Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([C@H:11]([F:29])[CH2:12][CH2:13][C:14]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[C:23]1([C:14]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12][C@@H:11]([F:29])[C@@H:10]3[C@H:15]2[CH2:16][NH:8][CH2:9]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: Cl
Solvent: C1COCCO1
Product: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 2.25 g of (3aR,7R,7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7-fluoroperhydroisoindole in 25 cm3 of dioxane is treated with a 5.8N solution of hydrochloric acid in dioxane and stirred for 2 hours at 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is concentrated by adding 100 cm3 of isopropyl oxide, the solid is filtered and dried to give 1.8 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, in the form of a cream-colored powder. Proton NMR spectrum (DMSO-d6): 1.0-1.35 (mt, 1H of CH2 in 6); 4.9 (broad d, J=50, 1H, CHF); 7.1 to 7.5 (mt, 14H, aromatics); 9.05 and 9.9 (2 mf, 2×1H, NH2+).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:36]=CC(N)=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.CN(C=[O:56])C>CN(C1C=CN=CC=1)C>[CH:1]1([C:4]2[C:12]([N:13]([CH2:30][CH2:36][OH:56])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Reactant: CN(C)C=O
Reactant: Nc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1

Procedure:
NB: 5-Cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (14) was prepared following the procedure described in Method F using 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (13) in place of 2-(4-fluorophenyl)-5-methoxy-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (10). 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (13) in turn was prepared according to Method A using 4-fluoroaniline in place of 4-bromoaniline in Step d. Alternatively, esterification may be carried out as for Compound (116) with a suitable carboxylic acid using a coupling agent (e.g. DCC), 4-DMAP in DMF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[O:13]=[S:14]1(=[O:28])[CH2:19][CH2:18][N:17]([CH2:20][C:21]2C=CC(N)=CC=2)[CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.[CH:40]1[CH:41]=[CH:42][C:43]2N(O)N=[N:46][C:44]=2[CH:45]=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:46][C:44]1[CH:45]=[CH:40][C:41]([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][S:14](=[O:28])(=[O:13])[CH2:15][CH2:16]2)=[CH:42][CH:43]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: On1nnc2ccccc21
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2ccc(CCN3CCS(=O)(=O)CC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methoxy-benzoic acid (500 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (519 mg), EDAC (830 mg), HOBT (585 mg) and N-methylmorpholine (712 μl) in DMF (3 ml) was stirred at room temperature for 18 h. The mixture was then diluted with water (30 ml) and the resulting solid collected by filtration and dried (882 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.O.O.[Cl-].[Ca+2].[Cl-].CCO>[Zn].O>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc(CNc2ccc([N+](=O)[O-])cc2OC)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2ccc(N)cc2OC)cc1
Yield: 71.6 %

Procedure:
This compound was prepared by General Method 10 (EXAMPLE 19) from (2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine (1.92 g, 6.65 mmol), zinc dust (1.87 g, 28.6 mmol), and calcium chloride dihydrate (2.10 g, 14.3 mmol) in 350 mL 95:5 EtOH:water to afford 1.23 g (70%) of (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine, a light purple solid, after flash chromatography (CH2Cl2:MeOH 19:1). Data for (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine: Rf 0.80 (19:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, 2H, J=8.6), 6.87 (d, 2H, J=8.6), 6.47 (d, 1H, J=8.1), 6.28 (d, 1H, J=2.4), 6.23 (dd, 1H, J=8.1, 2.4), 4.20 (s, 2H), 4.10 (v broad s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.31 (broad s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([OH:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][C:36]([O:23][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[N:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:37]
Reactant: CC(C)CCCC(=O)Cl
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCCC(C)C)nc2n1
Yield: 60.3 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6.8 g) in methylene chloride (100 cc), triethylamine (10.1 g), 5-methylhexanoyl chloride (6.4 g) and 4-dimethylaminopyridine (50 mg). The residue obtained after treatment is purified by chromatography on silica gel (0.063-0.2 mm; 100 g) contained in a column 2.8 cm in diameter (eluant: methylene chloride), collecting 30-cc fractions. Fractions 19 to 94 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After the residue obtained has been recrystallized in heptane (75 cc), 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (5.6 g), m.p. 105° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[CH:10]=[C:11]([CH2:13][N:14]([CH3:16])[CH3:15])[N:12]=[C:4]2[CH:3]=1.[OH-:17].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([OH:17])[N:5]2[CH:10]=[C:11]([CH2:13][N:14]([CH3:16])[CH3:15])[N:12]=[C:4]2[CH:3]=1
Reactant: CSc1nc(Cl)cc2nc(CN(C)C)cn12
Reactant: [OH-]
Agent: [K+]
Product: CN(C)Cc1cn2c(O)nc(Cl)cc2n1

