Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:31]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:31])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2N)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A suspension of the product of Example 51B (1.198 g, 2.20 mmol), iron powder (756 mg, 13.53 mmol), and ammonium chloride (771 mg, 14.41 mmol) in water (15 mL) and ethanol (30 mL) was heated at 90° for 1 hour. The reaction was cooled to room temperature. The mixture was diluted with ethyl acetate (200 mL) and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a light yellow solid (1.08 g, 95%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Fc1ccc(Br)cc1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 1-bromo-4-fluorobenzene
Reaction SMILES: O1CCCC1.Cl.[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43]>O>[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH:21][S:42]([C:34]4[CH:35]=[C:36]([N+:39]([O-:41])=[O:40])[CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:44])=[O:43])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:16]1)[CH2:8]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1N
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 40 °C
Reaction time: 7 h
Yield: 36.2 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 250 mg of 4-(1-adamantyl)-2-methylaniline hydrochloride and 200 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 230 mg of 2-chloro-5-nitrobenzenesulfonylchloride was dropwise added, followed by stirring at about 40° C. for about 7 hours. After the mixture was left to stand for cooling, water was added thereto, extraction with chloroform, drying over salt cake and concentration under reduced pressure were carried out to obtain crude crystals. The crude crystals were recrystalized from ether to obtain 150 mg of N-(4-(1-adamantyl)-2-methylphenyl)-2-chloro-5-nitrobenzenesulfonamide (Compound No. 48) having a melting point of 238° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.C(OCC)(=O)C>[CH3:17][S:18]([O:8][CH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=S1(=O)CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCS(=O)(=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
Triethylamine (7.80 mL, 55.9 mmol) was added to a solution of 4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (3.5 g, 23.3 mmol) in dichloromethane (35.0 mL). The reaction solution was cooled to 0° C. and methanesulfonyl chloride (3.25 ml, 41.9 mmol) was added. After 10 minutes, the reaction solution was warmed to room temperature and stirred for 3 h. The reaction was quenched via the addition of saturated aqueous ammonium chloride solution (15 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford an off-white solid. The solid residue was suspended in ethyl acetate (20 mL) and filtered. The filtered solid was then collected and dried in vacuo affording 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (5.1 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.56 (m, 4H) 2.94-3.06 (m, 2H) 3.10 (s, 3H) 3.23-3.39 (m, 2H) 5.03 (tt, J=4.74, 2.49 Hz, 1H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([O:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)[CH:34]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40 mg (0.18 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 50 mg (0.18 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred for 1 h at RT. Then another 40 mg (0.18 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo-[4,5-b]pyridin-2-one were added and the mixture was stirred overnight. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([C@@H:13]([CH3:15])[OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O.Cl>C(Cl)Cl>[C:9]([O:8][C:6]([NH:5][C@@H:4]([C@H:13]([O:14][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:15])[C:3]([O:2][CH3:1])=[O:16])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-threonine methyl ester (Aldrich) (717 mg, 3.07 mmol) in DCM (10 mL) was cooled in an ice-water bath and treated with 2,6-dimethylpyridine (Aldrich) (1.07 mL, 9.22 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (Fluka) (0.85 mL, 3.69 mmol). The solution was stirred for 16 h, poured into 1 M aq. HCl (100 mL), and extracted with DCM (2×50 mL). The organic extracts were washed with saturated aq. NaHCO3 (100 mL), dried (MgSO4), filtered, and concentrated to give (2S,3R)-methyl 2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoate (614a) (1.07 g, 3.08 mmol, 100% yield) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]([C@:30]1(C)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=O.C(Cl)Cl>C(OCC)C>[CH3:28][C@@:30]1(/[CH:8]=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:36][C@H:35]2[N:32]([C:33](=[O:37])[CH2:34]2)[C@H:31]1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C(Cc1ccccn1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@]1(/C=C/c2ccccn2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 353 mg (1.0 mmol) of (2-picolyl)methylene-triphenylphosphorane and 381 mg (1.00 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo-[3.2.0]heptane-2-carboxylate in 10 ml of diethyl ether was stirred at room temperature under argon for 2 hours. The mixture was treated with 10 ml of methylene chloride, insoluble material was removed by suction filtration and the filtrate was concentrated. The residue remaining behind was chromatographed over silica gel (particle size 0.040-0.063 mm) with methylene chloride:ethyl acetate (95:5) as the eluent.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:23][C:24]([F:31])([F:30])[C:25](OCC)=[O:26]>C(#N)C>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25](=[O:26])[C:24]([F:31])([F:30])[F:23])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a solution of 5.07 g (23.7 mM) of tert-butyl 4-aminomethylpiperidine-1-carboxylate and 5.0 ml (35.9 mM) of triethylamine in acetonitrile (40 ml) was added 5.6 ml (47.1 mM) of ethyl trifluoroacetate at room temperature and the mixture was stirred at room temperature for 1.5 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. The solvent was then distilled off under reduced pressure to provide the title compound as light-yellow solid (6.40 g, 87%).
