Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[S:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:42])[F:41])=[CH:32][N:33]=1>C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[S:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:43])([F:41])[F:42])=[CH:32][N:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1-c1cnc(CBr)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: O=c1n(Cc2ncc(-c3ccccc3C(F)(F)F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
40 mg (0.13 mmol) of the compound from Example 5A were dissolved in 7 ml of acetonitrile, and 66 mg (0.20 mmol) of cesium carbonate and 42 mg (0.13 mmol) of the compound from Example 89A were added. The mixture was stirred at 80° C. for 1 h. For work-up, the mixture was cooled to RT, diluted with 5 ml of methanol and filtered. The filtrate was concentrated under reduced pressure and the crude product was then purified chromatographically [Method 19]. This gave 47 mg (66% of theory) of the target compound.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1O
Yield: 76.9 %

Procedure:
Piperidine (0.25 mL, 2.5 mmol) was added to a suspension of 3-hydroxy-4-methoxybenzaldehyde (0.39 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.50 g, 2.2 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3-Hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.53 g, 76%) was obtained as a yellow crystalline solid; mp 215-216° C., lit [25] 219-222° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 6.59 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.10-7.13 (m, 2H, H2′, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.47 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.99 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H).
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[CH:14]C=CN=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C1([NH2:19])CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:14]1[C@@H:15]([NH2:19])[C@@H:10]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC1
Reactant: O=C1CCC(CO)(c2ccccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyridin-2-yl)cyclohexanone (410 mg, 2.0 mmol, 1.0 equiv) in 1,2-dichloroethane (15 mL) was treated at 0° C. with cyclopropylamine (280 uL, 4.0 mmol, 2 equiv), acetic acid (0.1 mL) and NaBH(OAc)3 (848 mg, 2.0 equiv) successively. After being stirred at 25° C. for 12 h, the reaction mixture was carefully diluted (sat.NaHCO3) and extracted (10% MeOH/CH2Cl2). The organics were washed (brine), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 5% MeOH/CH2Cl2 containing 2.5% NH4OH) to provide the trans amine. Further elution afforded the cis amine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][C:23]=3[CH:37]=[O:38])[CH2:12][C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(=O)(=O)([OH:41])N.Cl([O-])=O.[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:24][C:23]=3[C:37]([OH:41])=[O:38])[CH2:12][C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NS(=O)(=O)O
Reactant: CCCCn1c(-c2ccccc2)nc(C=O)c1N(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: CCCCn1c(-c2ccccc2)nc(C(=O)O)c1N(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde 213 (263 mg, 0.5 mmol) in actone (10 mL) and water (5 mL) is added sulfamic acid (107 mg, 1.1 mmol) at room temperature and the mixture is stirred for 30 min. Sodium chlorite (63 mg, 0.7 mmol) is added and the mixture is stirred for additional 30 men at room temperature. Evaporation of most actone and the residure is extracted with chloroform. The organic phase is washed with water, brine and dried over sodium sulfate. The solvent is removed aid the product is dried in vacuo. Yield: 281 mg; LC-MS (MH+): 542.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:4]=1[C:5]([OH:7])=[O:6].[C:15](Cl)(Cl)=[O:16]>O.O1CCCC1>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:3]2[NH:2][C:15](=[O:16])[O:7][C:5](=[O:6])[C:4]=12)([O-:14])=[O:13]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2c(=O)o1
Reaction time: 3 h

Procedure:
A solution of 56.5 g of 2-amino-6-nitrobenzoic acid hydrochloride in 200 ml of demineralized water and 200 ml of tetrahydrofuran is cooled to 10° while stirring and treated with phosgene at 10°-30° for 1 hour, a precipitate resulting. The mixture is subsequently diluted with 300 ml of demineralized water and air is conducted through the suspension vigorously for about 3 hours (until the sample is negative for phosgene). The precipitate is filtered off, washed with water and dried in vacuo over phosphorus pentoxide. There is obtained 6-nitroisatoic acid anhydride as beige crystals of m.p. 220°-222° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl

Procedure:
To a solution of 35 g of 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone in 250 ml pyridine, 34.6 g of hydroxylamine HCl is added. The mixture is refluxed for 4 hours. The pyridine is evaporated in vacuo. The residue is partitioned between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone oxime as a mixture of isomers, mp 150°-156° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11](F)[CH:10]=1.C(N(CC)CC)C>CS(C)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:3][C:15]=2[CH:16]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Yield: 91.8 %

