Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:6]1[C:5]2=[O:19].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:25]([N:12]2[C:7]3=[N:8][C:9]4[C:4]([C:5](=[O:19])[N:6]3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=3)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=4)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=c1c2cc(Cl)ccc2nc2[nH]c3ccccc3n12
Reactant: O=C(Cl)C1CCCC1
Product: O=C(C1CCCC1)n1c2ccccc2n2c(=O)c3cc(Cl)ccc3nc12

Procedure:
6-Cyclopentanoyl-2-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one and cyclopentanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Product: N[C@@H](CCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 94 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-chlorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid, gave (S)-2-amino-N-(4-(4-chlorophenoxy)phenyl)-4-phenylbutanamide (320 mg, 94%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:13]I>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH3:13])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CI
Reactant: COC(=O)Cc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cccs1
Temperature: -30 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution of methyl 2-(thiophen-2-yl)acetate (4.90 g, 31.4 mmol) in THF (25 ml) was added dropwise to a suspension of sodium hydride (1.20 g, 31.4 mmol, 60%) in THF (25 ml) at −50° C. under an atmosphere of nitrogen. After the reaction mixture was stirred for 1 h, methyl iodide was added (1.76 ml, 28.2 mmol) as solution in THF (25 ml) slowly at −50° C. over a period of 15 min. The reaction mixture was warmed up to −30° C. and continued to stir for another 2 h. It was quenched with aqueous ammonium chloride, extracted with DCM (2×30 ml) and washed with brine (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The crude was purified by column chromatography over silica gel (100-200 mesh) using ethyl acetate (5%) in petroleum ether as eluent to get 2.2 g (41.7%) of methyl 2-(thiophen-2-yl)propanoate as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1)\[CH2:7][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(C(F)(F)F)c1
Yield: 56.6 %

Procedure:
To a stirred mixture of (E)-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (5.33 g, 0.019 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (5.20 g, 0.029 mol) and benzoyl peroxide (470 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (3.80 g, 55%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[O:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[C:10]4[N:9]5[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]5=[C:7]([CH3:16])[C:6]=4[CH:5]=[C:4]([Cl:17])[CH:3]=3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc5c(c4)OCO5)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (78 mg, 88%), MS (ISP) m/z=355.4 [(M+H)+], mp 244.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available benzo[d][1,3]dioxol-5-ylboronic acid (53.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:3]1[CH3:19].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([CH3:26])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:19])=[C:4]2[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccc(-c2c(C)n(C)c3ccc(O)cc23)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(C)cc1)c(C)n2C

Procedure:
The above compound was prepared from 1,2-dimethyl-3-(4-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12](OCC)=[O:13])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Al].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[N:3]=1
Reactant: CCOC(=O)CCCSc1nccc(N)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Al]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccnc(SCCCCO)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6.03 g (25 mmol) of 4-amino-2-(3-ethoxycarbonylpropylthio)pyrimidine in 150 ml of tetrahydrofuran, 0.949 g (150 mmol) of lithium aluminum hydride was added at room temperature, followed by stirring at 60° C. for 2 hours. After the reaction mixture was cooled, water was added little by little to decompose the excess aluminum reagent. After anhydrous magnesium sulfate was added to the mixture, the precipitate was filtered off, after which the solvent was distilled off to yield 8.85 g (88.8%, white crystal) of the desired product.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[NH2:18][C:19]1[C:20](=[O:41])[N:21]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])[CH:22]=[CH:23][C:24]=1[C:25](OCC)=[O:26].Cl>CN(C)C=O>[CH3:40][O:39][C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[CH2:30][N:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:26])[N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=3)[C:2](=[S:3])[NH:18][C:19]=2[C:20]1=[O:41]
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Reactant: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3c(=O)n(-c4ccc(OCC(F)(F)F)cc4)c(=S)[nH]c3c2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To a solution of 1-isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (375 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 193 mg) under ice-cooling, and the mixture was cooled to 0° C. A solution of ethyl 3-amino-1-(2,4-dimethoxybenzyl)-2-oxo-1,2-dihydropyridine-4-carboxylate (535 mg) in N,N-dimethylformamide (5 ml) was added dropwise thereto, and the mixture was stirred at 0° C. for 15 min. The reaction mixture was poured into 0.3M hydrochloric acid (15 ml), and the precipitate was collected by filtration. The obtained solid was suspended in toluene, and the suspension was concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (527 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:43])[N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([CH3:46])[C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:43])[N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([CH3:46])[C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Cl)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1cc2c(cc1F)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Yield: 97 %

