Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2](F)(F)[C:3]([C:8]([F:11])([F:10])[F:9])=[C:4](F)[O:5][CH3:6].C(O)(=O)C.[CH:18]([NH2:20])=[NH:19].[OH-].[Na+]>O.ClCCl>[F:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[C:4]([O:5][CH3:6])[N:20]=[CH:18][N:19]=1
Reactant: N=CN
Reactant: COC(F)=C(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1ncnc(F)c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a rapidly stirred mixture of 1,1,1,3-tetrafluoro-2-(trifluoromethyl)-4-oxapent-2-ene (N-1) (10.0 g, 47.15 mmol) and formamidine acetate (7.37 g, 70.73 mmol) in a mixture of water (50 mL) and dichloromethane (50 mL) at 0° C., a solution of sodium hydroxide (7.54 g, 189 mmol) in water (40 mL) is added dropwise and the resulting mixture is stirred for 30 min after complete addition. The dichloromethane layer is separated, washed with 1M aqueous HCl solution and water, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford 4-fluoro-6-methoxy-5-(trifluoromethyl)pyrimidine (N-2) as a yellow solid. The product is used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18]C)([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2].[B].O>C(Cl)Cl>[N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][OH:18])([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: COCC1(C)CCc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Agent: [B]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(CO)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
9.5 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethylchroman was dissolved in 80 ml of methylene chloride and 31.4 ml of a 1M boron tribromidemethylene chloride solution was added under a nitrogen gas flow at 0° C., followed by stirring at 0° C. for 3 hours. After the completion of the reaction, the reaction solution was poured into water and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 4.5 g of the objective product.
Reaction SMILES: [CH2:1]([C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH2:7][NH:8]1)[N:5]([CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])[C:4]2=[O:28])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:7][NH:8]1)[N:5]([CH2:17][C:18]([OH:20])=[O:19])[C:4]2=[O:28])[CH3:2]
Reactant: CCC12CCC(c3ccccc3)(CN1)N(CC(=O)OCc1ccccc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC12CCC(c3ccccc3)(CN1)N(CC(=O)O)C2=O

Procedure:
A mixture of benzyl (4-ethyl-3-oxo-1-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)acetate from Step A (127 mg, 0.336 mmol) and 10% Pd/C (20 mg) in MeOH (5 mL) was stirred under a balloon of hydrogen. The reaction mixture was filtered and concentrated in vacuo to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:8].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[C:6]([C:7]([NH:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][O:17][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15]2)=[O:8])[C:5]([CH3:19])=[N:4][CH:3]=1
Reactant: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of trans-5-chloro-N-(4-hydroxymethyl-cyclohexyl)-2-methyl-nicotinamide (Intermediate E, step 2) (100 mg, 0.354 mmol) and pyridine (3.6 ml) in dry DCM (3.5 ml) under nitrogen was cooled to approx. 0° C. using an ice-water bath. Methanesulfonyl chloride (0.030 ml, 0.389 mmol) was added dropwise. The reaction mixture was allowed to warm to room temp and stirred at this temp for 4 hours. The reaction was quenched by the addition of sat. NH4Cl at room temp and then extracted with diethyl ether (3×20 ml). The Et2O extracts were combined, washed with sat brine (20 ml), dried (MgSO4), filtered and evaporated to give the title compound as a colourless solid. LCMS 361.2/363.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.52 (1H, d), 7.65 (1H, d), 5.68 (1H, br d), 4.09 (2H, d), 3.96 (1H, m), 3.04 (3H, s), 2.65 (3H, s), 2.21 (2H, m), 1.96 (2H, m), 1.79 (1H, m), 1.27 (4H, m).
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:2][CH2:3][CH3:4].B>C1COCC1.C(OCC)C>[CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1cccc(OC)c1OC
Agent: B
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCNCc1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
N-Butyl-2,3-dimethoxybenzamide (5.37 g, 22.6 mmol) was dissolved in freshly distilled THF (230 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (11 mL) and the mixture was stirred for four hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL) and washed with aqueous 2 M K2CO3 (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (160 g) with ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol in ethyl acetate as the eluent yielded 2.74 g (54%) of a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[C:13]2[CH:16]([F:18])[F:17])[CH:11]=[CH:10][CH:9]=[N:8]3)=[CH:4][CH:3]=1.[CH2:19]([Li])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([C:13]1([CH:16]([F:18])[F:17])[C:12]2[CH:11]=[CH:10][CH:9]=[N:8][C:7]=2[NH:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:14]1=2)[CH2:20][CH2:21][CH3:22]
Reactant: [Li]CCCC
Reactant: FC(F)c1c2cc(Cl)ccc2nc2ncccc12
Solvent: C1CCOC1
Product: CCCCC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Temperature: -78 °C
Reaction time: 5 h
Yield: 2.1 %

