Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:23](O)(=[O:34])[CH2:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:20][C:23]([CH2:24][NH:25][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Product: O=C(CNC(=O)c1ccccc1)NC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 1.1 from C,C-bis-(4-trifluoromethyl-phenyl)-methylamine (example 4.1) and hippuric acid.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc([N+](=O)[O-])cc2)CC1
Yield: 85 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-nitrobenzaldehyde (0.87 g) were reacted and treated in the same manner as in Example 121 to give 2.3 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-nitrobenzylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][N:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12](=[O:18])[C:13]1[S:17][CH:16]=[CH:15][CH:14]=1.[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][N:10]=1)[N:7]([C:19]([NH2:20])=[O:25])[C:6](=[O:11])[CH:5]2[C:12](=[O:18])[C:13]1[S:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Nc2cnc(Cl)cc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CC#N
Solvent: CS(C)=O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ncc21

Procedure:
The title compound was prepared from 5-chloro-3-(2-thenoyl)-6-azaoxindole (Example 3C) according to the procedure of Example 2C, using 5-chloro-3-(2-thenoyl)-6-azaoxindole (140 mg, 0.5 mmol), N-chlorosulfonyl isocyanate (65 L, 0.75 mmol), and acetonitrile (5 mL). The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO for 2 hours in a flask open to the air. The product was precipitated by addition of water and was collected by filtration. The solid was recrystallized from methanol. Yield: 27 mg (17%).
Reaction SMILES: [C:1]12([CH2:13][CH:12]3[CH2:14][CH:9]1[CH2:10][CH2:11]3)[CH2:3][CH:2]2[C:4]([O:6]CC)=[O:5].C1(C(OCC)=O)C2(CCCCC2)C1>>[C:1]12([CH2:13][CH:12]3[CH2:14][CH:9]1[CH2:10][CH2:11]3)[CH2:3][CH:2]2[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C1CC12CC1CCC2C1
Agent: CCOC(=O)C1CC12CCCCC2
Product: O=C(O)C1CC12CC1CCC2C1

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 36B for the product from Example 1A. MS (ESI) m/z 165 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCCO)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-hydroxyphenyl)-1-propanol (3 g, 19.7 mmol) in acetone (30 mL) is added potassium carbonate (4.08 g, 29.5 mmol) and methyl bromoacetate (2.8 mL, 29.3 mmol) and the reaction is heated at reflux for 15 h. The reaction mixture is allowed to cool to RT, filtered, and the solvent removed in vacuo. The residue is purified by chromatography (SiO2, EtOAc:iso-hexane, 2:3) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.14 (2H, d), 6.85 (2H, d), 4.64 (2H, s), 3.82 (3H, s), 3.69 (2H, t), 2.68 (2H, t), 1.82 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:59])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:56][CH2:57][CH3:58])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([O:39]CC4C=CC=CC=4)[C:36]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[CH:35][C:34]=3[CH2:54][CH3:55])=[CH:23][CH:24]=2)[O:19]1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:59])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:56][CH2:57][CH3:58])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[C:34]([CH2:54][CH3:55])=[CH:35][C:36]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[C:37]([OH:39])[CH:38]=3)=[CH:23][CH:24]=2)[O:19]1)=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Yield: 81.8 %

Procedure:
2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate (110 mg) was dissolved in methanol/chloroform (2:1, 5 mL) with 10% Pd/C (24 mg) and hydrogen gas bubbled in for 2 hours. The mixture was filtered through Celite®, rinsed with methanol, and concentrated under vacuum to afford 80 mg of 2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(6-ethyl-4-(4-fluorophenyl)-3-hydroxyphenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate. Mass Spec (EI): 723.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:12]([S:13](Cl)(=[O:15])=[O:14])=[CH:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].B.O1CCCC1>[Cl-].[NH4+].O.CO.C1COCC1>[Br:1][C:2]1[C:12]([S:13]([N:24]([CH2:23][C:22]2[CH:30]=[CH:31][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:15])=[O:14])=[CH:11][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(S(=O)(=O)Cl)c(Br)cc2N1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: B
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3c(cc2Br)NCCO3)cc1
Reaction time: 0.08 h
Yield: 25.7 %

