Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:18]=[C:19](C)[CH:20]=1)[O:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:8].[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:3]=[CH:2][CH:20]=[CH:19][CH:18]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(COc1ccccc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 89 %

Procedure:
A mixture of 6-(2-phenoxyacetylamino)-n-hexanoic acid (made in analogy to Intermediate 15, 3.15 g, 11.9 mmol, 1.1 eq), 2-(m-nitrobenzenesulfonyl)ethanol (2.5 g, 10.8 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in 100 mL of benzene was refluxed overnight with Dean-Stark trap. Thereafter water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure. The residual oil was purified by column chromatography (1% MeOH in CH2Cl2) to give 4.6 g (89%) of 6-(2-phenoxy-acetylamino)-n-hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1>CN(C=O)C>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:8]([C:7]3[CH:6]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=4)[CH2:5][C:4](=[O:21])[NH:3][C:2]=3[CH3:1])=[O:9])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.1 %

Procedure:
The product of step 2 (450 mg, 1.60 mmol, 1 equiv) was combined with 1H-indazol-5-amine (212 mg, 1.60 mmol, 1 equiv) and polystyrene-bound carbodiimide (1.78 g, 1.1 mmol/g, 1.97 mmol, 1.2 equiv) in 6 mL DMF. The reaction mixture was stirred for 22 hours at room temperature. The resin was removed by filtration and washed alternately with CH2Cl2 and MeOH, ending with CH2Cl2. The volatile solvents were removed en vacuo and water was added, providing a solid residue. The residue was triturated with ethyl acetate, affording 140 mg of the title compound as a white crystalline solid. MS (ES+) m/e 397 [M+H]+
Reaction SMILES: [CH:1]1[CH:6]=[C:5](Cl)[CH:4]=[C:3]([C:8]([O:10]O)=[O:9])[CH:2]=1.C([O-])(O)=O.[Na+].C([CH:25]([O:32][C:33]([NH:35][CH2:36][C:37]1([CH2:43][C:44]([OH:46])=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:8]([O:10][CH:25]([O:32][C:33]([NH:35][CH2:36][C:37]1([CH2:43][C:44]([OH:46])=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CC1(CNC(=O)OC(C(=O)c2ccccc2)c2ccccc2)CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
mCPBA (77%, 2.07 g, 9.24 mmol) and NaHCO3 (0.78 g, 9.24 mmol) was added to a solution of 1-{[(α-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid (15) (1.89 g, 4.62 mmol) in 40 mL of CH2Cl2 at room temperature and the resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified with citric acid, extracted with CH2Cl2 and the organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford 960 mg (49%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:26]([C:25]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[CH3:19])=[O:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1cnccc1C(=O)O
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)c2ccncc2C)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.7 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (0.1 g, 0.411 mmol), 3-methylpyridine-4-carboxylic acid (0.056 g, 0.411 mmol), N,N′-dicyclohexylcarbodiimide (0.093 g, 0.452 mmol) and 4-dimethylaminopyridine (0.055 g, 0.452 mmol) in dry dichloromethane (2.0 ml) were stirred at room temperature for 4 h. To the reaction mixture was added 10 ml of water and the product extracted with dichloromethane (10 ml×3). Combined dichloromethane layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 7 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-3-methylpyridine-4-carboxamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 10.05 (bs, 1H), 8.7 (t, 1H), 8.45-8.55 (m, 2H), 7.4 (d, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 7.0 (d, 1H), 4.6 (d, 1H), 3.72-3.85 (m, 3H), 3.4-3.6 (m, 3H), 3.1-3.2 (m, 3H), 3.0 (s, 3H), 2.4 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH3:34])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-hydroxytetrahydrofuran-3-yloxy)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>C(OCC)(=O)C.CN(C)C=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22]([CH2:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])=[O:23]
Reactant: O=C(CCl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)OC(C)(C)C
Reaction time: 3.5 h
Yield: 90.2 %