Procedure:
Prepared in 97% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (600 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.30 (br. s., 1H), 7.14 (d, J=6.2 Hz, 1H), 7.10 (d, J=10.3 Hz, 1H), 5.86-5.58 (m, 1H), 4.60 (d, J=4.4 Hz, 1H), 4.00-3.95 (m, 1H), 3.90 (br. s., 1H), 3.84-3.77 (m, 1H), 3.47-3.41 (m, 1H), 3.38-3.32 (m, 1H), 2.43 (br. s., 3H), 2.34 (br. s., 1H), 2.28 (s, 3H), 2.01-1.49 (m, 10H), 1.19 (br. s., 3H), 1.16 (s, 9H), 1.03 (d, J=5.5 Hz, 3H); LCMS (ESI, M): 691.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[CH:29]=[CH:28][NH:27][C:24]2=[N:25][CH:26]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[CH:29]=[CH:28][N:27]([CH2:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[C:24]2=[N:25][CH:26]=1)=[O:20]
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Product: COC(=O)c1cnc2c(ccn2Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Yield: 73 %

Procedure:
Compound 36 was prepared following general method 3A, using compound 17 as a starting material and 1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester as the heterocycle. Yield: 73%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][C:29]=1[NH2:35].O>ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:35][C:29]3[CH:30]=[N:31][C:32]([CH3:34])=[CH:33][C:28]=3[CH3:27])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1cc(C)c(N)cn1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Temperature: 70 °C
Yield: 97.7 %

Procedure:
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (247 mg, 0.819 mmol) was added to a solution of triethylamine (0.114 mL, 0.819 mmol) and 4,6-dimethyl-3-pyridinamine (100 mg, 0.819 mmol) in dichloromethane (1 mL). The mixture was heated at 70° C. for 2 hours. To the mixture was added water (5 mL) then the organic layer separated and purified by silica (Si) chromatography (100% ethyl acetate). The relevant fractions were combined and concentrated to give the title product (310 mg) as a yellow solid. LCMS (2 min, formic) Rt 0.63 mins, m/z (ES+) 388 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)[O:3]1.ClS([N:19]=[C:20]=[O:21])(=O)=O.O1C=CC=C1>C(#N)C.O.C(Cl)Cl>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:14])([CH3:1])[O:3][B:4]([C:9]2[CH:13]=[C:12]([C:20]([NH2:19])=[O:21])[O:11][CH:10]=2)[O:5]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Solvent: c1ccoc1
Solvent: ClCCl
Solvent: CC#N
Product: CC1(C)OB(c2coc(C(N)=O)c2)OC1(C)C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-furan (5.0 g, 25.77 mmol) is dissolved in dry acetonitrile (30 mL). Chlorosulfonylisocyanate (5.47 g, 38.65 mmol, 1.5 equiv.) in solution in dry acetonitrile (20 mL) is added in one portion at room temperature to the furan producing a pink solution that subsides overnight to turn yellow. The resulting solution is cooled with an ice bath and water (5 mL) is added, causing an exotherm. The resulting mixture is partitionned between DCM (100 mL) and water (30 mL). The aqueous layer is extracted 3 more times with DCM (50 mL), then the organic layers are gathered, washed with brine (10 mL), dried over anhydrous Na2SO4 and finally the solvent is removed under vacuum. The oily residue is dissolved in DCM (3 mL), sonicated to give a suspension of a crystalline solid. The solid is separated by filtration, and the cake is washed with a very small amount of DCM, then diethyl ether and dried under suction to afford 3 g of the title compound as a white powder.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([Cl:15])[CH:9]=1>C1COCC1.[Cl-].[NH4+]>[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([O:2][CH3:1])[N:11]=[C:10]([Cl:15])[CH:9]=1
Reactant: CO
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)nc(OC)c1
Reaction time: 2 h

