Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3](CCCC)[CH2:4][NH2:5])C.[C:10]([OH:19])(=O)[CH:11]([CH:13]([C:15]([OH:17])=O)[OH:14])[OH:12].[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22]C=1>>[CH3:3][CH2:4][N:5]1[C:10](=[O:19])[CH:11]([OH:12])[C:13]([CH2:26][CH2:20][CH2:25][CH2:24][CH2:23][CH3:22])([OH:14])[C:15]1=[O:17]
Reactant: Cc1ccccc1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CCCCC(CC)CN
Product: CCCCCCC1(O)C(=O)N(CC)C(=O)C1O
Temperature: 100 °C

Procedure:
N-2-Ethylhexyl tartarimide was prepared by the reaction of 2-ethylhexyl amine with DL-tartaric acid. The procedure described in U.S. Pat. No. 4,237,022 was followed on a smaller scale. DL-Tartaric acid (10.034 g, 66.853 mmole) and toluene (17.328 g, 188.06 mmole) were weighed into a 250 mL 3-necked round-bottomed flask equipped with a teflon-coated magnetic stir bar. A Dean-Stark trap was placed in the center neck, and a condenser was placed in the neck of the Dean-Stark trap. A nitrogen inlet adapter was placed on the condenser. In the left neck was placed a pressure-equalizing addition funnel containing 2-ethylhexyl amine (8.639 g, 66.84 mmole) and toluene (6.092 g, 66.12 mmole) added to ensure complete transfer of the amine). In the right neck was placed a rubber septum which held a thermocouple. The apparatus was purged with nitrogen for 10-15 minutes and then heated to ˜100° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][N:21]=1)#[N:19].CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:26][C:25]2[C:20]([C:18]#[N:19])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1CN(Cc1cccnc1C#N)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine in CH3CN with 2-cyano-3-bromomethyl-pyridine, KI and DIPEA gave 3-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridine-2-carbonitrile as a dark red oil. 1H NMR (CDCl3) δ 2.04 (s, 6H), 3.86 (s, 4H), 3.99 (s, 2H), 7.07 (m, 2H), 7.38 (m, 3H), 7.84 (d, 1H, J=9.0 Hz), 8.37 (m, 2H), 8.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([C:12]1[O:9][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[N:10][C:18]=1[CH3:20])=[O:14])[CH3:17]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC1(C(N)=O)CCCCC1
Solvent: CCO
Product: CCOC(=O)c1oc(C2(C)CCCCC2)nc1C
Temperature: 50 °C

Procedure:
25.0 g 1-Methyl-cyclohexanecarboxylic acid amide was suspended in 40 ml ethanol and warmed to 50° C. At this temperature 29.0 ml Ethyl 2-chloroacetoacetate were added and the reaction mixture heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by chromatography with the eluent petroleum ether:ethyl acetate=4:1 to obtain 21.0 g 4-Methyl-2-(1-methyl-cyclohexyl)-oxazole-5-carboxylic acid ethyl ester as an oil which solidifies upon standing.
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[C:48]1[CH2:67][C:59]3([CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61][CH2:60]3)[CH2:58][C:49]1=[C:50]2[C:55](=[O:57])[CH3:56].[NH:68]1[CH2:72][CH2:71][CH2:70][CH2:69]1>C1COCC1.CCCCCC.CCOC(C)=O>[CH3:66][C:62]1([CH3:65])[O:63][CH2:64][C:59]2([CH2:58][C:49]3=[C:50]([C:55](=[O:57])[CH3:56])[C:51]4[C:46]([CH:47]=[C:48]3[CH2:67]2)=[C:45]([N:68]2[CH2:72][CH2:71][CH2:70][CH2:69]2)[CH:54]=[CH:53][CH:52]=4)[CH2:60][O:61]1
Reactant: CC(=O)c1c2c(cc3c(Cl)cccc13)CC1(COC(C)(C)OC1)C2
Reactant: C1CCNC1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1c2c(cc3c(N4CCCC4)cccc13)CC1(COC(C)(C)OC1)C2
Yield: 35 %

