Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH3:15][N:16]([CH3:67])[C:17]([C@H:19]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[CH2:22][C@@H:21]([S:37][C:38]2[C@H:39]([CH3:66])[C@@H:40]3[C@@H:57]([C@H:58]([O:60][Si](C)(C)C)[CH3:59])[C:56](=[O:65])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[CH2:20]1)=[O:18]>CO>[CH3:67][N:16]([CH3:15])[C:17]([C@H:19]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[CH2:22][C@@H:21]([S:37][C:38]2[C@H:39]([CH3:66])[C@@H:40]3[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:65])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=2)=[O:44])[CH2:20]1)=[O:18]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 84.3 %

Procedure:
8 mg (0.039 mmol) of citric acid hydrate were added to 2 ml of a solution containing 55 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 18)in methanol, and the resulting mixture was stirred at room temperature for 35 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through 5 g of silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 42 mg (yield 84%) of the title compound as a vitreous solid.
Reaction SMILES: [CH:1]1[CH:6]=N[CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.[CH3:10]N1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH3:29][O:30][C:31](=[O:40])[C@H:32]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[NH2:33]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:40])[C:32]([NH2:33])([C:7](=[O:9])[C:3]1[CH:2]=[CH:1][CH:6]=[CH:10][CH:4]=1)[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: CN1CCOCC1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCC(N)(C(=O)OC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a solution of niacin (1.4 g, 11.42 mmol) in DCM (20 mL) were added N-methyl morpholine (3.76 mL, 34.2 mmol), EDCI.HCl (4.36 g, 34.2 mmol) and L-glutamic acid dimethyl ester (2.0 g, 11.42 mmol). The mixture was allowed to stir at room temperature (25° C.) over 3 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (100 mL), washed with water (3×50 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain required product as pale yellow oil (3.1 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[N:11][OH:12])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9](=[N:11][O:12][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NC(=NO)c1nc(Br)cnc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=NOC(=O)c1ccccc1)c1nc(Br)cnc1N
Reaction time: 1 h
Yield: 69.8 %

Procedure:
3-amino-6-bromo-N′-hydroxypyrazine-2-carboximidamide (770 mg, 3.318 mmol) was suspended in DCM (10 mL) and triethylamine (369.3 mg, 508.7 μL, 3.650 mmol) followed by benzoyl chloride (513.1 mg, 423.7 μL, 3.650 mmol) were added. After 1 hour, the solvent was removed in vacuo and the residue triturated with MeOH. The resultant filtrate was filtered off to furnish the product as an off-white solid (779 mg, 70% Yield).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([N:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44]CC)=[O:43])[CH2:38][CH2:37]4)[S:33][C:34]=3[CH3:35])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:48]=[CH:47][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([N:36]4[CH2:37][CH2:38][CH:39]([C:42]([OH:44])=[O:43])[CH2:40][CH2:41]4)[S:33][C:34]=3[CH3:35])=[C:26]([O:49][CH3:50])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(N3CCC(C(=O)O)CC3)sc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a mixture of ethyl 1-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]piperidine-4-carboxylate (0.28 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]piperidine-4-carboxylic acid as colorless crystals (0.23 g, yield 85%). Recrystallized from acetone-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]([O:12][C:13]([NH:15][C:16](=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])SC)=[O:14])([CH3:11])([CH3:10])[CH3:9].N[C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]2[CH:39]=[C:40]([CH:44]([NH:51][C:52](=[O:63])[CH:53]([C:55]3[C:60]([CH3:61])=[CH:59][C:58]([CH3:62])=[CH:57][CH:56]=3)[CH3:54])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]=[CH:42][CH:43]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:54][CH:53]([C:55]1[C:60]([CH3:61])=[CH:59][C:58]([CH3:62])=[CH:57][CH:56]=1)[C:52]([NH:51][CH:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([N:37]([NH:3][C:16]([NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])=[N:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[S:34]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:28][CH:29]=2)(=[O:36])=[O:35])[CH:39]=1)[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:63]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC(NC(=O)C(C)c1ccc(C)cc1C)c1cccc(NS(=O)(=O)c2cccc(N)c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)C(C)c1ccc(C)cc1C)c1cccc(N(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
0.12 ml of triethylamine, 195 mg of 1,3-bis(t-butoxycarbonyl)-2-methyl-2-thiopseudourea and 132 mg of mercuric chloride were added at 0° C. to a solution of 250 mg of (3d) in 10 ml of DMF. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. 15 ml of ethyl acetate were added, and it was stirred for 30 min before the precipitate was removed by filtration. The solution was concentrated and reused without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[CH:16]1([SH:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:15])[CH:4]([S:21][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1
Reactant: SC1CCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A solution of diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (Example 1; 193 mg, 0.79 mmol) in dichloromethane (10 mL) at 25° C. was treated with cyclopentyl mercaptan (0.21 mL, 1.97 mmol) followed by rhodium (II) acetate dimer (9 mg, 0.020 mmol) and the solution was stirred at 25° C. for 1 h. During this time no evolution of gas was detected, and examination of the black solution by thin layer chromatography indicated that only starting material was present. The reaction was heated to reflux and a second portion of rhodium (II) acetate dimer (10 mg, 0.024 mmol) was added and as the mixture was stirred at reflux for 10 min, a vigorous evolution of gas was observed. The reaction mixture was diluted with dichloromethane (10 mL), then was poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) to furnish rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid methyl ester (148 mg, 59% yield) as a colorless oil: EI-HRMS m/e calcd for C14H16Cl2SO2(M+) 318.0248, found 318.0244.
Reaction SMILES: [CH2:1](OC1C=CC(Cl)=CC=1C(Cl)=O)[CH:2]=C.[CH2:15]([O:18][C:19]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=1)=[O:22])[CH:16]=C.C(OC1C=CC(Cl)=CC=1C(NCCC1C=CC(CC(O)=O)=CC=1)=O)C=C>>[CH2:15]([O:18][C:19]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=1)=[O:22])[CH2:16][CH2:1][CH3:2]
Reactant: C=CCOc1ccc(Cl)cc1C(=O)Cl
Reactant: C=CCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)OCC)cc1
Agent: C=CCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)O)cc1
Product: CCCCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
with 2-allyloxy-5-chlorobenzoyl chloride, via ethyl 4-[2-(2-allyloxy-5-chlorobenzamido)-ethyl]-phenylacetate, 4-[2-(2-allyloxy-5-chlorobenzamido)-ethyl]-phenylacetic acid; m.p. 104°-105° C., after recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.CCOC(C)=O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Yield: 45.2 %

