Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.[Mn]([O-])(=O)(=O)=[O:14].[K+].[OH-].[K+]>O>[CH2:1]1[CH2:12][O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:14])=[O:6])[O:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cccc2c1OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc2c1OCCO2
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
Into a 500 ml round bottom flask fitted with a 250 ml addition funnel and a magnetic stir bar were placed 2,3-ethylenedioxybenzaldehyde (4.07 g, 24.7 mmol) and 100 ml of water. The mixture was heated to 80° and potassium permanganate (7.84 g, 49.6 mmol) in 150 ml of water was added dropwise via the addition funnel over 20 minutes. After the addition was complete the mixture was allowed to stir at 80° for 1.5 hours. The mixture was made basic with a 10% potassium hydroxide solution and the solids filtered. The filter cake was washed with hot water. The filtrate was extracted with ether, made acidic, then extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated to give 2.96 g of subtitled product (66%) which was used directly in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:18]>CCO>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[C:6]([C:4]([NH2:18])=[O:3])[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: N
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Crude 3-(4-hydroxy-phenyl)-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 1; 1.9 g, 8.15 mmol) was taken up in a solution of EtOH saturated with NH3. The mixture was stirred overnight at room temperature under nitrogen. The solvent was evaporated to give 3-(4-hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (1.17 g, 70%) as a flaky white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][C:2]([C:3]([O:5][CH3:6])=[O:4])([CH3:1])[CH3:27])=[CH:13][CH:12]=3)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CC(C)(C)C(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(CC(C)(C)C(=O)OC)cc3)cc3ccccc23)CC1
Yield: 95 %

Procedure:
Methyl 2,2-dimethyl-3-(4-tributylstannylphenyl)propionate (2.81 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.18 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.17 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]isoquinoline (1.51 g) as a brown viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CCCC(C)CBr
Solvent: CO
Product: CCCC(C)COc1ccc(OC)cc1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
Sodium metal (6.99 g, 304 mmol) was dissolved in dry methanol (120 ml) under Ar to give a 2.5M solution of sodium methoxide. A solution of 4-methoxyphenol (31.4 g, 253 mmol) in dry methanol (150 ml) was added and this mixture was heated to reflux for 30 min. After cooling to room temperature, a solution of 1-bromo-2-methylpentane (46.0 g, 279 mmol) in dry methanol (100 ml) was added. The mixture was then heated to reflux for 16 hours. The solvent was removed in vacuo, the residue dissolved in ether (200 ml), washed with dilute aqueous sodium hydroxide (250 ml) and water (500 ml), dried over MgSO4 and concentrated in vacuo again. Distillation at 80° C./0.5 mm Hg afforded 14.0 g (27%) 1-methoxy-4-(2'-methylpentyloxy)benzene, 1H NMR (250.1 MHz, CDCl3): δ=0.94(t,3 H), 1.02 (d, 3 H), 1.16-1.56 (m, 4 H), 1.93 (m, 1 H), 3.64-3.82 (m, 2 H), 3.77 (s, 3 H), 6.81-6.89 (m, 4 H), 13C NMR (100.6 MHz, CDCl3): δ=14.3, 17.0 (both CH3), 20.1, 35.8 (both CH2), 33.0 (CH), 55.7 (OCH3), 73.9 (OCH2), 114.6, 115.4 (arom. CH), 153.5, 153.6 (ipso C). IR(film): 2956(m), 1509(s), 1232(s), 1045(m), 824(m) cm-1, MS(EI) :m/z (%)=208 (100), 124 (32), Calcd. for C13H20O2 : C 74.96, H 9.68 found: C 75.03, H 9.70.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH2:23][CH2:24][C:25]([CH2:31][CH:32]2[CH2:34][CH2:33]2)([OH:30])[CH2:26][C:27]([CH3:29])=[CH2:28])[CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]([N:22]2[CH2:23][CH2:24][C:25]([CH2:31][CH:32]3[CH2:34][CH2:33]3)([CH2:26][C:27]([CH3:29])=[CH2:28])[O:30][C:2]2=[O:4])[CH3:21])=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CC1(CC2CC2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (653 mg) was added to a solution of 1-[(S)-1-(4-bromophenyl)ethylamino]-3-(cyclopropylmethyl)-5-methylhex-5-en-3-ol (800 mg) and triethylamine (667 mg) in CH2Cl2 (15 mL) at 0° C. The mixture was stirred at room temperature overnight and the reaction was then quenched with water. The resulting mixture was extracted with CH2Cl2 and the combined organic layer was washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to afford the title compound. Yield 670 mg (78% of theory).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:68]=[CH:67][C:48]([C:49]([N:51]2[C:59]3[C:54](=[CH:55][C:56]([O:60][CH3:61])=[CH:57][CH:58]=3)[C:53]([CH2:62][C:63](O)=[O:64])=[C:52]2[CH3:66])=[O:50])=[CH:47][CH:46]=1>C(#N)C>[CH:1]1([N:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[C:63](=[O:64])[CH2:62][C:53]2[C:54]3[C:59](=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=3)[N:51]([C:49](=[O:50])[C:48]3[CH:47]=[CH:46][C:45]([Cl:44])=[CH:68][CH:67]=3)[C:52]=2[CH3:66])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: c1csc(NC2CCCCC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)c(CC(=O)N(c1nccs1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a suspension of 2 g (0.02 mol) of N-Cyclohexyl-N-thiazol-2-yl amine in 20 mL of acetonitrile at rt was added 6.1 mL (0.044 mol) of triethylamine and 10.24 g (0.022 mol) of PyBroP [bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (Aldrich or NovaBiochem)]. To the reaction mixture was then added 3.93 g (0.01 mol) of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid and the reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then cooled to 0° C. and the white precipitate was isolated by filtration. The filtrate was concentrated to ˜10 mL, recooled to 0° C., refiltered and the filtrate was concentrated to an oil. The residue was dissolved in 100 mL of dichloromethane and the solution was washed twice with 1N HCl, and once with 1N NaHCO3 solution. The organic phase was dried (Na2SO4) filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 0-50% EtOAc in heptane) to give the title compound. 1H NMR (CDCl3) δ 7.74 (1H, d), 7.66 (2H, d), 7.50 (2H, d), 7.40 (1H, d), 6.95 (1H, bs), 6.82 (1H, d), 6.67 (1H, dd), 4.59 (1H, bt), 3.84 (3H, s), 3.61 (2H, s), 2.22 (3H, s), 0.9-2.0 (10H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cn1cncn1)c1c(Cl)cccc1Cl
Reactant: ClCc1ccccc1
Product: Clc1cccc(Cl)c1C(=Cn1cncn1)OCc1ccccc1

