Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC.Br[C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1B(O)O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCc1cnccc1B(O)O
Reactant: COC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccccc1-c1ccncc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
20 ml of 1,2-dimethoxyethane were aerated with argon, and 230 mg (0.2 mmol) of Pd(PPh3)4 and 0.86 g (4 mmol) of methyl 2-bromobenzoate were added. After 10 min, 1.51 g (6 mmol) of 3-(tert-butoxycarbonylaminomethyl)pyridine-4-boronic acid and finally 4 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux under argon for 13 h, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 1.15 g (84%) of a viscous pale yellow oil were obtained. MS (ES+): m/z=343 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:30][CH:29]=1>>[O:23]=[S:22]1(=[O:24])[C:8]2[C:7]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:32][CH:33]=3)=[N:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:19][CH2:20][CH2:21]1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: O=S1(=O)CCCc2nc(-c3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: NC(=O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 60.8 %

Procedure:
Following general procedure G, 5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.125 g, 0.31 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.051 g, 0.34 mmol) to afford the desired product (0.077 g, 61%) as a white solid. MW=408.47. 1H NMR (DMSO-d6, 500 MHz) δ 8.74 (s, 1H), 8.30-8.25 (m, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.59-7.50 (m, 3H), 7.48 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 3.77-3.71 (m, 2H), 3.40 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 409 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:34][O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:11]([NH:13][C@@H:14]2[C:32](=[O:33])[N:16]3[C:17]([C:29]([O-:31])=[O:30])=[C:18]([CH2:21][N+:22]4[N:23]([CH3:28])[C:24]([NH2:27])=[CH:25][CH:26]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.C(Cl)Cl>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:34][O:35][CH2:36][C:37]([OH:39])=[O:38])[C:11]([NH:13][C@@H:14]2[C:32](=[O:33])[N:16]3[C:17]([C:29]([O-:31])=[O:30])=[C:18]([CH2:21][N+:22]4[N:23]([CH3:28])[C:24]([NH2:27])=[CH:25][CH:26]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.3 %

Procedure:
To a suspension of 7β-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (syn isomer) (1.2 g) in anisole (1.2 ml) and methylene chloride (3.6 ml) was added dropwise trifluoroacetic acid (2.4 ml) under ice-cooling. After being stirred at ambient temperature for 3 hours, the mixture was added dropwise to isopropyl ether (200 ml). The resultant precipitate was collected by filtration. The precipitate was dissolved in water (30 ml) and the solution was adjusted to pH 2 with 5% aqueous sodium bicarbonate solution, and then subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20". The desired product was eluted with 5% aqueous isopropyl alcohol solution, and isopropyl alcohol was evaporated. The aqueous layer was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (131.3 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:4].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Cc1ccc(C(NC(=O)CN)c2ccccc2)cc1
Product: Cc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2ccccc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-(phenyl-p-tolyl-methyl)-acetamide (Example 3.3) and 4-fluorobenzoic acid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][OH:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][O:23][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccncc1
Reactant: OCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Product: c1cc(OCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)ccn1
Yield: 60 %

Procedure:
The title compound (75 mg, 60%) was prepared from {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanol and 4-bromopyridine similarly to the procedure used for example 152. 1H NMR (400 MHz, CDCl3) δ 1.76-1.82 (m, 4H), 1.98-2.04 (m, 2H), 2.12-2.17 (m, 4H), 2.49-2.58 (m, 4H), 2.61-2.66 (m, 2H), 3.54-3.60 (m, 2H), 3.81-3.85 (m, 2H), 3.87 (s, 2H), 4.03 (t, 2H), 6.71 (d, 2H), 6.91 (d, 2H), 7.29 (d, 2H), 8.36 (d, 2H). HRMS ESI+ m/z 397.2479 [MH]+.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.[OH-].[Li+]>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([CH2:4][C:3]([OH:34])=[O:2])=[CH:6][O:7][C:8]=4[CH:13]=3)=[CH:17][CH:18]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)Cc1coc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1coc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12

