Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:3])[CH3:2].[CH:32]1N=CN(C(N2C=NC=C2)=O)C=1.CO>CN(C=O)C>[CH3:32][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid in 2 ml DMF was added 0.4 mmol CDI, and the mixture heated at 50° C. for 30 min. 5.2 mmol methanol was then added, and the mixture was stirred at RT for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 451.2 (M+H+, 100%)
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](/[CH:17]=[CH:18]/[N+:19]([O-])=O)[CH:14]=[CH:13][C:12]=3[O:22][CH:23]([CH3:25])[CH3:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:1]12([C:11]3[CH:16]=[C:15]([CH2:17][CH2:18][NH2:19])[CH:14]=[CH:13][C:12]=3[O:22][CH:23]([CH3:24])[CH3:25])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)Oc1ccc(/C=C/[N+](=O)[O-])cc1C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)Oc1ccc(CCN)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of the product of Step B (0.27 g, 0.8 mmol) in anhydrous Et2O (10 ml) was added drop wise to the stirred slurry of LiAlH4 (0.040 g) in anhydrous Et2O (5 ml). After addition the mixture was stirred for 1 h at room temperature and then quenched with a mixture of Et2O:EtOAc:MeOH:H2O; 80:15:4:1. The white solid was separated and filtered through Celite bead. The filtrate was evaporated to dryness to give the title compound (0.235 g; 96%). 1H-NMR CDCl3) 1.35 (d, 6H, J=5.9 Hz); 1.59 (s, 6H); 1.7 (s, 9H); 1.73 (s, 6H); 2.03-2.12 (m, 9H); 2.69 (m, 2H); 2.93 (m, 2H); 4.55-4.6 (m, 1H); 6.72 (d, 1H, J=8.46 Hz); 6.9-6.99 (m, 2H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 17.8 %

Procedure:
To a stirring solution of 190 mg (0.28 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 39, in 15 mL of a 10% solution of formic acid in absolute ethanol is added 200 mg of 10% palladium on carbon. The resulting black suspension is heated at reflux for 6 h, then cooled to RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 3/2 as eluent followed by further purification via silica gel MPLC using an Si60 column and hexane/EtOAc 2/1 as eluent and lyophilization afforded 30 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.48-6.98 (m, 17H), 6.70 (d, 1H, J=7.8), 4.86 (m, 1H), 4.27 (m, 2H), 3.81 (s, 3H), 2.87 (dd, 2H), 1.29 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 602 (MH+), 437, 279, 223.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:27]([N+:35]([O-:37])=[O:36])=[CH:26][CH:25]=1.[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[C:46]1[C:51]([C:52]2[NH:53][CH:54]=[CH:55][N:56]=2)=[CH:50][N:49]=[C:48]([NH:57][CH2:58][CH2:59][NH:60]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:47]=1>>[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[C:46]1[C:51]([C:52]2[NH:56][CH:55]=[CH:54][N:53]=2)=[CH:50][N:49]=[C:48]([NH:57][CH2:58][CH2:59][NH:60][C:24]2[N:29]=[C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:27]([N+:35]([O-:37])=[O:36])=[CH:26][CH:25]=2)[N:47]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CS(=O)(=O)Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro(2-pyridyl)}(methylsulfonyl)amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and (6-chloro-3-nitro(2-pyridyl))(methylsulfonyl)amine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)C(=C)C>CCN(C1C=CC=CC=1)CC>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:11]=1[CH2:10][C:9](=[CH2:8])[CH3:12]
Reactant: C=C(C)COc1ccc(C(C(=O)OC)C2CCCC2)cc1
Solvent: CCN(CC)c1ccccc1
Product: C=C(C)Cc1cc(C(C(=O)OC)C2CCCC2)ccc1O
Temperature: 200 °C

Procedure:
7.6 g (0.026 mol) of the compound from Example IV are dissolved in 50 ml of freshly distilled diethylaniline and the mixture is heated overnight at 200° C. (Claisen rearrangement). After cooling, the solvent is distilled off in vacuo, the residue is taken up in 200 ml of dichloromethane and the solution is washed twice with 40 ml of 2N hydrochloric acid in order to extract residues of diethylaniline. It is then washed until neutral, dried with sodium sulphate and concentrated to a small volume. Purification is carried out by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:28](O)=[O:29])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[N:18]=[CH:19][CH:20]=[CH:21]3)=[O:29])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2cccnc12
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CN(C(=O)c2cccc3cccnc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A, except using 1-tert-butoxycarbonyl-2(S)-n-butyl-piperazine (0.261 g, 1.078 mmol), 8-quinoline carboxylic acid (0.187 g, 1.078 mmol), EDC.HCl (0.217 g, 1.13 mmol), HOBT (0.157g, 1.02 mmol) in DMF at pH 7 (adjusted with triethylamine). The crude product was chromatographed on silica gel with 5% methanol in chloroform. The title compound was obtained as an oil (0.253 g).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([F:16])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:17]C)[CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[C:15]([F:16])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([OH:17])[CH:7]=1
Reactant: COC(=O)c1cc(F)c(Br)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(Br)cc1O