Procedure:
Method GG: A solution of 7-chloro-9-difluoromethyl-4-azaacridine (396 mg 1.5 mmol) in THF (10 mL) was cooled under N2 to −78° C. n-Butyl lithium was added dropwise over 15 min and the reaction mixture was stirred at −78° C. for 5 h. The reaction was quenched with sat. NH4Cl solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried and concentrated. Column chromatography (SiO2, 10% EtOAc-hexane-1% Et3N) afforded the desired material 5-Butyl-7-chloro-5-difluoromethyl-5,10-dihydro-benzo[b][1,8]naphthyridine as a viscous yellow oil (10 mg, 2.1%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:7][C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:5][C:4]=2[N:3]=1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:16]1([NH:15][S:12]([C:8]2[C:9]3[CH:10]=[CH:11][C:2]([CH:28]4[CH2:30][CH2:29]4)=[N:3][C:4]=3[CH:5]=[C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(C3CC3)nc2c1
Temperature: 110 °C

Procedure:
A mixture of 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (23 mg, 0.057 mmol), cyclopropaneboronic acid (50 mg, 10 equiv) dppf PdCl2 (8 mg, 20 mol %), potassium carbonate (60 mg) and dioxane (1 mL) was purged with nitrogen and heated at 110° C. for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC to give the desired product, N-cyclopentyl-2-cyclopropyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4C(F)(F)F)[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29]C1C=CC=CC=1C(Cl)=O>>[Cl:29][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:7]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)=[O:28]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Product: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1Cl

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 2-chlorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride. Data: LCMS (M/Z): 356 (M+H); 1H NMR (acetone) δ: 9.51 (br. s., 1H), 8.18 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.2, 2.0 Hz, 1H), 7.60 (dd, J=7.0, 1.7 Hz, 1H), 7.36-7.52 (m, 5H), 5.13 (d, J=4.8 Hz, 1H), 2.32 (quin, J=8.2 Hz, 1H), 1.82-1.92 (m, 1H), 1.63-1.74 (m, 2H), 1.52-1.59 (m, 2H), 1.30-1.40 (m, 1H), 1.07-1.15 (m, 1H), 0.80-0.89 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:25]2[C:26]([CH:31]=O)=[N:27][CH:28]=[CH:29][CH:30]=2)([CH3:24])[CH3:23])=[CH:18][CH:17]=1.[BH-](O[C:43]([CH3:45])=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:18][C:19]1[C:43]([CH2:45][N:14]([CH2:31][C:26]2[C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)([CH3:24])[CH3:23])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:27][CH:26]=[C:25]([CH3:30])[CH:22]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(F)cc2)C2CCNCC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-amino-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 with 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 gave the amine. 1H NMR (CDCl3) δ 1.10 (m, 2H), 1.43 (s+m, 12H), 1.66 (s, 6H), 2.21 (m, 1H), 2.62 (m, 2H), 3.33 (m, 1H), 3.87 (br d, 2H), 6.97 (t, 2H, J=7.5 Hz), 7.11 (dd, 2H, J=9.0, 3.0 Hz), 7.25 (dd, 1H, J=7.5, 3.0 Hz), 7.86 (d, 1H, J=9.0 Hz), 8.46 (d, 1H, J=3.0 Hz).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([C:25]1[C:26]([Cl:35])=[N:27][C:28]3[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>C(#N)C>[Cl:35][C:26]1[C:25]([C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O)ccc21