Procedure:
To a suspension of tert-butyl 2-hydroxyimino-3-oxobutyrate (46.8 g) and potassium carbonate (51.8 g) in ethyl acetate (70 ml) and N,N-dimethylformamide (70 ml) was added 2,2,2-trichloroethyl chloroacetate (56.5 g), and the mixture was stirred at 45° to 48° C. for 3.5 hours. After the insoluble inorganic substance was filtered off, to the filtrate were added water and ethyl acetate. The separated ethyl acetate solution was washed with water and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave tertbutyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyrate (84.9 g).
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].Cl[P:9]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12]>BrCCBr.C(OCC)C>[CH2:18]([N:15]([P:9]([N:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[CH2:16][CH3:17])[CH3:19]
Reactant: CCN(CC)P(Cl)N(CC)CC
Reactant: C[Si](C)(C)CCl
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Product: CCN(CC)P(C[Si](C)(C)C)N(CC)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
In a 50 ml three-necked flask equipped with a dropping funnel and a magnetic stirrer, 0.36 g (14.8 mmol) of magnesium and 10 ml of anhydrous diethyl ether were charged at room temperature in a nitrogen gas atmosphere. After several drops of 1,2-dibromoethane were added so as to activate magnesium, 2.0 ml (14.2 mmol) of chloromethyltrimethylsilane were added dropwise carefully to avoid heat build-up. When the reaction solution was stirred for 1 hour while it was heated mildly with a drier, the solution darkened. Then, after the solution was cooled to −78° C., 3.0 g (14.2 mmol) of chlorobis(diethylamino)phosphine synthesized in (a) were added dropwise to the solution, and the resultant mixture was then returned to room temperature and refluxed for 1 hour. The resulting crystals were filtered off, washed with anhydrous diethyl ether, and purified by vacuum-distillation (0.2 kPa, 74.3-79.5° C.) to obtain 2.29 g of bis(diethylamino)(trimethylsilylmethyl)phosphine in the form of a colorless transparent liquid; the yield was 62%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:22])[N:3]=1.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:22])[N:3]=2)=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Product: Cc1nc(Nc2ccc(C(C)(C)C)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Using procedures analogous to those already described, (4-tert-Butyl-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine is prepared by condensing 4-chloro-2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline with 4-tert-butylaniline. Mass spec. 436.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O-:10])=O)[C:4]([O:6]C)=[O:5].[NH3:11]>C(Cl)Cl>[CH3:1][O:2][CH:3]([C:8]([NH2:11])=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(OC)C(=O)[O-]
Reactant: N
Solvent: ClCCl
Product: COC(C(N)=O)C(=O)O

Procedure:
A solution of 10.4 g of monomethyl methoxymalonate in 70 ml of methylene chloride was added dropwise at -10° C. to 26 ml of 25 percent aqueous ammonia. After stirring the mixture was evaporated and the residue was dissolved in water and chromato- graphed on a cation exchanger with water. The eluate was concentrated and the residue was triturated with diethyl ether and filtered off. The precipitate was washed with water and dried. There were obtained 8.9 g of methoxymalonamic acid, m.p. 128°-130° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:12][CH:11]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.CC(O)C>[CH2:17]([N:14]([CH2:15][CH3:16])[C:13]1[CH:19]=[CH:20][C:10]([NH:9][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCN(CC)c1ccc(Nc2cc(N)ncn2)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 4-amino-N,N-diethylaniline (0.82 mL, 5 mmol), 2-propanol (5 mL) and HCl conc. (0.225 mL, ˜2.5 mmol) is shaken for 36 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-saturated K2CO3-solution and ethyl acetate. The precipitate thus formed is filtered off, washed with H2O and ethyl acetate and dried in vacuo to afford the title compound. Greyish solid, HPLC: tR=2.37 min (gradient F), ESI-MS: 258.3 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[CH:10][C:5]2=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[CH:19]12[O:24][CH:22]([CH2:21][CH2:20]1)[CH2:23][N:17]([C:4]1[N:3]=[C:2]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:7]=[C:6]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:9]=[CH:10][C:5]=13)[CH2:18]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(-c3ccccc3)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(-c4ccccc4)c3n2)cc1

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2.5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 mmol) are dissolved in a microwave vial in DME (18 mL). Na2CO3 (2.5 mL, 2M in water) is added along with a catalytic amount of tetrakis triphenylphosphine palladium. The mixture is heated in a sealed tube under microwave irradiation at 185 C for 40 min. The mixture is diluted with 50 mL EtOAc and washed with a saturated solution of NaHCO3 (2×50 mL). The aqueous layers are extracted with EtOAc (50 mL) and the combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. Purification gives the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>O1CCCC1.C(N(CC)CC)C>[N+:22](=[C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]1=[O:12])=[N-:23]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=C1C(=O)Oc2ccccc2C1=O
Yield: 70.6 %

Procedure:
To a 100 ml round-bottom flask fitted with a mechanical stirrer, nitrogen inlet and bubbler was charged 4-hydroxycoumarin (3.1 g, 18.8 mmol) dissolved in dry terahyrofuran (THF) (21.6 g) and triethylamine (1.8 g). A solution of p-toluenesulfonyl azide (5.3 g, 28.3 mmol) in dry THF (14.4 g) was then added to this solution dropwise over a period of 15 minutes. The reaction was continued until all of 4-hydroxycoumarin had reacted as monitored by high pressure liquid chromatography (HPLC) (ca. 2.0 hours). The precipitated reaction product was filtered in a small Buchner funnel and the filtrate was packed in powdered dry ice to produce a second crop of crystals, which was also isolated by filtration. The combined filtercakes were dried overnight under house vacuum at 60° C. to obtain orange colored crystals of 3-diazo-4-oxocoumarin; yield 2.5 g (70.6% yield). The crude product was further purified by dissolving it in 75.0 g of acetone and precipitating by pouring into 150.0 g ice-water yielding pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[S:19][C:20]3[C:26]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:25][CH:24]=[C:23]([O:33][CH3:34])[C:21]=3[N:22]=2)=[O:17])[CH:11]([OH:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:35])[CH:12]([NH:15][C:16]([C:18]2[S:19][C:20]3[C:26]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:25][CH:24]=[C:23]([O:33][CH3:34])[C:21]=3[N:22]=2)=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3O)nc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3=O)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of 0.56 g 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in 10 ml dimethylsulfoxide were added 0.93 ml triethylamine, 10 ml dichlotomethane and a solution of 0.58 g sulfur trioxide pyridine complex in 8 ml dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. Extraction with water/ ethylacetate and chromatography on silicagel with dichloromethane/methanol 97:3 yielded 0.49 g (87%) 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester as yellow solid; M.p.: 95–97° C.; MS (ISP): m/e=505 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1.C(Cl)Cl.[CH:18]([C@@:21]1([C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:25][C@H:24]([NH2:26])[CH:23]=[CH:22]1)([CH3:20])[CH3:19].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]([C@@:21]1([C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=3)[CH2:33][CH2:34]2)=[O:28])[CH2:25][C@H:24]([NH:26][CH:8]2[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH:3]2[O:2][CH3:1])[CH:23]=[CH:22]1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)N1CCC(=O)C(OC)C1
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)C=C[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(N[C@@H]2C=C[C@@](C(=O)N3CCN(c4cc(C(F)(F)F)ccn4)CC3)(C(C)C)C2)C(OC)C1
Reaction time: 8 h