Procedure:
A 50-mL round-bottom flask was charged with 6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (Enamine, Kiev, Ukraine, 1.002 g, 3.07 mmol), N-(4-methoxybenzyl)thiazol-2-amine (0.811 g, 3.68 mmol), and THF (15.34 ml) to give a thick suspension. The flask was cooled in a dry ice-acetone bath for 10 min. Lithium bis(trimethylsilyl)amide (1M in THF) (6.75 ml, 6.75 mmol) was added dropwise over 5 min. After another 5 min, the flask was transferred to an ice-bath. After 25 min, the mixture was diluted with saturated aq. ammonium chloride and water. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM (2×, to help remove residual EtOAc and water). The flask was flushed with Ar (g), and the mixture was taken up in THF (15 mL) to give a thin suspension. Borane-tetrahydrofuran complex (1M in THF) (7.67 ml, 7.67 mmol) was added over 20 s, resulting in some bubbling and then a clear, amber solution. The mixture was stirred overnight for 16 h, then MeOH (ca. 20 mL) was added carefully. The resulting solution was stirred for 3 h, and the mixture was concentrated. The residue was concentrated from MeOH (1×), then from MeOH/DCM (3×). The residue was taken up in MeOH, which formed a partial slurry with some floating gummy solid. The mixture was sonicated for 2 min, then stirred vigorously for 4 h. The mixture was filtered, and the collected solids were washed with MeOH (2×), then dried under a stream of N2 (g) overnight. The material was dried further under high vac to give 6-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (391.2 mg, 0.788 mmol, 25.7% yield) as an off-white solid: m/z (ESI) 495.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=2)[OH:16])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:34](OS(C(F)(F)F)(=O)=O)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=2)[O:16][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(C(O)c2ccnn2COCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC(c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)c1ccnn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2-benzyloxymethyl-2H-pyrazol-3-yl)-(3-benzyloxy-4-nitrophenyl)-methanol (392 mg, 0.881 mmol), TBSOTf (0.25 mL, 1.09 mmol) and 2,6-lutidine (0.153 mL, 1.32 mmol) in CH2Cl2 is stirred at RT for 2 h. The mixture is partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase is dried over MgSO4 and concentrated. The residue is purified by flash chromatography to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=C(C3C=C(C)N=C(NCC)N=3)O[N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH2:35]([NH:39][C:40]1[N:45]=[C:44]([C:46]([OH:48])=O)[CH:43]=[C:42]([CH3:49])[N:41]=1)[CH:36]([CH3:38])[CH3:37].OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH2:35]([NH:39][C:40]1[N:45]=[C:44]([C:46]2[O:48][N:23]=[C:19]([C:17]3[CH:18]=[C:3]([CH3:1])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:15]([CH3:34])[CH:16]=3)[N:20]=2)[CH:43]=[C:42]([CH3:49])[N:41]=1)[CH:36]([CH3:37])[CH3:38]
Reactant: Cc1cc(C(=O)O)nc(NCC(C)C)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)nc(NCC(C)C)n1

Procedure:
rac-N-(3-{4-[5-(2-Isobutylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-isobutylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.96 min; [M+H]+=485.31.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccn1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccccn4)c23)C1