Procedure:
A solution of tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate 1-7 (2.50 g, 4.91 mmol, 1 equiv) and triethylamine trihydrofluoride (3.60 mL, 22.1 mmol, 4.50 equiv) in acetonitrile (100 mL) was stirred at 23° C. for 20 h. The reaction mixture was concentrated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate (1-8) as a tan colored foam. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J=9.0 Hz), 8.17 (s, 1H), 8.07 (d, 1H, J=8.4 Hz), 7.86 (d, 1H, J=8.1 Hz), 7.77 (br t, 1H, J=8.4 Hz), 7.61 (br t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=2.6 Hz), 6.93 (dd, 1H, J=8.8, 2.6 Hz), 6.55 (s, 1H), 1.26 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:32])[C:18]([C:21]([NH:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:22])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:35])[CH:3]=1.CC[N:38]([CH:42]([CH3:44])[CH3:43])[CH:39](C)C.ClC(Cl)([O:48]C(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1>C1COCC1>[CH:42]1([NH:38][C:39](=[O:48])[NH:1][C:2]2[CH:34]=[CH:33][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:17]([CH3:32])[C:18]([C:21]([NH:23][CH2:24][CH2:25][N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[O:22])=[CH:19][N:20]=5)[S:15][C:8]=34)=[C:4]([F:35])[CH:3]=2)[CH2:43][CH2:44]1
Reactant: Cn1c(C(=O)NCCN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: C1CCOC1
Product: Cn1c(C(=O)NCCN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(NC(=O)NC4CC4)cc3F)c2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
To a suspension of aniline 216 (130 mg, 0.262 mmol) in THF (10 mL) at 0° C. was added DIPEA (0.137 mL, 0.785 mmol) and triphosgene (38.8 mg, 0.131 mmol). The reaction mixture was stirred at 0° C. for 1 hr before cyclopropylamine (0.054 mL, 0.785 mmol) was added and the mixture was stirred for 10 min at 0° C. The reaction mixture was slowly warmed to room temperature and stirred over weekend then partitioned between NaHCO3 saturated solution and EtOAc. The organic layer (suspension) was concentrated, the residue was dry-loaded onto a column (Biotage, MeOH/DCM, 0-25%, SNAP 10 g cartridge), purified twice then triturated with ether and acetone to give title compound 217 (30.4 mg, 0.052 mmol, 20% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 8.59 (d, 1H, J=5.5 Hz), 8.48 (m, 1H), 8.07 (s, 1H), 7.78-7.74 (m, 1H), 7.71 (s, 1H), 7.42 (t, 1H, J=9.0 Hz), 7.25-7.22 (m, 1H), 6.74 (d, 1H, J=5.5 Hz), 6.61-6.60 (m, 1H), 4.22 (s, 3H), 3.62 (t, 4H, J=4.5 Hz), inside 3.38-3.33 (m, 2H), 2.60-2.57 (m, 1H), 2.52-2.46 (m, 6H), 0.71-0.67 (m, 2H), 0.48-0.46 (m, 2H). MS: 580.6 (MH)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(O[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1)(=O)=O.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([O:22][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)On1nnc2ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)On1nnc2ccccc21)OCc1ccccc1
Reaction time: 1 h
Yield: 62.3 %