Procedure:
Preparation according to Preparation 7, using boron tribromide (1.0 M, 25.0 ml, 25.2 mmol) in DCM (25 ml) and methyl 4-bromo-5-fluoro-2-methoxybenzoate (2.2 g, 8.4 mmol) in DCM (15 ml). Yield: 2.1 g. MS m/z (rel. intensity, 70 eV) 250 (M+, 40), 248 (M+, 41), 218 (99), 216 (bp), 188 (41), 186 (41), 81 (39).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:10]=[N+:11]=[N-:12].[Na+]>C(O)C.O>[N:10]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7])=[N+:11]=[N-:12]
Reactant: C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NC1CCCCC1O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of cyclohexene oxide (150 g, 1.53 mol) in a mixture of ethanol (600 ml) and water (600 ml) is added ammonium chloride (168 g, 3.1 mol) followed by sodium azide (198 g, 3 mol). The resulting solution is stirred gently at 50° C. for 12 hours before being allowed to cool. The volatiles are removed in vacuo, and 6M hydrochloric acid (˜120 ml) is added to bring the reaction to pH 7. The reaction is extracted with ethyl acetate (2×750 ml), and the organic extracts are washed with brine (750 ml) and dried over sodium sulfate. Removal of the solvent in vacuo affords 2-azido-cyclohexan-1-ol as a slightly yellow oil (171.8 g, 80%), which is used in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1cc(F)c(C#N)cc1F

Procedure:
Using 2,4,5-trifluorobenzonitrile (153 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (247 mg) and lithium carbonate (97 mg), the title compound was obtained as white crystals (yield: 183 mg) by an operation similar to that in Example 3.
Reaction SMILES: [C:1]1([N:11]2[CH:15]=[N:14][NH:13][C:12]2=[S:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])=[O:20].N1C=CC=CC=1>CS(C)=O.O>[C:1]1([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[S:16][CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: S=c1[nH]ncn1-c1cccc2ccccc12
Reactant: O=C(CBr)Nc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(CSc1nncn1-c1cccc2ccccc12)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 2.2 %

Procedure:
A solution of 2,4-dihydro-4-(1-naphthalenyl)-3H-1,2,4-triazole-3-thione (129 mg, 0.50 mmol) in DMSO (2 mL) was added slowly to a solution of 2-bromo-N-(2-nitrophenyl)acetamide (113 mg, 0.50 mmol) and pyridine (121 μL, 1.49 mmol) in DMSO (1 mL) at room temperature. The mixture was stirred at room temperature for 18 h, then diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (3×) and brine, dried (MgSO4), filtered and concentrated under reduced pressure. A mixture of Et2O and hexane (1:1) was added, the resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC using a gradient of MeCN/H2O containing TFA (0.06%) (CombiPrep ODS-AQ 50×20 mm, 5μ, 120 Å). The pure fractions were combined and concentrated to give the title compound (4.5 mg, 2% yield).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=O)[CH:6]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:11][CH:10]=1)[CH3:8].C(Cl)(=O)C(Cl)=O.[CH3:31][NH2:32]>CO.ClCCl.CN(C)C=O.C1COCC1>[CH3:31][NH:32][C:5](=[O:4])[CH:6]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: COC(=O)C=C(C)c1ccc(OCc2cccc(F)c2)cc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)C=C(C)c1ccc(OCc2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
0.224 g (4 mmol) of KOH is dissolved in 10 ml methanol. 0.4 g (1.33 mmol) of 3-[4-(3-fluoro-benzyloxy)-phenyl]-but-2-enoic acid methyl ester is added and the resulting solution refluxed for 6 hours, concentrated and acidified with 2N aqueous hydrochloric acid. Extraction with ethyl acetate gives 325 mg (85%) of the crude acid. This acid is dissolved in 10 ml of dichloromethane, 2 drops of N,N-dimethylformamide are added and the mixture is cooled to 0° C. Slow addition of 0.380 g (3 mmol) of oxalylchloride yields a yellow solution which is stirred for additional 1.5 hours at RT. Evaporation of the reaction mixture leaves a yellowish resin which is dissolved in 5 ml THF and slowly added at 0° C. to a mixture of 5 ml THF and 5 ml aqueous methylamine (40%). The resulting slurry is stirred at RT for 1 hour, evaporated, diluted with water and extracted three times with ethyl acetate. Chromatography on silica gel (cyclohexane/ethyl acetate 1:1) gives 220 mg (50%) of a colorless solid. MS: m/e=300.2 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1.CO>[Si:18]([O:17][CH2:16][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11][CH2:12][OH:13])([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
To a solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)pentanoate (40 g, 0.111 mol) in THF (100 mL) and MeOH (5.0 mL) was added LiBH4 (2M in THF, 56.0 mL, 0.112 mol) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and slowly quenched with saturated NaHCO3 solution. The resulting mixture was stirred RT overnight and filtered. The solid was washed with EtOAc. The combined filtrate was diluted with an additional EtOAc (200 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-ylcarbamate (39.5 g), which was used without further purification. LRMS (M+Na+) m/z 356.4.2.
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:13]([C@H:15]1[C@@H:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C@H:19]2[CH2:30][C@@H:16]1[CH2:17][CH2:18]2)=[O:14])C.[I:31][C:32]1[CH:47]=[CH:46][C:35]2[NH:36][C:37]([CH2:42][C:43](O)=[O:44])=[N:38][S:39](=[O:41])(=[O:40])[C:34]=2[CH:33]=1.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]2[C:43](=[O:44])[C:42]([C:37]3[NH:36][C:35]4[CH:46]=[CH:47][C:32]([I:31])=[CH:33][C:34]=4[S:39](=[O:41])(=[O:40])[N:38]=3)=[C:13]([OH:14])[C@H:15]3[C@@H:20]2[C@H:19]2[CH2:30][C@@H:16]3[CH2:17][CH2:18]2)=[CH:28][CH:27]=1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 49.3 %