Procedure:
Analogously to Example 1a,b, after reacting 1-(2,6-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone with benzyl chloride there was obtained 1-[2-(2,6-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-[1,2,4]triazole. After reaction with oxalic acid there was obtained a salt with the composition C17H13N3OCl2.C2H2O4, which decomposed at >71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][N:39]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([O:37][CH3:36])[CH:43]=1)=[O:9]
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)c1cc(Cl)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2cc(Cl)ccc2F)ccn1
Yield: 47.3 %

Procedure:
A solution of 5-chloro-2-fluoro-benzoic acid (5.0 g, 28.64 mmol), HATU (10.89 g, 28.64 mmol), 2-methoxypyridin-4-amine (3.6 g, 28.64 mmol) and Et3N (15.98 mL, 114.60 mmol) in dichloromethane (45.0 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 47%) as a white solid. ESI-MS m/z calc. 280.04. found 281.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCC1CCCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCC3CCCC3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were introduced portionswise at 20° C in a stirred mixture of 4 g of cyclopentylmethyl amine, 8 g of triethyl amine and 100 ml of ethanol and the reaction mixture was allowed to stand over night. The solvent was distilled off under reduced pressure and the amorphous end product was crystallized under 80 ml of water. Colorless solid body, decomposition beginning at 80° C, γ C=N 1620 cm-1.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[C:17]([CH2:20][Br:8])[CH:16]=[CH:15]2
Reactant: Cc1ccc2cccc(Br)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cccc(Br)c2c1
Reaction time: 0.02 h
Yield: 100 %

