Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[I:12][C:13]1[CH:22]=CC2[C:15](=[CH:16][NH:17][C:18](=O)[N:19]=2)[CH:14]=1>ClCCCl>[I:12][C:13]1[CH:22]=[C:7]2[C:16](=[CH:15][CH:14]=1)[N:17]=[CH:18][N:19]=[C:6]2[Cl:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1nc2ccc(I)cc2c[nH]1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
To a stirred solution of DMF (6.3 mL) in DCE (20 mL) cooled to 0° C. was added dropwise a solution of oxalyl chloride (60 mL of a 2M solution in DCE). After addition was complete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10 g, 36.8 mmol) was added as a solid. The resulting mixture was heated to reflux under nitrogen for 3 hours. Upon cooling to room temperature, the reaction was quenched cautiously with H2O. CH2Cl2 was added and the bilayer transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (2×50 mL) and the combined organic layers dried (Na2SO4). The solvent was removed in vacuo to provide a yellow solid which was triturated with diethyl ether to remove any remaining impurities. The resulting yellow solid obtained by filtration was shown to be pure by NMR. 1HNMR (CDCl3, 400 MHz): δ: 9.05 (s, 1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H).
Reaction SMILES: [F-].[Na+].[CH3:3][OH:4].[F:5][C:6]1([C:20]([F:23])([F:22])[F:21])[O:11][C:10]([F:13])([F:12])[C:9](F)([C:14]([F:17])([F:16])[F:15])[O:8][C:7]1=[O:19].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:5][C:6]([C:20]([F:23])([F:22])[F:21])([O:11][C:10]([F:13])([F:12])[C:9](=[O:8])[C:14]([F:15])([F:17])[F:16])[C:7]([O:4][CH3:3])=[O:19]
Reactant: CO
Reactant: O=C1OC(F)(C(F)(F)F)C(F)(F)OC1(F)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [F-]
Agent: [Na+]
Product: COC(=O)C(F)(OC(F)(F)C(=O)C(F)(F)F)C(F)(F)F
Reaction time: 65 h
Yield: 84.6 %

Procedure:
A suspension of 50.4 g (1.2 mol) of NaF in 128 g (4.0 mol) of methanol was stirred and cooled with an ice bath while 310 g (1.0 mol) of perfluoro(3,6-dimethyl-2-oxo-1,4-dioxane) was added at a rate sufficient to maintain a temperature of 25°-30° C. The ice bath was removed after completion of the addition and the reaction mixture was stirred overnight. The NaF.HF was filtered off, the filter cake was rinsed well with ether, and the filtrates were added to 213 g (1.5 mol) of P2O5. The resultant mixture was allowed to stand for about 65 h and then distilled to give 272.6 g (85%) of methyl perfluoro(2-methyl-5-oxo-3-oxahexanoate), bp 48°-51° (50 mm), identified by IR and NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[C:11](Cl)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[CH2:20]Cl>N1C=CC=CC=1>[O:5]=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][C:7]([O:9][C:2]([CH3:1])([CH3:10])[CH3:20])=[O:8]
Reactant: ClCCl
Reactant: CCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Product: CCCCCCC(=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a mixture of 100 ml of dichloromethane and 32 ml of pyridine was dissolved 25.0 g of meldrum's acid. Under cooling with ice, 10.0 g of hexanoyl chloride was added dropwise to the solution, followed by stirring under room temperature for 1 hour. The solvent was removed and to the residue was added water. The mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in 100 ml of tert-butanol, followed by reflux under heating for 3 hours. The solvent was removed under reduced pressure. The residue was subjected to distillation under reduced pressure to yield 22.0 g of the oily titled compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]([O:11][CH:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH3:9].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CC(C)=O>[O:7]=[C:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: CC(=O)OC(Br)c1ccccc1
Reactant: O=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCN(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
To a stirred suspension of 4-piperidone (10.0 g, 65.0 mmol) and bromobenzyl acetate (14.9 g, 65.2 mmol) in acetone (100 ml) was added K2CO3 (9.0 g) and Et3N (9.1 ml, 65.2 mmol). The reaction mixture was stirred at room temperature for two days, and then the solvent was evaporated. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The organic extracts were combined and dried over Na2SO4. The solvent was evaporated to afford the title compound (13.3 g, 53.8 mmol, 83%) as a thick oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.37 (m, 5H), 5.18 (s, 2H), 3.42 (s, 2H), 2.91 (t, J=6.1 Hz, 4H), 2.50 (t, J=6.1 Hz, 4H).
Reaction SMILES: [OH:1][CH:2](O)[C:3](=O)[CH3:4].[NH3:7].Cl.[C:9](=[NH:15])(OCC)[CH2:10][CH3:11]>>[CH2:10]([C:9]1[NH:15][C:3]([CH2:2][OH:1])=[CH:4][N:7]=1)[CH3:11]
Reactant: CC(=O)C(O)O
Reactant: N
Reactant: CCOC(=N)CC
Agent: Cl
Product: CCc1ncc(CO)[nH]1
Temperature: 90 °C

