Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[C:11](=[O:17])[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:7]=1.[CH3:28][O:29][C:30]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:31]=1[CH2:32][N:33]([C:46]1[S:50][N:49]=[CH:48][N:47]=1)[S:34]([C:37]1[CH:42]=[C:41]([F:43])[C:40](F)=[CH:39][C:38]=1[F:45])(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][C:40]2[C:41]([F:43])=[CH:42][C:37]([S:34]([N:33]([CH2:32][C:31]3[CH:51]=[CH:52][C:53]([O:55][CH3:56])=[CH:54][C:30]=3[O:29][CH3:28])[C:46]3[S:50][N:49]=[CH:48][N:47]=3)(=[O:35])=[O:36])=[C:38]([F:45])[CH:39]=2)=[C:6]([C:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[C:11](=[O:17])[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: COc1ccc(Cn2cc(-c3cc(Cl)ccc3O)n3cncc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Cn2cc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)N(Cc4ccc(OC)cc4OC)c4ncns4)cc3F)n3cncc3c2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a solution of 5-(5-chloro-2-hydroxyphenyl)-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one (0.12 g, 0.31 mmol) and N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.15 g, 0.33 mmol) in dimethylsulfoxide (2 mL) was added potassium carbonate (0.051 g, 0.37 mmol). The reaction mixture was stirred at ambient temperature for 20 h and diluted with ethyl acetate (80 mL). The organic phase was washed with water (20 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with a 20-80% gradient of ethyl acetate in hexanes to afford 4-(4-chloro-2-(7-(4-methoxybenzyl)-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a colorless foam in 83% yield (0.203 g): 1H NMR (300 MHz, CDCl3) δ8.18 (s, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.54-7.44 (m, 3H), 7.25-7.13 (m, 3H), 6.89-6.80 (m, 3H), 6.51 (dd, J=9.6, 6.1 Hz, 1H), 6.37 (s, 1H), 6.31 (dd, J=8.4, 2.1 Hz, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.29 (s, 2H), 4.97 (s, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 3.66 (s, 3H); MS (ES+) m/z 806.8 (M+1), 808.8 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@H:18]3[CH:23]=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:33](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C@@H:18]3[C:23]#[CH:33])[CH:4]=[C:3]([C:2]([F:32])([F:1])[F:31])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=C[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#C[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
(1R*,2R*,5S*,6R*)-2-{(3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-formyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 47; 165 mg, 0.3 mmol) in methanol (3 ml) at 0° C. was treated with potassium carbonate (83 mg, 0.6 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (81 mg, 0.5 mmol) and stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and hexane. The organics were collected, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a white crystalline solid (123 mg, 75%).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](F)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(F)C(F)F
Reactant: COC(=O)C=CN1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (96.7%, 50.7 g, 289 mmol) and triethylamine (31.07 g, 307 mol) were initially charged in toluene (300 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (30.1 g 307 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (150 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 69.7 g; purity according to GC: 92.3%; yield: 90%). 1H-NMR (CDCl3): δ=1.75 (m, 6H), 3.3 (m, 2H), 3.62 (m, 2H), 3.75 (s, 3H), 6.62 (t, 1H), 7.89 ppm (s, 1H).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[C:22]([F:23])=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.Cl>C(Cl)Cl.CC(O)C>[F:43][C:2]([F:1])([F:42])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[C:22]([F:23])=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COCCOc1ccc2cc(F)c(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: COCCOc1ccc2cc(F)c(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl (3S)-1-((1R)-2,2,2-trifluoro-1-(3-(3-fluoro-7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.096 g, 0.159 mmol) in DCM (0.5 mL) was added 5 N HCl (0.530 mL, 2.65 mmol) in IPA. The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The crude residue was suspended in ACN (5 mL) and stirred at ambient temperature for 10 minutes. The solid was collected by filtration to give (3S)-1-((1R)-2,2,2-trifluoro-1-(3-(3-fluoro-7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (0.078 g, 0.135 mmol, 85% yield) as a solid. LCMS APCI (+) m/z 505 (M+H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].Cl>CN(C)C=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C@H:18]([O:19][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