Procedure:
N-Benzyloxycarbonyl-L-phenylalanine (1.5 g) and triethylamine (0.7 ml) are dissolved in ethyl acetate (15 ml). To the solution is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.1 g) under ice-cooling and the mixture is stirred for 1 hour. After allowing to stand overnight, to the reaction mixture are added ethyl acetate and water. The ethyl acetate layer is separated, washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and to the residue is added ether. The precipitated crystals are separated by filtration to give 1-(N-benzyloxycarbonyl-L-phenylalanyloxy)-1,2,3-benzotriazole (1.3 g), melting point: 120°-125° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21]C)=O)[CH:15]=2)[CH2:10]1)=[O:8].[K].[NH2:24][OH:25].C(O)(=O)C>CO>[OH:25][NH:24][C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:8])[CH2:18][CH2:17]2)=[O:21]
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)c1cccn1C)C2
Reactant: NO
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cccc1C(=O)N1CCc2cc(C(=O)NO)ccc2C1
Yield: 16.2 %

Procedure:
Methyl 2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate in a vial was dissolved in MeOH (1 mL) and hydroxylamine potassium salt (0.682 mL, 1.2 mmol; 1.76 M in MeOH) was added. The solution was shaken at rt for 2 h before acetic acid (0.0682 mL, 1.2 mmol) was added to neutralize the reaction. The solvent was then completely evaporated and to the residue was added DMSO (1.2 mL). After filtration, the solution was purified by prep-HPLC to yield N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (0.0073 g, 16.2%). LC-MS: (AA) ES+ 301; 1H NMR (Methanol-d4, 400 MHz) δ 7.87 (d, J=8.0 Hz, 1 H), 7.72 (d, J=8.0 Hz, 1 H), 6.86 (t, J=1.8 Hz, 1 H), 6.52 (dd, J=3.8, 1.5 Hz, 1 H), 6.12 (dd, J=3.8, 2.5 Hz, 1 H), 4.96 (s, 2 H), 4.07 (t, J=5.8 Hz, 2 H), 3.74 (s, 3 H), 3.11 (t, J=6.0 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:29][Si:27]([CH3:30])([C:23]([CH3:26])([CH3:25])[CH3:24])[O:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2COc2ccc(O)cc21
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 10 g of 2-hydroxy-6,11-dihydrodibenz[b,e]oxepin-11-one in 50 ml of dimethylformamide are added 6.5 g of imidazole and 7 g of t-butyldimethylchlorosilane and the mixture is stirred for 1 hour. After adding 300 ml of toluene, successively washing with water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 13 g of 2-(dimethyl-t-butylsilyloxy)-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 340(M+).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]=[O:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:16]=[O:17].[Br-].C(C1SC2C=CC=CC=2[NH+]=1)C.C(N(CC)CC)C>C(O)C>[OH:17][CH2:16][C:14](=[O:15])[CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:7][CH:8]=1
Reactant: C=O
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Agent: CCc1[nH+]c2ccccc2s1
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCC(=O)CO)cc1

Procedure:
A mixture of 1.1 g (5 mmol) of 3-(4-carbethoxyphenyl)propanal and 150 mg (5 mmol) of paraformaldehyde in 10 mL of ethanol, together with 230 mg (0.9 mmol) of ethyl benzothiazolium bromide and 90 mg (0.9 mmol) of triethylamine, is heated at about 70° C. for 16 hours. The reaction mixture is concentrated in vacuo and the product further purified by chromatography on silica gel, eluting with 15:85 ethyl acetate:hexane, to yield ethyl 4-(4-hydroxy-3-oxobutyl)benzoate as a colorless oil which solidifies upon standing; m.p. 51°-52° C. Anal. calcd for C13H16O4 : C, 66.09; H 6.83. Found: C, 66.29; H, 6.70.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[C:14](=O)[CH2:13][C@@H:12]([CH:16]2[CH2:18][CH2:17]2)[N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCO.O.[NH2:30]N.CCOC(C)=O.C[N:39]([CH:41](OC)OC)C>>[Si:1]([O:8][CH2:9][CH:10]1[C:14]2=[N:30][NH:39][CH:41]=[C:13]2[C@@H:12]([CH:16]2[CH2:17][CH2:18]2)[N:11]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)C(=O)C[C@H]1C1CC1
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)c2n[nH]cc2[C@H]1C1CC1
Temperature: 110 °C
Yield: 87 %

