Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1)[CH3:4].[C:16]([C:18]1[C:23]2[N:24]([CH2:27][C:28](O)=[O:29])[CH:25]=[N:26][C:22]=2[CH:21]=[CH:20][CH:19]=1)#[N:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:16]([C:18]1[C:23]2[N:24]([CH2:27][C:28]([NH:2][C@H:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([C:12]#[N:13])([CH3:14])[CH3:15])=[CH:7][CH:6]=3)[CH3:4])=[O:29])[CH:25]=[N:26][C:22]=2[CH:21]=[CH:20][CH:19]=1)#[N:17]
Reactant: CC(N)c1ccc(C(C)(C)C#N)cc1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C(C)(C)C#N)cc1
Reaction time: 18 h
Yield: 66 %

Procedure:
2-[4-(1-Aminoethyl)phenyl]-2-methylpropanenitrile hydrochloride prepared according to scheme 6 (557 mg, 2.49 mmol), (7-cyano-1H-benzimidazol-1-yl)acetic acid (500 mg, 2.49 mmol) prepared according to scheme 3 and DMAP (601 mg, 4.97 mmol) are mixed in DMF (10.0 mL). HATU (945 mg, 2.49 mmol) is added, and the mixture is stirred for 18 hours. The reaction mixture is filtered and then purified on HPLCMS: Waters prep LCMS, Flow rate: 27 ml/min, Column: SynerSi (4μ) Polar RP, 21.2×50 mm, Mobile phase: A=water (0.05% TFA) B=MeCN, Gradient used 40% to 70% B in A, in 10 min. The fractions are combined, NaOH 1N is added and the desired compound is extracted with ethyl acetate. The combined organic fractions are concentrated under reduced pressure to yield the product (610 mg, 1.64 mmol, 66%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.50 (d, J=7.03 Hz, 3H) 1.68 (s, 6H) 4.98-5.09 (m, 1H) 5.33 (s, 2H) 7.37-7.43 (m, 3H) 7.46 (d, J=8.20 Hz, 2H) 7.68 (d, J=7.62 Hz, 1H) 7.97 (dd, J=8.20, 0.98 Hz, 1H) 8.28 (s, 1H) 8.89 (d, J=7.62 Hz, 1H), MS [M+H], calcd: 372.2, found: 372.3.
Reaction SMILES: O.[Sn](Cl)Cl.[Cl:5][C:6]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:7]=1[C:8]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=1[O:23][CH3:24])=[O:12])=[O:9].CN1CCCC1=O>C(OCC)(=O)C.CO>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([O:23][CH3:24])=[C:14]([NH:13][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:6]=2[Cl:5])=[O:12])[CH:19]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reaction time: 1 h
Yield: 64.9 %

Procedure:
5.8 g (25.9 mmol) of tin dichloride hydrate were added to 2.0 g (5.2 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea in 20 ml of ethyl acetate/methanol mixture at 70° C. After 1 hour, 30 ml of N-methyl-2-pyrrolidinone were added, and the mixture was stirred for a further 2 hours. After cooling, the reaction mixture was made basic and the resulting precipitate was filtered off with suction. The phases were separated. The organic phase was then washed three times with water, dried and concentrated under high vacuum. 1.2 g (67%) of the desired product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]3[CH2:27][C@@H:26]3[CH3:28])[C:18]=12.O>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:13]2[N:14]=[N:15][CH:16]=[C:17]3[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]4[CH2:27][C@@H:26]4[CH3:28])[C:18]=23)=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(Cl)nncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of p-fluorobenzyl alcohol (1.45 g, 11.5 mmol) in tetrahydrofuran (2 ml) was added dropwise to a solution of sodium hydride (0.26 g, 10.8 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of 7-chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (2.50 g, 10.0 mmol) in tetrahydrofuran (13 ml) was added dropwise to the reaction mixture and the mixture was heated under reflux for 3 hours. After this time the reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the residue, and the precipitate was collected by filtration and then recrystallized from a mixture of ethyl acetate and hexane to afford the title compound (2.25 g, 66.4%) as pale brown crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Nc1ccc(CCO)cc1
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-6-methoxy-3-nitropyridine and 4-aminophenylethyl alcohol.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: CCCOC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, n-propyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-n-propoxycarbonyl-quinoline (compound 8, 96 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][S:8][CH2:7][CH2:6][CH2:5][S:4][CH2:3]1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=[CH2:12]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.O1CCCC1>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH:2]([O:1][C:19]([NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[O:20])[CH2:3]1
Reactant: OC1CSCCCSC1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCNC(=O)OC1CSCCCSC1
Temperature: 55 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of 3-hydroxy-1,5-dithiacyclooctane (5.00 grams, 30 millimoles), 2-isocyanatoethyl methacrylate (4.72 grams, 30 millimoles), tetrahydrofuran (15 milliliters), and one drop of dibutyltin dilaurate were stirred at 55° C. for three hours. The solvent was then removed under reduced pressure and the crude product was purified by column chromatography over silica gel using a mixture of ethyl acetate/hexane (30/70). The product was isolated as a white solid (7.72 grams, 79% yield). Purity and structure verification of Example 9 were confirmed by 1H NMR.
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][N:3]2[CH2:4][CH2:5][CH2:6][C@@:2]2([CH3:1])[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1
Reactant: C[C@@]1(C(=O)O)CCCN1
Reactant: COc1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CCN2CCC[C@@]2(C)C(=O)O)cc1
Yield: 73.6 %

