Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])CCC.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19](N1CCOCC1)=[O:20]>C1COCC1.CCOCC>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]([C:5]1[O:1][CH2:2][CH2:3][CH:4]=1)=[O:20]
Reactant: Cc1cccc(C(=O)N2CCOCC2)c1Br
Reactant: C1=COCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(=O)C2=CCCO2)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,3-dihydrofuran (0.70 mL, 9.25 mmol) in THF (9.0 mL) under inert atmosphere was cooled to −78° C. A solution of n-butyllithium, 1.7 M in pentanes (5.98 mL, 10.17 mmol), was added dropwise over 10 min. The reaction was maintained at that temperature for 30 min, and allowed to warm to 0° C. for 30 min. It was cooled back down to −78° C. and then added via cannula to a solution of (2-bromo-3-methylphenyl)(morpholino)methanone (2.02 g, 7.12 mmol) in Et2O (17.92 mL), also at −78° C. The solution was stirred at that temperature for 10 min and then allowed to warm to 0° C. The mixture was partitioned between Et2O and water and the organics were washed with water and brine. The solution was dried over Na2SO4 and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography eluting with a gradient of Et2O in hexane, to provide (2-bromo-3-methylphenyl)(4,5-dihydrofuran-2-yl)methanone as a colorless oil. This oil was immediately re-dissolved in Et2O and placed under nitrogen before storing in the freezer for further use.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=O.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.N.O>CN(C=O)C>[NH2:30][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
356 mg (1 mmol) of (Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 10 ml of DMF and combined with 194 mg (1 mmol) of CDI. The mixture is stirred for 2 hours at ambient temperature, 2 ml of methanolic ammonia solution are added, then stirring is continued for 16 hours at ambient temperature. Then water is added, the precipitate is removed by suction filtering, washed with water and a little ether and dried at 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH2:25][CH2:26][CH3:27])(OC(C)(C)C)=O>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH:10]([C:12]([NH:30][C:28](=[O:29])[C@@H:23]([NH2:22])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[CH3:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Product: CCCC[C@H](N)C(=O)NC(=O)C(C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine (from Example B above) and L-norleucine amide (from Example F above), the title compound was prepared. The reaction was monitored by tlc (Rf=0.15 in 3% methanol/dichloromethane) and purification of this compound was by thin layer chromatography with 3% methanol/dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]#[C:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][C:9]=1[NH:10][C@@H:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[O:4].[CH3:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]#[C:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:8][C:9]=1[N:10]([C:29]([C@H:26]1[CH2:27][CH2:28][C@H:23]([CH3:22])[CH2:24][CH2:25]1)=[O:30])[C@@H:11]([CH3:15])[CH2:12][CH2:13][O:14][C:29]([C@H:26]1[CH2:27][CH2:28][C@H:23]([CH3:22])[CH2:24][CH2:25]1)=[O:30])=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@@H](C)CCO
Solvent: c1ccncc1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCOC(=O)[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)3-(3-hydroxy-1-(S)-methyl-propylamino)-thiophene-2-carboxylic acid methyl ester (4.0 g, 12.94 mmol) was taken up in pyridine (100 mL). Trans-4-methyl-cyclohexanecarbonyl chloride (12.40 g, 77.66 mmol) was added and the reaction was placed in a 100° C. preheated oil bath and stirred for 16 h. After cooling to rt the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and 2N HCl(aq), the organics dried over Na2SO4, and the solids filtered. Solvent was removed under reduced pressure and 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methylcyclohexanecarbonyl)-[1-(S)-methyl-3-(trans-4-methyl-cyclohexanecarbonyloxy)-propyl]-amino]-thiophene-2-carboxylic acid methyl ester (4.15 g, 58%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4].[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>CN(C=O)C>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1ccccc1NC(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1NC(=O)CNc1ccccc1F
