Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Cl:38])=[C:7]([C:9](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.O>[NH2:3][C:4]1[S:5][C:6]([Cl:38])=[C:7]([C:9](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g) in methanol (15 ml), and conc. hydrochloric acid (0.52 g) and tetrahydrofuran (3.0 ml) was stirred for 3.0 hours at ambient temperature. The reaction mixture was added to water and ethyl acetate, and adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 3.0 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated under reduced pressure to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.02 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.Br[C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([F:36])[C:28]=1[CH:29]=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:36][C:31]1[C:28]([CH:29]=[O:30])=[C:27]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)[C:34]([CH3:35])=[CH:33][CH:32]=1
Reactant: Cc1ccc(F)c(C=O)c1Br
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)C4CC4)ncc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(F)c(C=O)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 120 °C
Yield: 95.7 %

Procedure:
A mixture of N-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]cyclopropanecarboxamide (100 mg, 0.30 mmol), 2-bromo-6-fluoro-3-methyl-benzaldehyde (77 mg; 0.35 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (21 mg, 0.03 mmol) and saturated aqueous sodium carbonate solution (0.1 mL) in acetonitrile (1 mL) was heated under microwave irradiation (Biotage) at 120° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-60% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as light brown solid (100 mg, 97%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.O>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1(c2ccc(N)cc2)CC1
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(c2ccc(N)c(Br)c2)CC1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of methyl 1-(4-aminophenyl)cyclopropanecarboxylate (10.38 g, 0.05 mol) in acetonitrile (200 mL) was added NBS (9.3 g, 0.05 mol) at room temperature. The mixture was stirred overnight. Water (200 mL) was added. The organic layer was separated and the aqueous phase was extracted with EtOAc (80 mL×3). The organic layers were dried with anhydrous Na2SO4 and evaporated to give methyl 1-(4-amino-3-bromophenyl)cyclopropanecarboxylate (10.6 g, 78%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=2.0 Hz, 1H), 7.08 (dd, J=1.6, 8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 3.62 (s, 3H), 1.56-1.54 (m, 2H); 1.14-1.11 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2([CH2:60][NH2:61])[CH2:59][CH2:58]2)=[CH:53][CH:52]=1.Cl>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:61][CH2:60][C:57]2([C:54]3[CH:53]=[CH:52][C:51]([Cl:50])=[CH:56][CH:55]=3)[CH2:59][CH2:58]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: NCC1(c2ccc(Cl)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCC2(c3ccc(Cl)cc3)CC2)cc1F
Temperature: 25 °C

Procedure:
To a mixture of 4-amino-3-fluorobenzoic acid (180.0 mg, 1.160 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 0.44 g, 1.2 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) at 0° C. were added N,N-diisopropylethylamine (0.61 mL, 3.5 mmol) and C-[1-(4-chloro-phenyl)-cyclopropyl]-methylamine; hydrochloride (303.7 mg, 1.392 mmol). The reaction mixture was slowly warmed to rt. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% methanol in chloroform).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH2:31][CH:32]([F:34])[F:33])[C:16]=2[N:17]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18]2)=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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]>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH2:31][CH:32]([F:34])[F:33])[C:16]=2[N:17]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18]2)=[O:10])=[N:4][C:5]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[F:35])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1ccc(Br)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Nc1ccc(-c2ccccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 33 %