Procedure:
A solution of ethyl thioglycolate (0.65 g, 5.42 mmol), 4-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) and triethylamine (1.25 mL, 12.3 mmol) in DMSO (5 mL) was heated at 75° C. for 2 h. The mixture was partitioned between H2O (50 mL) and CH2Cl2 (2×50 mL), and the combined organic layers were dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as an oil (1.29 g, 92%).
Reaction SMILES: Cl[C:2]1(Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:14].C[OH:17].O>>[Cl:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2](=[O:17])[C:3](=[O:14])[NH:4]2
Reactant: CO
Reactant: COc1ccc2c(c1Cl)C(Cl)(Cl)C(=O)N2
Solvent: O
Product: COc1ccc2c(c1Cl)C(=O)C(=O)N2

Procedure:
Hydrolysis of 3,3,4-trichloro-5-methoxy-1,3-dihydro-indol-2-one in MeOH-water mixture according to the procedure published in Tetrahedron 27, 3263-70 (1971) provided 4-chloro-5-methoxy-1H-indole-2,3-dione as a deep-brown shiny crystals in 96% Y.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.C(#N)C.[NH2:24][C:25]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]2[C:26]=1[CH:27]=[N:28][N:29]2[C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39]>C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:24][C:25]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]3[C:26]=2[CH:27]=[N:28][N:29]3[C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=2)[C:38]([O:40][CH3:41])=[O:39])[CH:7]=1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-n2ncc3c(NC[C@](O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Temperature: 83 °C

Procedure:
(2R)-2-{2-[5-Fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (530 mg, 1.81 mmol) was added to acetonitrile (2.5 mL), followed by the addition of methyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (590 mg, 2.1 mmol) and yttrium trifluoromethanesulfonate (197 mg, 0.37 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was then heated to reflux (83° C.) overnight, then allowed to cool down to room temperature and diluted with ethyl acetate (7 mL). The mixture was washed successively with saturated sodium bicarbonate (10 mL) and water (10 mL), dried and concentrated. The residue was then purified by column chromatography (10% ethyl acetate in cyclohexane) to give, after concentration, the title compound (540 mg).
Reaction SMILES: Cl.NCC([C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1)=O.[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:26][CH2:29][C:30](=[O:32])[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:6]=2)[NH:12][C:11](=[O:15])[CH2:10]3)=[O:32])[CH2:27][CH2:28]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CN1CCC(Cc2ccccc2)CC1
Reactant: NCC(=O)c1ccc2c(c1)NC(=O)C2
Agent: Cl
Product: O=C(CN1CCC(Cc2ccccc2)CC1)NCC(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Condensation of 6-(2-aminoethanoyl)-1,3-dihydroindol-2-one hydrochloride with (4-benzylpiperidin-1-yl)acetic acid, following the procedure described in Example 6, Step 6, gave 2-(4-benzyl-piperidin-1-yl)-N-[2-oxo-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl]acetamide:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:14]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([CH2:3][CH2:2][Br:1])=[CH:5][CH:6]=1)(=[O:16])[CH3:15]
Reactant: OCCOc1ccc(CCBr)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCOc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[4-(2-bromoethyl)phenoxy]ethanol (900 mg), acetic anhydride (0.5 mL), triethylamine (1.0 mL) and DMAP (13 mg) in DCM (5 mL) was stirred at room temperature for 0.5 h. The reaction was quenched by pouring into aq. NaHCO3 and the organic layer was washed with 2M HCl, dried (MgSO4) and concentrated in vacuo to give the title compound (1.03 g). LCMS RT=3.32 min.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl.O>O1CCOCC1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(Cl)cc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 53 %

Procedure:
1-Thiomorpholino-3-piperazino-5-nitro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-nitro-isoquinoline by heating for 5 hours with piperazine in dioxane at 100°C. M.p. of its hydrochloride: 245°-247°C (from water); yield: 53% of theory.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].CCN(CC)CC.S([N:25]=[N+:26]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[N+:25](=[C:1]1[C:2](=[O:3])[CH2:4][O:5][C:6]1=[O:7])=[N-:26]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1COC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)COC1=O
Reaction time: 2 h
Yield: 29.7 %

Procedure:
To tetronic acid (5.00 g, 49.9 mmol) in CH2Cl2 (250 mL) at 0° C. were added Et3N (8.3 mL, 59.6 mmol) and tosyl azide (7.37 g, 37.4 mmol). After a period of 2 h at r.t., the reaction mixture was partitioned between NH4OAc (25%) and CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (20% to 35% EtOAc in Hexane) to provide 1.4 g of the title compound as a white solid.
Reaction SMILES: B(O)O.[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1.N1C=CC=CC=1.CC1N([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)N=C(C(OCC)=O)C=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)[N:6]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc3cc(OC)ccc3c2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)nn1-c1ccc2cc(OC)ccc2c1
Reaction time: 96 h
Yield: 37 %

