Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.CO>[Pd]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)(=[O:11])=[O:12])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)CCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)CCc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To 1-nitro-4-(4-(trifluoromethyl)phenethylsulfonyl)benzene (3.99 g, 0.0111 mol) in methanol (84 mL, 2.1 mol) under argon was added 10% palladium on carbon. The reaction mixture was stirred under hydrogen overnight, filtered over Celite, concentrated and purified on silica gel (hexane-EtOAc) to give 3.13 g of a white solid. LCMS: M+330.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[Cl:25][C:26]1[C:27](F)=[CH:28][C:29]([F:46])=[C:30]([S:32]([N:35]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=2)COC)(=[O:34])=[O:33])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[Cl:25][C:26]1[C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=2[CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:28][C:29]([F:46])=[C:30]([S:32]([NH:35][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=2)(=[O:34])=[O:33])[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(F)(F)F)ccc2O)CC1
Reactant: COCN(c1ccc(F)cn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(Nc1ccc(F)cn1)c1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2C2CCNCC2)cc1F
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 4-[2-hydroxy-5-(trifluoromethyl)phenyl]piperidine-1-carboxylate (Preparation 317, 51 mg, 0.15 mmol), 5-chloro-2,4-difluoro-N-(5-fluoropyridin-2-yl)-N-(methoxymethyl)benzenesulfonamide (Preparation 349, 50 mg, 0.1 mmol) and potassium carbonate (28 mg, 0.20 mmol) in anhydrous dimethyl sulfoxide (2 mL) was heated at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a light yellow thick oil, which was used in the next step without further purification. The residue was diluted with dichloromethane (2 mL), trifluoroacetic acid (210 uL, 2.7 mmol) was added and solution stirred at room temperature for 18 hours. The reaction solution was concentrated in vacuo and purified by preparative HPLC to afford the title compound as a white powder, 55.3 mg (as the trifluoroacetic acid salt)
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:23]=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.C([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO[C:39]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C@@H](O)C1)(=O)C(C)C>>[C:1]([NH:9][C:10]1[CH:23]=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19][O:20][C:39]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1
Agent: N#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound was prepared from N4 -benzoyl-2'-deoxycytidine by the same procedure used for the preparation of N2 -isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]([O:21][CH3:22])[CH:6]1[CH2:10][S:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[N:7]1.[CH3:23][N:24](C=O)[CH3:25]>>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][O:4][CH:5]([O:21][CH3:22])[CH:6]1[CH2:10][S:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[N:7]1
Reactant: CN(C)C=O
Reactant: COC(OCCBr)C1CSC(c2nc3ccc(O)cc3s2)=N1
Product: COC(OCCN(C)C)C1CSC(c2nc3ccc(O)cc3s2)=N1
Reaction time: 28 h

Procedure:
To a vial containing 2-(4-((2-bromoethoxy)(methoxy)methyl)-4,5-dihydrothiazol-2-yl)benzo[d]thiazol-6-ol (16 mg) in DMF (200 uL) dimethylamine (40 uL of 2M in THF) was added. After 28 hours at room temperature, the reaction was purified by preparative RP-HPLC to yield 8 mg. 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=9.2, 1H), 7.14 (d, J=2.2, 1H), 6.97 (d, J=8.9, 1H), 4.74-4.59 (m, 2H), 4.12-3.78 (m, 1H), 3.21 (dd, J=7.2, 14.9, 1H), 3.10 (s, 2H), 2.63 (s, 5H), 1.29 (t, J=7.3, 1H). mass (MH+) calc and found 368.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ncc(C)s2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 15) (100 mg, 0.23 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1M , 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.96 (1H, d, J=1.7 Hz), 7.95 (2H, d, J==8.0 Hz), 7.65 (2H, d, J=8.0 Hz), 7.64 (1H, s), 7.53 (1H, dd, J=1.7, 8.0 Hz), 7.46 (1H, d, J=8.0 Hz), 6.59 (1H, t, J=4.5 Hz), 2.50 (3H, s), 2.39 (2H, d, J=4.5 Hz), 1.27 (6H, s).