Procedure:
The title compound was prepared in the manner analogous to example 1 using {6-[4-(4-trifluoromethyl-benzyloxy)-benzyloxy]-benzofuran-3-yl}-acetic acid methyl ester and lithium hydroxide. mp 161–163° C.; IR (thin film) cm−1: 1715, 1514, 1331, 1226, 1119, 1069; 400 MHz 1H NMR (DMSO-d6) 12.38 (br s, 1H), 7.68–7.72 (m, 3H), 7.61 (d, 2H, J=8.1 Hz), 7.29–7.41 (m, 3H), 7.18 (d, 1H, J=2.2 Hz), 6.96–7.00 (m, 2H), 6.87–6.89 (m, 1H), 5.19 (s, 2H), 5.01 (s, 2H), 3.58 (s, 2H); MS m/z 455 (M−1). Anal. Calc'd for: C25H19F3O5: C, 65.79; H, 4.20; found: C, 65.54; H, 4.02.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:28])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:10]1>C(Cl)Cl>[F:28][C:9]1([F:8])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(F)(F)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CCN(CC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 66 h
Yield: 84 %

Procedure:
TFA (766.5 mg, 517 μL, 6.722 mmol) was added to a stirred solution of tert-butyl 4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidine-1-carboxylate (2.046 g, 6.722 mmol) in DCM (15 mL) and the reaction stirred at ambient temperature for 66 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 50 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo to give 4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidine as a pale yellow solid (1.15 g, 84% Yield over 2 steps). MS (ES+) 205.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22]C(=O)OC(C)(C)C)[C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][N:15]=2)[NH2:22])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nnc(-c2ccccc2)o1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
(S)-tert-Butyl 2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethylcarbamate (17A, 110 mg, 0.27 mmol) was dissolved in 2.7 mL of methanol and to it was added 0.7 mL of 4M HCl in 1,4-dioxane. The reaction mixture was allowed to stir at ambient temperature for 1 hour and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with methanol/methylene chloride to afford 90 mg of (S)-2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine (0.26 mmol) which was dissolved in 5 mL of DMF and to it were added 2-(5-fluoro-1H-indol-3-yl)acetic acid (61 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.226 mL, 1.3 mmol). The reaction mixture was cooled down to 0° C. and to it was added HATU (119 mg, 0.31 mmol). The reaction mixture was allowed to stir at ambient temperature for overnight and then purified by reverse phase HPLC eluting with acetonitrile/water (0.1% TFA) to afford the desired product. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.79 (d, J=8.2 Hz, 1H), 7.94-7.73 (m, 2H), 7.56 (m, 3H), 7.27 (dd, J=8.7, 4.5 Hz, 1H), 7.12 (m, 2H), 7.00 (m, 3H), 6.84 (td, J=9.2, 2.5 Hz, 1H), 5.44 (m, 1H),), 3.52-3.12 (m, 4H). MS (m/z): 477.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH:9]([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:13]([CH3:12])(=[O:15])=[O:14])[CH:6]=[C:7]([CH:9]([F:10])[F:11])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(C(F)F)c1
Product: CS(=O)(=O)Nc1cc(Br)cc(C(F)F)c1
Yield: 104.6 %

Procedure:
3-Bromo-5-(difluoromethyl)aniline (876 mg, 3.95 mmol) was treated with methanesulfonyl chloride (458 μl, 5.92 mmol) according to the method described in Preparation 15b to give 1.24 g (100% yield) of the title compound. Purity 95%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH:54]=[CH2:55]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:58]([O:57][C:53]([CH:54]=[CH:55][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:56])[CH3:59]
Reactant: C=CC(=O)OCC
Reactant: Brc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1

Procedure:
A degazed solution of 1-{3-[(4′-bromobiphenyl-4-yl)oxy]propyl}piperidine (2.8 g), triethylamine (2.8 mL), tri(o-tolyl)phosphine (365 mg), palladium acetate (170 mg) and ethyl acrylate (2.9 mL) in acetonitrile (5 mL) is stirred at a temperature close to 60° C. for one hour, then at room temperature overnight and finally 6 h at a temperature close to 90° C. The solution is concentrated under reduced pressure, redissolved in dichloromethane, filtered and chromatographied over silica gel to give 1.3 g of 1-(3-{[4′-(2-ethoxycarbonylethen-1-yl)biphenyl-4-yl]oxy}propyl)piperidine.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:16]2[C:30]([O:32]CC)=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[Li+].[OH-].CO.C1COCC1>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:16]2[C:30]([OH:32])=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(N2CCCCC2)c2ccccc2n1CCCOc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(N2CCCCC2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 74A (30 mg) in 1N aqueous LiOH/methanol/THF (1 mL/1 mL/1 mL) was stirred at room temperature overnight. The reaction mixture was acidified with 1NHCl (1 mL), and extracted with ethyl acetate. The organic phase was dried (Na2SO4) filtered, and concentrated. The concentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (400 MHz, DMSO-d6) δ 16.82 (s, 1H), 8.08 (d, 1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.69 (d, 1H), 7.48 (m, 3H), 7.36 (t, 1H), 7.24 (m, 1H), 7.13 (t, 1H), 6.83 (t, 1H), 4.89 (t, 2H), 4.16 (t, 2H), 3.24 (br, 4H), 2.33 (m, 2H), 1.70 (br, 6H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([C:21]4[S:22][C:23]5[C:29]([C:30]6[CH:31]=[N:32]N[CH:34]=6)=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[C:17]([NH2:20])=[N:18][CH:19]=3)[CH:11]=[N:10]2)[CH2:5][CH2:4]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([C:21]4[S:22][C:23]5[C:29]([C:30]6[CH:34]=[CH:35][NH:32][CH:31]=6)=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[C:17]([NH2:20])=[N:18][CH:19]=3)[CH:11]=[N:10]2)[CH2:5][CH2:4]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(-c3cn[nH]c3)c2s1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(-c3cc[nH]c3)c2s1