Reaction SMILES: BrC[C:3]1[CH:13]=[C:12]([CH2:14]Br)[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8]C)=[O:6].[O:16]1CCOCC1.S(=O)(=O)(O)O>C(Cl)Cl>[OH:16][CH2:14][C:12]1[CH:11]=[C:10]2[C:4](=[CH:3][CH:13]=1)[C:5](=[O:6])[O:7][CH2:8]2
Reactant: CCOC(=O)c1ccc(CBr)cc1CBr
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C1OCc2cc(CO)ccc21
Temperature: 25 °C

Procedure:
A suspension of 2 (22.1 g, 65.7 mmol) in 700 mL of a 1:1 mixture of dioxane/sulfuric acid (1M) was heated under reflux for 20 h. After cooling to room temperature, the mixture was poured into 200 mL of DCM. The phases were separated and the aqueous phase was extracted with DCM (5×200 mL). The combined organic layers were washed with saturated NaHCO3 (3×200 mL) and brine (1×200 mL) and were dried over MgSO4. The solvent was removed in vacuo to yield 8.70 g (83%) of pure 3 as a colorless solid: 1H-NMR (400 MHz, DMSO-d6): δ 4.65 (s, 2H), 5.39 (s, 2H), 5.47 (br s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.78 (d, J=7.7 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6): δ 62.4, 69.7, 120.0, 123.3, 124.5, 126.9, 147.5, 149.7, 170.5; MS (Cl+ (NH3)) m/z=165.0 (M+H+, 100), 182.0 (M+NH4+, 49).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([F:24])([F:35])[F:36])=[O:34]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (927 mg, 4.19 mmol) and Et3N (645 μl, 4.63 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (633 μl, 4.19 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.06 g, 62%) as a white crystalline powder. mp 178-180° C.; 1H-NMR (CDCl3) δ1.44 (s, 9 H), 2.25 (s, 3 H), 3.51 (s, 2 H), 6.38 (br s, 1 H), 7.12-7.18 (m, 3 H), 7.36-7.37 (m, 1 H), 7.49-7.53 (m, 2 H), 8.13-8.16 (m, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:9](=[O:20])[N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[C:7]2=[O:32])(=[O:3])[CH3:2].[BH4-].[Na+].O.Cl>CO>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH2:21][N:8]1[C:7](=[O:32])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)[N:10]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:9]1=[O:20]
Reactant: COc1ccc(Cn2c(=O)c3cc(C(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3cc(C(C)O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.154 of the compound obtained in Step 7.1 and 0.026 g of NaBH4 in 30 ml of MeOH is stirred for 2 hours at room temperature. Water is added and the mixture is neutralized with 1N HCl. The resulting mixture is evaporated under reduced pressure and the residue is taken up in DCM. This solution is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with EtOAc to give 0.14 g of the expected product.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CO>[CH2:6]([C@@H:4]1[NH:5][C@H:1]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:2]([CH3:23])[C:3]1=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1c1ccccc1
Temperature: 50 °C
Yield: 32 %

Procedure:
A solution of (S)-phenylalanine methyl amide (5.0 g, 28.1 mmol), benzaldehyde (3.14 mL, 30.9 mmol), and p-toluenesulfonic acid monohydrate (535 mg, 2.8 mmol) dissolved in 40 mL of methanol was heated to 50° C. for 24 hours. Concentration of the reaction mixture followed by silica gel chromatography (3:1 ethyl acetate:hexanes) afforded the title compound in 32% yield (2.38 g, 8.9 mmol) and the more quickly eluting (2R, 5S) isomer in 58% yield (4.32 g, 16.2 mmol). IR (film) 3479, 3331, 3085, 3061, 3030, 2921, 2861, 2242, 1959, 1891, 1815, 1696, 1603, 1494, 1475, 1436, 1370, 1335, 1282, 1206, 1098, 1028, 1002, 920.0, 760.0, 743.2, 700.7 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.25 (m, 8H, ArH), 6.82 (m, 2H, ArH), 5.10 (m, 1H, NCHN), 3.84 (dd, J=4.5, 4.5 Hz, 1H, CHCO), 3.22 (dd, J=14.1, 5.7 Hz, IH, one of CH2Ph), 3.11 (dd, J=14.1, 4.5 Hz, 1H, one of CH2Ph), 2.52 (s, 3H, CH3), 1.87 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 174.6, 138.8, 137.1, 130.1, 129.7, 129.2, 129.1, 127.4, 127.1, 60.7, 37.2, 27.5; HRMS (CI) exact mass calc'd for (C17H18N2O) requires m/z 266.1419, found m/z 266.1421. [α]D=−101.8 (c=1.0, CHCl3). The enantiopurity of the catalyst was confirmed (>99% ee) by HPLC analysis (AD column, 10% isopropanol in hexanes, 1 mL/min, 254 nm); (2S, 5S) isomer tr=17.1 min, (2R, 5R) isomer tr=15.5 min.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]2[C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][N:26]=[C:10]12.[C:31]([N:38]1[CH:42]=[CH:41]N=[CH:39]1)(N1C=CN=C1)=[O:32].[C:43]1(=[O:53])[C:47]2(CCNC[CH2:48]2)[CH2:46][CH2:45][NH:44]1>O1CCCC1.ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]2[C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:25][N:26]=[C:10]2[C@H:9]([NH:8][C:31]([N:38]2[CH2:39][CH2:48][C:47]3([C:43](=[O:53])[NH:44][CH2:45][CH2:46]3)[CH2:41][CH2:42]2)=[O:32])[CH2:15][CH2:14]1