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A solution of ethyl 2-((bromoacetyl)amino)benzoate (1.0 g, 3.5 mmol) and 2-fluoroaniline (1.0 g, 0.87 mL, 9 mmol) in anhydrous DMF (30 mL) was heated to 90°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with 3×50 mL of ethyl acetate. The layers were separated, and then the organic layer was dried (MgSO4), filtered and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (3:1), afforded 0.75 g (68%) of the title compound, mp 79°-81° C.: 1H NMR (DMSO-d6) δ11.41 (s, 1H), 8.59 (dd, J=8.4, J=0.8, 1H), 7.91 (dd, J=8.0, J=1.2, 1H), 7.61 (ddd, J=8.8, J=7.6, J=1.6, 1H), 7.17 (ddd, J=8.0, J=7.6, J=1.2, 1H), 7.08 (ddd, J=9.2, J=8.0, J=1.2, 1H), 6.93 (ddd, J=8.8, J=8.0, J=1.2, 1H), 6.63-6.54 (m, 2H), 6.34 (t, J=5.6, 1H), 4.18 (q, J=7.2, 2H), 3.90 (s, J=5.6, 1H), 1.21 (t, J=7.2, 3H); 13C NMR (DMSO-d6) δ170.08, 166.60, 151.12 (d, J=237), 139.59, 135.99 (d, J=11.3), 134.19, 130.67, 124.76 (d, J=3.1), 123.04, 120.08, 117.07 (d, J=6.9), 116.37, 114.49 (d, J=18.2), 112.12 (d, J=3.0), 61.13, 48.31, 13.86; MS (EI, m/z) 316 (M+). Anal. Calcd for C17H1 7N2O3F: C, 64.54; H, 5.42; N, 8.86. Found: C, 64.18; H, 5.37; N, 8.83.
Reaction SMILES: [OH-].[Na+].CO.[NH:5]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:6]([C:19]([NH:21][C@H:22]([C:29]([NH:31][C@@H:32]([C:43]([NH:45][C@H:46]([C:48]([O:50]C)=[O:49])[CH3:47])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>O>[NH:5]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[C@H:6]([C:19]([NH:21][C@H:22]([C:29]([NH:31][C@@H:32]([C:43]([NH:45][C@H:46]([C:48]([OH:50])=[O:49])[CH3:47])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2N aqueous sodium hydroxide solution (7.5 mL, 15 mmol) was added to a methanol (500 mL) and water solution (200 mL) containing Boc-Lys(Boc)-His-D-Trp-Ala-OMe (10.35 g, 13.7 mmol). After the reaction was allowed to stir overnight at room temperature, HPLC analysis indicated that less than 3% of the starting material remained. The resulting solution was concentrated in vacuo to a volume of approximately 200 mL. Water (100 mL) was added and the pH was adjusted to approximately 12 by addition of 2N sodium hydroxide (1 mL). The resulting solution was extracted with ethyl acetate (2×500 mL). The pH of the aqueous phase was then adjusted to 5 by addition of aqueous HCl which resulted in the precipitation of an oil. The aqueous phase was decanted away from the oil and the oil was then rinsed with water (2×50 mL). This oil was converted to a solid foam upon drying to constant weight in vacuo (5.62 g, 55%). 1H NMR indicated the presence of a single isomer in high purity.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C@@H:3]([N:11]1[C:20](=[O:21])[C:19]2=[CH:22][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]3[C:18]2=[C:13]([CH:14]=[CH:15][N:16]=3)[CH2:12]1)[C:4]([O:6]C(C)(C)C)=[O:5].CO.[OH-].[Na+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:34])[C@@H:3]([N:11]1[C:20](=[O:21])[C:19]2=[CH:22][NH:23][C:17]3[C:18]2=[C:13]([CH:14]=[CH:15][N:16]=3)[CH2:12]1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(ccnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