Procedure:
2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2 mmol, 1 equiv) and iron (8.44 g, 151.1 mmol, 5 equiv) were mixed in acetic acid (100 mL) and EtOAc (50 mL) and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52%) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), 6.80 (d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMS RT=0.89 min, [M+H]+=235.1.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[NH:4][C:5]([C:21](F)([F:23])[F:22])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]([CH2:14][CH3:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].N12CCCNC1C=CCCC2.Cl>O1CCCC1>[F:23][CH:21]([F:22])[C:5]1[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([CH2:14][CH3:15])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:26])([F:1])[F:25])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1CC
Agent: C1=CC2NCCCN2CCC1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1CC
Temperature: 0 °C
Yield: 78.4 %

Procedure:
A mixture of 1558 g (4.00 moles) of diethyl 2,6-bis(trifluoromethyl)-1,4-dihydro-4-ethyl-3,5-pyridinedicarboxylate, 628 g (4.0 moles) of 1,8-diazabicyclo-[5.4.0]-undec-5-ene (DBU), and 500 ml of tetrahydrofuran is held at reflux for 19 hours, cooled and poured into a mixture of 2 kg of ice and 250 ml of concentrated hydrochloric acid. The organic layer is separated and the aqueous layer extracted with 500 ml of CH2Cl2 twice. The combined organic materials are dried (MgSO4) and concentrated. The residue is kugelrohr distilled at 1 torr (pot temperature of 150°-160° C.) to give 1158 g (78.5%) of desired product, nD25 1.4458.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc(C=O)c(Cl)c1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 2,3-dichloro-4-methoxybenzaldehyde (158 gm., 0.77 mole), malonic acid (146 gm., 1.4 mole), pyridine (450 ml.) and piperidine (15 ml.) is heated and stirred on a steam bath for 23/4 hours. The hot reaction mixture is poured, with stirring into a mixture of concentrated hydrochloric acid (770 ml.) and crushed ice (3.1 kg.).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.O.[NH2:13][NH2:14]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:13][NH2:14])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(Br)cc1
Yield: 67 %

