.1 mmol) of 4-hydroxybiphenyl, 83 ml of ethanol, 6 g (43.2 mmol) of 3-bromo-1-propanol and a NaOH aqueous solution (1.73 g (43.2 mmol) of NaOH/6 ml of water) were sequentially added, and the mixture was heated and refluxed for 6.5 hours. To the reaction solution, 50 ml of water was added, whereupon precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 4.0 g (yield: 43%) of 4-(3-hydroxypropoxy)biphenyl (1) as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>O>[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:24][CH2:23]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc([N+](=O)[O-])cc3)c3nccn3n2)CC1
Reaction time: 8 h

Procedure:
In a 2 dram reaction vial was added crude 6-chloro-N-(4-nitrophenyl)imidazo[1,2-b]pyridazin-8-amine (0.42 g, 1.4 mmol) from 1a and trans-1,4-diaminocyclohexane (1.0 g, 8.0 mmol). The mixture was allowed to melt at 160° C. for 8 hrs. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was concentrated to provide crude N6-((trans)-4-aminocyclohexyl)-N8-(4-nitrophenyl)imidazo[1,2-b]pyridazine-6,8-diamine which was used without further purification.
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:23]([N:25](CC)CC)[CH3:24]>[Pt]>[N:25]1[C:3]2[C:2](=[CH:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=[CH:24][CH:23]=1
Reactant: Cc1cccc(O)c1
Reactant: CCN(CC)CC
Agent: [Pt]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: c1ccc2ncccc2c1

Procedure:
A 5-inch platinum wire was coated with a thin film of the polymer of Example 1, by dipping the wire into a 5% solution of the polymer in a m-cresol/P2O5 mixture. The film-coated wire was neutralized by dipping into a 10% triethylamine--90% ethanol solution and dried in a vacuum oven at 60° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:6]2[O:5][C:4]([NH:7][C@@H:8]3[CH2:10][C@H:9]3[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]2=[O:1])=[CH:23]1
Reactant: CCOC(=O)C1=C(N[C@@H]2C[C@H]2c2ccccc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N[C@@H]2C[C@H]2c2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 14.4 %

Procedure:
To a solution of ethyl 4-oxo-2-{[(1R,2S)-2-phenylcyclopropyl]amino}-4,5-dihydrofuran-3-carboxylate (0.090 g, 0.31 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.045 g, 0.30 mmol) in ethanol (5.0 mL), L-proline (0.0035 g, 0.031 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the solvent was removed under reduced pressure then the residue was purified by preparative HPLC to afford the titled compound as solid (0.018 g, y. 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:13])([F:14])[F:15])[CH:4]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)c(C(F)(F)F)c1
Yield: 96 %