Procedure:
N,N-diisopropylethylamine (1.79 mL, 10 3 mmol) and (benzotriazol-lyloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (1.52 g, 3.44 mmol) were added sequentially to a solution of (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 1.0 g, 3.43 mmol) and (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852, 1.26 g, 3.44 mmol) in N,N-dimethylformamide (25 mL) at 25° C. The resulting solution was stirred at 25° C. for 19 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting orange oil was dissolved in ethanol (50 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (3.33 mL, 10.3 mmol) was added and the reaction mixture was heated at 60° C. for 3 h. After cooling to 25° C., the reaction mixture was concentrated in vacuo to approximately 5 mL volume and was then partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (1.0 g, 1.69 mmol, 49%), as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.21 (3H, m), 1.38-1.41 (1H, m), 1.46-1.61 (3H, m), 2.62 (1H, d, J=2.4 Hz), 2.98 (1H, d, J=9.4 Hz), 3.52 (1H, d, J=9.3 Hz), 4.40 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=15.6 Hz), 7.14 (2H, d, J=17.9 Hz), 7.11-7.16 (2H, m), 7.30-7.34 (3H, m), 7.97 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 8.07 (1H, d, J=1.5 Hz). LC-MS (ESI) calcd for C24H21FIN3O4S 593.03, found 594.2 [M+H+].
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([OH:16])[CH2:8][CH2:7]1)=O.[OH-].[Na+]>CO.O.C(Cl)Cl>[NH2:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([OH:16])[CH2:8][CH2:7]1
Reactant: O=C(N[C@H]1CC[C@H](O)c2ccccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: N[C@H]1CC[C@H](O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.9 %

Procedure:
To a grey solution of Intermediate 5a (5.55 g, 21.4 mmol) in MeOH (50 mL), NaOH (1.28 g, 32.1 mmol) in water (15 mL) was added, and the mixture stirred at room temperature for 3 days. NaOH (1.28 g, 32.1 mmol) was further added and the brown solution was stirred for 5 h. The solution was applied directly to an SCX-2 column, washing with MeOH and eluting with 2M NH3 in MeOH, and concentrated under vacuum to leave a grey solid. The solid was suspended in DCM (50 mL) with sonication, then filtered and dried under vacuum to leave a pale grey solid (2.93 g, 84%). 1H NMR (400 MHz, d6-DMSO): 1.41-1.64 (2H, m), 2.02-2.13 (2H, m), 3.82 (1H, dd), 4.55 (1H, dd), 5.08 (1H, br s), 7.13-7.22 (2H, m), 7.35-7.49 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Yield: 38 %

Procedure:
A solution of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (238 mg, 0.43 mM) in 20 mL THF and 25 mL concentrated aqueous ammonium hydroxide was sonicated for 20 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 86.9 mg (38%) of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.7 (m, 1H), 7.55 (d, 1H, J=8 Hz), 7.45 (m, 2H), 7.3 (m, 2H), 7.15 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.2 (d, 1H, J=8 Hz), 5.75 (s, 2H). IR (CHCl3, cm−1) 3500, 3400, 3200 (br), 1649, 1597, 1585, 1446, 1431, 1331, and 1269. MS (ES) m/e 349, 351, 353.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.[NH2:36][C:37]1[N:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([C:21]([NH:36][C:37]3[N:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=3)=[O:23])[N:18]([CH3:20])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(N)cn1C
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
0.3 gm of boc protected 6 (0.94 mmol, 1.2 eq) was dissolved in DMF (5 mL) to which 2.0 eq of EDCl and 2.5 eq of DMAP were added. The mixture was allowed to stir for 30 minutes after which methyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (0.121 g, 0.79 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hours at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed saturated aqueous NaHCO3 (50 mL), water (50 mL), brine (50 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 11a (0.48 gm) was used for the boc deprotection step to afford 11. For boc deprotection, the crude intermediate was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 2 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (11). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 11. Yield 0.35 gm, 81% over two steps.