Procedure:
First, 3.0 g (13.9 mmol) of methyl-4-bromobenzoate was put in a 100-mL three-neck flask, 10 mL of ethanol was added therein, and the mixture was stirred. Thereafter, 4.0 mL of hydrazine monohydrate was added therein, and the mixture was heated and stirred at 78° C. for 5 hours. The obtained solid was washed with water and collected by suction filtration; thus, 2.0 g of a white solid of 4-bromobenzohydrazide that was an object was obtained (yield: 67%).
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl-].[NH4+].[CH3:15][C@H:16]1[CH2:21][CH2:20][C@H](N)[CH2:18][CH2:17]1>>[CH3:15][C@H:16]1[CH2:21][CH2:20][C@H:12]([N:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]2)[CH2:18][CH2:17]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)c1cn([C@H]2CC[C@H](C)CC2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (Liebigs Annalen der Chemie, 1979, p. 1444) (1.52 g) was dissolved in trans-4-methylcyclohexylamine (3.07 g), and the solution was stirred at 70° C. for 4 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=2/1-1/2) to obtain the title compound (1.90 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=3[C:10]=2[N:11]=1.[N+:17]([O-])([OH:19])=[O:18]>>[OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]3[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=3[C:10]=2[N:11]=1
Reactant: Oc1nc2ccc3c(c2nc1O)CCCC3
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2c1CCCC2
Temperature: -10 °C

Procedure:
7,8,9,10-Tetrahydro-2,3-dihydroxybenzo (f) quinoxaline (0.43 g, 2 mmol) was dissolved in 5 ml of nitric acid (d 1.48) by portionwise addition, with vigorous stirring on a salt/ice - bath at -10° C. After stirring at this temperature for 2 min, the mixture was poured onto 50 ml of ice/water. The precipitate was filtered off, washed with water, a small amount of ethanol, and ether affording 0.48 g (92%) of the mononitro compound; m.p. >300° C.; IR (KBr): 1720cm-1, (C=0); 1H-NMR (DMSO-d6): 1.5-1.9 (m, 4H, 2×CH2), 2.5 - 3.0 (m, 4H, 2×CH2), 7.50 (s, 1H, H-5), 11.2 (broad s, 1H, 0H), 11.9 (broad s, 1H, 0H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29]O)=[CH:24][CH:23]=1>CC#N>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:31]=[C:13]([CH:12]([N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[CH3:16])[O:15][N:29]=2)=[CH:24][CH:23]=1
Reactant: N=C(NO)c1ccc(F)cc1
Reactant: CC(C(=O)O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Solvent: CC#N
Product: CC(c1nc(-c2ccc(F)cc2)no1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.7 %

Procedure:
To 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]propanoic acid (0.06 g, 0.212 mmol) in CH3CN (3 mL) was added CDl (0.034 g, 0.212 mmol). After 5 min, 4-fluoro-N-hydroxybenzenecarboximidamide (0.033 g, 0.212 mmol) was added. The resulting mixture was stirred at rt and then heated to 150° C. in a microwave for 20 min. Concentration was followed by column chromatography (EtOAc/hexanes) to obtain the desired product (0.0065 g, 8% yield): MS (APCl) m/z 401 (M+1).
Reaction SMILES: [C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(C3C=CC(OC=CCC(O)=O)=CC=3)CC3CC(CC(C3)C1)C2.[H][H]>CO.[Pd]>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:22][CH:23]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: [H][H]
Reactant: O=C(O)C=CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Pd]
Agent: O=C(O)CC=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: CO
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 24 h

Procedure:
A solution of 0.9 g of the mixture of 4-[4-(1-adamantyl)-phenoxy]-2-butenoic acid and 4-[4-(1-adamantyl)-phenoxy]-3-butenoic acid in 30 ml of absolute methanol is hydrogenated with 0.3 g of palladium (5% strength on charcoal) until 1 equivalent of hydrogen has been taken up (normal pressure, about 25° C). The catalyst is then filtered off, and the filtrate is mixed with 10 ml of 2 N sodium hydroxide solution and left to stand for 24 hours at about 25° C. It is then evaporated in vacuo to half its volume. The evaporation residue is partitioned between 50 ml of 2 N hydrochloric acid and 3 times 50 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from ethanol gives 4-[4-(1-adamantyl)-phenoxy]-butyric acid of melting point 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10]CC)=O)=[C:4]([CH3:7])[S:5][CH:6]=1.C([CH:15]([C:19](Cl)=[O:20])[C:16](Cl)=[O:17])C.[H-].[Na+].O.[O:25]1CCO[CH2:27][CH2:26]1>>[CH2:26]([O:25][C:19]([C:15]1[C:16](=[O:17])[NH:1][C:2]2[C:3]([C:8]=1[OH:10])=[C:4]([CH3:7])[S:5][CH:6]=2)=[O:20])[CH3:27]
Reactant: CCOC(=O)c1c(N)csc1C
Reactant: C1COCCO1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(O)c2c(C)scc2[nH]c1=O
Temperature: 50 °C
Yield: 52 %