Procedure:
A solution of (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (4.90 g, 22.06 mmol) in methanol (40 mL) was treated with concentrated sulfuric acid (7 drops). The reaction mixture was heated under reflux for 2 h. The reaction was then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid methyl ester (5.02 g, 96%) as a colorless oil.
Reaction SMILES: [CH2:1](I)C.[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH3:17])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1>>[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH2:17][CH3:1])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1
Reactant: CCI
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1
Product: CCO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as described in Example 64 using ethyl iodide in place of methyl iodide. MS (+) m/z 416 (M+1) detected; 1H NMR (400 MHz, 10:1 CDCl3:CD3OD) δ 7.39 (m, 7H), 7.30 (m 1H), 7.20 (m, 1H), 4.85 (br q, 1H, J=6.3 Hz), 3.68-3.53 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.58 (m, 1H), 2.21 (m, 1H), 1.72 (m, 1H), 1.47 (d, 3H, J=6.3 Hz), 1.24 (m, 3H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([NH:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])=[O:14]>CN(C)C=O.C(OCC)(=O)C>[F:26][C:12]([F:11])([F:25])[C:13]([NH:15][C:16]1[CH:21]=[C:20]([N:22]([CH3:23])[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:19]=[CH:18][C:17]=1[F:24])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNc1ccc(F)c(NC(=O)C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A solution of 2-chloro-5-nitropyridine (201 mg, 1.27 mmol) and 2,2,2-trifluoro-N-[2-fluoro-5-(methylamino)phenyl]acetamide (300 mg, 1.27 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 140° C. for 22 hr. The reaction mixture was cooled to room temperature, and suspended in ethyl acetate (5 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate/hexane to give the title compound (221 mg, 49%) as yellow crystals.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2]1.[ClH:10]>C(OCC)C>[Cl:10][CH2:2][C@H:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC[C@@H]1CO1
Reactant: Cl
Solvent: CCOCC
Product: CCCCCC[C@@H](O)CCl
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Under nitrogen atmosphere, 10 g (65.5 mM) of (R)-1,2-epoxyoctane and 100 ml of dry diethyl ether (Et2O) were placed in a 200 ml two-necked round-bottomed flask and cooled on an ice bath. Into the mixture, hydrogen chloride gas was blown, followed by stirring for 2.5 hours. Then, the ice bath was removed and the mixture was further stirred for 2 hours at room temperature. After the reaction, the reaction mixture was poured into 250 ml of ice water and subjected to extraction with diethyl ether. The organic layer was washed with distilled water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to obtain 10.4 g of (R)-1-chloro-2-octanol.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=O)=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([O:35][C:36](=[O:46])[CH2:37]P(OCC)(OCC)=O)[CH3:34].O>CN(C=O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13](/[CH:23]=[CH:37]/[C:36]([O:35][CH2:33][CH3:34])=[O:46])=[CH:14][N:15]3[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was dissolved in 20 ml of DMF, and 2.0 g of potassium carbonate and 2.8 ml of ethyl(diethoxyphosphoryl)acetate were added, followed by overnight stirring at 60° C. The resulting reaction mixture was cooled to room temperature, water was added, and then the insoluble materials were collected by filtration to obtain 1.2 g of ethyl (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]acrylate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[CH3:12])=[O:6]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(O)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure D from 2-fluoro-4-hydroxy-benzoic acid and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (Intermediate 11). MS (ES+) 307.3.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]2[O:9][C:10]3[C:15]([C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:19]=[CH:18][N:17]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[C:6]2=[CH:5][CH:4]=1)[CH3:2].[CH:28]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH:1]([C:3]1[N:8]=[C:7]2[O:9][C:10]3[C:15]([C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:19]=[CH:18][N:17]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[C:6]2=[CH:5][CH:4]=1)([CH3:28])[CH3:2]
Reactant: CCc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-ethyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.15 g, 14.70 mmol) was charged into the reaction mixture with 120 mL of THF. This mixture was cooled to −78° C. Lithium diisopropylamide in THF (9.19 mL, 18.37 mmol) was added dropwise to the cooled reaction mixture over a 10 minute period. The reaction mixture was then stirred for 2 hours at −78° C. Iodomethane (3.13 g, 22.05 mmol) was then dissolved in 10 mL of THF. This solution was then added via syringe to the cold reaction mixture. Stirring was continued as the reaction mixture was allowed to gradually warm to room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride then was extracted 2×300 mL ethyl acetate. The organics were combined, were washed with aqueous LiCl then were dried over magnesium sulfate. These organics were then filtered and concentrated under vacuum. The crude residue was dissolved in DCM and was loaded onto a silica gel column. The column was eluted with 3-4% ethyl acetate/DCM. Clean product fractions were combined and solvents were evaporated yielding 2-isopropyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (4.1 g, 11.25 mmol, 77% yield).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[NH2:10][C:11]([NH2:13])=[O:12]>CN(C=O)C>[OH:5][C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:10][C:11]([NH2:13])=[O:12])=[O:6]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: NC(=O)NCC(C(=O)O)C(F)(F)F
Temperature: 90 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and urea (342 mg; 5.7 mmoles) in DMF (3 ml) was heated at 90° C. with stirring for 6 hours. DMF was evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel (ethyl acetate) to give 540 mg (yield: 54%) of (2-hydroxycarbonyl-3,3,3-trifluoropropyl)urea. m.p.: 149°-149.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1.C(Cl)Cl>[Pd].CCO>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: COC(=O)C=Cc1ccnc(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCc1ccnc(OC)c1
Yield: 93 %