A mixture of (R)-tert-Butyl 3-methyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate (840 mg, 1.74 mmol), MeOH (4 mL), and aqueous NaOH (1N, 2 mL) was stirred for 40 min at room temperature. The material was diluted with DCM and washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/DCM) gave a yellow oil (390 mg), which dissolved in TFA/DCM (50%) and stirred at room temperature for 1 h. The solution was concentrated and dried under vacuum to give the title compound as a tan solid (320 mg, 67%). 1H NMR (500 MHz, CD3OD) δ 0.88 (d, J=7.0 Hz, 3H), 1.10 (d, J=7.0 Hz, 3H), 2.35-2.44 (m, 1H), 4.95-5.33 (m, 3H), 7.34 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 8.33 (d, J=6.0 Hz, 1H). [M+H] calc'd for C14H15N3O3, 274; found, 274.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1>>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2cccnc2)CCC1
Yield: 54 %

Procedure:
Prepared as described above from 3-bromocyclohex-2-enone and 3-pyridinylboronic acid. Purification by automated flash chromatography using gradient elution (20 to 60% ethyl acetate/hexanes) yielded the product (42 mg, 54%) as a dark orange solid. 1H NMR (300 MHz, CDCl3): δ 7.80 (ddd, J=7.8, 2.4, 1.5 Hz, 1H), 7.34 (ddd, J=7.8, 4.5, 0.6 Hz, 1H), 6.41 (t, J=1.5 Hz, 1H), 2.78 (t, J=5.8 Hz, 2H), 2.51 (t, J=6.6 Hz, 2H), 2.19 (quintet, J=6.2 Hz, 2H). 13C (75 MHz, CDCl3): 199.2, 156.5, 150.8, 147.3, 133.4, 126.6, 123.6, 37.4, 28.0, 22.9. LCMS (ESI): mass calcd for (C11H11NO) m/z 173.08; measured [M+H]+: m/z 174.16.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:46]1[CH2:45][CH2:44][CH:43]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH2:48][CH2:47]1)[CH3:2]
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(c3ccncc3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.04 mmol) 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:39]2[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:41][CH:40]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(Nc1scc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O)c1cc2ccccc2o1
Reaction time: 2 h
Yield: 24.3 %

Procedure:
tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (85, 50 mg, 0.102 mmol), 4-(trifluoromethoxy)phenylboronic acid (32 mg, 0.153 mmol), Tetrakis(triphenylphosphine)palladium(0) (1.0 mg, 0.001 mmol), and sodium carbonate (42 mg, 0.407 mmol), were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70 C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, purified by preparative layer chromatography (10% ethyl acetate/Hexane) then treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 87 as a white powder (11.1 mg, 25%). 1H NMR (500 MHz, DMSO d6) δ=13.35 (br, 1H), 12.55 (br, 1H), 7.87 (d, 1H), 7.86 (s, 1H), 7.76 (d, 1H), 7.57 (t, 1H), 7.49 (d, 2H), 7.42 (t, 1H), 7.36 (d 2H), 7.08 (s, 1H) ppm. ESI MS
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12](Cl)(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC(C)=O.[NH3:23]>O>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([NH2:23])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)Cl
Reactant: N
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(N)(=O)=O

Procedure:
4-Chloro-3,5-dinitro-o-toluenesulfonyl chloride (10 grams, 0.0318 mole) is dissolved in 150 ml. of acetone and chilled to -15° C. Ammonia (1.08 grams, 0.064 mole) is condensed and then vaporized into the acetone solution. When the addition is complete, the reaction mixture is poured into an equal volume of water and the precipitated solid collected. The crude yield of white solid is 6.8 grams with melting point 205° C. to 215° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([S:11][C:12]2[CH:13]=[CH:14][C:15]3[O:24][CH2:23][CH2:22][N:21]4[C:17](=[N:18][C:19]([C:25]5[N:26]([CH:30]([CH3:32])[CH3:31])[N:27]=[CH:28][N:29]=5)=[CH:20]4)[C:16]=3[CH:33]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([S:11]([C:12]2[CH:13]=[CH:14][C:15]3[O:24][CH2:23][CH2:22][N:21]4[CH:20]=[C:19]([C:25]5[N:26]([CH:30]([CH3:31])[CH3:32])[N:27]=[CH:28][N:29]=5)[N:18]=[C:17]4[C:16]=3[CH:33]=2)=[O:35])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C)CC3)ccc1OCC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)(C)C)CC3)ccc1OCC2