(4S)-4-Benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one (37.54 mmol) was dissolved in N,N-dimethylformamide (40 mL) and then imidazole (2.97 g, 43.6 mmol) and tert-butyldimethylsilyl chloride (6.12 g, 40.6 mmol) were added. The reaction was stirred at room temperature for 19 h, poured into 0.1 N hydrochloric acid (500 mL) and extracted with 1:1 ethyl acetate-hexane (500 mL). The organic layer was washed with water (2×500 mL), brine (300 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from methanol (55 mL) by heating to a light boil and cooling slowly to room temperature over 18 h. The crystals were filtered cold and washed with cold methanol (45 mL) to afford (4S)-4-benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one (16.04 g, 88% yield) as a white crystalline solid; mp 87.6° C.; Rf 0.66 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.36-7.18 (m, 7H), 6.99 (t, J=8.7 Hz, 2H), 4.69-4.61 (m, 2H), 4.18-4.13 (m, 2H), 3.27 (dd, J=13.5, 3.2 Hz, 1H), 2.96-2.89 (m, 2H), 2.73 (dd, J=13.5, 9.7 Hz, 1H), 1.82-1.63 (m, 4H), 0.88 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+354.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:15](N(CC)C(C)C)(C)C.CI.C(OCC)(=O)C.CCCCCC>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: CSc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])ccc1SC
Reaction time: 18 h

Procedure:
Combine 2-methylthio-5-nitrobenzoic acid, (3.2 g, 15 mmol), N,N-diisopropylethylamine (17.0 mL, 100 mmol), and methyl iodide (12.45 mL, 200 mmol) in acetonitrile (50 mL). After 18 hours, dilute the reaction mixture with ethyl acetate, extract with brine, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 20% ethyl acetate/hexane to give methyl 2-methylthio-5-nitrobenzoate. Rf=0.58 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=O)=[CH:26][CH:25]=1.N1CCCCC1>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:26][CH:25]=1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: COc1ccc(CCC=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(CCC=C2SC(=O)N(CCCCSc3cccc4nccn34)C2=O)cc1

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 657 mg (4.0 mmol) of 3-(4-methoxyphenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.08 g (76.8%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:34]2[C:29]([O:28][CH3:27])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1cccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1
Yield: 66 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 2-methoxy-3-pyridineboronic acid, the expected product is obtained in the form of a white powder with a yield of 66%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(N(CC)CC)C.C(O)=O>C(#N)C.[Pd]>[N+:14]([C:3]1[CH:4]=[C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][CH:2]=1)([O-:16])=[O:15]
Reactant: CC(C)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C(=O)O)c1cccc([N+](=O)[O-])c1
Yield: 92.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 6.3 g of 2-(4-chloro-3-nitrophenyl) -2-methylpropionic acid, 7.62 ml of triethylamine, 0.6 g of 5% palladium-on-charcoal and 1.46 ml of formic acid in 100 ml of acetonitrile. 5.0 g of 2-(3-nitrophenyl)-2-methylpropionic acid are thus obtained in the form of an orange oil [NMR spectrum (DMSO-d6, 200 MHz): 1.57 (s, 6H); 7.65 (t, J=7 Hz, 1H); 7.9 (d, J=7 Hz, 1H); 8.13 (d, J=7 Hz, 1H); 8.15 (s, 1H); 12.5 (broad s, acidic OH)].
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[S:14][CH:15]=1.C([O:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:29][CH2:28][CH2:27][CH2:26][OH:25])[CH2:20][CH2:21]2)[S:14][CH:15]=1
Reactant: c1cc2c(cc1-c1csc(C3CCNCC3)n1)CCCC2
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCCCN1CCC(c2nc(-c3ccc4c(c3)CCCC4)cs2)CC1

Procedure:
The preparation is carried out as described starting from 39 mg (0.13 mmol) of 4-[4-(5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine and 30 μl (0.20 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 2N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[NH:6][C:5]1=[O:17])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]1=[O:17])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CBr
Reactant: [N-]=[N+]=NC1CCCCc2ccccc2NC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCCCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 3-azido-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (8.9 g) in dry dimethylformamide (100 ml) is added during 30 minutes to a solution of potassium t-butoxide (4.5 g) in dry dimethylformamide (100 ml) maintained at 0° under an atmosphere of dry nitrogen. The reaction mixture is stirred at 0° for 2 hours, when a solution of ethyl bromoacetate (5.8 g) in dimethylformamide (10 ml) is added during 5 minutes. The reaction mixture is stirred at 0° for 2 hours, then evaporated under reduced pressure. The residue is distributed between ethyl acetate (250 ml) and water (150 ml), and the ethyl acetate solution washed with water (100 ml) and dried over sodium sulfate. The solvent is removed under reduced pressure to give 3-azido-1-ethoxycarbonylmethyl-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCCC1.NC1NC2C=CC=CC=2N=1.[CH:59]1([CH2:65][C@H:66]([N:75]2[CH2:83][C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:76]2=[O:84])[C:67]([NH:69][C:70]2SC=CN=2)=[O:68])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:70]1[NH:69][C:67](=[O:68])[CH:66]([N:75]1[CH2:83][C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:76]1=[O:84])[CH2:65][CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nc2ccccc2[nH]1