Procedure:
Dihydroxyacetone (65 g) was added slowly to liquid ammonia (250-300 ml), followed by ethyl propanimidate hydrochloride (65 g). The suspension was transferred to an autoclave and heated at 90° C. for 16 h. The ammonia was allowed to evaporate and then the reaction mixture concentrated in vacuo. The residue was dissolved in methanol, washed with charcoal, and then purified by chromatography, eluting with a gradient of System C (300:8:1 to 50:8:1). Trituration with acetone gave the title compound (29.83 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH2:12])=[O:14])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2ccc(Br)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)C1(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-bromo-pyridin-2-yl)-cyclopropanecarbonitrile (0.18 g) and sulfuric acid (95%, 1.8 mL) was stirred at room temperature overnight. The solution was poured on crushed ice and the resulting solution was basified using 4 M aqueous NaOH solution. The solution was extracted with dichloromethane, the combined extracts were dried (Na2SO4), and the solvent was evaporated to give the title compound as a colorless solid. Yield: 0.20 g (quantitative); LC (method 2): tR=2.38 min; Mass spectrum (ESI+): m/z=241/243 (Br) [M+H]+.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C(=O)N(C)C.[H-].[Na+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCCCN1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C(=O)N(C)C
Solvent: CS(C)=O
Product: O=C1CCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.9 g (0.3 mol) of caprolactam are dissolved in 200 ml of absolute dimethylsulphoxide and 100 ml of absolute tetramethyl urea and 14.4 g (0.33 mol) of 55% sodium hydride/oil dispersion is added in batches. The resulting jelly-like precipitate is stirred for 2 hours at ambient temperature. Then 38 g=34.4 ml (0.3 mol) of benzyl chloride are added dropwize, the mixture is stirred for 2 hours at ambient temperature and then poured onto ice water. The aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed four times with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue remaining is distilled in vacuo. Yield: 49.9 g (81.8% of theory), Bp 0.27 mm Hg: 110°-114° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].ON1C2C=CC=CC=2N=N1.Cl.CNC(N=C=NCC)CCNC>C(#N)C>[CH3:21][O:20][N:19]([CH3:18])[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1
Reactant: CNOC
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)c1cccnc1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
Add triethylamine (11.9 mL, 84.5 mmol) dropwise to a suspension of nicotinic acid (10 g, 81.2 mmol), N,O-dimethylhydroxylamine hydrochloride (8.3 g, 85.3 mmol, 1.05 eq), 1-hydroxybenzotriazole (3.29 g, 24.36 mmol, 0.3 eq) and 1,3-dimethylamino propyl-3-ethylcarbodiimide hydrochloride (18.68 g, 97.44 mmol, 1.2 eq) in acetonitrile (100 mL) at room temperature under nitrogen. After 2 h a white precipitate forms. Add water (100 mL) and acetonitrile and evaporate under vacuum. Extract with ethyl acetate (3×100 mL), dry the organic phase over anhydrous sodium sulfate and concentrate to afford 13.19 g (98%) of the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.Cl.[CH3:28][NH:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]([CH3:30])[CH3:28])[CH2:18]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN(C)C)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.5 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.20 g), dimethylamine hydrochloride (411 mg) and potassium carbonate (1.74 g) in DMF (12 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (620 mg) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O.CN(C)C=O>CCOCC>[CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCC1CC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCC1CC1