Procedure:
To a solution of the above-prepared boronic acid (0.84 g, 3.2 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in 20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrous powder of copper(II) acetate (1.15 g, 6.3 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 4 days under argon. The mixture was diluted with DCM. It was filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated and purified by flash column to separately afford ethyl 3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate [37% yield. Rf 0.80 (1:1 EtOAc:hexane). ES-MS: (M+H)+311] and ethyl 5-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-3-carboxylate [25% yield. Rf 0.69 (1:1 EtOAc:hexane). ES-MS: (M+H)+311]in a 1.5:1 ratio.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].ClCCl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:5][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(CC)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To the 250 ml 3-necked flask was added 10.0 gm 2-ethyl 1-hexanol, 100 ml dichloromethane, and 6.0 gm pyridine and the contents were stirred for 10 minutes. To this mixture, 14.2 gm 4-nitro benzoyl chloride was added slowly and stirred under reflux conditions for 2 hrs. The reaction mixture was then cooled, washed with 20% aqueous ammonium hydroxide. The organic layer was washed with 1N hydrochloric acid and brine, and dried over anhydrous sodium sulfate to give a crude product (˜65% yield).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH2:36])=[O:35]>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([NH2:36])=[O:35])=[N:5]2)=[CH:10][CH:11]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C(N)=O)c3)nn12
Yield: 14.9 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 3-Amino-benzamide (118 mg, 0.000870 mol) were dissolved in 2-Methoxyethanol (3.05 mL) and the reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 23.30 mg of 3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-benzamide as a lyophilized powder. (M+H)=360.11. 1H NMR (400 MHz, CDCl3) δ 9.39 (m, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.86 (d, 1H, J=7.64 Hz), 7.63 (d, 1H, J=8.00 Hz), 7.57 (d, 1H, J=7.80 Hz), 7.50 (t, 1H, J=7.56 Hz), 7.36 (t, 1H, J=7.88 Hz), 7.19 (d, 1H, J=5.00 Hz), 7.13 (m, 3H), 3.83 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1(Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[CH:10]1([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(OC2CCCC2)cc1

Procedure:
A solution of 4-hydroxybenzaldehyde (100 mg, 0.819 mmol), cyclopentyl bromide (176 μl, 1.64 mmol), potassium carbonate (340 mg, 2.46 mmol), acetonitrile (4 mL) and potassium iodide (136 mg, 819 μmol) was stirred at 60° C. for 18 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product 4-(cyclopentyloxy)benzaldehyde. This was used as crude in the following Step. Analytical LCMS (M+H)+: m/z=191.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: CI
Reactant: Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2ccccc12
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-methylindole (15.0 g, 114 mmole) in dry DMF (200 mL) was added NaH (60% dispersion in oil, 5.0 g, 125 mmole) in portions. Gas evolution was observed. The mixture was stirred for 30 min, then iodomethane (8 mL, 129 mmole) was added in one portion. The reaction became exothermic and was cooled in an ice bath. After 16 hr at RT, the reaction was concentrated under vacuum and the residue was taken up in ethyl acetate. The solution was washed with H2O then with brine, dried (MgSO4), and concentrated to dryness. Purification by short path distillation under vacuum (bp 88-92° C., 0.5 mmHg) gave the title compound (16.10 g, 97%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=7.9 Hz, 1 H), 7.35 (d, J=8.2 Hz, 1 H), 7.13 (t, 1 H), 7.06 (s, 1 H), 7.00 (t, 1 H), 3.71 (s, 3 H), 2.24 (s, 3 H).
Reaction SMILES: [C:1]([C:4]1[C:27](=[O:28])[O:26][C:7]2=[N:8][C:9]([N:12]3[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].[Br:29]Br>C(Cl)(Cl)Cl>[Br:29][CH2:2][C:1]([C:4]1[C:27](=[O:28])[O:26][C:7]2=[N:8][C:9]([N:12]3[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14][CH2:13]3)=[CH:10][CH:11]=[C:6]2[CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)nc2oc1=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3cc(C(=O)CBr)c(=O)oc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
tert-Butyl 4-(3-acetyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (350 mg, 0.903 mmol) in 10 mL of chloroform was treated with bromine (1M in CHCl3, 0.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitated solid was filtered and the mother liquor was concentrated. The residue was purified on silica gel to yield tert-butyl 4-(3-(2-bromoacetyl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (132.2 mg, 32%). MS m/z 489 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:40])[C@@H:10]([NH:22][C:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:48]1([C:54](Cl)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)(Cl)Cl>[C:28]([O:27][C:25]([N:24]=[C:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:22][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:54]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:40])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-5-oxopentylcarbamate and triethylamine (170 mg) in chloroform (30 ml) was added triphenylmethyl chloride (470 mg), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (4S)-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (850 mg) as an oil.