Procedure:
The procedure for 5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3-[7-(1H-pyrazol-4-yl)benzothiazol-2-yl]pyridin-2-ylamine dihydrochloride was followed, except that TFA in DCM was used for removing the Boc group. 1H NMR (400 MHz, CD3OD): δ=2.24-2.43 (m, 4H), 3.19-3.29 (m, 2H), 3.60 (d, J=13.1 Hz, 2H), 4.60 (ddd, J=10.2, 5.3, 5.2 Hz, 1H), 6.66 (q, J=2.5 Hz, 1H), 6.92 (q, J=2.7 Hz, 1H), 7.28-7.36 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.59-7.65 (m, 1H), 7.86-7.93 (m, 1H), 8.00 (s, 1H), 8.19-8.31 (m, 2H), 8.57 (d, J=2.0 Hz, 1H), 10.76 (br. s., 1H). MS (ES+): m/z=442.19 (100) [MH+]. HPLC: tR=2.38 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(=O)O)ccc2ccccc12
Product: COc1c(C(=O)Cl)ccc2ccccc12

Procedure:
Using 1-methoxy-2-naphthoic acid (1 g) and thionyl chloride (3 ml), a reaction as that described in Example 24 is carried out to give 1-methoxy-2-naphthoyl chloride, which is allowed to react with 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.8 g). The product is purified by silica gel column chromatography (hexane:acetone=3:2-1:2) and then converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether. Thus-obtained powder is recrystallized from ethyl acetate to afford 1-(1-methoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzyl) piperazine hydrochloride (1.7 g) as colorless crystals, m.p. 194°-197° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1
Reactant: CCc1cc([N+](=O)[O-])c(OC)nc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(N)c(OC)nc1C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
A solution of 2-methoxy-3-nitro-5-ethyl-6-methylpyridine (535 mg, 2.72 mmol) in methanol (8 mL) and tetrahydrofuran (8 mL) containing 5% palladium on carbon (83 mg) was hydrogenated at atmospheric pressure for 5 hours. The catalyst was filtered off the solvent evaporated to yield 436 mg (98%) of oily product.
Reaction SMILES: [NH2:1][C:2]1([C:18]2[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.C([O-])(=O)C.[K+].[N:30]#[C:31]Br.C(Cl)Cl>CO>[Br:17][C:5]1[CH:4]=[C:3]2[C:2]3([C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:23]=4[O:24][C:31]([NH2:30])=[N:1]3)[C:15]3[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=3[O:9][C:8]2=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: NC1(c2ncccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NC1=NC2(c3cc(Br)ccc3Oc3cnc(Cl)cc32)c2ncccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)pyridin-3-ol (0.40 g, 1.00 mmol) in MeOH 5 mL was added potassium acetate (0.13 mL, 1.99 mmol) followed by the dropwise addition of cyanogen bromide, 3.0M solution in DCM (0.40 mL, 1.20 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated, washed with saturated NaHCO3, extracted with DCM, dried over sodium sulfate and concentrated. The resulting product was dissolved in 1,2-dichloroethane followed by the addition of 4.0 M HCl in dioxane (15 mL) and stirred at RT for 1.5 h. The reaction mixture was concentrated, diluted with DCM and washed with sat NaHCO3, brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel using 0-100% EtOAc/hexanes to give 0.18 g of desired product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(C(F)(F)F)=O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[B:20]([OH:22])[OH:21]>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]=1[B:20]([OH:21])[OH:22]
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c([N+](=O)[O-])cc1B(O)O
Temperature: -35 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To fuming nitric acid (1 ml) cooled to −40° C. was added TFA (1 ml). The resulting mixture was allowed to warm slightly to −35° C. and 2,4-dimethyl phenyl boronic acid (150 mg, 1 mmol) was added in one portion. After 1 h, ice was added and the heterogenous mixture was filtered. The resulting solid was suspended in Et2O and extracted with 3N NaOH (aq) (1 ml) then water (2 ml). The aqueous phase was acidified with 3N HCl (aq) (1 ml) and back extracted with EtOAc (3×5 ml). The pooled organics were washed with brine, dried with Na2SO4 decanted and concentrated to give 2,4-dimethyl-5-nitro-phenyl boronic acid (93 mg, 47%). LCMS (ESI+) [M+H]/z Calc'd 196, found 196.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)[N:11]=[N:10][C:9]=1[C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[C:30]2N(O)N=[N:33][C:31]=2[CH:32]=1.C1(N)CC1.CCN=C=NCCCN(C)C.C(=O)([O-])O.[Na+]>C(#N)C.CN(C=O)C>[CH2:1]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)[N:11]=[N:10][C:9]=1[C:24]([NH:33][CH:31]1[CH2:32][CH2:30]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2Cc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 177 %

