Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].O=[C:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH:3]([OH:4])[CH2:2][NH:1][CH:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:31][CH:32]=1
Reactant: NCC(O)c1ccc2ccccc2c1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1ccc2ccccc2c1

Procedure:
A procedure similar to that described in Preparation 10, below, was followed, but using 520 mg of 2-amino-1-(2-naphthyl)ethanol [prepared as described in Preparation 8], 650 mg of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione [prepared as described in Preparation 9], 150 ml of benzene, 100 ml of absolute methanol and 1.25 g of sodium borohydride, to give the title compound in crude form. This crude product was then purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 490 mg of the title compound melting at between 115° C. and 145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:22][N:21]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: COc1ccnc(CSCCN)c1OC
Solvent: c1ccncc1
Product: COc1ccnc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1OC

Procedure:
A mixture of 2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamine (0.95 g, 4.16 mmol), 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (0.925 g, 3.74 mmol) and pyridine (3.5 ml) was heated under reflux for 24 hours and evaporated to dryness. The residue was purified by elution from silica gel with methanolchloroform (1:7) and recrystallisation from ethanol to give 2-[2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone 121°-1.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]([OH:30])=O)=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=1)([O-:35])=[O:34]>>[CH3:32][C:20]1[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[C:27]2[C:22]([C:21]=1[CH3:31])=[CH:23][C:24]([C:28](=[O:30])[NH:44][C@H:42]([C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=1)[CH3:43])=[CH:25][CH:26]=2
Reactant: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc([N+](=O)[O-])cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].B(F)(F)F>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:10]([C:18](=[O:20])[CH3:19])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5 mmol) in toluene (225 mL) at room temperature was added acetic anhydride (4.6 mL, 48.6 mmol). Boron trifluoride diethyletherate (5.6 mL, 44.6 mmol) was then added dropwise and the resultant solution was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of aqueous sodium bicarbonate. Ether was added and the organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by recrystallization from ethyl acetate-hexanes to give 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (9.0 g, 77%) as redish needles. 1H NMR (CDCl3): δ 8.41 (d, 1 H), 7.59 (m, 2 H), 7.45 (dd, 1 H), 7.26-7.13 (m 3 H), 2.15 (s, 3 H); 19F NMR (CDCl3) δ −112.06; MS m/289 (M+1).
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](Br)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].[N-:37]=[N+:38]=[N-:39].[Na+].CN(C)C=O>C1OCCOCCOCCOCCOC1.O>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([N:37]=[N+:38]=[N-:39])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C1COCCOCCOCCOCCO1
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(CC)C(N=[N+]=[N-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A mixture of diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.05 g, prepared as described in Example 29), sodium azide (0.60 g), 15-Crown-5 (0.02 g), water (1.2 ml) and N,N-dimethylformamide (10 ml) was heated at 100° C. for five hours, cooled, poured into water, and extracted with ethyl acetate. The extracts were washed with water and brine, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-azido-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.64 g, m.p. 82°-84° C.). NMR (CDCl3): δ1.3(6H,dt), 1.6-2.0(2H,m), 2.2-2.3(2H,m), 4.1(4H,m), 4.65(1H,t), 7.1(6H,m), 7.3(9H,m), 8.0(1H,s). M/S: MH+ 531.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][C:17]([F:22])=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:10])=[CH:12]2)[CH:29]=[CH:30][CH:31]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccc(F)cc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-6-fluoro-1H-quinolin-4-one, 8 mg (0.20 mmol) of 60% sodium hydride and 51 mg (0.20 mmol) of 2-bromo-6-bromomethyl-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 38 mg of a white solid: LC-MSD, m/z for C23H17BrFN3O2 [M+H]+=466.2, 468.1; HPLC retention time: 2.1 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=S)[NH:14][C:15]=2[CH:16]=1)=[O:4].[NH3:21]>>[NH2:21][C:13]1[CH:12]2[CH2:18][CH2:19][CH2:20][CH:11]2[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:16][C:15]=2[N:14]=1
Reactant: COC(=O)CCc1ccc2c(c1)NC(=S)C1CCCC21
Reactant: N
Product: COC(=O)CCc1ccc2c(c1)N=C(N)C1CCCC21
Yield: 28 %