Procedure:
To boiling CCl4 (250 mL) was added NBS (20.4 g, 0.114 mol) and AIBN (1.4 g, 0.009 mol). After 1 minute, a solution of 1-bromo-7-methylnaphthalene (24.1 g, 0.109 mol) in CCl4 (15 mL) was added all at once. Within 1 minute, the reaction became quite exothermic and the heating mantle was removed for several minutes. Heating was resumed for 30 minutes. The mixture was cooled, filtered, and the filtrate was concentrated to give an off-white solid (32.7 g). The product was combined with similarly prepared material (32.6 g) and recrystallized from ethyl acetate/hexane to give the product (29.6 g, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[NH2:14][OH:15].Cl>[OH-].[Na+]>[OH:15][NH:14][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([I:12])=[CH:11][C:2]=1[OH:1]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NO)c1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23.3 g (84 mmol) of methyl 2-hydroxy-4-iodobenzoate and 360 ml of sodium hydroxide solution (1 N) are introduced into a three-necked flask under a stream of nitrogen. 8 g (113 mmol) of hydroxylamine hydrochloride are added and the mixture is stirred at room temperature for two hours. The reaction medium is adjusted to pH 7-8 with concentrated hydrochloric acid and the solid is filtered off. The solid is dissolved in ethyl acetate and washed with water, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue is triturated from heptane, filtered and dried. 17.6 g (71.5%) of the expected product are collected, with a melting point of 195-6° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([N:18]([CH3:30])[CH2:19][C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH3:29])=[O:17])=[CH:10][CH:9]=1.O=C1CCC(=O)N1C1N=CC(/C=C/C([N:48]([CH3:60])[CH2:49][C:50]2[N:51]([CH3:59])[C:52]3C(C=2)=CC=CC=3)=O)=CC=1.CN1CCNCC1.N>>[CH3:30][N:18]([CH2:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]=1[CH3:29])[C:16](/[CH:15]=[CH:14]/[C:11]1[CH:10]=[CH:9][C:8]([NH:3][C:4](=[O:7])[CH2:5][CH2:6][C:2]([N:48]2[CH2:49][CH2:50][N:51]([CH3:59])[CH2:52][CH2:60]2)=[O:1])=[N:13][CH:12]=1)=[O:17]
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)CCC2=O)nc1
Reactant: Cc1c(CN(C)C(=O)C=Cc2ccc(N3C(=O)CCC3=O)nc2)sc2ccccc12
Agent: CN1CCNCC1
Agent: N
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(NC(=O)CCC(=O)N3CCN(C)CC3)nc2)sc2ccccc12
Yield: 51 %

Procedure:
According to the procedure of Example 110 except substituting 3-[6-(2,5-dioxo-pyrrolidin-1-yl)pyridin-3-yl]-N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide for the (E)-3-[6-(2,5-dioxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide, and substituting 1-methylpiperazine for the ammonia, the title compound (0.53 g, 51%) was prepared as a light yellow solid: 1H NMR 300 MHz, DMSO-d6) δ 10.71 (br s, 1H), 8.74-8.61 (m, 1H), 8.22-8.15 (m, 1H), 8.13-8.05 (m, 1H), 7.91-7.85 (m, 1H), 7.78-7.71 (m, 1H), 7.60-7.50 (m, 1H), 7.39-7.33 (m, 3H), 5.15-4.88 (m, 2H), 3.75-3.61 (m, 2H), 3.38-3.28 (m, 3H), 3.19-3.10 (m, 2H), 3.05-2.75 (m, 4H), 2.71-2.51 (m, 7H), 2.41 (s, 3H); MS (ESI) m/e 520 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].C(#N)C.Br[CH2:14][CH:15]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1>C(OCC)C>[O:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16][CH:15]1[CH2:14][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ncn(CC2COc3ccccc3O2)c1Cl
Temperature: 25 °C
Yield: 51.2 %

