Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:21]([OH:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:21]([O:23][CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: O=C(O)c1nn(-c2ccc(Cl)cc2)c2c1CCc1ccccc1-2
Solvent: CC(C)O
Product: CCN(CC)CCOC(=O)c1nn(-c2ccc(Cl)cc2)c2c1CCc1ccccc1-2

Procedure:
A mixture of 10 parts of 1-(4-chlorophenyl)-4,5-dihydro-1H-benz[g]indazole-3-carboxylic acid, 5parts of 2-diethylaminoethyl chloride and 160 parts of anhydrous 2-propanol is heated at reflux for 16 hours. The 2-propanol is then removed under reduced pressure and the resulting residue is partitioned in ether and dilute hydrochloric acid. The aqueous layer is separated and washed twice with ether. It is then made alkaline with cold aqueous sodium hydroxide solution and then extracted with ether. The combined ether extracts are dried over potassium carbonate and the solvent is evaporated to leave a residual free base. This is recrystallized from a mixture of benzene and hexane to give 2-diethylaminoethyl 1-(4-chlorophenyl)-4,5-dihydro-1H-benz[g]indazole-3-carboxylate melting at about 102°-103°C.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])[CH3:7].[H-].[Na+].[CH2:18]=[O:19].[Cl-].[NH4+].Cl>C1COCC1>[CH2:6]([C:8]([CH2:18][OH:19])([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])[CH3:7]
Reactant: CCCCC(CC)C(=O)O
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC(CC)(CO)C(=O)O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
113 ml (0.305 mol) of n-butyllithium (2.7 M in heptane) are added dropwise at 0° C. to a solution of 46 ml of disiopropylamine (0.327 mol) in 320 ml of THF and the mixture is stirred at 0° C. for 30 min (Solution 1). 40 g (0.277 mol) of 2-ethylhexanoic acid are added dropwise at 25° to a suspension of 7 g of NaH 95% (0.277 mol) in 320 ml of THF within approx. 15 min, and the reaction mixture is stirred at 50° C. for 30 min (Solution 2). Solution 1 is added at 0° C. to Solution 2 and subsequently heated to 50° C. for 1.5 h. The clear solution is cooled to 0° C. and admixed with 25 g (0.833 mol) of paraformaldehyde. After 10 min, the mixture is stirred at RT for 18 h. The mixture is admixed with saturated aqueous solution of ammonium chloride and adjusted to pH=1-2 with 6N HCl. The organic phase is removed, the aqueous phase is re-extracted 1× with MTBE and the combined organic phases are concentrated on a rotary evaporator. The yield of pure product is 71% (GC).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:3][CH2:2]1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:11]=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:3][CH2:2]1
Reactant: COC(=O)CCCCCCC(=O)Nc1ccccc1NC1CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCc1nc2ccccc2n1C1CC1
Temperature: 110 °C
Yield: 67.7 %

Procedure:
To a solution of methyl 8-(2-(cyclopropylamino)phenylamino)-8-oxooctanoate (390 mg) in toluene was added a drop of acetic acid. The reaction was heated to 110° C. overnight and concentrated. The residue was purified by biotage column chromatography to give methyl 7-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)heptanoate (249 mg)
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: OB(O)c1ccccc1F
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccccc4F)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 2-fluorobenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 538 ([MH]+).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:16])(=[O:14])=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>O1CCCC1>[C:17]1([CH:15]2[S:12](=[O:14])(=[O:13])[NH:11][CH2:10][CH2:9][O:8][CH2:16]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C(c1ccccc1)S(=O)(=O)NCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=S1(=O)NCCOCC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of N-(2-((Tert-butyldimethylsilyl)oxy)ethyl)-1-phenylethenesulfonamide (717 mg, 2.1 mmol) in tetrahydrofuran (7 mL) at 0° C. was added tetrabutylammonium fluoride (1.0 M in THF) (2.2 mL, 2.2 mmol) dropwise and the reaction was stirred at room temperature for 16 hours. Saturated NH4Cl was then added and the product was extracted with dichloromethane (×2), dried with MgSO4, concentrated and purified by silica gel column chromatography (0-100% EtOAc in heptane) to give 3-phenyl-1,4,5-oxathiazepane 4,4-dioxide (401 mg, 84% yield). (24 g, 70% yield). LCMS (ESI), m/z, 228. [M+H]+. (Reference: P. Hansen, et al. Org. Lett. 2008, 2951).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13](=[O:27])[N:12]([CH3:28])[C:11]=2[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([NH2:37])[CH2:31]1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[NH2:37][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][N:30]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:16]3[C:15](=[O:17])[N:14]([CH2:18][C:19](=[O:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:13](=[O:27])[N:12]([CH3:28])[C:11]=3[N:10]=2)[CH2:31]1
Reactant: Cn1c(=O)n(CC(=O)c2ccccc2)c(=O)c2c1nc(Br)n2Cc1ccccc1
Reactant: NC1CCCCNC1
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cn1c(=O)n(CC(=O)c2ccccc2)c(=O)c2c1nc(N1CCCCC(N)C1)n2Cc1ccccc1
Reaction time: 5 h

