Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[CH:13]=[N:12]2)=[C:4]([F:20])[CH:3]=1>C(O)C.[Pt]=O>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:20])=[C:5]([N:11]2[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[CH:13]=[N:12]2)[CH:6]=1
Reactant: Cn1c(=O)cnn(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: O=[Pt]
Solvent: CCO
Product: Cn1c(=O)cnn(-c2cc(N)c(Cl)cc2F)c1=O
Yield: 80.1 %

Procedure:
A solution of 18.0 g (0.060 mole) of 2-(4-chloro-2-fluoro-5-nitrophenyl)-4-methyl-1,2,4-triazine-3,5-(2H,4H)dione in 200 mL of ethanol was placed in a 500 mL Parr hydrogenation bottle with 0.5 g of platinum oxide. The bottle was placed in a Parr hydrogenator and the reaction mixture hydrogenated. Upon complete hydrogenation the reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to a residual oil. The oil was purified using column chromatography on silica gel. Elution was accomplished with 1:1--ethyl acetate: heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield 13.0 g of 2-(5-amino-4-chloro-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; m.p. 150-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH2:23])[CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:23][CH2:21][CH3:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Reactant: CCN
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(NC)n1
Yield: 2.5 %

Procedure:
2.5 g (0.007 mol) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide were stirred with 80 ml of ethylamine in an autoclave at 160° C. for 40 hours. The residual ethylamine was left to evaporate and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:2, then 2:3 and finally 1:1. The thus-obtained 0.67 g of brown oil was suspended in 200 ml of 1N NaOH, suction filtered and the filtrate was neutralized with 1N HCl. It was again suction filtered, the filtrate was saturated with NaCl and extracted with ethyl acetate. The organic phase was dried. There was obtained 0.055 g (2.5%) of 4-amino-N-(2-ethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide as pale brown crystals; MS (ISN): me/e=320 (C14H18N5O2S-).
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=[O:12])[C:7]([CH3:14])=[N:6]1.CC1[C:20]([C:21]([O:23][CH2:24]C)=O)=C(C)NN=1.BrCC(OC)CC>>[CH3:24][O:23][CH2:21][CH2:20][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=[O:12])[C:7]([CH3:14])=[N:6]1
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Reactant: COCCn1nc(C)c(C(=O)O)c1C
Agent: CCC(CBr)OC
Product: COCCCCn1nc(C)c(C(=O)O)c1C
Yield: 41 %

Procedure:
Prepared by following the same method as the preparation of Intermediate 42, ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate (280 mg) was reacted with 1-bromo-2-methoxybutane (367 mg) to afford white solid (185 mg, 41%). ESI-MS m/z 227.4 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[O:8][CH:9]=1)=[O:4].CO.[OH-].[Na+].Cl>O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:7]2[O:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1coc(Cc2ccc(OC)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Cc2nc(C(=O)O)co2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid methyl ester (40 mg, 0.16 mmol), methanol (2 mL) and 1N NaOH (1 mL) was heated at 60° C. for 2 hours and allowed to stand at 25° C. for 30 minutes. After dilution with water, the mixture was adjusted to pH 2 with 2N HCl and extracted with ether. The organic layers were combined, dried with MgSO4 and evaporated to dryness to yield 25 mg (66%) of 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid as a white solid. ESI-MS m/z calc. 233.2, found 234.2 (M+1)+. Retention time of 2.27 minutes.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 92.8 %

Procedure:
A mixture of 2-bromo-1-methyl-3-nitrobenzene (1.0 g, 4.63 mmol), phenylamine (506 μL, 5.56 mmol), Cs2CO3 (2.11 g, 6.48 mmol) and (R)-BINAP (5 mol %, 143 mg, 0.23 mmol) in toluene (10 mL) was degassed with a stream of nitrogen prior to addition of Pd(OAc)2 (25 mg, 0.11 mmol) and was stirred at 110° C. under a nitrogen atmosphere for 20 h. After cooling to RT, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-35% DCM in cyclohexane) affording (2-Methyl-6-nitrophenyl)phenylamine as a red solid (981 mg, 93%). LCMS: RT 3.88 min [M+H]+ 229.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][NH:21][CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CNCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) (1.0 g, 3 mmol) in dichloroethane (50 mL) was added methylamine (0.48 g, 6.1 mmol, 2 eq) in water (40%) and 1 mL of ACOH. The solution was allowed to stir at RT for 1 h followed by the addition of sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 2.8 eq). The resulting mixture was stirred at RT for 16 h and quenched with MeOH. After stirring for 30 min the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel by eluting with EtOAc/MeOH to give 0.62 g (60%) of tert-butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.47 (bs, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 7.23 (m, 1H), 5.97 (bs, 1H), 3.18-2.82 (m, 2H), 2.45 (s, 3H), 1.74 (s, 3H), 1.40 (s, 9H). MS (ESI) m/e 342.9 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[C:13]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O.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]>[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[C:13]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1csc(Br)n1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1csc(-c2c(F)cc(OC)cc2F)n1
Temperature: 100 °C
Yield: 73.4 %