Procedure:
Following the procedures of Examples 101 or 112, (R)-3-amino-6-bromo-N-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-yl)picolinamide was prepared. In a microwave reaction tube, (R)-3-amino-6-bromo-N-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-yl)picolinamide (284 mg, 0.51 mmol), (2-fluorophenyl)boronic acid (215 mg, 1.54 mmol), and Pd(dppf)2Cl2 (37 mg, 0.051 mmol) were dissolved in acetonitrile (4 mL). 1.0M potassium acetate (0.77 mL, 0.77 mmol) and 1.0 M sodium carbonate (0.77 mL, 0.77 mmol) were added. The mixture was irradiated under microwave at 120° C. for 30 min. It was cooled and filtered through Celite and washed with methanol. The filtrate was concentrated and purified by flash chromatography eluting with 0 to 10% methanol in methylene chloride to give (R)-3-amino-N-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide (98 mg, 33%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:60])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][C@@H:50]7[CH2:52][C@H:47]6[CH2:48][N:49]7C(OC(C)(C)C)=O)[CH:40]=5)[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[C@H:47]12[CH2:52][C@H:50]([NH:49][CH2:48]1)[CH2:51][N:46]2[CH2:45][C:41]1[CH:40]=[C:39]([C:37]2[C:36]([F:60])=[CH:35][CH:34]=[C:33]([CH2:32][NH:31][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:61][CH3:62])=[O:22])[CH:24]=3)=[O:30])[CH:38]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl (1S,4S)-5-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}-carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.0488 g, 0.058 mmol) was dissolved in CH2Cl2 (9 mL) and treated with trifluoroacetic acid (1 mL) at 0° C. and then allowed to warm to room temperature. This mixture was stirred for a total of 2 h. The solvents were pumped off, and the material was passed though 2 quaternary ammonium hydroxide cartridges, but 19F NMR still indicated residual TFA. The product was taken up in EtOAc and washed 3× with 0.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a tan solid. LC-MS m/z 746 (M+H)+, 1.30 min (ret time); mp 129-133° C. Analytical HPLC shows 96.8% purity, (ret time 9.820 min).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2C=CC=[CH:38][C:33]=2N=N1.N1CCC1.O>ClCCl>[N:30]1([C:22]([C:9]2[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:14][C:15]=3[C:4]3[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=3[CH:8]=2)=[O:24])[CH2:38][CH2:33][CH2:34]1
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C1CNC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c3c(c(C(=O)N4CCC4)cc2n1C)CCC(c1ccccc1)O3
Temperature: 40 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a suspension of 0.31 g (0.96 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (10 ml) were added 0.34 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was heated at 40° C. for 4 h. 102 mg (1.0 mmol) Azetidine were added and the mixture was stirred for 3 h. The reaction mixture was poured into water and the extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=1:5) and crystallized with diisopropyl ether to afford 212 mg (61%) of the title compound as a white solid. m.p. 246°-248° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[C@H:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3[C@H](O)CSCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzylsulfanyl)-ethanol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Chloronicotinonitrile (0.80 g, 5.8 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2 g, 7.49 mmol) using the method in Example 14 part a). Purification by chromatography on silica gel eluting with dichloromethane gave 2-(2-fluoro-5-nitrophenyl)nicotinonitrile as a yellow solid: δH (360 MHz, CDCl3) 8.97 (1H, dd, J 5 and 2), 8.56 (1H, dd, J 6 and 3), 8.40-8.45 (1H, m), 8.15 (1H, dd, J 8 and 2), 7.55 (1H, dd, J 8 and 5), 7.43 (1H, dd, J 9 and 9); m/z (ES+) 244 (M++H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[N:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:42][NH2:43]>O1CCOCC1>[NH:42]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[N:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:43]
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6cnccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6cnccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
To a stirred solution of 10-2 (0.5 g, 0.9 mMol) in anhydrous 1,4-dioxane (5 mL) was added hydrazine (0.56 mL, 17.8 mMol). The solution was heated to 100° C. in a microwave reactor for 20 minutes. The solvent was removed in vacuo and was dried azeotropically with toluene three times. The crude solid was triturated with a saturated NaHCO3 solution for 20 minutes. The suspension was filtered and washed with copious amounts of water. The solid was dried azeotropically with toluene three times to yield 10-3 as a brown solid. LC/MS (M+1) calculated: 555.6; observed: 555.2
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])[CH3:3].C[Si](C=[N+]=[N-])(C)C.[NH2:28][OH:29].Cl.[OH-].[K+].Cl>CCOCC.CO.C(Cl)Cl.CO>[OH:29][NH:28][C:18]([C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: NO
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)NO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
A solution of crude Boc-Hfe-OH (10.0 mmol theoretical) in 4:1 CH2Cl2/MeOH (50.0 mL) was treated with (trimethylsilyl)diazomethane (12.0 mmol; 6.00 mL of a 2.0 M solution in Et2O) dropwise over 0.25 h at 22° C. CAUTION: vigorous gas evolution. The resulting yellow solution was stirred an additional 0.25 h to ensure complete methylation. Excess (trimethylsilyl)diazomethane was consumed by the dropwise addition of glacial AcOH, then all volatiles removed in vacuo. The crude ester was redissolved in MeOH (50.0 mL), cooled to 0° C. and treated with a previously prepared suspension of H2NOH.HCl (2.08 g, 30.0 mmol) and KOH (3.37 g, 60.0 mmol) in MeOH (50.0 mL); a large bore cannula needle was required for the transfer. The resulting suspension then warmed slowly to 22° C. overnight as the ice bath melted. After 14 h, the suspension was acidified with conc. HCl to pH 4-5 then all volatiles removed in vacuo. The solids were triturated with several portions of hot EtOAc (5×10 mL) and removed by filtration through a scintered glass funnel of medium porosity. The combined filtrates were collected and concentrated in vacuo to an off-white powder. Purification through recrystallization from hot EtOAc (200 mL) afforded a white microcrystalline solid (1.47 g, 4.99 mmol, 49.9%). The spectral data obtained for this material are in accord with that described for the product of Part 1A.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH3:16]>[Cl-].C([N+](CC)(CC)CC)C.O>[NH2:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: N
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 10 h