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (194 mg, 0.579 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.348 g, 1.74 mmol) in n-BuOH (2 mL) was stirred at 149° C. for 24 hours in a sealed tube and concentrated in vacuo. The residue obtained was dissolved in ethyl acetate (20 mL) and successively washed with water (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+) on Biotage SP4 unit eluting with gradient of 10-90% CH3CN/water to provide (R)-tert-butyl 1-(5-bromo-3-(picolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. This material was dissolved in DCM (3 mL), treated with TFA (0.5 mL) and stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL) and treated with 2N HCl in ether (3 mL). The solid formed was collected by filtration and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide hydrochloride (0.022 g, 0.0419 mmol, 7% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.90 (br s, 1H), 11.35 (br s, 1H), 8.87 (d, 1H), 8.36 (br s, 3H), 8.31 (s, 1H), 8.21-8.11 (m, 3H), 7.74 (t, 1H), 4.04-3.94 (m, 1H), 3.76-3.67 (m, 1H), 3.58-3.48 (m, 1H), 3.43-3.34 (m, 1H), 3.08-3.00 (m, 1H), 2.44-2.37 (m, 1H), 2.27-2.14 (m, 1H), 1.90-1.81 (m, 1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 415.1, 417 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1.C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[N:10]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Brc1cc2[nH]c(-c3cnco3)cc2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)OC(=O)n1c(-c2cnco2)cc2cnc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
5-(6-Bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)oxazole (Preparation 139, 156 mg 0.59 mmole) was azeotroped with benzene (3 mL) and then dissolved in DMF (1.5 mL). The solution was placed under nitrogen and a solution of sodium hexamethyldisilazide (1M in THF, 0.9 mL, 0.9 mmole) was added and stirred at room temperature for 20 minutes. A solution of isopropyl chloroformate (1M in toluene, 0.9 mL, 0.9 mmole) was added and stirred at room temperature for 4 hours. The reaction was diluted with ethyl acetate (25 mL) and the solution was washed with water (3×10 mL), brine, dried and evaporated to a residue. This was purified using preparative TLC eluting with 3:1 ethyl acetate:cyclohexane. The product band was recovered with acetone to afford the title compound (154 mg, 74%). 1H-NMR (CDCl3, 500 MHz): δ 1.36 (d, J=6.31 Hz, 6H), 5.23 (sept, J=6.31 Hz, 1H), 6.94 (d, J=0.63 Hz, 1H), 7.41 (s, 1H), 8.02 (s, 1H), 8.32 (t, J=0.95 Hz, 1H), 8.69 (d, J=0.95 Hz, 1H).
Reaction SMILES: [CH3:1][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:27][C:28]1[CH:29]=[C:30]([C:35](=O)[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:31]=[CH:32][C:33]=1[Cl:34].O>C1C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([C:35](=[CH2:1])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
1.75 g (49.0 mmole) of methyltriphenylphosphonium bormide and 5.50 g (49.0 mmole) of potassium t-butoxide were suspended in 200 ml of dried benzene, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. At the end of this time, 8.50 g of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] were dissolved in 40 ml of benzene, and the resulting solution was added to the reaction mixture. The mixture was then stirred for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl either ranging from 19:1 to 23:2 by volume as the eluent, to give 4.20 g of the title compound as a pale orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([C:14]#[C:15][Si](C)(C)C)=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCC.Cl>CO.CCCCC>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([C:14]#[CH:15])=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[N:3]1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(C#C[Si](C)(C)C)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: CO
Product: C#Cc1sc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96.3 %