Procedure:
Ethyl 4-amino-2-methyl-thiophene-3-carboxylate (12.8 mmol, 2.37 g) was dissolved in 1,4-dioxane (20 ml) and ethyl malonyl chloride (90%) (19.2 mmol, 2.73 ml) was added. The reaction mixture was heated at 50° C. for 1 h and was then allowed to reach room temperature. The reaction mixture was poured onto ice (60 g) and the product was collected by filtration, washed with water and dried (3.32 g, 87%). The malonic amide was dissolved in N,N-dimethylacetamide (DMA, 35 ml) and sodium hydride (NaH 60%, 2.0 equiv., 22.1 mmol) was added. The reaction mixture was heated at 60° C. for 1 h. After cooling and addition of water (50 ml) the product was precipitated by addition of 1 M hydrochloric acid (HCl, aq.) (30 ml). The precipitate was collected by filtration and was re-crystallized from ethanol giving 4,5-dihydro-7-hydroxy-1-methyl-5-oxo-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (1.46 g, 52%). The carboxylic acid ethyl ester was dissolved in dimethylformamide (DMA, 40 ml) and NaH (3.0 equiv., 17.3 mmol, 692 mg) was added. The reaction mixture was heated to 40° C. for 15 minutes and was then cooled to 10° C. Iodomethane (1.3 equiv., 7.49 mmol, 0.47 ml) was added, the reaction mixture was stirred at ambient temperature for 2 hrs and was then poured onto 0.5 M HCl (aq) (50 ml). The precipitate was collected by filtration and re-crystallized from ethanol and then again from methyl isobutyl ketone to give the title compound (524 mg, 89%).
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:2][CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.P(Br)(Br)[Br:19]>C(Cl)(Cl)Cl>[Br:19][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: BrP(Br)Br
Reactant: CC(C)CCOCCCCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)CCOCCCCBr
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 6.4 g (0.4 mol) of 4-isopentyloxy-butanol and 0.32 g (0.004 mol) of pyridine in 40 ml of chloroform are added over a period of 15 minutes with stirring at 0° , 1.42 ml (0.015 mol) of phosphorus tribromide. The mixture is stirred for a period of one hour at 20° and then for 20 hours at 60°C. After cooling to room temperature, the reaction mixture is poured into an ice cold saturated aqueous sodium bicarbonate solution and the reaction product is extracted with chloroform. The chloroform extract is then first washed with water and then with saturated aqueous sodium chloride solution and afterwards dried with sodium sulphate. The chloroform is then evaporated off under reduced pressure. The residue is chromatographed on a silica gel column with hexane/ethyl acetate (99:1 to 98.2) as eluent. After fractional distillation of the practically pure chromatographic fractions, pure 1-bromo-4-isopentyloxy-butane is obtained, as a colourless oil. (Boiling point 40° to 46° 0.03 mm Hg).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>C1COCC1>[C:1]([C:3]1([C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)OCC)cc(C2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 5-(cyanomethyl)benzene-1,3-dioate (500 mg, 1.9 mmol) in 18.6 mL THF was added potassium bis(trimethylsilyl)amide (1.1 g, 5.7 mmol) and the reaction was stirred at rt for 5 min. 1,4-Dibromobutane (0.25 mL, 2.1 mmol) was added, the mixture was stirred for 45 min and then quenched with 1N HCl. Ethyl acetate was added, the layers separated and the organic layer washed with water and brine. Drying, solvent evaporation and flash chromatography (silica gel, 0->15% EtOAc/hexanes) gave diethyl 5-(1-cyanocyclopentyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.63 (m, 1H), 8.31 (m, 2H), 4.43 (q, J=7.1 Hz, 4H), 2.56 (m, 2H), 2.14-1.99 (m, 6H), 1.43 (t, J=7.1 Hz, 6H).