Procedure:
To a solution of dry methanol (2.2 mL, 53 mmol) in THF (200 mL) was added sodium hydride (2.12 g, 53 mmol) in portions under a stream of nitrogen. When gas evolution ceased, 2,6-dichloro-isonicotinic acid methyl ester (10.0 g, 48.5 mmol) was added. After stirring for 2 hours, the reaction was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (4×50 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to afford 2-chloro-6-methoxy-isonicotinic acid methyl ester.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)[N:10]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)[N:10]=1
Reactant: COCc1nc(Cn2ncc([N+](=O)[O-])n2)cs1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1nc(Cn2ncc(N)n2)cs1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(methoxymethyl)-4-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazole (200 mg, 0.78 mmol), iron powder (133 mg, 2.35 mmol) and NH4Cl (212 mg, 3.92 mmol) in a mixture of EtOH (10.0 mL) and water (5.0 mL) was stirred at 100° C. for 2 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (40 mL) was added followed by 1N NaOH (20 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound which was purified by preparative HPLC to give a colorless oil. LC-MS-conditions 07: tR=0.47 min, [M+H]+=226.30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:12][NH:13][O:14][CH3:15].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ncc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ncc(Br)cc1F

Procedure:
5-Bromo-3-fluoropicolinic acid (1.4 g, 6.5 mmol), N,O-dimethylhydroxylamine.HCl (0.82 g, 8.45 mmol), (2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (3.2 g, 8.45 mmol) and triethylamine (2.3 mL, 16.3 mmol) were stirred in DMF (30 mL) at room temperature for 1 d. EtOAc and sat. aq. Na2CO3 solution was added and the aqueous phase extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel and eluting with 20-80% EtOAc in isohexane to afford 5-bromo-3-fluoro-N-methoxy-N-methylpicolinamide.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[N:3]=1.[N+](=[CH2:13])=[N-]>>[CH3:13][O:9][C:8](=[O:10])[CH2:7][C:4]1[N:3]=[C:2]([CH3:1])[O:6][N:5]=1
Reactant: C=[N+]=[N-]
Reactant: Cc1nc(CC(=O)O)no1
Product: COC(=O)Cc1noc(C)n1

Procedure:
Using the procedure of Example 10, 10 g of crude 5-methyl-1,2,4-oxadiazol-3-yl acetic acid were reacted with diazomethane to obtain 5.9 of methyl-5-methyl-1,2,4-oxadiazol-3-yl-acetate with a b.p. of 70°-72° C. at 0.6-0.7 mm and a refractive index nD =1.4495.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1cccc2cc3ccccc3nc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])c2cc3ccccc3nc12
Reaction time: 1 h
Yield: 70 %