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 9-(1-tert-butylpiperidin-4-ylsulfanyl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene, also named as 10-(1-tert-butylpiperidin-4-ylthio)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 139 (280 mg, 0.60 mmol) in DCM (30 mL) at 0° C. was added TFA (139 μL, 1.81 mmol) followed by a solution of m-CPBA (114 mg, 0.66 mmol) in DCM (10 mL). The resulting mixture was stirred for 30 min then washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-12% 2M NH3/MeOH in DCM then C18, gradient 10-35% MeOH in H2O) affording racemic 140 as a white solid (227 mg, 78%). LCMS: RT 2.55 min [M+H]+ 483.4. 1H NMR (DMSO, 400 MHz): δ 8.77 (1H, d, J=2.30 Hz), 7.94 (1H, s), 7.81 (1H, s), 7.58 (1H, dd, J=8.59, 2.31 Hz), 7.29 (1H, d, J=8.58 Hz), 5.89-5.88 (1H, m), 4.59 (4H, s), 3.18 (2H, s), 2.23 (2H, s), 1.91 (1H, s), 1.87 (2H, s), 1.69-1.64 (2H, m), 1.56 (6H, dd, J=6.63, 3.37 Hz), 1.07 (9H, s)
Reaction SMILES: [ClH:1].[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][N:4]=1.N1C2C(=CC=CC=2)C=N1.[CH3:23][CH2:24][OH:25]>CCOCC>[ClH:1].[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[NH:13])[O:25][CH2:24][CH3:23])[CH:10]=2)[NH:5][N:4]=1
Reactant: N#Cc1ccc2[nH]nc(Br)c2c1
Reactant: CCO
Agent: Cl
Agent: c1ccc2[nH]ncc2c1
Solvent: CCOCC
Product: CCOC(=N)c1ccc2[nH]nc(Br)c2c1
Reaction time: 2 h

Procedure:
Passed HCl (g) slowly into a suspension of indazole 3-bromo-1H-indazole-5-carbonitrile (7 g) in EtOH (USP, 300 ml) at 0° C. Stirred at 0° C.-5° C. for approximately 2 hours until precipitation occurred, and stirred overnight at room temperature. Diluted with Ether (ca. 300 ml) and filtered out white solid, dried at room temperature to yield ethyl 3-bromo-1H-indazole-5-carbimidate hydrochloride (7.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([OH:23])[CH2:22][CH2:21][C:16]3([O:20]CCO3)[CH2:15][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16](=[O:20])[CH2:21][CH2:22]3)[O:23][C:25]2=[O:27])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](NCCC1(O)CCC2(CC1)OCCO2)c1ccc(Br)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Yield: 6 %

Procedure:
The title compounds are prepared from 8-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-1,4-dioxa-spiro[4.5]decan-8-ol and triphosgene following a procedure analogous to that described in step 3 of Intermediate 1. The ketal group is partially cleaved under these conditions to give a mixture of the title compounds that is separated by chromatography on silica gel (cyclohexane/ethyl acetate 9:1→1:1). 11-[(S)-1-(4-bromo-phenyl)-ethyl]-1,4,9-trioxa-11-aza-dispiro[4.2.5.2]pentadecan-10-one: Yield: 6% of theory; LC (method 1): tR=3.65 min; Mass spectrum (ESI+): m/z=410/412 (Br) [M+H]+.
Reaction SMILES: CS(C)=O.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:22]=[CH:21][C:13]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].C(O)(=O)C.[BH4-].[Na+]>O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2cccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a dimethyl sulfoxide (15.0 mL) solution of 3-(4-((E)-2-nitro-vinyl)-phenoxy)pyridine (2.00 g, 8.26 mmol) described in Manufacturing Example 76-1-2 and acetic acid (2.00 mL) was added sodium borohydride (500 mg, 13.2 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (819 mg, 40.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41](Br)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-(4-chloro-benzyl)-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[S:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[S:44][C:45]1[CH:46]=[C:47]([NH:48][C:13]([NH:12][C:11]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:49]=[CH:50][CH:51]=1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 71 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 172B (0.145 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.177 g, 71%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.74 (s, 1H), 8.68 (d, 1H), 7.78 (s, 1H), 7.45 (m, 6H), 7.37 (s, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 6.85 (s, 1H), 4.34 (m, 2H), 3.99 (s, 3H), 3.76 (m, 2H), 3.35 (s, 3H), 2.41 (s, 3H); LC-MS (ESI) m/z 625 (M+H)+.