Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]2=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[OH:8][C:7]1[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3](=[O:11])[C:2]=1[CH3:1].[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: CC1(C)CCC2OC2(C)C1=O
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1=C(O)CCC(C)(C)C1=O
Product: CC1=CCCC(C)(C)C1=O
Reaction time: 1 h

Procedure:
15.4 g of 1,3,3-trimethyl-7-oxabicyclo-[4.1.0]heptan-2-one, 1.8 g of triphenylphosphine and 2.76 g of 1,2-bis-(diphenylphosphino)-ethane were placed under argon gasification in a round flask equipped with a thermometer and a reflux condenser and the mixture was treated with 2.0 g of bis-(dibenzylidene acetone)palladium(O). The reaction vessel was then immersed in an oil-bath preheated to 150° C. and the reaction mixture was stirred at this temperature with a magnetic stirrer for 1 hour under continued argon gasification. A gas-chromatographical analysis of the mixture obtained without an internal standard gave peaks for 3-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one (81.9 area %) and 2,6,6-trimethyl-2-cyclohexen-1-one (18 area %). For the working-up, the reaction mixture, cooled to room temperature, was taken up in 20 ml of ethyl acetate and filtered over silica gel in a sintered glass suction filter. The content of the suction filter was rinsed three times with 150 ml of ethyl acetate each time. The filtrate was evaporated to constant weight in a rotary evaporator under a water-jet vacuum at a bath temperature of 40° C. The residue (21.5 g of a yellowish oil) was dissolved in 100 ml of diethyl ether and the solution was added to a separating funnel S1. Two further separating funnels S2 and S3 were each charged with 100 ml of diethyl ether. Then, three 150 ml portions of 3N sodium hydroxide solution were passed in succession and with good intermixing through the three extraction vessels S1 -S3. The ether phases were discarded. The combined alkaline extracts were acidified cautiously (pH about 1) with about 300 ml of concentrated hydrochloric acid while cooling with ice and then saturated with 500 g of sodium chloride while stirring. Three separating funnels S4 -S6 were each charged with 200 ml of ethyl acetate. Thereafter, the aqueous product solution and subsequently three 150 ml portions of saturated sodium chloride solution were passed in succession and with good intermixing through the three extraction vessels S4 -S6. The combined organic phases were dried over sodium sulphate. The drying agent was filtered off under suction and rinsed on the suction filter twice with 100 ml of ethyl acetate each time. The filtrate was evaporated in a rotary evaporator under a water-jet vacuum at a bath temperature of 40° C. and the residue was dried in a high vacuum. There were obtained 10.1 g (65.6%) of 3-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one in the form of colourless crystals with a purity of 99.6%: m.p. 112°-114° C. after recrystallization from diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([C:9]#[N:10])[O:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([C:9]#[N:10])[O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(C#N)oc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc2ccc(CBr)cc2o1
Temperature: 25 °C

Procedure:
6-methylbenzofuran-2-carbonitrile (12 g, 76 mmol), NBS (13.59 g, 76 mmol), and AlBN (1.25 g, 7.64 mmol) were dissolved in carbon tetrachloride (191 ml). The mixture was heated to reflux overnight. After 18 h the reaction was cooled to RT and concentrated under reduced pressure. The product was then crashed out using MeOH and the slurry was placed in the fridge overnight. The slurry was filtered and the collected PPT was washed with MeOH. The collected PPT was pure 6-(bromomethyl)benzofuran-2-carbonitrile (13.864 g). 1H NMR (400 MHz, DMSO-d6) δ 4.87 (s, 2H), 7.52 (dd, J=8.2, 1.4 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.87 (d, J=1.5 Hz, 1H), 8.11 (d, J=1.0 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[CH3:27]N(C)C=O>CI>[C:22]([C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]=1[OH:21])[N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)[CH3:27])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Reactant: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(c1ccc(C(=O)O)cc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 3.4 g (0.010 mole) of 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (prepared in Example 1) in 35 ml of N,N-dimethylformamide and 3.5 ml of methyl iodide was heated at 95° C. for about 48 hours under nitrogen. The reaction mixture was poured into cold water and the resulting solid was collected and then taken up in chloroform. The chloroform solution was filtered, washed with water, dried with magnesium sulfate and evaporated to give a tan solid. This material was recrystallized first from benzene and then from a mixture of ethanol and water to give 1.5 g of white crystalline 4-(3,5-di-tertiary-butyl-4-hydroxy-N-methylanilino)benzoic acid, m.p. 240°-244° C. Analysis: Calculated for C22H29NO3 : % C, 74.3; % H, 8.2; % N, 3.9. Found: % C, 74.4; % H, 8.3; % N, 3.5.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:12])[NH:32][CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from (4-fluoro-benzoylamino)-acetic acid (CA [366-79-0]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]). MS (m/e): 429.4 (MH−, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[NH:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1c(N2C(=O)NC(CNC(=O)OC(C)(C)C)C2=O)ccc(C#N)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1c(N2C(=O)C(CNC(=O)OC(C)(C)C)N(C)C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of the hydantoin 13A (1.00 g, 2.64 mmol) in DMF (10 mL) was added KHMDS (530 mg, 2.64 mmol) followed by iodomethane (0.16 mL, 2.64 mmol) and the resulting solution was stirred at rt for 2 h. The solution was then diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 100:0 to 80:20 gradient) to afford the title compound (608 mg) as a white foam. 1H NMR (CDCl3) δ 1.41, 1.43 (s, 9H), 2.26, 2.28 (s, 3H), 3.11, 3.12 (s, 3H), 3.60-3.86 (m, 2H), 4.08-4.12 (m, 1H), 4.77, 4.83 (br s, 1H), 7.16, 7.20 (d, J=8.3 Hz, 1H), 7.60, 7.61 (d, J=8.3 Hz, 1H); HPLC a) column: Phenominex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 3.05 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.86, 2.96 min retention time (98%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% isopropanol/hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 14.40 min retention time (97%); MS (ES) m/z 391 [M−H]−.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][CH:8]([CH3:12])[CH2:9][CH:10]=O.[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cu]Br>[CH2:21]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH:8]([CH3:12])[CH3:7])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C#CCCCC
Reactant: CC(C)CC=O
Agent: [Cu]Br
Product: CCCCC#CC(CC(C)C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A 10 ml schlenk tube was charged with copper (I) bromide (3.6 mg, 0.025 mmol), (R,Sax)-[4-(2-diphenylphosphanylnaphthalen-1-yl)-phthalazin-1-yl]-(1-phenylethyl)-amine (15.4 mg, 0.028 mmol) and 4 Å molecular sieves (0.3 g). The schlenk tube was flushed with argon for 5 min and then toluene (2 ml) was added. The resulting suspension was stirred for 1 hr at 23° C. To the reaction mixture was subsequently added 1-hexyne (41 mg, 0.50 mmol), 3-methylbutanal (43 mg, 0.50 mmol) and dibenzylamine (99 mg, 0.50 mmol). The resulting reaction mixture was stirred at 23° C. for 5 days and purified by flash chromatography on silica gel to give 128 mg of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1ccncc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccncc1F