Procedure:
A suspension of 3-(2-methoxy-pyridin-4-yl)-acrylic acid methyl ester (1.3 g, 6.72 mmol, 1 eq) and Pd/C, 10% (357 mg, 0.05 eq, 10%) was stirred in a DCM (15 ml)/absolute EtOH (15 ml) solvent mixture under hydrogen atmosphere for 1 hour at room temperature. Palladium was filtered off over a celite pad, the solvent was evaporated and obtained crude was purified by chromatography on BIOTAGE SP1 purification device using 25 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 3-30% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(2-methoxy-pyridin-4-yl)-propionic acid methyl ester (1.22 g, yield=88.2%, purity=95%) in form of transparent colourless oil. MS: [M+H]+=196.14 1H NMR (300 MHz; CDCl3) δ/ppm 2.63(t, J=7.91 Hz, 2H), 2.90 (t, J=7.91 Hz, 2H), 3.68(s, 3H), 3.92 (s, 3H), 6.57 (s, 1H), 6.72 (dd, J=5.33 Hz, J=1.29 Hz, 1H), 8.06 (d, J=5.33 Hz, 1H)
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3C=C(C=CC=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].IC1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[S:24][CH:25]=[C:26]([CH3:28])[N:27]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: Cc1csc(I)n1
Product: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) by replacing 3-bromobenzonitrile by 2-iodo-4-methylthiazole (Intermediate O) in step 3;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:17][C:14]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:19]([F:22])([F:21])[F:20])[CH:4]=2)=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To the solution of 2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}-5-(hydroxymethyl)benzonitrile (700 mg, 2.249 mmol) in DCM (40 mL), was added thionyl chloride (2.462 mL, 33.7 mmol) dropwise. The mixture was stirred at room temperature for 1.5 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, and concentrated in vacuo to afford the title compound (665 mg, 90% yield) as a light yellow solid. LCMS: rt=3.71 min
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C@@H:45]([CH2:50][OH:51])[C:46]([O:48][CH3:49])=[O:47])([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C@@H:45]([CH2:50][O:51][S:61]([CH3:60])(=[O:63])=[O:62])[C:46]([O:48][CH3:49])=[O:47])([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:22][CH2:23]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](CO)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](COS(C)(=O)=O)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-hydroxypropanoate (132 mg, 0.173 mmol; Example 270, Step A) and triethylamine (97 μL, 0.69 mmol) in DCM (2.2 mL) was added a solution of methanesulfonyl chloride (27 μL, 0.35 mmol) in DCM (2.2 mL) at 0° C. Then the reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched (water), extracted (2×EtOAc) and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure to provide a crude mesylated compound, (S)-methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-(methylsulfonyloxy)propanoate.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH2:37][CH3:38])[CH2:3][C:4]1[N:8]([CH3:9])[C:7]([CH:10]([N:25](C)[C:26](=O)OCC2C=CC=CC=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)=[N:6][CH:5]=1>CO.[Pd]>[CH3:1][C:2]([CH3:39])([CH2:37][CH3:38])[CH2:3][C:4]1[N:8]([CH3:9])[C:7]([CH:10]([NH:25][CH3:26])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)=[N:6][CH:5]=1
Reactant: CCC(C)(C)Cc1cnc(C(Cc2ccc(-c3ccc(F)cn3)cc2)N(C)C(=O)OCc2ccccc2)n1C
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(-c3ccc(F)cn3)cc2)NC)n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pd (10 wt % on activated carbon) (catalytic) was added to a degassed, ambient temperature solution of benzyl {1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}methylcarbamate (11 mg, 0.02 mmol) in methanol (3 mL). After stirring at ambient temperature under an atmosphere of hydrogen for 4 h, the reaction mixture was filtered through cotton and concentrated in vacuo to afford the title compound. (M+H) found: 395.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([N:14]3[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]3=[O:22])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:23])[CH2:2][CH3:3].[BH4-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([N:14]3[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[CH:18]3[OH:19])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:23])[CH2:2][CH3:3]
Reactant: CCCN1C(=O)COc2ccc(N3C(=O)C(C)=C(C)C3=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1C(=O)COc2ccc(N3C(=O)C(C)=C(C)C3O)cc21
Reaction time: 3 h
Yield: 69.1 %

Procedure:
1.15 g of 1-[4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-3,4-dimethyl-2,5-dioxo-2,5-dihydropyrrole was dissolved in 100 ml of methanol, and 0.09 g of sodium borohydride was added at room temperature. The mixture was stirred at this temperature for 3 hours. One drop of acetic acid was added, and methanol was evaporated. The concentrated residue was extracted with dichloromethane, washed with water and dried. The solvent was evaporated, and the precipitated crystals were recrystallized with ethanol to give 0.8 g of 1-[4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole. m.p. 124°-125° C.