Procedure:
In analogy to Example 33A, 150 mg (98% of theory) of the product are obtained from 150 mg (0.58 mmol) of 1-[7-chloro-5-(methylsulphanyl)imidazo[1,2-c]pyrimidin-2-yl]-N,N-dimethylmethanamine (Example 97A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].CN(C)C(=C(C)C)C.[F:22][C:23]([F:33])([F:32])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:25].CCOC(C)=O>C(Cl)Cl>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8](=[O:10])[NH:25][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([F:22])([F:32])[F:33]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: NC(c1ccccc1)C(F)(F)F
Agent: CC(C)=C(C)N(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)C(F)(F)F)c1ccc(B(O)O)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-borono-2-fluorobenzoic acid (54 mg, 0.294 mmol) in DCM (1468 μL) was cooled to 0° C. Then ghosez reagent N,N,3-trimethylbut-2-en-2-amine (65.8 μL, 0.587 mmol) was added and the whole mixture was stirred at rt for 20 min. The mixture was added into a mixture of TEA (246 μL, 1.762 mmol), 2,2,2-trifluoro-1-phenylethanamine (59.1 mg, 0.338 mmol) and DCM (1468 μL). The reaction was stirred at room temperature for 2 h. To the reaction mixture was added EtOAc, and washed with sat. sodium bicarbonate, water, and dried over Na2SO4. Filtered and concentrated to provide the crude product which was taken to the next step without further purification. LCMS (m/z): 342.2 (MH+), 0.84 min.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][NH:10][C:11]([CH:13]([C:19]([O:21]CC)=O)[C:14]([O:16]CC)=O)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:33][CH2:34][C:35]([OH:37])=[O:36].Cl>O1CCOCC1.C1CCN2C(=NCCC2)CC1>[CH:24]1([N:30]2[C:19]([OH:21])=[C:13]([C:14]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:16])[C:11](=[O:12])[N:10]([CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC(=O)O
Reactant: O=C=NC1CCCCC1
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Yield: 7.3 %

Procedure:
A microwave tube containing sodium hydride (60% suspension in oil, 46 mg, 1.15 mmoles) in dioxan (3 mL) was treated with diethyl {[(phenylmethyl)amino]carbonyl}-propanedioate (example 1a, 100 mg, 0.34 mmoles) and stirred under argon until evolution ceased. Cyclohexyl isocyanate (90 uL, 0.7 mmoles) was added and the mixture was heated at 100° C. for 30 minutes in a microwave reactor. Glycine (48 mg, 0.65 mmoles) and DBU (4 drops) was added, the flask re-sealed and heated at 160° C. for 1 hour in a microwave reactor. The mixture was poured into 1 molar hydrochloric acid and extracted with dichloromethane (×3). The combined extracts were washed with 1 molar hydrochloric acid and brine, dried and evaporated to give the crude product. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) gave the title compound (10 mg, 7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (t, J=5.18 Hz, 1 H), 7.23-7.34 (m, 6 H), 4.99 (s, 2 H), 4.65 (t, J=11.62 Hz, 1 H), 4.10 (d, J=5.81 Hz, 2 H), 2.21-2.32 (m, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.62 (s, 3 H), 1.22-1.33 (m, 3 H), 1.06-1.17 (m, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20](=[O:22])[CH3:21])[N:15]=[CH:14]3)[S:9][CH:10]=1)=[O:5])[CH3:2].CCN(CC)CC.C1C[O:33]CC1>>[C:20]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)=[CH:19][CH:18]=2)[CH:14]=[N:15]1)(=[O:22])[CH3:21].[CH3:6][C:4]([O:3][C:1]([CH3:2])=[O:33])=[O:5]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1csc(-c2ccc3c(cnn3C(C)=O)c2)n1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2cc(-c3nc(C(=O)O)cs3)ccc21

Procedure:
In a manner similar to Preparation CW from 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid ethyl ester to give 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid as a yellow solid following re-protection with Ac2O, Et3N, and THF. MS m/z: 286.1 (M−H). Calc'd for C13H9N3O3S 287.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][C:6]=2[CH:22]=1.C([NH:30][C@@H:31]([C:43](O)=[O:44])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])(OC(C)(C)C)=O>>[C:36]([N:20]([C@@H:11]([CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=2[N:7]=1)[OH:21])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:43](=[O:44])[C@H:31]([NH2:30])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H](CCc1ccccc1)C(O)c1nc2cc(Cl)ccc2o1
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2cc(Cl)ccc2o1