Procedure:
4-Methoxyacridine (1.4 g, 6.67 mmole) was dissolved in acetic anhydride (5 ml) and cooled to 0°. Concentrated nitric acid (1 eq, 0.7 ml) was added, followed by concentrated sulphuric acid (1 eq, 0.7 ml). After stirring for 1 hr, the product was filtered and the residue was extracted into methylene chloride and washed with sodium bicarbonate solution. It was then dried and evaporated in vacuo to give 1.2 g (70%) of 4-methoxy-1-nitroacridine. NMR (CDCl3, 90 MHz) δ=4.20, s, 3H; 6.95, d, 9 Hz, 1H; 6.70-8.00, m, 3H; 8.34, d, 9 Hz, 1H; 8.55, d, 9 Hz, 1H; 9.82, s, 1H. The methoxy compound (500 mg) was converted to the 4-hydroxy derivative by heating with KOH (2 ml of an 11M aqueous solution) in DMSO (20 ml). This was tosylated with pyridine and toluenesulfonyl chloride to give the 4-tosyloxy derivative (260 mg, 34%). NMR (CDCl3, 90 MHz) δ 2.2, s, 3H; 7.00, m, 2H, 6.30-6.80, m, 7H; 8.20, d, 9 Hz, 1H; 9.45, s, 1H. The tosyloxy compound (600 mg, 1.5 mmole) was dissolved in acetonitrile (4 ml) and 1,7-diaza-4,10,13-trioxacyclopentadecane (110 mg, 0.5 mmole) were added, followed by 1,8-bis(dimethyl-amino)naphthalene (290 mg, 2 mmole) and the reaction mixture heated under reflux overnight. The reaction mixture was evaporated in vacuo and the residue taken into chloroform and purified by column chromatography (silica gel, ethyl acetate, hexane 1:1) to give the N,N-bis-(1-nitro-4-acridinyl)-diaza[15]-crown-5 as a yellow gum (180 mg, 27%). NMR (CDCl3, 90 MHz) δ 3.40, s, 4H; 3.82, m, 16H; 6.50, d, 9 Hz, 2H; 6.95, d, 9 Hz, 2H; 7.30, t, 9 Hz, 4H; 7.65, d, 9 Hz, 2H; 8.20, d, 9 Hz, 2H; 9.68, s, 2H.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH:7]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1cc(Nc2cccc3[nH]ccc23)ncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 37.9 %

Procedure:
4,6-Dichloropyrimidine (1.01 g, 6.6 mmol), 4-aminoindole (900 mg, 6.6 mmol) and N,N-diisopropylethylamine (3.14 ml, 18 mmol) were dissolved in N,N-dimethylformamide (20 ml), and the reaction mixture was stirred at 80° C. for 6 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was subjected to re-extraction with ethyl acetate, and the combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; and a small amount of methanol was added to the residue to crystallize; and the crystals were filtered off, washed with methanol and ethyl acetate, and dried under aeration to yield the title compound (599 mg, 2.5 mmol, 37%) as pale brown crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[F:16][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
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: COCCOC
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (3 g, 12.6 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.2 g, 25.2 mmol), and Na2CO3 (2.7 g, 25.2 mmol) in DME (18 mL)/water (6 mL) was sparged with nitrogen for 20 min. Pd(PPh3)4 (729 mg, 0.63 mmol) was added and the resulting mixture was heated to 100° C. for 16 h. The solvent was removed under reduced pressure and the crude product was suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo. and purified via silica gel chromatography to give 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (2 g, 56% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.96 (m, 1H), 6.85-6.72 (m, 2H), 6.56 (m, 1H), 5.15 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 285.0 (M+H+).
Reaction SMILES: [NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:36])[CH3:35])[NH:32][C:30](=[O:31])[C@@H:29]2[CH2:47][CH2:48][CH2:49][N:28]2[C:26](=[O:27])[C@@H:21]([CH2:22][C:23](=[O:25])[OH:24])[NH:20][C:18](=[O:19])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C)=O)[CH:5]=1.[CH3:50][NH2:51].CO>>[NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:35])[CH3:36])[NH:32][C:30](=[O:31])[C@@H:29]2[CH2:47][CH2:48][CH2:49][N:28]2[C:26](=[O:27])[C@@H:21]([CH2:22][C:23](=[O:25])[OH:24])[NH:20][C:18](=[O:19])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([NH:51][CH3:50])=[O:16])[CH:5]=1
Reactant: COC(=O)Cn1cc(C[C@H]2NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC(=O)O)NC2=O)c2ccccc21
Reactant: CN
Solvent: CO
Product: CNC(=O)Cn1cc(C[C@H]2NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC(=O)O)NC2=O)c2ccccc21

Procedure:
cyclo(-DTrp(CH2COOCH3)-DAsp-Pro-DVal-Leu-) prepared in Example 90 was allowed to react with 40% methylamine/methanol as the same procedure described in Example 91 to give the title compound.