Reaction SMILES: Br[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH:6]=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:8]([N:15]1[CH:2]2[CH:6]1[CH2:5][CH2:4][C:3]2=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC=C1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: O=C1CCC2C1N2Cc1ccccc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2-bromocyclopent-2-enone (1.00 g, 6.21 mmol) in H2O (25 mL), tetrabutylammonium bromide (400 mg, 1.24 mmol) and benzyl amine (790 mg, 7.45 mmol) were added at room temperature. The reaction mixture was stirred for 24 hours and then extracted with EtOAc (100 mL). The organic layer was separated, washed with brine, and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 30% EtOAc/Hexanes afforded 6-benzyl-6-azabicyclo[3.1.0]hexan-2-one. MS ESI calc'd. for C12H13NO [M+H]+ 188. found 188.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[CH:3]=1.[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2B2OC(C)(C)C(C)(C)O2)[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(=O)OCC.C(Cl)Cl>[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[C:2]2[C:7]3[N:8]=[CH:9][N:10]=[CH:11][C:6]=3[C:5](=[O:12])[N:4]([CH3:13])[CH:3]=2)[CH2:15][CH2:16]1
Reactant: Cn1cc(Br)c2ncncc2c1=O
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2ncncc2c1=O
Temperature: 100 °C
Yield: 33.7 %

Procedure:
The title compound of step 3 (100 mg, 0.42 mmol), the title compound of Example 90, step 1 (147 mg, 0.42 mmol), Pd(dppf)Cl2 (62 mg, 0.08 mmol), K3PO4 (221 mg, 1.04 mmol) in dioxane (4 mL) and H2O (0.5 mL) was purged with N2 and heated at 100° C. for 18 h. Following CH2Cl2 extractive work up, silica gel chromatography (PE:EA=2:1˜0:1) and preparative HPLC, the title compound (54.57 mg, yield: 34.2%) was obtained as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.54 (s, 1H), 9.30 (s, 1H), 8.18 (s, 1H), 7.93 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 3.91 (d, J=6.8 Hz, 2H), 3.61 (s, 3H), 3.20 (s, 3H), 0.94-0.92 (m, 1H), 0.35-0.30 (m, 2H), 0.10-0.06 (m, 2H). LCMS: 386.0 (M+H)+
Reaction SMILES: C(O[C@H]1C[C@H]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])CN(C(OCC2C=CC=CC=2)=O)C1)(=O)C1C=CC=CC=1.[Si:34]([O:41][C@@H:42]1[CH2:47][C@@H:46](O)[CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>>[C:20]([O:19][C:17]([NH:16][C@H:46]1[CH2:47][C@@H:42]([O:41][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:36])[CH3:35])[CH2:43][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[CH2:45]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1

Procedure:
Followed method to synthesis of (3S,5S)-benzyl 3-(benzoyloxy)-5-(tert-butoxycarbonylamino)-piperidine-1-carboxylate starting from (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate. LC/MS (m/z): 365.2 (MH+-Boc), Rt:1.37.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][N:11]=[C:10]([C:13]([N:26]3[CH2:27][CH2:28][N:23]([C:19]4[S:18][CH:22]=[CH:21][N:20]=4)[CH2:24][CH2:25]3)=[O:15])[CH2:9]2)[CH2:16][CH2:17]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1csc(N2CCNCC2)n1
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)C1CCC2(CC1)CC(C(=O)N1CCN(c3nccs3)CC1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (120 mg, 0.51 mmol), 1-thiazol-2-ylpiperazine (110 mg, 0.51 mmol), 4-methylmorpholine (101 mg, 1.02 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (288 mg, 0.65 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were washed with sat. aq. NaCl solution, dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, hexane/EtOAc 3:1), the desired product (8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-(4-thiazol-2-ylpiperazin-1-yl)methanone was obtained as a trans isomer (50 mg, 26% of the theoretical amount) and as a cis isomer (100 mg, 51% of the theoretical amount).