Procedure:
(5S)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-cyclopropyl-3-oxopyrrolidine-1-carboxylate (34) (1.52 g, 4.11 mmol) was dissolved in DMF-DMA (5 mL) and heated to 110° C. for 1 h. The reaction mixture was concentrated under vacuum and to the resulting residue was added EtOH (8 mL) and hydrazine monohydrate (0.99 mL, 20.5 mmol). The resulting solution was stirred at rt for 5 h after which EtOAc (10 mL) was added. The solution was washed with brine (10 mL), dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1) to give 1.41 g (87%) of (4R)-tert-butyl 6-((tert-butyldimethylsilyloxy)methyl)-4-cyclopropyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (35). Retention time (min)=2.086, method [1], MS (m/z) 394.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[N-:12]=[N+:13]=[N-:14].[Na+].CN(C)C=O.O>[Cl-].[NH4+]>[N:12]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: NS(=O)(=O)c1cnccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccncc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
4-Chloro-pyridine-3-sulfonic acid amide (4 g, 20.77 mmol) and sodium azide (13.7 g, 210 mmol) were combined. Anhydrous N,N-dimethylformamide (80 mL) and water (30 mL) were added. The mixture was stirred at 90° C. for 2 h. Upon cooling, the mixture was diluted with saturated aqueous ammonium chloride solution (200 mL). The product was extracted into ethyl acetate (6×200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product, 4-azido-pyridine-3-sulfonic acid amide (3.75 g, 18.83 mmol, 91%), as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.54 (2H, bs), 7.57 (1H, d, J=5.4 Hz), 8.68 (1H, d, J=5.5 Hz), 8.81 (1H, s).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][C:15]1([NH2:19])[CH2:18][O:17][CH2:16]1.[S:20]1(=[O:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][NH:23][CH2:22][CH2:21]1>>[NH2:19][C:15]1([CH2:14][NH:13][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]3[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:20](=[O:31])[CH2:21][CH2:22]3)[N:11]=2)[CH2:18][O:17][CH2:16]1
Reactant: O=S1CCNCc2ccccc21
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NCC1(N)COC1
Product: NC1(CNc2nc(N3CCS(=O)c4ccccc4C3)nc3ccccc23)COC1

Procedure:
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4-dichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.91-7.90 (t, J=7.2, 0.8 Hz, 1 H), 7.81-7.74 (m, 2 H), 7.58-7.54 (m, 1 H), 7.51-7.43 (m, 3 H), 7.16-7.12 (m, 1 H), 5.32-5.28 (d, J=15.2 Hz, 2 H), 4.68-4.53 (m, 6 H), 4.10 (s, 2 H), 3.37-3.34 (m, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:30])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)[C:10](=[O:29])[CH:9]=[CH:8]2)[CH3:2].C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl.CO>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:11]2[C:12]3[C:7](=[N:6][CH:5]=[C:4]([F:30])[C:3]=3[CH2:1][CH3:2])[CH:8]=[CH:9][C:10]2=[O:29])[CH2:20][CH2:19]1
Reactant: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c12
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(N)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[2-(8-ethyl-7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}carbamate (0.234 g, 0.559 mmol) in DCM (2 ml) was added TFA (1 ml) and the reaction was allowed to stirred at rt for 1 h before evaporation of solvent. The residue was dissolved in 1:1 DCM and MeOH (2 ml) and then treated with MP-Carbonate resin until the pH reached 8. The reaction was then filtered, resin washed with MeOH and the filtrate was evaporated to dryness to give a yellow oil (0.176 g, 99%).