Agent: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nc2ccccc2[nH]1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 60 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A, 287 mg; 1.0 mmol and 2-amino-benzimidazole (119 mg; 1.0 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) to provide crude N-(5-Bromo-thiazol-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide. The crude product was purified by reverse-phase HPLC (Rainin Dynamax SD-1 instrument) using a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column. The combined fractions containing product were concentrated to remove most of the acetonitrile and then extracted with ethyl acetate. The extracts were dried (sodium sulfate) and concentrated in vacuo to give 240 mg (60%) of N-(1H-Benzoimidazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white solid: EI-HRMS m/e calcd for C24H26N4O2 (M+) 402.2056, found 402.2056.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]([Cl:1])=[O:4]
Reactant: CNC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C(=O)Cl)C1CCCCC1
Yield: 295.9 %

Procedure:
To a solution of triphosgene (4.35 g) in toluene (70 ml) is added dropwise N-methylcyclohexylamine (5 g). To the mixture is added dropwise pyridine (3.5 g), and the mixture is refluxed for 4 hours. The mixture is allowed to cool, and the organic layer is separated, washed with 0.1 N hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give N-methyl-N-cyclohexylaminocarbonyl chloride (7.62 g) as a colorless oil.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23](OC(C)=O)=[O:24]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:23]([N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])(=[O:24])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(C)=O)C1CCCCC1
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (10.5 g, 35.7 mmol) and 4-dimethylaminopyridine (100 mg) in pyridine (25 ml) is dropwise added acetanhydride (5 ml, 52.9 mmol). The mixture is stirred 2 h and evaporated. The residue is dissolved in toluene (100 ml), washed with water (5×20 ml), dried over MgSO4 and evaporated to afford 9.58 g of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CN=C(N)C=1C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C.ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: Cc1ccnc(N)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The compound (3R)-1-benzyl-pyrrolidin-3-ol (1.0 g, 5.65 mM) was dissolved in triethylamine (2.0 ml, 14.3 mM), and dimethyl amino pyridine (DMAP) (0.002 g), dichloromethane (20.0 ml) and methanesulfonyl chloride (0.9 ml, 11.7 mM) was added dropwise at 0-5° C. The reaction mixture was maintained at the same temperature for about half an hour. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50.0 ml), washed with saturated sodium bicarbonate and brine solution. It was further dried over anhydrous sodium sulphate and concentrated to get the title compound as oil. Yield=95% (1.2 g, 5.38 mM). This material was used as such in the next step.
Reaction SMILES: [C:1](O[BH3-])(=O)C.[Na+].[CH3:7][N:8]([CH3:49])[C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[C:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[N:19]([S:27]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][NH:36][CH2:37]3)=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:18]1=[O:40])=[O:10].C(O)(=O)C.C=O>>[CH3:7][N:8]([CH3:49])[C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[C:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[N:19]([S:27]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([CH3:1])[CH2:37]3)=[CH:32][CH:31]=2)(=[O:28])=[O:29])[C:18]1=[O:40])=[O:10]
Reactant: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc3c(c2)CNCC3)c2ccc(Cl)cc21
Reactant: [BH3-]OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc3c(c2)CN(C)CC3)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
Sodium acetoxyborohydride (0.36 mmol, 76.27 mg) was added to a solution of Example 61 (0.24 mmol, 0.15 g), acetic acid (0.24 mmol, 14.4 mg) and aq. formaldehyde (37%, 0.26 mmol, 21.42 mg). The mixture was stirred at RT for 12 h and evaporated in vacuo. The residue was solved in H2O and extracted with ethyl acetate. The organic phase was dried, filtrated and evaporated. The crude product was then purified on a column of silica gel eluted with 5% MeOH in CH2Cl2 to afford 100 mg of the required product.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1COCC1.CCOC(C)=O.O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
To a suspension of 1-methylpiperazine dihydrochloride (8.5 g, 49.2 mmol) and triethylamine (22.8 mL, 164.0 mmol) in THF (150 mL) was added tert-butyl 2-bromoacetate (8.0 g, 41.0 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and H2O (100 mL). The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (6.0 g, 69%).