Reactant: O=C1NCCC12CCNCC2
Reactant: CC(C)(O)c1nnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(O)c1nnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)N1CCC2(CCNC2=O)CC1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Triethylamine (18 μL, 0.126 mmol) was added to a solution of the bis hydrochloride salt of 2-[(6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl]propan-2-ol (20 mg, 0.051 mmol) and 1,1′-carbonyldiimidazole (14 mg, 0.09 mmol) in tetrahydrofuran (1.0 mL) at 0° C. After 10 min, additional 1,1′-carbonyldiimidazole (8.0 mg, 0.05 mmol) was added. After 30 min, the hydrochloride salt of 2,8-diazaspiro[4.5]decan-1-one (12 mg, 0.06 mmol) and dichloromethane (1.0 mL) were added and the mixture was heated to 60° C. After 16 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (20 mg). MS 503.2570 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:11](N)(=O)[CH3:12]>C(O)C>[CH3:11][C:12]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: NC(=O)c1ccccc1N
Reactant: CC(N)=O
Solvent: CCO
Product: Cc1nc2ccccc2c(=O)[nH]1
Temperature: 180 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A mixture of 2-amino benzamide (20 g, 0.147 mol) and acetamide (43 g, 0.735 mol) was heated to 180° C. for 20 h. The dark brown reaction mixture was cooled and suspended in ethanol (200 ml). After stirring for 2 h, it was filtered and dried under suction to afford 11 g (47%) of the titled compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]([C:4]12[CH2:13][C:8]3([OH:14])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([Cl:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3].CN(C)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]([C:4]12[CH2:13][C:8]3([O:14][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([Cl:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(Cl)C12CC3CC(O)(C1)CC(C(=O)Cl)(C3)C2
Agent: CN(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC12CC3CC(C(=O)Cl)(C1)CC(C(=O)Cl)(C3)C2

Procedure:
The 1,3-dichloroformyl-5-hydroxyadamantane was dissolved in methylene chloride. To this solution were added a small amount of trimethylamine, and then an eguimolar amount of trimethylsilyl chloride. Reaction was carried out at room temperature to obtain 1,3-dichloroformyl-5-trimethylsiloxyadamantane.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].CCN(C(C)C)C(C)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1.[C:50](N1C2C=CC=CC=2N=N1)(=[NH:52])[NH2:51]>CN(C=O)C>[C:39]1([CH3:49])[CH:40]=[CH:41][C:42]([S:45]([OH:48])(=[O:46])=[O:47])=[CH:43][CH:44]=1.[C:50]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)(=[NH:51])[NH2:52]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: N=C(N)n1nnc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(C(=N)N)CC1
Reaction time: 24 h

Procedure:
Morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride (0.2 g, 0.47 mmol) was dissolved in 3 mL of DMF and 2 equiv of Hunig's base was added followed by 1-carbamimidoyl-1,2,3-benztriazole p-toluenesulfonate (0.16 g, 0.47 mmol). The reaction was stirred 24 hours at which time the solvent was removed in vacuo. The resulting paste was purified by preparative HPLC to give the title compound; MS, m/z 434, M+1-p-toluene sulfonate).
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.CN(C(O[N:41]1N=N[C:43]2C=CC=N[C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(N)C>CN(C=O)C.C1COCC1>[CH2:42]([NH:41][C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8])[CH3:43]
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To a stirred solution of 3-Fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 6, 0.2 g, 0.391 mmol) in dry DMF (3 mL) was added HATU (0.223 g, 0.58 mmol), HOBt (0.06 g, 0.43 mmol), DIPEA (0.102 g, 0.79 mmol) and 2M solution of ethyl amine in THF (2 mL) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×30 mL). Combined organic layer was washed with brine (2×20 mL), saturated solution of lithium chloride (2×20 mL), water (20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1% methanol in DCM to afford off white solid (0.20 g, 64%). 1H-NMR (400 MHz, CDCl3) δ: 1.15 (t, 3H, J=7.28 Hz), 2.67-2.78 (m, 2H), 2.84-2.96 (m, 2H), 3.22-3.26 (m, 1H), 3.28-3.35 (m, 2H), 3.67 (d, 1H, J=17.24 Hz), 4.07 (d, 1H, J=17.2 Hz), 5.43 (bs, 1H), 7.56 (d, 2H, J=8.36 Hz), 7.64-7.66 (m, 4H); LC-MS (m/z): [M−H] 535.00.