Procedure:
Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0020 g, 0.0028 mmol), LHMDS (0.23 mL of a 1.0 M solution in THF, 0.23 mmol), 5a (0.040 g, 0.12 mmol) in THF (0.3 mL), pyrrolidine (0.014 mL, 0.17 mmol). The title compound was isolated (n-hexane/AcOEt 8:2, 0.016 g, 35% yield) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.C(#N)C.[CH3:31][N:32]([CH3:52])[CH2:33][CH2:34][O:35][C:36](=[O:51])[C@@H:37]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38][CH2:39][C:40](O)=[O:41].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O>[CH3:52][N:32]([CH3:31])[CH2:33][CH2:34][O:35][C:36](=[O:51])[C@@H:37]([NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:38][CH2:39][C:40](=[O:41])[NH:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reactant: CN(C)CCOC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Product: CN(C)CCOC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-(2-dimethylamino-ethyl)ester (370 mg, 0.70 mmol; 77% purity) described in Manufacturing Example 3-1 and ethanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-(2-dimethylamino-ethyl)ester (300 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 0.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-(2-dimethylamino-ethyl)ester (crude, 190 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (160 mg, 0.42 mmol) in this order at 0° C., which was stirred overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=30:1), so as to obtain the titled compound (56 mg, purity of 75%).
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].C([C@H]1N([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)C2C(=CC(F)=CC=2)NC1=O)C>CCOCC>[CH2:1]([C@@H:3]1[N:12]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2]
Reactant: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Reactant: CC[C@@H]1Nc2cc(F)ccc2NC1=O
Solvent: CCOCC
Product: CC[C@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 82 %

Procedure:
(3S)-3-Ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one in ether was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (82%). MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C(N(CC)CC)C.O>CS(C)=O>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C@@H:14]2[CH3:13])=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Yield: 32.9 %

Procedure:
Heat a mixture of 1,4-dichlorophthalazine (10.0 g, 50.2 mmol), (S)-tert-butyl 3-methylpiperazine-1-carboxylate (15.1 g, 75.4 mmol) and triethylamine (21.0 mL, 150.7 mmol) in DMSO (200 mL) at 120° C. for 2 d. Pour the reaction mixture into water, rinsing with CH2Cl2. Extract with Et2O. Wash the organic layer with water (2×), dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 20% EtOAc in CH2Cl2) to provide the title compound as a pale yellow solid (6.0 g, 33%). ES/MS m/z (35Cl) 363.0 (M+1).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39].Cl>O.C1COCC1>[CH:36]([C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[OH:39])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=Cc1ccccc1O
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCCC=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a stirred suspension of pentyl triphenylphosphonium bromide (10.4 g, 25.2 mM) in freshly distilled THF (40 ml) was added LiN(SiMe3)2 (1M in THF, 50 ml). The reaction was stirred at ambient temperature for 1 hour. Salicylaldehyde (2.8 g, 22.9 mM) was added to the reaction mixture which was stirred at ambient temperature for 60 hours. The reaction was then treated with water, the pH adjusted with 1N aqueous HCl to pH7 and extracted twice with ethyl acetate. The organic layers were combined, dried over (MgSO4) and evaporated. The residue was purified by chromatography to give 2-(1-hexenyl)phenol, (3.57 g, 88%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:3]1.N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:3]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCCN1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methyl pyrrolidine (1.60 g), pyridine (0.43 ml) and N,N-dimethylaminopyridine (0.54 g) in dichloromethane (20 ml) was added methanesulfonyl chloride (0.37 ml) under ice-cooling and the mixture was stirred under the same condition for 1 hour and then allowed to stand at ambient temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.90 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([CH3:17])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C(N(C(C)C)CC)(C)C>>[CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:21]=[CH:20][C:19]([O:23][CH3:24])=[O:22])=[C:12]([CH3:17])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)OCc2ccccc2)ccc1Br
Reactant: C=CC(=O)OC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)cc1C
Temperature: 110 °C
Yield: 84.7 %