Procedure:
To a mixture of 1-methyl-3-(2-chloro-6-fluorophenyl)-5-(3,4-dichloro-5-(2-trimethylsilyl-ethynyl)-thien-2-yl) [1,2,4]triazole (5.0g, 10.9 mmol) in methanol (20 mL) was added potassium carbonate (1.66 g, 12 mmol) at 0° C., and the resulting off-white suspension was stirred at 0° C. for 3.5 hours. TLC analysis (10% EtOAc/Pentane) indicates complete conversion to product. The reaction was acidified with 2 N hydrochloric acid and extracted with ether (2×100 mL). The organics were combined, washed with brine, dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give a tan solid. Trituration with pentane affords 4.06 g (96%) of product as a tan powder: mp 145-165 (slow decomposition) 1H NMR (CDCl3) δ3.77 (s, 1H,), 4.04 (s, 3H), 7.08-7.14 (m, 1H), 7.29-7.40 (Ar-m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[N:11]2[C:7](=[N:8][N:9]=[CH:10]2)[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]([CH2:16][C:17]([N:19]([CH:26]([CH3:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[C:3]1=[O:29].[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH:26]([N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:17](=[O:18])[CH2:16][N:4]1[C:3](=[O:29])[CH:2]([NH:1][C:37]([NH:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[N:11]2[C:7](=[N:8][N:9]=[CH:10]2)[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]1=2)([CH3:27])[CH3:28]
Reactant: CC(C)N(C(=O)CN1C(=O)C(N)n2cnnc2-c2ccccc21)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CC(C)N(C(=O)CN1C(=O)C(NC(=O)Nc2ccccc2)n2cnnc2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A mixture of 2-(4-Amino-5-oxo-4,5-dihydro-1,2,3a,6-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide (140 mg, 0.361 mmol), prepared as in Intermediate 36, and phenyl isocyanate (39.2 uL, 0.361 mmol) in 5 mL dry DCM is stirred at ambient temperature under nitrogen overnight. After concentrating in vacuo, the residue is chromatographed on flash grade silica gel using 95% ethyl acetate in n-hexane. The fractions containing the product are combined, concentrated in vacuo, and triturated with hexane. After removing the solvent in vacuo, the product is dried overnight at ambient temperature under high vacuum to provide the title compound (84 mg, 0.165 mmol) as a white solid. The product is lyophilized from acetonitrile/water. 1H NMR (300 MHz, d6-DMSO): 0.89-0.96 (m, 6H); 4.02 (d, J=16.3 Hz, 1H); 4.16 (d, J=16.3 Hz, 1H); 4.62-6.73 (m, 1H); 5.99-6.05 (m, 1 H); 6.93 (t, J=7.2 Hz; 1H); 7.10-7.89 (m, 14H); 8.10 (s, 1H); 9.30 (s, 1H). MS (FAB): [M+H]+ 510.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17])([CH2:13][CH3:14])[CH3:12].C(N(CC)CC)C.Cl>ClCCl>[CH:11]([CH:15]([CH2:18][CH:19]=[CH2:20])[CH:16]=[O:17])([CH2:13][CH3:14])[CH3:12]
Reactant: C=CCC(CO)C(C)CC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCC(C=O)C(C)CC
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
Dimethyl sulfoxide (18.20 mL, 256.4 mmol) was added dropwise over 15 minutes to a dichloromethane (280 mL) solution of oxalic acid chloride (16.90 g, 133.1 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 25 minutes. Subsequently, a dichloromethane (75 mL) solution of 2-sec-butylpent-4-en-1-ol (12.20 g, 85.8 mmol) was added dropwise thereto over 30 minutes, and the mixture was stirred at −78° C. for 1 hour. Triethylamine (60.80 g, 600.8 mmol) was added dropwise thereto over 5 minutes, and the mixture was then stirred at room temperature for 2 hours. The mixture was neutralized with 2 N hydrochloric acid (310 mL). The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a yellow oil substance as a mixture containing the compound of interest. This compound was used in the next reaction without being further purified.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[N:19]([CH3:20])[N:18]=[N:17][N:16]=2)(=[O:9])=[O:8])=[N:5][N:4]=[N:3]1.[OH:21]O.O>C(O)=O>[CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([C:15]2[N:19]([CH3:20])[N:18]=[N:17][N:16]=2)=[O:21])(=[O:8])=[O:9])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCCS(=O)(=O)c1nnnn1C
Reactant: OO
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S(=O)CCCCS(=O)(=O)c1nnnn1C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiobutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (1 g) is dissolved in formic acid (10 ml), and thereto is added with stirring 30% hydrogen peroxide (0.4 g) at room temperature, and the mixture is stirred for 3 hours. Water is added to the mixture and the precipitated crystals are collected by filtration and recrystallized from ethanol-chloroform to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfinylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (0.4 g) as colorless scales, m.p. 147°-149° C.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23]>O.C(O)C>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23])#[N:2]
Reactant: [C-]#N
Reactant: O=c1cc(-c2ccc(Cl)cc2)oc2ccc(CBr)cc12
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc2oc(-c3ccc(Cl)cc3)cc(=O)c2c1
Temperature: 60 °C

Procedure:
3.2 g (0.05 mole) of potassium cyanide dissolved in 50 ml of water is placed in a reaction vessel. The solution is heated to 60° C and a solution of 8.3 g (0.023 mole) of 6-bromomethyl-2-(p-chlorophenyl)chromone in 1600 ml of ethanol is added in four portions, one every 20 minutes. Once the addition is complete the mixture is refluxed for 3 hours, evaporated to dryness and dissolved in water. The solid is filtered off and recrystallised from alcohol.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1ccc(N)cc1C(=O)O
Reaction time: 2 h
Yield: 79.5 %

Procedure:
2-Isopropoxy-5-nitrobenzoic acid (6.02 g, 26.75 mmol) was suspended in EtOH (100 ml) and 10% Pd on C (wet basis) (600 mg) was added. The mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered through celite and the volatiles were removed in vacuo. The residue was triturated with IPA, and the resulting solid filtered off, washed with MTBE and dried in vacuo to give 4.15 g of 5-amino-2-isopropoxybenzoic acid (79.5%) as a pale yellow solid.