Procedure:
To a solution of methyl 2-bromothiazole-4-carboxylate (3.27 mmol, 741 mg) in tetrahydrofuran (15 mL) and water (1.5 mL) was added 2,6-difluoro-4-methoxyphenylboronic acid (1.8 equiv., 5.88 mmol, 1160 mg) and potassium fluoride (3.3 equiv., 10.8 mmol, 627 mg). The mixture was degassed with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (0.2 equiv., 0.654 mmol, 617 mg) and tri-tert-butylphosphine (1.0 M in toluene; 0.4 equiv., 1.31 mmol, 1.3 mL) were added and the reaction mixture was heated under microwave at 100° C. for 30 minutes. The reaction mixture was concentrated and the residue was purified on silica eluted with 0 to 50% EtOAc in heptane to afford methyl 2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxylate (2.40 mmol, 685 mg, 74% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:25][O:26][CH2:27][CH3:28])[N:21]([CH2:22][CH2:23][CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:41])[C:13]3[N:19]=[C:20]([CH2:25][O:26][CH2:27][CH3:28])[N:21]([CH2:22][CH2:23][CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCc4ccccc4)cc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCc4ccccc4)cc3c21
Reaction time: 0.42 h

Procedure:
8-Benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinoline (2.0 g, 5.3 mmol) was dissolved in chloroform (20 mL). 3-Chloroperoxybenzoic acid (60% pure, 1.53 g, 5.3 mmol) was added in one portion and the mixture was stirred for 25 minutes. Ammonium hydroxide (20 mL) was added and the biphasic mixture was stirred for 10 minutes. p-Toluenesulfonyl chloride (1.0 g, 5.3 mmol) was added in one portion and the reaction was stirred for an additional 1 hour. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined and washed successively with 5% aqueous sodium carbonate, water and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography. The purification was carried out eluting with chloroform:CMA in a gradient from 99:1 to 93:7 to provide a red-brown solid. The solid was recrystallized from acetonitrile to yield 1.1 g of 8-benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as red brown crystals, mp 152.5-154.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Br)(Br)[Br:14]>C(=O)([O-])[O-].[Na+].[Na+]>[Br:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][N:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1ccc2cc(Cl)ncc2[nH]1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1cc2ccc(Br)nc2cn1
Temperature: 130 °C
Yield: 50 %

Procedure:
A mixture of 6-chloro-1,7-naphthyridin-2(1H)-one (1.0 g, 5.5 mmol) and phosphorus tribromide (10 mL) was heated in a sealed tube at 130° C. for 20 hours. The cooled reaction mixture was poured onto ice, diluted with saturated aqueous sodium carbonate solution (100 mL), and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-80% ethyl acetate in heptane) to afford the title compound as a white solid (700 mg, 50%). 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J=8.7 Hz, 1H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:11]1([C:14]#[CH:15])[CH2:13][CH2:12]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@:26]23[C:32]([CH3:34])([CH3:33])[C@@:29]([CH3:35])([CH2:30][CH2:31]2)[C:28](=[O:36])[O:27]3)=[O:25])=[C:19]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[CH:18]=1>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@:26]23[C:32]([CH3:33])([CH3:34])[C@@:29]([CH3:35])([CH2:30][CH2:31]2)[C:28](=[O:36])[O:27]3)=[O:25])=[C:19]([C@@:37]([OH:42])([C:15]#[C:14][CH:11]2[CH2:13][CH2:12]2)[C:38]([F:39])([F:40])[F:41])[CH:18]=1
Reactant: C#CC1CC1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
1M LiHMDS (7.4 mL, 7.4 mmol) was added slowly to a solution of cyclopropyl acetylene (0.49 g, 7.4 mmol) in THF (4 mL) in an ice-salt bath under argon, and then (1S, 4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (9, 1 g., 2.48 mmol) in THF (1.5 mL) was added slowly. The mixture was stirred at −15° C. for 20 minutes. TLC showed the formation of the product. The reaction mixture was worked up similarly to the example 6, and (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10) was isolated as an off-white solid. 1H NMR spectrum of the product was identical to that of Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[C:3]=1[Cl:10].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:18])[CH:5]=[C:4]([Br:9])[C:3]=1[Cl:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)c(Cl)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: Clc1c(Br)cc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To 1,3-dibromo-2-chloro-5-methylbenzene (1000 mg, 3.52 mmol) was added NBS (688 mg, 3.87 mmol) and AIBN (57.7 mg, 0.352 mmol). The mixture was stirred at room temperature for 30 minutes and then heated to 80° C. overnight. The solution was evaporated and the residue was purified by silica gel chromatography (0-5% EtOAc/heaxnes) to provide the title compound (740 mg) as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CO.Cl[Pd]Cl>[F:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:21])([F:22])[F:23])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC1(C)OB(c2ccc(OC(F)(F)F)cc2F)OC1(C)C
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(OC(F)(F)F)cc2F)c1
Temperature: 100 °C
Yield: 81.3 %