Yield: 91.9 %

Procedure:
To a mixture of 1.2 g of 3-fluoroisonicotinaldehyde and 5 ml of ethanol was gradually added 0.36 g of sodium borohydride under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with saturated brine and dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure to obtain 1.12 g of (3-fluoropyridin-4-yl)methanol.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19](O)=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:33][OH:34].Cl.[OH-].[K+]>C1COCC1.CO>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19](=[O:20])[NH:33][OH:34])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Compound 5a (711 mg, 1.95 mmol) was dissolved in dry THF (5 mL). ECF (160 μL, 1.95 mmol), and NMM (180 μL, 1.95 mmol) were added and this mixture was stirred for 40 min at 0° C. NH2OH.HCl (136 mg, 1.95 mmol) and KOH (109 mg, 1.95 mmol) were dissolved in dry MeOH (5 mL) and stirred at 0° C. for 30 min. The solids were filtered off, and the THF solution was added dropwise to the methanol filtrate and stirred for 2 h at 0° C. The reaction mixture was filtered, the solvent evaporated, and the residue dissolved in H2O (25 mL). After adjusting the pH to 1-2, the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4, evaporated in vacuo, and co-evaporated with EtOAc (3×3 mL) to yield the pure product as light-pink solid. Yield: 565 mg, 1.10 mmol, 56%. 1H-NMR (DMSO-d6): δ 7.87 (d, 2H, 2JHH=9.0 Hz, ArH), 7.42 (d, 2H, 2JHH=9.0 Hz, ArH), 7.35 (s, 2H, ArH), 6.98 (d, 1H, 3JHH=9.0 Hz, ArH), 6.90 (d, 2H, 3JHH=9.0 Hz, ArH), 4.07 (s, 2H, 2×CH2CO2H), 3.85 (s, 2H, 2×CH2CONHOH). ESI-MS calcd for C16H16N2O7S 380.07 [M-H]−, obsd 381.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.Br[CH2:42][C:43]([NH2:45])=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.FC(F)(F)C(O)=O.ClCCl>[NH2:45][C:43]([CH2:42][N:12]1[C:13](=[O:24])[CH2:14][CH:15]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[CH3:23])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:32])[CH:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:44]
Reactant: NC(=O)CBr
Reactant: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1CC(=O)N(CC(N)=O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
In a manner similar to the method described in example 146d and 146e racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (50 mg g, 0.08 mmol) was reacted with 2-bromo-acetamide (35 mg, 0.25 mmol) and cesium carbonate (163 mg, 0.50 mmol) in DMF (2 ml). The resulting residue was dissolved in a mixture solution of trifluoroacetic acid (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO4 and concentrated. The residue was triturated purified by Prep-HPLC to give racemic (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1.[C:16](Cl)(=O)[C:17](Cl)=[O:18].Cl.C([O:26][C:27](=[NH:39])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH3:38])[CH:30]=1)(C)C>>[CH3:14][CH:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:12]=2)[C:8]([C:16]2[C:17](=[O:18])[NH:26][C:27](=[O:39])[C:28]=2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[CH:9]1)[CH3:15]
Reactant: COCc1ccc2ccn(C(C)C)c2c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: Cl
Product: COCc1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cn(C(C)C)c2c1

Procedure:
6-Methoxymethyl-1-(2-propyl)indole was reacted with oxalyl chloride and then 2-(1-methyl-1H-indol-3-yl) ethanimidic acid isopropyl ester hydrochloride as described in Example 3b to yield 3-[1-(2-propyl)-6-methoxymethyl-1H-indol-3-yl]-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccncc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 4-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-4-ylmethoxy)-ethoxy)-phenyl}-piperidine-1-carboxylate as a colourless oil.