Procedure:
A mixture of 0.85 g. of 9-cyclopropylnonanoic acid, 0.45 ml. of thionyl chloride (density 1.656) and 0.10 ml. of dimethylformamide (density 0.945) in 10 ml. ether is stirred overnight at room temperature. The upper layer of the reaction mixture is then separated and the solvent removed by evaporation to yield 9-cyclopropylnonanoyl chloride to which is added at 0° under nitrogen 0.474 g. of 1-octanol and 40 ml. of ether. To this mixture is added dropwise 0.52 ml. of pyridine (density 0.98). The reaction mixture is then stirred 1/2 hours at 0° and overnight at room temperature. An additional 0.20 g. of 1-octanol is then added and the reaction mixture is stirred for 1 day. The mixture is filtered, 3 equivalents of water are added and then the mixture is stirred for 1 hour. Ether is added to dilute the reaction mixture which is washed in turn with 2N sulfuric acid (2 × 50 ml.), 10% aqueous sodium carbonate (2 × 50 ml.), water (2 × 50 ml.) saturated aqueous copper sulfate, water (2 × 50 ml.) and saturated aqueous sodium chloride (1 × 50 ml.). The solution is then dried over calcium sulfate and the solvent removed by evaporation to yield 1.14 g. of octyl 9-cyclopropylnonanoate which is purified by preparative thin layer chromotography (15% ether/hexane solvent).
Reaction SMILES: C(NC(C1SC(N2C(O)CN(CC3C=CC(F)=CC=3)C2=O)=NC=1C)=O)C1C=CC=CC=1.[F:32][C:33]1[CH:63]=[CH:62][C:36]([CH2:37][CH2:38][N:39]2[CH2:43][CH:42](O)[N:41]([C:45]3[S:46][C:47]([C:51]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:52])=[C:48]([CH3:50])[N:49]=3)[C:40]2=[O:61])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH2:38][N:39]2[CH:43]=[CH:42][N:41]([C:45]3[S:46][C:47]([C:51]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:52])=[C:48]([CH3:50])[N:49]=3)[C:40]2=[O:61])=[CH:62][CH:63]=1
Reactant: Cc1nc(N2C(=O)N(CCc3ccc(F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Agent: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccn(CCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 14 %

Procedure:
Following the procedure as described in Example 17, making variations as required to replace N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide with 2-(3-(4-fluorophenethyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide 2, the title compound was obtained as a colorless solid in 14% yield: mp 160-162° C. (ethyl acetate/hexanes): 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J=5.8 Hz, 1H), 8.50-8.49 (m, 1H), 8.42 (dd, J=4.7, 1.8 Hz, 1H), 7.68 (td, J=7.8, 1.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.22-7.17 (m, 3H), 7.11-7.03 (m, 2H), 6.84 (d, J=3.2 Hz, 1H), 4.38 (d, J=5.8 Hz, 2H), 3.83 (t, J=7.1 Hz, 2H), 2.92 (t, J=7.1 Hz, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.0, 161.9, 159.8, 153.8, 151.6, 150.3, 149.3, 148.5, 135.6, 135.3, 134.6, 131.0, 123.9, 120.7, 115.7, 106.7, 44.6, 40.9, 33.8, 17.4; MS (ES+) m/z 438.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:14]=4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[N:10]=[C:11]([C:13]4[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[C:14]=4[F:30])[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3o2)n(C)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: CC(=O)N[C@@H](C)COc1nn(C)c(-c2nc3ccc(OCC4CC4)cc3o2)c1F
Temperature: 60 °C
Reaction time: 7 h
Yield: 5.5 %

Procedure:
A mixture of N-[(1S)-2-({5-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-1-methyl-1H-pyrazol-3-yl}oxy)-1-methylethyl]acetamide (193 mg), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (427 mg) and acetonitrile (10 mL) was stirred at 60° C. for 7 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (11.2 mg).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][Cl:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21])=[N+]=[N-].Cl>CO.[Pd].C(O)C>[ClH:20].[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][Cl:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 2 h
Yield: 157.3 %

Procedure:
0.16 g of 5'-azido-2',5'-dideoxy-5-(2-chloroethyl)uridine was dissolved in 100 ml of methanol and 1.9 ml of a 0.27M solution of hydrogen chloride in methanol was added. A slurry of 25 mg of 5% palladium-on-charcoal catalyst in 10 ml of ethanol was added under a nitrogen atmosphere and the mixture was hydrogenated at room temperature and under atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give a solid which, after crystallization from a mixture of 15 ml of methanol and 30 ml of diethyl ether, gave 0.13 g of 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride melting point 229°-230° C. (decomposition).
Reaction SMILES: [H][H].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([NH:37][C:38](=[O:40])[NH2:39])=[C:32]([C:34](=[O:36])[NH2:35])[CH:33]=2)=[CH:25][CH:24]=1)[C:12]([O:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CC(O)C.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:12]([O:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:30][C:31]([NH:37][C:38](=[O:40])[NH2:39])=[C:32]([C:34](=[O:36])[NH2:35])[CH:33]=2)=[CH:27][CH:28]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCc1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Hydrogen gas was bubbled through a suspension of Wilkinson's catalyst (767 mg, 0.829 mmol) in IPA (10 ml) and toluene (5 ml). After 5 minutes, a solution of cyclopentyl(2S,4E)-2-[(tert-butoxycarbonyl)amino]-5-{4-[4-carbamoyl-5-(carbamoylamino)-2-thienyl]phenyl}pent-4-enoate (300 mg, 0.553 mmol) in IPA (10 ml) was added. The mixture was kept under an atmosphere of hydrogen and placed in a preheated oil bath at 80° C. After 4 hrs the reaction was judged to be complete by LC-MS. The mixture was filtered whilst still hot and the filtrate evaporated in vacuo. The residue was subjected to column chromatography eluting with 4% MeOH in DCM. Yield=120 mg, 0.198 mmol, 36% yield. LCMS purity 90%: m/z 543 [M−H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].CC([O-])=O.[K+].[NH2:21]O.Cl.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:21])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOc1cc(C=O)ccc1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc(C#N)ccc1OC
Temperature: 130 °C
Yield: 89.3 %