Procedure:
To a solution of 4-bromo-3-methyl-benzoic acid benzyl ester (36 g, 118 mmol) in propronitrile (1000 mL) is added methyl acrylate (43.3 mL) and diisopropylethyl amine (42 mL), the solution is degassed and filled with nitrogen for three times. To this mixture are added tri-o-tolyl-phosphane (14.5 g) and palladium acetate (5.34 g) under nitrogen, then heated at 110° C. overnight, cooled to room temperature, filtered through celite. The solvent is evaporated, the residue is taken into ethyl acetate and washed with water and brine, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate gave the title compound (31 g, 84.7%).
Reaction SMILES: [CH2:1]1[CH:11]2[C:5](=[N:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10]2=[O:12])[CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.CCCCCC>[CH2:17]([N:9]1[C:10](=[O:12])[CH:11]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]2=[N:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2N=C2CCCCC12
Solvent: CCO
Solvent: CCCCCC
Product: O=C1C2CCCCC2=Nc2ccccc2N1Cc1ccccc1
Yield: 66 %

Procedure:
Using 1,2,3,4,10,11a-hexahydro-11H-dibenzo [b,e][1,4]diazepin-11-one and benzyl bromide, the titled compound was synthesized in substantially the same procedure as in Working Example 4. Yield 66%. m.p. 123°-125° C. (ethanol-hexane).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:23]=2)[CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:47][OH:48]>O1CCCC1>[NH3:23].[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:23]=2)[CH2:18][C:19]([NH:47][OH:48])=[O:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccccn2)no1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccccn2)no1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 143.2 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(2-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid trifluoroacetate (Preparation 59) (214 mg, 0.45 mmol) in anhydrous tetrahydrofuran (5 ml) was treated with 1,1′-carbonyldiimidazole (194 mg, 1.20 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 2 hours. Hydroxylamine hydrochloride (83 mg, 1.20 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water then brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as a colourless oil (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[CH:5]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)=O>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH2:12])[CH:5]=1
Reactant: C=C(c1ccccc1)c1cc(C(=O)OC)ccc1O
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: C=C(c1ccccc1)c1cc(C(=O)OC)ccc1OCc1ccccc1
Yield: 79.7 %

Procedure:
To a solution of 1.50 g (5.9 mmole) 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid methylester and 1.04 g (6.1 mmole) benzyl bromide in 10 ml abs. acetone 1.24 g (8.9 mmole) potassium carbonate are added. The reaction mixture is then heated for 4 hours with recycling. Following cooling of the suspension, it is filtered and the residue is washed with 50 ml diethtylether. The solvent is removed and the raw product obtained is cleaned by column chromatography (silica gel, petroleum ether/MTBE=5/1 (v/v)). 1.62 g (4.7 mmole, 80%) 4-benzyloxy-3-(1-phenyl-vinyl)-benzoic acid-methylester are obtained.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([CH2:26]Cl)=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CS(C)=O>[C:10]([O:14][C:15]([N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([CH2:26][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C(Cc1cn(C(=O)OC(C)(C)C)c2ncccc12)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To acetylacetone (0.563 g, 5.62 mmol) in dimethyl sulfoxide (29.0 mL) was added sodium hydride (0.225 g, 60% in mineral oil, 5.62 mmol). After 20 minutes, 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (512, 1.00 g, 3.75 mmol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a colorless oil (513, 0.59 g, 48.0%). MS (ESI) [M+H+]+=331.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:26](OC(C)(C)C)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]2[CH:13]=[N:26][NH:1][C:2]=2[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Cl)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 equiv.) in chloroform (13 mL per 1 mmol), potassium acetate (1.05 equiv.) and acetic anhydride (2 equiv.) were added and reaction mixture stirred at room temperature for 12 h. After this time, tert-butyl nitrite (4 equiv.) and 18-crown-6 (0.35 equiv.) were added and the reaction stirred again at 65° C. for 3 h. On completion, the reaction mixture was cooled to room temperature, diluted with chloroform (500 mL) and washed with sat. sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated to afford the title compound (yield 90-95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.CCOCC.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH2:6][CH2:7][NH2:8]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: NCCOc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 109.9 %

Procedure:
A solution of 2-[2-(3,5-dichloro-phenoxy)-ethyl]-isoindole-1,3-dione (1.29 g, 3.84 mmol) and hydrazine hydrate (202 mg, 4.05 mmol) in MeOH (16 mL) was heated at reflux for 2 h. The mixture was cooled to room temperature and Et2O was added. The suspension was shaken with 40% aqueous potassium hydroxide. The aqueous solution was extracted with Et2O (3×) and the combined organic layers were dried (K2CO3), filtered, and concentrated to provide the title compound (870 mg). 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.80 (m, 2H), 3.95 (m, 2H), 3.07 (t, 2H), 1.70 (bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](O)[CH2:26][OH:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]1[O:27][CH2:26][CH2:25][O:6]1
Reactant: OCCO
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1C1OCCO1
Temperature: 50 °C
Reaction time: 12 h
Yield: 95.5 %