Procedure:
The title compound was prepared by taking ethyl 3-methoxy-4-oxopiperidine-1-carboxylate (148 mg, 0.000737 mol) in Methylene chloride (3 mL, 0.04 mol) and adding (1S,4S)-4-isopropyl-4-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopent-2-en-1-amine (0.31 g, 0.00081 mol;), Triethylamine (0.8 mL, 0.006 mol;) and Sodium triacetoxyborohydride (0.312 g, 0.00147 mol). The reaction was stirred overnight. The reaction was quenched with (20 mL) NaOH and extracted with (3×10 mL) CH2Cl2. The organic layers were collected, dried over MgSO4 and concentrated in vacuo. The crude was taken on to the next step as-is (410 mg, 98%). MS calculated for C28H40F3N5O4: (M+H) 568; found 568.1.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]3[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][N:21]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:20][C@H:19]3[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:16]=2)(=[O:9])=[O:10])=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(S(C)(=O)=O)C[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of N-(4-chloro-benzyl)-N-isobutyl-4-((+/−)trans-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (185 mg, 304 μmol) in DCM (5 mL) was added DIPEA (106 μL, 609 μmol) followed by methanesulfonyl chloride (1 mL of a 231 μL, 3 mmol solution in 10 mL of DCM) and the reaction stirred at room temperature for 1 hour. Saturated aqueous NaHCO3 was then added, extracted with DCM, filtered through a phase separator and concentrated to give N-(4-Chloro-benzyl)-N-isobutyl-4-((+/−)trans-1-methanesulfonyl-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (271 mg, 100%). LCMS (m/z, Method A) ES+ 709 [M+23]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.5 %

Procedure:
To a solution of 3-bromophenol (2 g, 11.56 mmol) in dimethylformamide (10 mL) was added sequentially cesium carbonate (11.30 g, 34.7 mmol) and ethyl 4-bromobutanoate (1.66 mL, 11.6 mmol) at room temperature. The heterogeneous reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was partitioned between ether (75 mL) and water (50 mL). The ether layer was collected, washed with brine (50 mL), dried over sodium sulfate, and concentrated to yield ethyl 4-(3-bromophenoxy)butanoate (3.3 g, 11.5 mmol, 99% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.25-1.29 (m, 3H), 2.07-2.15 (m, 2H), 2.48-2.54 (m, 2H), 3.99 (t, J=6.16 Hz, 2H), 4.13-4.15 (m, 1H), 4.16-4.19 (m, 1H), 6.80-6.84 (m, 1H), 7.05 (t, J=1.98 Hz, 1H), 7.06-7.09 (m, 1H), and 7.11-7.16 (m, 1H).
Reaction SMILES: [C:1]([O:9][N:10]=[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:9][N:10]=[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=NOC(=O)c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CON=C(c2ccccc2)C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8 g (20 mmol) of tert-butyl 2-[[(benzoyloxy)imino](phenyl)methyl]-1-pyrrolidinecarboxylate dissolved in 400 ml of a mixture of 30% trifluoroacetic acid in dichloromethane are introduced into a 500 ml round-bottomed flask equipped with a magnetic stirrer, and the mixture is stirred for 4 hours at room temperature. After evaporating the reaction medium to dryness under reduced pressure, the residue is diluted with aqueous ammonia and dichloromethane, and the aqueous phase is separated out and extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulfate and evaporating the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]1CC2C(CC(CC2)=O)CC1>>[C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[CH2:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC2CCCCC2C1
Reactant: CC(C)(C)C1CCC(=O)CC1
Product: C=C1CCC(C(C)(C)C)CC1

Procedure:
The title compound was prepared as described in Example 45A substituting 4-tert-Butyl cyclohexanone, commercially available from Aldrich, for 2-decalone.