Procedure:
5-Benzyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (354 mg, 1.01 mmol) obtained in Example 99a), HOBt (69.0 mg, 0.505 mmol, 0.5 eq.) and cyclopropylamine (0.094 ml, 1.31 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 6 ml), WSC (217 mg, 1.11 mmol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 3.5 hr. 1% aqueous sodium hydrogen carbonate solution (20 ml) was added to the reaction mixture, and the mixture was stirred. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (348 mg, 0.894 mmol, 88.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][CH:7]([CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@@H:32]2[CH2:36][O:35]C(C)(C)[O:33]2)=[CH:26][CH:25]=1)[CH2:8][NH:9][C:10]([C:12]1[C:17]([NH2:18])=[N:16][C:15]([NH2:19])=[C:14]([Cl:20])[N:13]=1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:33][C@@H:32]([CH2:36][OH:35])[CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][CH2:21][CH:7]([NH:6][CH2:5][C:4]2[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=2[O:2][CH3:1])[CH2:8][NH:9][C:10]([C:12]2[C:17]([NH2:18])=[N:16][C:15]([NH2:19])=[C:14]([Cl:20])[N:13]=2)=[O:11])=[CH:29][CH:28]=1
Reactant: COc1ccc(CNC(CCCc2ccc(OC[C@@H]3COC(C)(C)O3)cc2)CNC(=O)c2nc(Cl)c(N)nc2N)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNC(CCCc2ccc(OC[C@@H](O)CO)cc2)CNC(=O)c2nc(Cl)c(N)nc2N)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid {2-(2,4-dimethoxy-benzylamino)-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentyl}-amide (391 mg, 0.62 mmol) in DCM (3 mL) is added TFA (3 mL) and the reaction is stirred at RT for 72 h. The solvent is removed in vacuo and the residue is diluted with water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous phase is neutralised with aqueous sodium hydroxide and then extracted with EtOAc (2×20 mL). The EtOAc extracts are combined and dried (MgSO4), filtered and the solvent is removed in vacuo. Chromatography (SiO2, MeOH:DCM, 1:9) affords the title compound as a colourless solid as a mixture of diastereoisomers. [M+H]+ 589. 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, br), 7.05 and 7.04 (1H, 2×d), 6.98 and 6.97 (2H, 2×d), 6.73 and 6.71 (2H 2×d), 6.36 and 6.35 (1H, 2×d), 6.34 and 6.30 (1H, 2×s), 5.15 (2H, br), 4.08-3.59 (8H, m), 3.71 (3H, s), 3.65 (3H, s), 3.50-3.41 (2H, m) 2.55 and 2.49 (2H, 2×t), 1.80-1.29 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH:24]1[CH:28]=[C:27]([CH2:29][N:30]2[C:34](=[O:35])[CH2:33][S:32][C:31]2=[O:36])[N:26]=[N:25]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:33]4/[C:34](=[O:35])[N:30]([CH2:29][C:27]5[N:26]=[N:25][NH:24][CH:28]=5)[C:31](=[O:36])[S:32]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=C1CSC(=O)N1Cc1c[nH]nn1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C1S/C(=C\c2ccc3c(c2)nnn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1Cc1c[nH]nn1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-(1H-1,2,3-triazol-4-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(1H-[1,2,3]triazol-4-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 85) following General Procedure F.