Procedure:
Analogously to Example 4, 7-(methoxycarbonylethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (150 mg, 0.52 mmol) in 7N methanolic ammonia solution (20 ml) is reacted to form 40 mg (28%) of product.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:50])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:34]([CH2:36][CH:37]=[CH2:38])[CH3:35])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:7][CH2:6]1)C=C.[BH4-].[Na+]>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.CCOC(C)=O>[C:46]([O:45][C@@H:40]([C:12]1[C:13]([CH3:39])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:50])([O:4][CH2:1][CH2:38][CH2:37][CH2:36][C@H:34]([CH3:35])[O:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:47])[CH3:49]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)ccc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.17 g, 0.25 mmol, 1 equiv) in DCE (50 mL) was heated to 80° C. The Hoyveda Grubbs 2nd generation catalyst (31 mg, 0.05 mmol, 0.2 equiv) was added. The pale green brown solution was stirred for 1.5 h and then allowed to cool to ambient temperature. The reaction was concentrated in vacuo. The dark residue was then taken up in MeOH (5 mL) and NaBH4 (13 mg, 0.35 mmol, 1.4 equiv) was added. After stirring 30 min, the reaction was diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a colorless film (62 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.39-7.31 (m, 1H), 7.09 (s, 1H), 7.05-6.87 (m, 3H), 5.93-5.82 (m, 1H), 4.68-4.42 (m, 2H), 4.27-4.17 (m, 1H), 3.84-3.68 (m, J=3.5 Hz, 4H), 3.56-3.22 (m, 2H), 3.03-2.85 (m, 1H), 2.62 (br. s., 3H), 2.02-1.70 (m, J=12.8 Hz, 10H), 1.26-1.21 (m, 12H), 1.15 (d, J=6.0 Hz, 3H). LCMS (M+1)=659.45.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]Br>CO>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrBr
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
To a stirred suspension of 5-Nitro-1H-indazole (15.0 g, 92.0 mmol) in 400 ml methanol was added bromine (4.7 ml, 92.0 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to afford the title compound, (25.0 g, 100%); MS (ES+) m/e 243 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:33])([F:32])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]=3[N:22]=[C:23]([CH2:25][O:26][CH3:27])[N:24]=2)=[CH:14][CH:13]=1.Cl[C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[Cl:41][C:40]1[C:35]([N:29]2[CH2:30][CH2:31][C:20]3[C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:32])[F:33])=[CH:13][CH:14]=4)=[N:24][C:23]([CH2:25][O:26][CH3:27])=[N:22][C:21]=3[CH2:28]2)=[N:36][CH:37]=[CH:38][CH:39]=1
Reactant: Clc1cccnc1Cl
Reactant: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Agent: CCN(CC)C(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 11.9 %

Procedure:
A mixture of diisopropylethylamine (490 mg, 3.8 mmol), N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine (˜1.9 mmol) and 2,3-dichloropyridine (562 mg, 3.8 mmol) in dioxane (5 mL) and N,N-diethylacetamide (1.0 mL) was irradiated in microwave at 180° C. for 10 h. Solvent was removed in vacuo and the residue was purified by column chromatography. The product was obtained as a beige solid (102 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[CH:15]=[O:16]>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=3[F:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C1CC2(CCN1)OCCO2
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(F)c1

Procedure:
The title compound was prepared from 1,4 dioxa-8-azaspiro[4.5]decane and 3,4-difluorobenzaldehyde according to the procedure of Example 56 as an orange oil; 1H NMR (300 MHz, CDCl3) δ 1.88 (t, J=5.7 Hz, 4H), 3.35 (t, J=5.8 Hz, 4H), 4.01 (s, 4H), 6.96 (t, J=7.8 Hz, 1H), 7.47-7.49 (m, 1H), 7.53-7.58 (m, 1H), 9.81 (s, 1H); MS (ES) m/z: 265.8 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:14]1C=CC(Br)=CC=1.[Li]CCCC.CCCCCC.C1(=O)CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9][CH2:14]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O=C1CCCC1
Product: OC1(c2ccc(Br)cc2)CCCC1
Yield: 39 %

Procedure:
The title compound was synthesized in analogy to 1-(4-bromo-phenyl)-cyclobutanol (described in example S97) using 3 g of 1,4-dibromobenzene (12.7 mmol), 7.95 ml of a 1.6 molar solution of n-BuLi in hexane (12.7 mmol) and 1.24 ml of cyclopentanone (14.0 mmol). The isolated residue was purified by flash column chromatography (1:4 diethyl ether/pentane) to give 1.2 g of 1-(4-bromo-phenyl)-cyclopentanol (39%) as a colorless liquid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:37][CH2:36][CH2:35][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].CCOCC>Cl.O1CCOCC1>[NH:1]1[CH2:37][CH2:36][CH2:35][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.75 h