Procedure:
7-Benzyl-8-bromo-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione (77B) (227 mg, 0.5 mmol) and azepan-3-ylamine (342 mg, 3 mmol), and triethylamine (0.35 ml, 2.5 mmol) were dissolved in 20 ml of DMSO and the mixture was subjected to microwaves (method F, 100° C., 300 W) for five hours. To the reaction mixture was added 100 ml of water and 100 ml of dichloromethane, and the organic layer was separated and dried over sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=8.77 min.). Evaporation of the solvent afforded the title compound as an yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[N:13])[C:9]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[S:16][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[C:12]([C:10]1[C:9]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[S:16][C:8]=2[C:7]([OH:25])=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[N:11]=1)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2nc(-c3cccc(OC)c3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nc3c(C#N)nc(C(=O)NCC(=O)O)c(O)c3s2)c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A mixture of 4-cyano-7-hydroxy-2-(3-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (34 mg, 0.10 mmole) and glycine (538 mg, 7.16 mmole) in 0.5 M sodium methoxide/methanol (9.5 ml) was refluxed for 21 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 ml) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (7 ml). The suspension was extracted with ethyl acetate and dichloromethane. The organic layers were combined and washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (34 mg). MS: (+) m/z 385.17 (M+1), MS: (−) m/z 383.13 (M−1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:15][CH3:16]>>[O:13]=[C:7]([C:5]1[N:6]=[C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:3][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(C(=O)C(=O)OCC)cs2)cc1

Procedure:
The title compound was prepared from ethyl (2-amino-4-thiazolyl)glyoxylate and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (14.5 mg) with purity >90%. LCMS (pos) m/z 383.2.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([O:16][CH2:17][CH2:18][CH3:19])[CH2:15][C:11]=2[C:10]([C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N-:23]=[N+:24]=[N-:25].[Na+].Cl>CC(O)C.[Br-].[Zn+2].[Br-]>[CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([O:16][CH2:17][CH2:18][CH3:19])[CH2:15][C:11]=2[C:10]([C:20]2[N:23]=[N:24][NH:25][N:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOC1Cc2c(C#N)nn(Cc3ccccc3)c2C1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCOC1Cc2c(-c3nn[nH]n3)nn(Cc3ccccc3)c2C1
Temperature: 90 °C