Procedure:
260 g of 3-nitro-2,5-dichlorobenzotrifluoride, 130 ml of water and 10 g of tetraethylammonium chloride were introduced into an autoclave as the initial charge, and 120 ml of liquid ammonia were injected. The mixture was then heated to 130° C. and stirred at this temperature for 10 hours. After cooling, the batch was filtered off, the removed precipitate washed with water and dried to give 194 g of 2-amino-3-nitro-5-chloro-benzotrifluoride of melting point 67° C.
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24](COCC[Si](C)(C)C)[CH:23]=[CH:22]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCCC1.C(N)CN>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[OH:1][C:2]1([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(O)(c2ccc3[nH]ccc3c2)N1Cc1ccccc1
Temperature: 70 °C
Yield: 4 %

Procedure:
A solution of 3-hydroxy-2-(phenylmethyl)-3-[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indol-5-yl]-2,3-dihydro-1H-isoindol-1-one was taken up in 1M tetrabutylammonium fluoride in tetrahydrofuran (6.0 mL, 6.0 mmol), and ethylenediamine (0.22 mL, 3.6 mmol) was added. The solution was heated to 70° C. for 45 min. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Purification was undertaken via HPLC (reverse-phase, acetonitrile/water with 0.1% trifluoroacetic acid), followed by column chromatography (silica gel, 5% methanol/dichloromethane). The resultant yellow solid was taken up in ethyl acetate and washed with 10% aqueous citric acid solution (3×), dried (sodium sulfate), filtered and concentrated in vacuo. Lyophilization gave 0.0045 g (4%) of 3-hydroxy-3-(1H-indol-5-yl)-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one. 1H NMR (400 MHz, d6-DMSO): 8.20 (d, 1H), 7.91 (dt, 2H), 7.84 (dt, 1H), 7.75 (d, 1H), 7.71 (m, 1H), 7.56 (d, 1H), 7.35 (m, 6H), 4.65 (m, 2H); MS (EI) for C23H18N2O2: 354 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19](C(=O)C(F)(F)F)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[Na+]>CC(O)=O>[NH:19]1[CH2:18][CH2:17][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:8])=[O:9])=[CH:15][CH:14]=2)[CH2:21][CH2:20]1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nccs1)c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
Prepared using general procedure 16. To N-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide (1.5 g, 3.57 mmol) was added a solution of NaOH (1.43 g in 25 ml of H2O). The reaction was stirred at RT for 30 minutes. The pH was adjusted to 10 with HOAc, and the product crashed out as a pink solid which was then filtered, azeotroped with acetonitrile and dried to give 4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (1 g, 87% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=324.3; tR=0.46 min.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCCC)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:36]([O:40][C:41]([N:43]1[CH2:50][CH2:49][NH:48][CH2:47][C:44]21[CH2:46][CH2:45]2)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH2:50][CH2:49][N:48]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:31])[F:32])=[CH:29][C:3]=3[C:2]([F:34])([F:35])[F:1])[N:7]=[CH:8]4)[C:17](=[O:25])[N:18]=2)[CH2:47][C:44]21[CH2:45][CH2:46]2)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC12CC2

Procedure:
7-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4,7-Diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester following general procedure B.