Reaction SMILES: C(OC(=O)C(C1([N+]([O-])=O)CCCC1C)C(OCC)=O)C.[N+:21]([CH2:24][C:25]1([CH:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:29][CH2:28]CC1)([O-:23])=[O:22]>>[CH2:40]([O:39][C:37](=[O:38])[CH:31]([C:25]1([CH2:24][N+:21]([O-:23])=[O:22])[CH2:30][CH2:29][CH2:28]1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:41]
Reactant: CCOC(=O)C(C(=O)OCC)C1(C[N+](=O)[O-])CCCCC1
Agent: CCOC(=O)C(C(=O)OCC)C1([N+](=O)[O-])CCCC1C
Product: CCOC(=O)C(C(=O)OCC)C1(C[N+](=O)[O-])CCC1

Procedure:
Using a similar procedure, diethyl(1-nitro-methyl-1-cyclopentyl)malonate (compound 64) (1H-NMR (CDCl3) δ ppm: 1.27 (6H, t, J=7 Hz), 1.6-2.0 (8H, m), 3.79 (1H, s), 4.20 (4H, q, J=7 Hz), 4.71 (2H, s)) and diethyl (1-nitromethyl-1-cyclohexyl)malonate (compound 65) (1H-NMR (CDCl3) δ ppm: 1.27 (6H, t, J=7 Hz), 1.4-1.8 (10H, m), 3.88 (1H, s), 4.20 (4H, q, J=7 Hz), 4.96 (2H, s) were obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.C1OC1C.[C:16]([O:19][CH2:20][C:21]1[CH2:22][S:23][C@@H:24]2[C@H:35]([NH2:36])[C:34](=[O:37])[N:25]2[C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])[CH3:17]>C(OCC)(=O)C>[C:16]([O:19][CH2:20][C:21]1[CH2:22][S:23][C@@H:24]2[C@H:35]([NH:36][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=3)[C:34](=[O:37])[N:25]2[C:26]=1[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccncc1
Agent: CC1CO1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccncc3)[C@H]2SC1

Procedure:
A suspension of pyrid-4-ylacetyl chloride hydrochloride (6.0 g.) in ethyl acetate (50 ml) containing propylene oxide (12 ml.) was stirred, cooled in ice and treated dropwise with a solution of t-butyl 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (5.0 g.) in ethyl acetate (50 ml.). The mixture was stirred at 20° for 20 hours and then washed with saturated sodium bicarbonate solution and extracted with 2N hydrochloric acid. The aqueous extract was washed with ethyl acetate, neutralised with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and evaporated to small bulk whereupon crystallisation began. The crystalline solid was washed well with petroleum spirit (bp. 40°-60°) and dried to give the title ester as a buff coloured powder (5.4 g., 80% based on amine). A portion (250 mg.) was recrystallised from ethyl acetate as white needles (170 mg.), [α]D + 94° (c 0.9, DMSO) λmax. (EtOH) 256.5 nm (ε 9,900), νmax. (CHBr3) 3412 (NH), 1784 (β-lactam), 1736 (OAc), 1722 (CO2R), 1690 and 1512 cm.-1 (CONH), τ (d6 -DMSO) 0.81 (d, J 8 Hz; NH), 1.47 and 2.68 (2d, J 5 Hz; aromatic protons), 4.27 (q, J 8 and 5 Hz; C- 7H), 4.85 (d, J 5 Hz; C-6 H), 5.01 and 5.36 (2d, J 13 Hz; C-3CH2), 6.38 (s; CH2CONH), 6.39 (s; C-2CH2), 7.96 (s; OCOCH3), and 8.50 (s; C(CH3)3).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:17]([OH:24])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:24][C:17]1[C:18]([C:20]([O:22][CH3:23])=[O:21])=[N:19][C:10]([Br:9])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Br)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (2.53 ml, 21.2 mmol) was added to a mixture of methyl 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (3.0 g; 10.6 mmol) and cesium carbonate (6.9 g; 21.2 mmol) in DMF (30 ml), under stirring at room temperature. The reaction mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added. The organic phase was separated, washed with water and with a saturated NaCl solution. The organic phase was dried, filtered and concentrated to dryness. The crude material was purified by flash chromatography column over silica gel (eluting with a gradient hexane-ethyl acetate 10:1 to 2:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](OS(C(F)(F)F)(=O)=O)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reaction time: 1 h
Yield: 78.8 %

Procedure:
5-Bromoindole (14.04 g, 72 mmol) in tetrahydrofuran (50 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in oil; 3.04 g, 76 mmol) in tetrahydrofuran (100 ml) and the resultant solution stirred for one hour at room temperature. Triisopropylsilyltrifluoromethane sulphonate (23.3 g, 76 mmol) was added slowly and the solution stirred for a further one hour. The reaction mixture was washed with sodium hydrogen carbonate solution, dried (MgSO4), and concentrated. The crude mixture was purified by flash chromatography, with hexane as eluant, to give 5-bromo-1-triisopropylsilyl-1H-indole (20.0 g, 79%) as a clear oil; δH (CDCl3) 1.10 (18H, d, J 8.4 Hz, 6× CH3), 2.70 (3H, m, 3×CH), 6.55 (1H, d, J 3.9 Hz, ArH), 7.20 (2H, m, ArH), 7.35 (1H, d, J 8.5 Hz, ArH), and 7.75 (1H, d, J 1.4 Hz, ArH).