Procedure:
A mixture of (S)-2-methylproline (1.47 g) (prepared by the method of D. Seebach et al., JACS, 105, 5390 (1983)), 4-methoxyphenethyl bromide (1.72 g) and sodium carbonate (2.12 g) in ethanol (30 ml) was heated under reflux for 48 hours, adjusted to pH8 with 2M hydrochloric acid, treated with glacial acetic acid to pH7, filtered and evaporated under reduced pressure. The residue was triturated with ethanol, filtered and evaporated under reduced pressure to give the title compound as a brown gum, (1.55 g), which was used directly in Preparation 10 without further purification.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:21]#[N:22])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+].CO>>[C:21]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:7])[N:9]=1)#[N:22]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(OC)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-methoxy-isoquinoline-3-carboxylic acid butyl ester (104 mg, 0.35 mmol), glycine (523 mg, 6.97 mmol), and a 0.5 M solution of sodium methoxide in methanol (13.2 mL, 6.6 mmol) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 mL) and the solution was extracted with methyl tert-butyl ether (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (10 mL). The resulting white precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (82 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.53 (t, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.57 (m, 2H), 4.02 (d, J=6.2 Hz, 2H), 3.98 (s, 3H); MS: (+) m/z 302.00 (M+1).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:39])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:39][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:37])([F:36])[F:38])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccccc3OC(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 112.8 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.23 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 0.058 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.035 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1 H) 8.36 (d, J=7.82 Hz, 1 H) 8.06 (d, J=8.80 Hz, 2 H) 7.88-7.99 (m, 3 H) 7.74 (t, J=7.80 Hz, 1 H) 7.62 (d, J=8.10 Hz, 1 H) 7.55 (d, J=7.83 Hz, 2 H) 7.48 (d, J=7.82 Hz, 1 H) 6.94 (s, 1 H) 3.84 (s, 2 H) 2.05 (s, 3 H) MS calcd. for C26H19ClF3O5S [(M+H)+] 535, obsd. 535.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].[H-].[Na+].[Br:13][CH2:14][CH2:15]Br.Cl>CN(C=O)C>[Br:13][CH2:14][CH2:15][O:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)ccc1O
Reactant: BrCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1OCCBr
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a solution of 2-methoxy-4-methylphenol (1000 mg, 7.24 mmol) in DMF (40 mL) at rt was added sodium hydride (60% dispersion in mineral oil, 579 mg, 14.48 mmol). The reaction mixture was stirred for 1 h, then 1,2-dibromoethane (6.80 g, 136.18 mmol) was added. The resulting solution was heated at 50° C. for 24 h, then cooled to rt. The solution was treated with 2N HCl and extracted with EtOAc. The combined extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using a step gradient of 30 and 50% EtOAc/hexanes to give the title compound as a white solid (460 mg, 24%). GC/MS (EI) m/z 244 (M)+, RT 7.40 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5](=[O:6])[NH:7][C:8]2[C:9]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][C:11]([Cl:15])=[CH:12][C:13]=2[Cl:14])=[O:24]
Reactant: COC(=O)CC(=O)Nc1c(Cl)cc(Cl)cc1C(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)cc(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
Crude N-(2-benzoyl-4,6-dichloro-phenyl)-malonamic acid methyl ester (600 mg, 1.64 mmol, Eq: 1.00) from step A was suspended in methanol (16 ml) and a solution of sodium methanolate in methanol (13.8 ml, 0.5 M, 6.88 mmol, Eq: 4.2) was added. The reaction mixture was stirred at reflux for 1 h and was then allowed to cool to RT overnight. Most of the methanol was removed in vacuo and the remaining residue was poured onto ice. The mixture was acidified to pH 6 with 1N and 0.1N HCl and a light brown solid precipitated. The solid was filtered off, washed with water and a small amount of MeOH and dried. The resulting title compound (522 mg, light brown solid) was used in the next reaction step without further purification. MS (ESI): 348.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH2:31][C:32](=O)[CH3:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:32]([CH3:33])[CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:35])[F:36])[CH:26]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC(C)Cc1cccc(C(F)(F)F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 1-(3-trifluoromethyl-phenyl)-propan-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 14.2, 19.1, 19.5, 20.0, 21.1, 24.3, 26.6, 26.6, 36.1, 36.5, 43.5, 44.1, 54.6, 55.2, 56.0, 59.1, 60.8, 61.1, 67.3, 104.6, 104.7, 123.4, 126.2, 129.0, 129.2, 131.1, 133.0, 137.2, 140.1, 172.3; MS m/z 494.3 (M+1).
Reaction SMILES: N=C=N.[F:4][C:5]([F:24])([CH2:21][CH2:22][CH3:23])[CH2:6][CH:7]([NH:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:8]([OH:10])=O.C1C=C[C:28]2[N:33](O)N=[N:31][C:29]=2C=1.Cl.NCC#N.C(O)C(N)(CO)CO>C(Cl)Cl.C(N(CC)CC)C>[C:29]([CH2:28][NH:33][C:8]([C@@H:7]([NH:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[CH2:6][C:5]([F:4])([F:24])[CH2:21][CH2:22][CH3:23])=[O:10])#[N:31]
Reactant: CCCC(F)(F)CC(NC(=O)N1CCCOCC1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: N#CCN
Agent: N=C=N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCCOCC1)C(=O)NCC#N
Reaction time: 0.17 h