Procedure:
3.02 g (5.8 mmol) of Boc-Pro-Arg-Pro-Gly-Pro were suspended in 10 ml of 2N hydrochloric acid in dioxane and were incubated at room temperature for 45 min. Then, dry ether was added, and the precipitate was washed by decantation with dry ether. It was reprecipitated with ether from absolute methanol. The resulting precipitate was dissolved in 7.5 ml of 30% ethanol and applied to Amberlyst A-21 (Aco−-form) column for acetate/hydrochloride salt exchange. Peptide was eluted with 200 ml of 30% ethanol, evaporated to dryness under vacuum and precipitated with absolute ether from methanol.
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28](N)=[O:29].CC(C)=[O:33].CCCCCC>>[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28]([OH:29])=[O:33]
Reactant: NC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
3.0 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide is refluxed in a mixture of 20 ml. of acetic acid and 30 ml. of concentrated hydrochloric acid for 3 hours. The solution is cooled and poured into water. The mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to yield 90% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:30]3[CH2:31][CH2:32][CH:28]([CH2:27][O:26][CH3:25])[CH2:29]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC1CCNC1
Product: COCC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(methoxymethyl)pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ 1.51-1.66 (m, 1 H) 1.83-1.99 (m, 1 H) 2.36 (s, 3 H) 3.14 (s, 1 H) 3.22 (s, 2 H) 3.37-3.62 (m, 4 H) 7.56-7.61 (m, 1H) 7.65 (s, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 8.03-8.15 (m, 2 H) 8.31 (d, J=8.3 Hz, 1 H) 8.55-8.62 (m, 1 H) 13.07 (br. s., 1 H). MS m/z [M+H]+ 418.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:20][OH:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
4,4′-Dimethoxybenzophenone (25 g, 103 mmol) is suspended in ethanol (150 ml) and pyridine (30 ml). Hydroxylamine hydrochloride (21.50 g, 310 mmol) is added and the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 3 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer dried is over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained following crystallisation from ethylacetate/cyclohexane. 1H nmr (CDCl3, 400 MHz); 7.70(s, 1H), 7.40 (d of d, 4H), 6.95(d, 2H), 6.85(d, 2H), 3.85(s, 3H), 3.80(s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=2)=O)[C:4]=1[NH:27]C(=O)OC(C)(C)C.[I-:35].[Na+]>C(O)(=O)C.C(O)=O>[I:35][C:9]1[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:27]=[C:11]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=2)[CH:10]=1
Reactant: [I-]
Reactant: COCCOc1ccn2c(C(=O)C#Cc3cccc(OC)c3NC(=O)OC(C)(C)C)cnc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Product: COCCOc1ccn2c(-c3cc(I)c4cccc(OC)c4n3)cnc2c1
Temperature: 60 °C
Yield: 92 %

Procedure:
To tert-butyl 2-methoxy-6-(3-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)-3-oxoprop-1-ynyl)phenylcarbamate (2.51 g, 5.39 mmol) and sodium iodide (16.2 g, 108 mmol) was added acetic acid/formic acid (5 mL/5 mL). The reaction vessel was purged with N2 and heated to 60° C. for 3 hours. The reaction was then cooled to ambient temperature and diluted with H2O/DCM (50 mL/100 mL), followed by extraction with DCM. The combined organics were washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/MeOH 10:1) provided the desired product (92%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[O:47]1[C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=[N:48]1.C(N(CC)CC)C>O1CCCC1>[O:47]1[C:51]([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])=[CH:50][CH:49]=[N:48]1
Reactant: O=C(Cl)c1ccno1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added isoxazole-5-carbonyl chloride (0.066 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 698 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH:12][C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1)(=[O:11])=[O:10].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>CN(C=O)C>[C:24]([N:12]([C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1)[S:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:11])(=[O:26])[CH3:25]
Reactant: Cc1cc(C)n2nc(NS(=O)(=O)c3c(Cl)cccc3Cl)nc2n1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N(c1nc2nc(C)cc(C)n2n1)S(=O)(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 37.1 %

Procedure:
A solution of 0.50 g (1.3 mmol) of 2,6-dichloro-N-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidin-2-yl)benzenesulfonamide, 2.12 ml (22.5 mmol) of acetic anhydride and 0.18 ml (1.3 mmol) of triethylamine in 4 ml of DMF was heated at 85° C. for 3 days. After cooling to room temperature, the product separated from solution and was collected by filtration and dried in vacuo to yield 0.20 g (39 percent) of the desired product as a solid, mp 219°-222° C. The product was characterized by IR and NMR spectroscopy.