Procedure:
To a solution of the intermediate from step A (25 mg, 0.089 mmol) in 2-propanol (1 mL) was added water (2 mL), sodium azide (14 mg, 0.222 mmol) and zinc bromide (10 mg, 0.04 mmol). After heating the reaction mixture at 90° C. for 18 hours, it was cooled to room temperature and HCl (3 mL, 3N) was added. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by PTLC (SiO2) using 100% ethyl acetate to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[CH:31][N:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(OC2CCCCC2)cn1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(OC4CCCCC4)cn3)c2CC1)C(F)(F)F
Yield: 65 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (705 mg, 1.66 mmol) and 2-aminomethyl-5-cyclohexyloxy-pyridine (410 mg, 1.99 mmol). Purify the crude mixture by chromatography on silica gel (150 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient) to obtain 7-chloro-6-[(5-cyclohexyloxy-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (520 mg, 65%). MS (APCI+) m/z: 482 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[N:23]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1)=[C:24]=[O:25].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH:15][C:24](=[O:25])[NH:23][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (Intermediate 39) (112 mg, 0.329 mmol) and DCM (3 mL) was added ethyl 4-isocyanatobenzoate (65 mg, 0.340 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.172 mL, 0.986 mmol). The solution was stirred at rt. After 20 minutes, the reaction product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep®pre-packed silica gel column (4 g), eluting with 70% to 90% EtOAc in hexane, to provide the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7]2)(=[O:3])C.[OH-].[Na+].[O-]Cl.[Na+].[O-:21]S([O-])=O.[Na+].[Na+].II.OS(O)(=O)=O>O1CCOCC1.C(Cl)(Cl)(Cl)Cl>[CH3:14][C:9]1([CH3:15])[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([OH:3])=[O:21])[CH:5]=2)[O:10]1
Reactant: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: O=S([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCc2cc(C(=O)O)ccc2O1
Temperature: 65 °C
Yield: 92 %

Procedure:
A solution of 6-acetyl-2,2-dimethylchroman (Compound 215, 2.15 g, 10.5 mmol) and NaOH (2.0 g, 50 mmol) in dioxane (50 mL) and bleach (50 mL, 5.25% NaOCl) was heated at 65° C. for 4 days. Upon cooling to room temperature Na2SO3 was added until an aliquot of this solution remained colorless color when treated with of one drop of a solution of I2 in CCl4. The solution was acidified with H2SO4 (pH 4) and extracted with ether. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (EtOAc:hexanes 1:3) afforded 1.98 g (92%) of 2,2-dimethylchroman-6-carboxylic acid as a light tan solid. 1H NMR δ 7.78 (2H, m), 6.82 (1H, d, J=8.3 Hz), 2.83 (2H, t, J=6.7, Hz), 1.85 (2H, t, J=6.7 Hz), 1.37 (6H, s).
Reaction SMILES: C(OC([NH:6][N:7]=[C:8]([CH2:18][S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)C.[S:27](Cl)(Cl)=O>ClCCCl>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][S:10][C:9]1[S:27][N:6]=[N:7][C:8]=1[CH2:18][S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH3:17]
Reactant: CCOC(=O)CCSCC(CSCCC(=O)OCC)=NNC(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)CCSCc1nnsc1SCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of the hydrazone (7.2 g, 17.6 mmol) in 1,2-dichloroethane (20 mL) was added thionyl chloride (3.9 mL, 53 mmol) at 0° C. and stirred overnight at room temperature. The mixture was concentrated to a volume of 10 mL, diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and then concentrated to dryness, affording 6.47 g of 5-[(2-ethoxycarbonylethyl)thio]-4-[(2-ethoxycarbonylethyl)thiomethyl]-1,2,3-thiadiazole. 1H NMR (CDCl3) δ 1.2-1.3 (m, 6H), 2.60 (t, 2H, J=7), 2.68 (t, 2H, J=7), 2.77 (t, 2H, J=7), 3.24 (t, 2H, J=7), 4.07 (s, 2H), 4.1-4.2 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[Cs+].COCCOC>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.C(OCC)(=O)C.O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1-c1ccc(OC)nc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.35 g (5.89 mmol) of methyl (2-bromophenyl)acetate are introduced together with 1 g (6.55 mmol) of 6-methoxypyridin-3-ylboronic acid and 1.98 g (13.09 mmol) of caesium fluoride into 20 ml of 1,2-dimethoxyethane under argon. After addition of 0.22 g (0.19 mmol) of tetrakis(triphenylphosphine)palladium(0), the reaction mixture is stirred at 100° C. for 4 h. Cooling to room temperature is followed by addition of a mixture of ethyl acetate and water and extraction with ethyl acetate. After the organic phase has been dried over magnesium sulphate and the solvent has been removed in vacuo, the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 1.1 g (68% of theory) of the product are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1>[F:37][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccccc2c2cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 75 %