Procedure:
A suspension of Polystyrene bound carbodiimide (570 mg, 0.73 mmol) and 4,4-Difluoro-2-[([1,4]oxazepane-4-carbonyl)-amino]-heptanoic acid (135 mg) in DCM (10 mL) stirred for 10 min. HOBT (60 mg) added, stirred for 10 min. A suspension of amino acetonitrile hydrochloride (34 mg) and triethyl amine (52 μL) in DCM (5 mL) added and stirred overnight at room temperature. PS-Trisamine (493 mg) added and stirred at room temperature for 2 h 30 min. After filtration, filtrate diluted with DCM, washed with water, evaporated under reduced pressure and purified by column chromatography eluting with ethyl acetate heptane mixture to give Perhydro-1,4-oxazepine-4-carboxylic acid [(S)-1-(cyanomethyl-carbamoyl)-3,3-difluoro-hexyl]-amide as a solid.
Reaction SMILES: Cl.[OH:2][CH:3]([C:6]([CH3:20])([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1)Cl)[C:4]#[N:5].N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>>[C:27]([O:2][C:3](=[C:6]([CH3:20])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1)[C:4]#[N:5])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccsc1-c1ccc(C(C)(Cl)C(O)C#N)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C#N)=C(C)c1ccc(-c2sccc2C)cc1
Yield: 92 %