Procedure:
To a solution of 4-methoxy-3-(2-methoxyethoxy)benzaldehyde (10 g) in AcOH (80 mL) was added KOAc (9.5 g) and NH2OH.HCl (6.7 g). The resulting mixture was heated at 130° C. for 18 h under N2 atmospheres. After reaction finished, the mixture was poured into water (400 mL). The solid was collected, washed with water (100 mL) and air-dried to give 4-methoxy-3-(2-methoxyethoxy)benzonitrile (8.8 g) as a light yellow solid.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[Br:10]Br>CCOCC>[Br:10][CH:4]([CH:5]([O:8][CH3:9])[O:6][CH3:7])[CH:3]=[O:2]
Reactant: BrBr
Reactant: COC=CC(OC)OC
Solvent: CCOCC
Product: COC(OC)C(Br)C=O
Reaction time: 0.5 h

Procedure:
To a solution of 25.0 g (0.19 mole) of 1,3,3-trimethoxy-1-propene in 75 ml of ether at 5° C is added 22.4 g (0.14 mole) of bromine (bromine color begins to persist at this point) over a period of 40 minutes. The solvent is removed in vacuo at 25° C and the colorless liquid residue is added dropwise with stirring to a mixture of 25 g of sodium bicarbonate and 80 ml of 75% v/v dioxane at 0°-5° C. Stirring is continued for 30 minutes and the mixture is extracted with 200 ml and 150 ml portions of ether. The extract is dried over magnesium sulfate, evaporated in vacuo and the residue distilled through a Vigreux head to afford 2-bromo-3,3-dimethoxypropionaldehyde, b.p. 70°-73° C/8 mm.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[C:3]=12.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>CCCCO>[ClH:52].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:2]2[C:7]([F:8])=[CH:6][N:5]=[C:4]3[NH:9][CH:10]=[C:11]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[C:3]=23)[CH2:22]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(F)c(F)c12)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(F)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.21 g, 0.77 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.31 g, 1.53 mmol) and DIEA (0.13 mL, 0.77 mmol) in n-BuOH (3 mL) were stirred at 143° C. (bath) for 24 hours. The solvent was removed. The residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-80% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)-N-(4-(3-aminopiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.23 g, 66% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.89 (d, 1H), 10.38 (s, 1H), 9.33 (d, 1H), 8.88 (dd, 1H), 8.64 (dt, 1H), 8.18 (s, 1H), 8.17 (br s, 3H), 7.76 (dd, 1H), 7.60 (d, 1H), 3.64-3.56 (m, 1H), 3.25-3.17 (m, 2H), 3.16-3.07 (m, 1H), 3.04-2.95 (m, 1H), 1.87-1.75 (m, 1H), 1.62-1.52 (m, 1H), 1.48-1.38 (m, 1H), 1.35-1.22 (m, 1H); LCMS (APCI+) m/z 355.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:43])[C:13]([S:16][C:17]3[CH:34]=[CH:33][C:20]([CH2:21][NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[C:19]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:18]=3)=[N:14][N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:44]1(O)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2N=N1.C(N)CCCCC.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:43])[C:13]([S:16][C:17]3[CH:34]=[CH:33][C:20]([CH2:21][NH:22][C:23]4[CH:24]=[CH:25][C:26]([CH2:29][C:30]([NH:44][CH2:48][CH2:47][CH2:52][CH2:51][CH2:50][CH3:49])=[O:32])=[CH:27][CH:28]=4)=[C:19]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:18]=3)=[N:14][N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCCCCCN
Solvent: CN(C)C=O
Product: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)NCCCCCC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (4-{4-[5-(4-tert-butylphenyl)-4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl]-2-heptyloxybenzyl amino}phenyl)acetic acid (0.3 g, 0.5 mmol), benzotriazol-1-ol (0.074 g, 0.55 mmol) in dimethylformamide (10 ml) is stirred for 20 minutes. n-Hexylamine (0.066 ml, 0.5 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide (0.105 g, 0.55 mmol) are added and then the medium is stirred for 24 hours at room temperature. The addition of water causes the formation of a precipitate which is dried before being purified by chromatography on a silica column, eluted with a heptane/ethyl acetate (3/7) mixture. After evaporation of the solvents, 0.205 g (60%) of the expected compound is recovered.