Procedure:
To a solution of 3-bromo-9-(2-(2-methoxyethoxy)ethyl)-9H-carbazole (3.23 g, 9.3 mmol) in dry THF (50 ml) was added n-BuLi (1.6 M, 8.7 ml, 13.9 mmol) at −78° C. The resulting mixture was stirred for 50 min at −78° C. and then added with N-fluorobenzenesulfonimide (5.6 g, 18.6 mmol). The reaction mixture was allowed to warm to rt and stirred for 2 h before quenched with ammonia chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to give compound 5 in 75% yield. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=7.6 Hz, 1H), 7.73 (dd, J=2.4 Hz, J=8.8 Hz 1H), 7.50-7.44 (m, 2H), 7.39 (dd, J=4.4 Hz, J=8.8 Hz, 1H), 7.25-7.17 (m, 2H), 4.49 (t, J=6.4 Hz, 2H), 3.86 (t, J=6.4 Hz, 2H), 3.52-3.50 (m, 2H), 3.43-3.41 (m, 2H), 3.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.6, 156.2, 141.4, 137.1, 126.3, 123.4, 123.3, 122.6, 122.6, 120.6, 119.1, 113.6, 113.3, 109.7, 109.6, 109.2, 106.1, 105.9, 72.1, 71.0, 69.4, 59.2, 43.4. HRMS (MALDI-TOF) m/z Calcd for C17H18FNO2 287.1316 Found 287.1314[M]+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Yield: 13.6 %

Procedure:
In a similar manner to Example 1, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (51.5 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (46.3 mg) to obtain 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-8-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (8.6 mg, 14%).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1ccc2ccccc2n1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.71 min.; [M+H]+: 379.04 g/mol.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]([OH:9])=O)[CH:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:3]1.[N+]([O-])(O)=O.[N+:19]([O:22][CH2:23][CH2:24][NH2:25])([O-:21])=[O:20]>>[N+:19]([O:22][CH2:23][CH2:24][NH:25][C:7]([CH:5]1[CH:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:21])=[O:20]
Reactant: O=C1NC(C(=O)O)C(c2cccs2)O1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccs2)O1
Yield: 26.9 %

Procedure:
A procedure similar to that described in Example 19 was repeated, but using 500 mg of 2-oxo-5-(2-thienyl)oxazolidine-4-carboxylic acid and 480 mg of N-(2-nitrooxyethyl)amine nitrate, to obtain 190 mg of the title compound as pale yellow plates, melting at 101°-103° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]([N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=O.B>O1CCCC1>[NH2:5][CH2:3][CH:2]([OH:1])[CH:6]([N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(c1ccccc1)C(c1ccccc1)C(O)C(N)=O
Agent: B
Solvent: C1CCOC1
Product: CN(c1ccccc1)C(c1ccccc1)C(O)CN
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A solution of (2RS,3RS)-2-hydroxy-3-[methyl(phenyl)amino]-3-phenylpropanamide (226 mg, 0.836 mmol) in dry tetrahydrofuran (2 mL) under nitrogen was treated slowly with a solution of borane (1.0 M in tetrahydrofuran, 4.20 mL, 4.20 mmol), and the resulting solution was stirred at 70° C. for 1 hour. After cooling in an ice bath, the reaction mixture was quenched with methanol (1 mL), followed by an aqueous hydrochloric acid solution (1N, 1 mL). The resulting mixture was stirred at 50° C. for 20 minutes. All volatiles were removed under reduced pressure. Water (10 mL) was added, and mixture was made alkaline using saturated aqueous potassium carbonate solution, and then extracted with ethyl acetate (15 mL). The organic layer was washed with water, brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure to yield 201 mg (94%) (1RS,2SR)-3-amino-1-[methyl(phenyl)amino]-1-phenylpropan-2-ol as a colorless oil. This oil was dissolved in ethanol (1 mL) and treated with a solution of hydrochloric acid (0.5 mL, 4M in 1,4-dioxane). All volatiles were again removed under reduced pressure. The resulting white solid was recrystallized (warm isopropanol/ethyl ether/−20° C.) to yield 225 mg (82%) of (1RS,2SR)-3-amino-1-[methyl(phenyl)amino]-1-phenylpropan-2-ol hydrochloride as a white powder. MS (ESI) m/z 257.0 ([M−H]+); HRMS: calculated for C16H20N2O+H, 257.1648; found (ESI, [M+H]+), 257.1642.