Procedure:
To a stirred solution of 2-methoxy-4-nitro-benzaldehyde (4.61 g, 25.4 mmol) in toluene (51 mL), was added p-toluene sulfonic acid (483 mg, 2.54 mmol), followed by ethylene glycol (2.83 mL, 50.8 mmol). After heating the reaction mixture at 50° C. for 12 h, additional p-toluene sulfonic acid (483 mg, 2.54 mmol) and ethylene glycol (2.83 mL, 50.8 mmol) were added. After an additional 12 h, the solvent was removed under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL), dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound as a yellow solid (5.46 g, 95%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)=O)[CH2:3][CH2:2]1.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[Cl:13][C:8]1[CH:7]=[C:6]([C:4]2[C:17]3[N:16]([C:15]([CH3:14])=[N:19][CH:18]=3)[CH2:2][CH2:3][CH:1]=2)[CH:11]=[CH:10][C:9]=1[Cl:12]
Reactant: Cc1ncc[nH]1
Reactant: O=C(c1ccc(Cl)c(Cl)c1)C1CC1
Product: Cc1ncc2n1CCC=C2c1ccc(Cl)c(Cl)c1

Procedure:
Combine 10 g (46.5 mmol) of cyclopropyl-(3,4-dichlorophenyl)methanone with 20 g (0.24 mol) of 2-methylimidazole and heat to 175° C. under nitrogen for 70 hr. The title compound is isolated by column chromatography on silica gel using methylene chloride as the solvent.
Reaction SMILES: [N+:1]([C:4]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:23][CH3:24])=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C(OC1[C:47](OC)=[CH:46][C:42](C(Cl)=O)=[C:41]([N+:50]([O-])=O)[C:40]=1[O:53]C)C1C=CC=CC=1.N1(CO)CCCC1>CN(C=O)C.CC#N.C(Cl)Cl>[CH2:16]([O:15][C:11]1[C:10]([O:23][CH3:24])=[CH:9][C:5]([C:6]([N:50]2[CH2:47][CH2:46][CH2:42][CH:41]2[CH2:40][OH:53])=[O:8])=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=1[O:13][CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Reactant: COc1cc(C(=O)Cl)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: OCN1CCCC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Reaction time: 8 h
Yield: 70 %

Procedure:
A catalytic amount of DMF (5 drops) was added to a stirred solution of 124 (10 g, 30.0 mmol) and oxalyl chloride (4.65 g, 36.0 mmol) in dry CH3CN (115 mL) under a nitrogen atmosphere. The reaction mixture was allowed to stir overnight and the resulting acid chloride used directly in the next part of the procedure. 4-benzyloxy-3,5-dimethoxy-2-nitro-benzoyl chloride in anhydrous CH3CN (115 mL) was added dropwise over 0.5 hours to a stirring solution of pyrrolidine methanol (3.34 g, 33.03 mmol, 1.1 eq) and TEA (7.58 g, 75.1 mmol, 2.5 eq) in anhydrous DCM (100 mL) at 0° C. under a nitrogen atmosphere and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was washed with 1N HCl (2×100 mL), and the organic layer was washed with distilled H2O (2×100 mL), brine (2×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent yielded a brown glass (8.71 g, 20.9 mmol, 70%); 1H NMR (270 MHz, CDCl3) δ1.7-2.2 (m, 4H), 3.3-3.5 (m, 2H), 3.7-3.9 (m, 2H), 3.9 (s, 3H), 4.0 (s, 3H), 4.2-4.3 (m, 1H), 5.1 (s, 2H), 6.85 (s, 1H), 7.3-7.5 (m, 5H); 13C NMR (67.8 MHz, CDCl3) δ167.3, 156.8, 148.2, 142.3, 136.4, 136.0, 129.0, 128.5, 128.4, 104.8, 75.6, 65.7, 62.8, 61.4, 56.6, 50.2, 28.3, 24.5.