Procedure:
A 30-ml portion of the toluene solution containing 3.7 g (0.0145 mole) of 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidonitrile obtained in (1) was saturated with dried hydrogen chloride and stirred for a further one hour so that 2-hydroxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-3-chloropropionitrile may be formed. To the reaction mixture, which had been freed from the remaining hydrogen chloride by introducing dried nitrogen, was added 1.43 g (0.0181 mole) of pyridine and 1.70 g (0.0167 mole) of acetic anhydride, followed by adding 2.1 g (0.0207 mole) of triethylamine. After refluxing for 15 hours, the reaction mixture was washed with diluted hydrochloric acid, dried over anhydrous sodium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 4.2 g (92% yield) of oily 2-acetoxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]acrylonitrile.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.I[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C>[NH:3]1[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:6][N:5]=[N:4]1
Reactant: O=C(O)CCCCCCCCCCCI
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCc1nnn[nH]1
Reaction time: 0.25 h
Yield: 59001.4 %

Procedure:
A suspension of NaH (0.045 g, 80% suspension in oil) in DMF (1 ml) was added to a solution of tetrazole 44 (0.095 g, 1.35 mmmol) in DMF (1 ml). After stirring the reactants for 15 min, a solution of 12-iodo-dodecanoic acid 45 (0.2 g, 0.6 mmol) was added. The resulting mixture was stirred at room temperature for 1 h and at 55° C. for 1.5 h and then concentrated in vacuo. The residue was treated with 1N HCl(5 ml) and extracted with EtOAc (2×10 ml). The organic layer was washed with water, dried (Na2SO4), concentrated under reduced pressure and the residue was crystallized from EtOAc/Hexane to give the title compound 46 (0,095 g, 26%) as a 1:3 mixture of N-3 and N-1 isomers, respectively. This mixture was tested directly as a substrate for NMT. 1H NMR (CDCl3) δ: 8.59 and 8.5 (2s, 1H); 4.65 and 4.43 (2t, 2H, J=7.2 Hz); 2.35 (t, 2H, J=7.5 Hz); 1.95 (m, 2H); 1.63 (m, 2H); 1.26 (m, 14H). FABMS: m/z 269 (M+H); 251 and 241. HRMS: m/z=C13H24N4O2Li, calc: 275.2059, found: 275.2004 (M+Li).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][N:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]1=[O:18])=[O:4].[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][N:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]1=[O:18])=[O:4]
Reactant: CC(C)(C)OC(=O)NN1CCN(C(=O)CBr)C1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NN1CCN(C(=O)CI)C1=O

Procedure:
N-[3-(Bromoacetyl)-2-oxo-1-imidazolidinyl]carbamic acid, 1,1-dimethylethyl ester (20.9 g, 65 mmol) was dissolved in acetone (250 ml) containing sodium iodide (10.5 g, 70 mmol). The solution was stirred at reflux for three hours and filtered hot through Celite. The solution was evaporated in vacuo to give the title compound as a light yellow solid, 23.9 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH2:20]C3C4C(=CC=CC=4)C=CC=3)[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(C#N)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC([C@H]1N2C(=O)C(C#N)=C(C)C(C3C=CC=CC=3)=C2SC1)=O>>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH3:20])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(C#N)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(CN)c(=O)n21
Yield: 67 %

Procedure:
By following the procedure described for the preparation of 7a from 6a, 6c (36 mg, 0.11 mmol) gave 7c as a yellow solid (27 mg, 67%): [α]D−110 (c 0.13, CHCl3); IR λ 2956, 1747, 1631, 1575, 1490, 1442, 1216 cm−1; 1H NMR (400 MHz, CDCl3) δ7.49-7.30 (m, 3H), 7.25-7.15 (m, 2H), 5.64 (dd, J=8.5, 2.4, 1H), 3.92-3.69 (m, 7H), 3.62 (dd, J=11.5, 8.6, 1H), 3.41 (dd, J=11.6, 2.3, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 161.1, 152.0, 147.8, 136.4, 130.0, 129.9, 129.0, 128.9, 128.5, 118.0, 115.3, 64.0, 53.6, 37.9, 31.7, 18.0; MS (ES+) calcd 331 for C17H20N2O3S, obsd 331.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccc(Cl)cc4)c[nH]3)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccc(Cl)cc5)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A mixture of 4-chloro-6-{2-[4-(4-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (300 mg, 0.767 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (246 mg, 0.997 mmol), Na2CO3 (203 mg, 1.917 mmol) and Pd(PPh3)4 (89 mg, 0.077 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washed with EtOAc (150 mL), evaporated, and then chromatographed to afford the title compound (305 mg). LC-MS (ES) m/z=476 [M+H]+.