Reaction SMILES: C([N:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:10]([CH2:15][N:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12])(=O)C1C=CC=CC=1.C[O-].[Mg+2].C[O-]>CO>[C:32]([O:31][C:29]([NH:9][C@@H:10]([CH2:15][N:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)C(=O)c1ccccc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g of methyl (S)-2-(benzoyl-tert-butoxycarbonylamino)-3-diphenylaminopropionate were dissolved in 13 ml of methanol and admixed with 2.74 ml of a 1M solution of magnesium methoxide in methanol. The solution was stirred at RT overnight and concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The ethyl acetate phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from a little diisopropyl ether/heptane. Yield: 0.95 g (90% of theory) 1H NMR: 1.38 (s, 9H), 3.55 (s, 3H), 4.10-4.25 (m, 2H), 4.50-4.62 (m, 1H), 5.10-5.25 (m, 1H), 6.90-7.05 (m, 6H), 7.20-7.30 (m, 4H)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:17]([C:18]3[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][C:15]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.[ClH:41]>C(O)C>[ClH:41].[F:24][C:19]1[C:18]([C:17]2[N:13]([S:10]([C:6]3[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=3)(=[O:12])=[O:11])[CH:14]=[C:15]([CH2:25][NH:26][CH3:27])[CH:16]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(C(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of tert-butyl ({1-[(3-acetylphenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (106 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 44.3 mg, 48%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]1([CH:27]2[CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:36]([O:35][C:33]([CH:32]1[CH2:31][CH2:30][CH2:29][N:28]([C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH:27]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:34])[CH3:37]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCOC(=O)C1CCCNC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1c1ccccc1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 2-phenylpiperidine-3-carboxylate (54529-38-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=500.2 [MH+].
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.N[CH:24]([CH2:28][CH3:29])[C:25]([OH:27])=[O:26].[Cl:30][C:31]1[CH:32]=[C:33]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:34][N:35]([CH3:46])[C:36]([C:38]1[CH2:39][N:40](C)[C:41](=[O:44])[C:42]=1[OH:43])=[O:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:34][N:35]([CH3:46])[C:36]([C:38]1[CH2:39][N:40]([CH2:29][CH2:28][CH2:24][C:25]([OH:27])=[O:26])[C:41](=[O:44])[C:42]=1[OH:43])=[O:37]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CCC(N)C(=O)O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Yield: 21 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and -aminobutyric acid as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (42.1 mg, 21% yield). 1H NMR (300 MHz, CDCl3) δ: 7.42 (d, 1H, J=8.05), 7.36 (s, 1H), 7.11 (dd, 1H, J=8.05, J=1.10), 4.60 (s, 2H), 4.21 (s, 2H), 3.58 (t, 2H, J=6.22), 3.03 (s, 3H), 2.40 (t, 2H, J=6.95), 1.96 (t, 2H, J=6.59). HRMS (M−H) calcd for C17H17N2Cl2O5: 399.0514. found: 399.0509.