Reaction SMILES: C(N1CCN(CC2C=CC(NC(=O)C3C=CC(C)=C([N+]([O-])=[O:26])C=3)=CC=2C(F)(F)F)CC1)C.N1C=CC=CC=1.[CH3:39][NH:40][C:41]1[C:42]2[CH:49]=[CH:48][N:47]([S:50]([C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:43]=2[N:44]=[CH:45][N:46]=1.Cl[CH2:61][Cl:62]>>[Cl:62][C:61]([N:40]([C:41]1[C:42]2[CH:49]=[CH:48][N:47]([S:50]([C:53]3[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=3)(=[O:51])=[O:52])[C:43]=2[N:44]=[CH:45][N:46]=1)[CH3:39])=[O:26]
Reactant: ClCCl
Reactant: CCN1CCN(Cc2ccc(NC(=O)c3ccc(C)c([N+](=O)[O-])c3)cc2C(F)(F)F)CC1
Reactant: CNc1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C(=O)Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3 (3.45 g, 8.2 mmol, 1.0 eq.),) and pyridine (0.66 ml, 0.82 mmol, 1.0 eq.),) in dichloromethane (40 ml) at 23° C. is added carbamoyl chloride 6 (3 g, 8.2 mmol, 1.0 eq.) drop wise over a period of 15 minutes. The reaction mixture is further stirred at room temperature for a period of 8 hours after which, it is partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to provide crude product 7. The residue is purified using column chromatography with MeOH/CH2Cl2 (5:1) as eluent to afford the title product 7.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1>CO.[H][H].[Pd]>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[CH:2]=[N:7][CH:6]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1ncc2cc[nH]c2n1
Yield: 99.1 %

Procedure:
As shown in FIG. 1—step i, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 1001) (130 mg, 0.847 mmol) was dissolved in 3 mL of methanol and hydrogenated under 1 atm of hydrogen over Pd—C 10% for 16 hours. Concentration to dryness provided 100 mg (98%) of 7H-pyrrolo[2,3-d]pyrimidine [compound 1002, 1H-NMR (CD3OD): δ 9.4 (s, 1H); 9.1 (s, 1H); 7.9 (s, 1H); 7.1 (s, 1H)].
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[Br:11]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[Br:11][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a solution of 3H-oxazolo[4,5-b]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with Na2S2O5 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (11.5 g, 55% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[C-:13]#[N:14].[Na+].C(OC(=O)C)C>CS(C)=O.CCCCCC>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: N#CCc1ccccc1C(F)(F)F
Temperature: 90 °C
Yield: 88.5 %

Procedure:
A solution of 1-bromomethyl-2-trifluoromethyl-benzene (3.5 g, 14.641 mmol) in DMSO (18 mL) and sodium cyanide (1.076 g, 21.962 mmol) were taken in a flask and the flask was heated to 90° C. for 3 hours. The reaction was monitored by TLC (2% ethylacetate in hexane). The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 2.4 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:30][CH2:31][CH2:32][OH:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:30][CH2:31][CH2:32][OH:33])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
5-[(2,5-Difluorophenyl)[(4-methylphenyl)sulfonyl]meth yl]-4-methylpyridine-2-carboxylic acid (208 mg, 0.5 mmol), 2-aminoethanol (46 μl, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.75 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol), and triethylamine (209 μl, 1.5 mmol) were dissolved in methylene chloride (35 ml), and the resulting solution was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 6% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (125 mg, 0.27 mmol, 54%) as a white amorphous substance.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:18])[C@@H:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[N:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:19][CH2:20][C:21](=O)[CH2:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([CH:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:18])[C@@H:13]([NH:17][CH:21]([CH2:22][CH3:23])[CH2:20][CH3:19])[CH2:14][CH2:15][CH3:16])=[N:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(=O)CC
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(CC)CC)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC[C@H](NC(CC)CC)C(=O)Nc1ncc(C(CC)CC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid [5-(1-ethyl-propyl)-thiazol-2-yl]-amide (107 mg, 0.4 mmol) and 3-pentanone (34 mg, 0.4 mmol)in 3 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (131 mg, 0.62 mmol) and stirred at room temperature overnight. An additional sodium triacetoxyborohydride (167 mg)was added and the resulting mixture was stirred at room temperature for 4 hrs. The mixture was quenched with ammonium hydroxide/water and extracted with methylene chloride. The organic layer was separated, dried, filtered and concentrated to dryness to give a yellow oil. The oil was purified by Shimadzu HPLC to give 2-(S)-(1-Ethyl-propylamino)-pentanoic acid [5-(1-ethyl-propyl)-thiazol-2-yl]-amide as a colorless oil, RT=1.88 min, M+1=340.4.