Procedure:
(1R)-1-[(RS)-(5-Chloro-2-benzoxazolyl)hydroxymethyl]-3-phenylpropylamine (136 mg) was coupled with N,N′-bis-Boc-D-ornithine to afford the title compound (150 mg) as a glassy solid: mass spectrum (ES+) m/e 35Cl 653.4, 37Cl 655.4 (M+23 (Na)); 1H NMR (400 MHz, CDCl3, 7:3 mixture of diastereomers) δ 1.40 (m, 18H), 1.62 (m, 4H), 1.90 (m, 2H), 2.74 (m, 2H), 3.03-3.23 (m, 2H), 4.09 (m, 0.3H), 4.19 (m, 0.7H), 4.58 (m, 0.7H), 4.69 (m, 0,3H), 5.03 (m, 0.7H), 5.20 (m, 0.3H), 7.11-7.23 (m, 6H), 7.37 (m, 2H), 7.53 (m, 1H), 7.68 (m, 0.3H), and 7.76 (m, 0.7H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:19])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[OH:9][CH2:8][CH2:7][N:6]1[C:2]([NH:1][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:3]([NH:10][C:11](=[O:19])[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:4]=[N:5]1
Reactant: Nc1c(NC(=O)Oc2ccccc2)cnn1CCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a stirred solution of phenyl [5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]carbamate (5.45 g) in N,N-dimethylformamide (55 ml) were added triethylamine (8.69 ml) and trityl chloride (6.37 g), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a crude product, which was triturated with ethyl acetate-diisopropyl ether (1:2). The resulting solid was collected by filtration to give phenyl [1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (3.5 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[C:18]([C:23]([NH:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[O:24])[CH:19]=[CH:20][CH:21]=3)[C:16]([C:36](=[O:46])[C:37](=[O:45])[NH:38][C:39]3[CH2:40][O:41][C:42](=[O:44])[CH:43]=3)=[CH:15]2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][NH:25][C:23]([C:18]1[C:17]2[C:16]([C:36](=[O:46])[C:37](=[O:45])[NH:38][C:39]3[CH2:40][O:41][C:42](=[O:44])[CH:43]=3)=[CH:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:48][CH:47]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cccc2c1c(C(=O)C(=O)NC1=CC(=O)OC1)cn2Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)c1cccc2c1c(C(=O)C(=O)NC1=CC(=O)OC1)cn2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
Trifluoroacetic acid (0.1 ml) is added to a stirred solution of tert-butyl 2-{[(1-(4-chlorobenzyl)-3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indol-4-yl)carbonyl]amino}ethylcarbamate of Example 9 (50 mg) in CH2Cl2 (1 ml). After stirring at room temperature for 3 h the solvent is removed by roto-evaporation and the residue is taken up with water, adjusting the pH at about 8-9 with 1N NaOH. The precipitate is collected by filtration and thoroughly washed to give N-(2-aminoethyl)-1-(4-chlorobenzyl)-3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indole-4-carboxamide (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:13][C:7]=2[C:6]=1[OH:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:22])[C:8]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:13][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(-c3ccc(F)cc3)csc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(-c3ccc(F)cc3)csc2c1O
Yield: 61.8 %

Procedure:
A suspension of 3-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (100 mg, 0.33 mmol), example 31-f, N-bromosuccinimide (61.6 mg, 0.346 mmol), and benzoyl peroxide (8.0 mg, 0.033 mmol) in 0.83 mL of carbon tetrachloride was heated at reflux temperature for 5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate, brine, saturated ammonium chloride solution, and brine. The organic solution was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in methylene chloride to produce 77.9 mg of a light yellow solid. MS: (−) m/z 380.3, 382.1 (M−1, 79Br/81Br).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:3]([OH:33])[CH2:4][C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:41][O:42][C:43](=[O:44])[NH:45][C@@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[C:47](=[O:48])[NH:1][C@@H:2]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@@H:3]([OH:33])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:20][C:21](=[O:22])[C@H:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.7 %