Procedure:
Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.37 g, 17.55 mmol), potassium carbonate (1.812 g, 13.11 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated to yield a dark-brown solid. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 8:1 to 3:1 of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)isonicotinate (4.48 g, 81%) was yielded as a colorless solid. 1H NMR (600 MHz, cdcl3) δ 3.96 (s, 3H), 7.07 (d, 1H), 7.14 (d, 1H), 7.79-7.84 (m, 1H), 8.03-8.09 (m, 1H), 8.31 (s, 1H), 8.82-8.88 (m, 1H). MS m/z 316 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)=O.CSC.CO>C1COCC1>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:7]1[CH2:6][C:5]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R,R)-1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]-1,6-dioxohexane (0.001 mol) in dry THF was added to a solution containing 0.5 mL (0.005 mol) 10M BH3.DMS, and the solution was heated under reflux in an argon atmosphere. Heating was maintained for 2 hours, after which time the mixture was cooled and 10 mL anhydrous methanol was added dropwise. After gas evolution had subsided, 10 mL of saturated HCL-MeOH was added dropwise and the mixture heated under reflux for 15 minutes. The mixture was cooled to room temperature and the solvent removed in vacuo, leaving an oily residue whose volume was further reduced by Kugelrohr distillation (100° C., 0.05 Torr). Finally, the residue was dissolved in isopropyl alcohol, and ether was added until the solution became cloudy. Crystallization occurred overnight, giving (R,R)-1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9](OCC)=[O:10])[CH:2]=1.[NH3:15]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9]([NH2:15])=[O:10])[CH:2]=1
Reactant: N
Reactant: CCOC(=O)CC(C)c1cccnc1
Product: CC(CC(N)=O)c1cccnc1
Yield: 47 %

Procedure:
A solution of ethyl 3-(pyridin-3-yl)butanoate (0.50 g, 2.59 mmol) in methanolic ammonia (10 ml) was heated to 100° C. in a pressure bomb overnight. The solvent was evaporated under reduced pressure, washed with n-pentane and dried under reduced pressure to afford 0.2 g (47%) of 3-(pyridin-3-yl)butanamide as pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[Cl:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[O:23][C:24]=1[CH3:25].COC1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[Cl:13]
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Agent: COc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3OC)oc2C)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester (example 15 d]) was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole (prepared from 2-methoxy-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{2-chloro-4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[O:9]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cnccn1
Yield: 34 %

Procedure:
To a solution of 1.00 g (8.06 mmol) of 2-pyrazinecarboxylic acid and 1.21 g (10.5 mmol) of N-hydroxysuccinimide in 70 ml of methylene-chloride, 1.85 g (9.67 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Further, 1.94 g (8.06 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 0.751 g of the desired compound (34.0% yield, colorless powder).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1.O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminium hydride in dry tetrahydrofuran (50 ml) was added (3-bromophenyl)acetic acid (10 g) in tetrahydrofuran (100 ml) under ice cooling. The mixture was refluxed for 2 hurs. After cooling, to the reaction mixture were added water and aqueous Rochelle salt. The mixture was stirred for another 30 min. Aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 2-(3-bromophenyl)ethanol. This compound was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[C:21]5[C:28]([C:29]#[C:30][C:31]([CH3:38])([O:33][Si](C)(C)C)[CH3:32])=[CH:27][NH:26][C:22]=5[N:23]=[CH:24][N:25]=4)[CH2:16][CH2:15]3)[N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[C:39]([F:42])([F:41])[F:40].C1COCC1.[F-].CO>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[C:21]5[C:28]([C:29]#[C:30][C:31]([CH3:38])([OH:33])[CH3:32])=[CH:27][NH:26][C:22]=5[N:23]=[CH:24][N:25]=4)[CH2:18][CH2:19]3)[N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[C:39]([F:40])([F:41])[F:42]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3[nH]cc(C#CC(C)(C)O[Si](C)(C)C)c23)CC1
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3[nH]cc(C#CC(C)(C)O)c23)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 59.6 %

Procedure:
Charge 4-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-2-yl)piperidin-1-yl)-5-(3-methyl-3-(trimethylsilyloxy)but-1-ynyl)-7H-pyrrolo[2,3-d]pyrimidine (0.21 g, 1.0 eq) and THF (2 mL) in a round bottom flask. Cool the reaction mass to 0° C. Add tetra-buytlammonium fluoride (0.19 mL, 2.0 eq) drop wise. Stir the reaction mass at RT for 40 min. Monitor the reaction by TLC (10% MeOH in DCM). Charge ethyl acetate and give washing with saturated sodium bicarbonate solution and saturated aq. sodium chloride. Dry the organic layer over anhy. Na2SO4 and concentrate it under vacuum. Crystallize the product in diethyl ether and filtered it to give 4-(4-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-2-yl)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbut-3-yn-2-ol (0.11 g, 64%). MS (M+H): m/z=474.6.