Procedure:
4,5-Dichloroimidazole (0.68 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol) were added to a round bottom flask. Acetonitrile (2 mL) was added and the mixture was brought to reflux and stirred 30 min until all KOH was consumed. 2-(Bromomethyl)-1,4-benzodioxane (1.5 mL, 10 mmol) was added and the solution was returned to reflux overnight, during which time a white precipitate formed. The mixture was cooled to ambient temperature and filtered to remove the precipitate. The filtrate was concentrated via rotary evaporation at 75° C. until a yellow liquid remained. Upon cooling, the solution yielded a yellow solid. The solid was stirred in diethyl ether and filtered to yield a pale yellow solid (0.73 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To the suspension of 4-(4-chloro-phenyl)-1H-indole (1.52 g, 6.68 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.12 g, 20.0 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was suspended in water (500 mL) for 0.5 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (1.54 g, 94%) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:25][CH3:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C:16]1[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=1)=[CH:10][CH:9]=2)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH3:26])[C:6]([CH2:4][OH:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3nc4ccccc4s3)ccc2n1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(CO)cc2cc(Oc3nc4ccccc4s3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a cooled (−78° C.) solution of [5-(benzothiazol-2-yloxy)-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (1.05 g, 3.1 mmol) in THF (30 mL) was added LAH (1 M in THF, 0.8 mL, 0.72 g, 7.8 mmol) and the reaction mixture was stirred (−78° C., 1 h) and allowed to warm (rt, 12 h). The reaction mixture was treated with H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (5-15%) to provide the title compound as a colorless foam (0.5 g, 49%). MS (ESI): mass calcd. for C18H16N2O2S, 324.0; m/z found, 325.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.85 (d, J=7.2, 1H), 7.68 (d, J=7.6, 1H), 7.56 (s, 1H), 7.55 (d, J=6.4, 1H), 7.45-7.37 (m, 1H), 7.32-7.25 (m, 1H), 7.16 (dd, J=8.8, 2.4, 1H), 6.44 (s, 1H), 5.32 (s, 1H), 4.67 (s, 2H), 4.29 (q, J=7.1, 2H), 1.33 (t, J=7.1, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7].[O:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])=[CH:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][NH:2][C:28]([C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[CH:26]=2)=[O:29])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(O)c1cccc(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)CCCNC(=O)c1cccc(-c2ccoc2)c1
Yield: 83.9 %

Procedure:
1.00 g (3.3 mmol) of methyl 2-[(4-aminobutanoyl)amino]-5-chlorobenzoate hydrochloride, 0.61 g (3.3 mmol) of 3-(furan-3-yl)benzoic acid, 0.75 g (3.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.53 g (3.9 mmol) of 1-hydroxybenzotriazole were stirred in 10 mL of N,N-dimethylacetamide (DMAc) for 2 hours. After the completion of the reaction, ethyl acetate was added, and the mixture was diluted and washed with saturated sodium bicarbonate solution and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized using a mixed solvent of ethyl acetate and n-hexane, thereby giving 1.22 g of methyl 5-chloro-2-{[4-({[3-(furan-3-yl)phenyl]carbonyl}amino)butanoyl]amino}benzoate (yield: 85%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][C:16]=1[N+:24]([O-:26])=[O:25])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixture of 1.0 g (4.0 mmol) 4-ethoxalylaminobenzonitril in 4 ml glacial acetic acid was added 4 ml acetic anhydride. At 0° C. a solution of 1 ml 100% nitric acid in 2 ml glacial acetic acid was added dropwise, and after 15 min. further 1 ml 100% nitric acid was added. Stirring was continued at 0° C. for 1 h. The reaction mixture was poured into 50 ml ice-water to give 0.95 g (81%) of 4-ethoxalylamino-3-nitrobenzonitril. M.p. 151.8° C.
Reaction SMILES: O[C@H:2]([CH3:19])[CH2:3][N:4]1[C:18]2[C:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[N:5]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>O1CCCC1>[N:36]([C@@H:2]([CH3:19])[CH2:3][N:4]1[C:18]2[C:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[N:5]1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cn1ncc2ccc3oc(C(N)=O)nc3c21
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)nc3c21)N=[N+]=[N-]
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 18.3 %

Procedure:
To a suspension of the product from Step D (0.90 g, 3.45 mmol) in tetrahydrofuran (20 mL) was added triethylamine (1.93 mL, 13.9 mmol); this mixture was cooled (ice bath), methane sulfonic anhydride (1.20 g, 6.92 mmol) was added, and the mixture was stirred for 20 minutes. Sodium azide (2.25 g, 34.6 mmol) was added and the mixture was evaporated to a residue which dissolved in dimethyl sulfoxide (20 mL) and heated at 90° C. for 2.5 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with water (100 mL), dried (magnesium sulfate), filtered, and evaporated to solid (0.97 g). This residue was purified by chromatography (silica gel, ethyl acetate gradient) and recrystallized from methanol and ethyl acetate to give a colorless solid (0.18 g, 18%): mp 162–164° C.; LC/MS m/z 286.