Procedure:
A solution containing the product from Example 92J (0.049 g, 0.090 mmol) in THF (1 mL) was treated with the product from Example 1F (0.018 g, 0.095 mmol), DEPBT (0.040 g, 0.133 mmol), and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for 3 days, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The reaction was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and 10% Na2CO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.047 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79(s, 9H), 0.82(s, 9H), 1.58-1.43(m, 2H), 2.32(s, 3H), 2.79-2.68(m, 3H), 3.49(s, 3H), 3.55(s, 3H), 3.67-3.59(m, 1H), 3.843.80(d, J=9.93 Hz, 1H), 3.92-3.89(d, J=9.93 Hz, 1H), 4.19-4.01(m, 2H), 4.87-4.85(d, J=5.88 Hz, 1H), 6.63-6.60(d, J=9.19 Hz, 1H), 6.81-6.77(d, J=9.56 Hz, 1H), 7.19-7.12(m, 5H), 7.56-7.53(d, J=8.82 Hz, 1H), 7.68-7.64(m, 1H), 7.81-7.76(m, 3H), 7.86-7.83(d, J=8.09 Hz, 2H), 8.47(bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].C(O)(=[O:18])C.OO>[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10](=[O:18])[CH2:9][CH2:8][C:7]2=[O:12]
Reactant: Cc1c(C(=O)O)ccc2c1SCCC2=O
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1S(=O)CCC2=O
Reaction time: 3 h

Procedure:
7.0 g (31.5 mmol) of 8-methylthiochroman-4-one-7-carboxylic acid together with one spatula-tip full of sodium tungstate are introduced into 70 ml of acetic acid. 3.6 g (31.5 mmol) of a 30% strength hydrogen peroxide solution are added dropwise at 50° C. Stirring is continued for 3 hours. The reaction solution is then stirred into water. The product is extracted using ethyl acetate. The organic phase is dried and the solvent is removed. The product is purified by chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[S:12]([N:15]=C=O)(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][S:12](=[O:14])(=[O:13])[NH2:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc([N+](=O)[O-])c1

Procedure:
This compound was prepared according to the procedure used in Example 75. A mixture of 13.9 g (0.1 mole) of 3-nitrophenol and 14.8 g (0.105 mole) of chlorosulfonyl isocyanate in 100 ml of toluene gave 16.9 g (78%) of tan flakes, mp 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CO>[Pd].ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(N)ccc1OC
Reaction time: 17 h

Procedure:
Combine methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mrnol) and methanol. Add 5% palladium-on-carbon (0.66 g). Hydrogenate on a pressure apparatus at 50 psi. After 17 hours, filter through celite to remove the catalyst and evaporate the filtrate in vacuo to give a residue. Combine the residue and dichloromethane and extract with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-aminobenzoate. Rf =0.18 (silica gel, ethyl acetate/methanol 1/1). Elemental Analysis calculated for C9H11NO3 : C, 59.66; H, 6.12; N, 7.73. Found: C, 59.44; H, 6.04; N, 7.62.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:10]=[CH:9][N:8]([S:20](=[O:22])(=[O:21])[N:19]([CH3:24])[CH3:18])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc[nH]n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(S(=O)(=O)N(C)C)n1
Yield: 81.3 %

Procedure:
To a solution of 1.02 g (7.23 mmol) of 1H-1,2,4-triazole-3-carboxylic acid ethyl ester in 6 ml of DMF was added 1.46 g (1.44 mmol) of triethylamine. To the solution was added dropwise with stirring under ice-cooling 1.14 g (7.94 mmol) of dimethylsulfamoyl chloride. The mixture was stirred at room temperature for 8 hours. 30 ml of Water was added thereto and extracted with 20 ml of ethylacetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over Na2SO4 and evaporated under reduced pressure to give an oil. The obtained oil was purified with silica gel chromatography (eluate: hexane/ethylacetate=2:1) to give 1.46 g of 1-dimethylsulfamoyl-1,2,4-triazole-3-carboxylic acid ethyl ester as a white crystal. Yield: 82%.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH2:18]([NH2:21])[CH2:19][CH3:20]>C(#N)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH2:18][CH2:19][CH3:20])#[N:2]
Reactant: CCCN
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CC#N
Product: CCCNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 20 h

Procedure:
A solution of 12.3 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-napthyl)-S-methylisothiourea and 16 ml of n-propylamine in 100 ml of acetonitrile was heated at reflux with stirring for 20 hours. The reaction mixture was then allowed to stand in a refrigerator to give 8.63 g of N"-cyano-N-n-propyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 130.5°-131.5° C. A further quantity of the product was obtained by the concentration and subsequent cooling of the mother liquor.