Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]([C@H:15]1[CH2:19][CH2:18][NH:17][C@H:16]1[CH3:20])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Li+].[Li+]>>[Br:1][C:2]1[CH:9]=[C:8]([N:17]2[CH2:18][CH2:19][C@H:15]([C:12]([OH:11])([CH3:14])[CH3:13])[C@@H:16]2[CH3:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Br)c1

Procedure:
Using 2-bromo-4-fluorobenzonitrile (497 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (659 mg) and lithium carbonate (259 mg), the title compound was obtained as a yellow solid (yield: 608 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]=[O:20])=[C:16]([O:21][CH3:22])[C:15]([CH3:23])=[C:14]2[C:10]=1[C:11](=[O:24])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:25]([Mg]Br)[CH:26]=[CH2:27].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:20])[C:26]([CH3:27])=[CH2:25])=[C:16]([O:21][CH3:22])[C:15]([CH3:23])=[C:14]2[C:10]=1[C:11](=[O:24])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(O)Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde (5.25g) in THF (70 ml) at -70° C. was added 1N 2-propenylmagnesium bromide in THF (19 ml). The solution was kept at -40° C. for 15 minutes, then saturated aqueous ammonium chloride (80 ml) was added. The mixture was extracted with ether, and the extract dried and evaporated, to give 4-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-2-methylbut-1-ene, mp 133°-4° C. (tert-butylmethyl ether/hexane).
Reaction SMILES: [CH2:1]([C:8]1([O:13][C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][CH2:24][CH3:25])[C:18](OC)=[O:19])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:29]1([P:35](=[CH:48][C:49]#[N:50])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:49]([C:48](=[P:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:18]([C@@H:17]([NH:16][C:14](=[O:15])[O:13][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])#[N:50]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To 1.31 g (3.77 mmol) of methyl(2S)-2-({[(1-benzylcyclopentyl)oxy]carbonyl}amino)hexanoate in 12 mL of tetrahydrofuran:water (1:1) was added 221.5 mg (5.28 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with ethyl acetate. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 19 mL of dichloromethane, then 23.0 mg (188.5 μmol) of 4-dimethylaminopyridine was added. To this solution was added 1.19 g (3.96 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 799.2 mg (4.15 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 19 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 789.8 mg (34%) of 1-benzylcyclopentyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.31 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.76-7.66 (m, 3H), 7.64-7.54 (m, 12H), 7.20-7.14 (m, 5H), 6.90 (d, J=8 Hz, 1H), 4.58-4.50 (m, 1H), 3.24 (ABq, JAB=14 Hz, ΔνAB=31 Hz, 2H), 1.88-1.66 (m, 4H), 1.64-1.44 (m, 6H),1.42-1.14 (m, 4H), 0.89 (t, J=7 Hz, 3H); ES-LCMS m/z 617 (M+H).
Reaction SMILES: C(OC([NH:6][NH:7][C:8]([CH:10]([N:12]([S:21]([CH3:24])(=[O:23])=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:11])=[O:9])=O)C>C(O)C.[OH-].[Na+]>[NH:7]([C:8]([CH:10]([N:12]([S:21]([CH3:24])(=[O:23])=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:11])=[O:9])[NH2:6]
Reactant: CCOC(=O)NNC(=O)C(C)N(c1c(C)cccc1C)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1N(C(C)C(=O)NN)S(C)(=O)=O

Procedure:
A solution of N-[1-(2-(ethoxycarbonyl)hydrazinocarbonyl)ethyl]-2',6'-dimethylmethanesulphonanilide (5.6 g) in ethanol (75 ml) and 10% sodium hydroxide solution (75 ml) was heated on a steam bath for 21/2 hours, and then the ethanol was evaporated off. The aqueous solution remaining was acidified with dilute hydrochloric acid, heated on a steam bath for 1 hour, and then filtered. The filtrate was just neutralised with dilute sodium hydoxide solution, saturated with sodium chloride and extracted with chloroform. The chloroform solution was dried and evaporated, and the residue gave colourless crystals of N-[1-(hydrazinocarbonyl)ethyl]-2',6'-dimethylmethanesulphonanilide from a solution in toluene/60°-80° petrol. Yield 2.6 g (58%). Melting point 115°-118°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:44])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:19]=[CH:18][C:17]=4[O:28][CH2:29][C:30]4([CH3:34])[CH2:33][O:32][CH2:31]4)[CH2:14][C:13](=[O:35])[NH:12][CH:11]3[C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=3[CH3:43])[C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:44])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]#[CH:23])[CH:19]=[CH:18][C:17]=4[O:28][CH2:29][C:30]4([CH3:34])[CH2:31][O:32][CH2:33]4)[CH2:14][C:13](=[O:35])[NH:12][CH:11]3[C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=3[CH3:43])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(C#C[Si](C)(C)C)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OCC2(C)COC2)c(C2CC(=O)NC(c3cc(Cl)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(5-chloro-2-methyl-phenyl)-4′-[2-(3-methyl-oxetan-3-ylmethoxy)-5-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione in methanol (5 mL) was added K2CO3 (100 mg). The mixture was stirred at room temperature for 2 h, purified by prep-HPLC to give the title compound as a white solid (2.5 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:12])[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCCOS(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of methanesulphonyl chloride (23.7 ml) in dry dichloromethane (25 ml.) was added dropwise to a solution of hex-5-yn-1-ol (Lancaster Synthesis, 25 g) and triethylamine (47.3 ml) in dichloromethane (300 ml), and stirred under a nitrogen atmosphere at -70°. The resulting mixture was allowed to warm to room temperature over 16 hours. The mixture was then washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. Hex-5-ynyl methanesulphonate was obtained as an oil (43.6 g) and was used without purification.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([N+:13]([O-])=O)=[C:6](/[CH:8]=[CH:9]/N(C)C)[CH:7]=1>[Ni].CCO>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[NH2:16])[NH:13][CH:9]=[CH:8]2
Reactant: CN(C)/C=C/c1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
A suspension of (E)-2-(5-fluoro-2,4-dinitrophenyl)-N,N-dimethylethenamine (8.0 g, 31 mmol) and Raney Nickel (8 g) in EtOH (80 mL) was stirred under H2 (40 psi) at room temperature for 1 h. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give 5-fluoro-1H-indol-6-amine (1.0 g, 16%) as a brown solid. 1HNMR (DMSO-d6) δ 10.56 (br s, 1H), 7.07 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8 Hz, 1H), 6.17 (s, 1H), 3.91 (br s, 2H); MS (ESI) m/e (M+H+) 150.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:16]=[C:15]([C:28]([OH:30])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:58]1[CH2:62][CH2:61][NH:60][CH2:59]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)[N:16]=[C:15]([C:28]([N:60]3[CH2:61][CH2:62][S:58][CH2:59]3)=[O:30])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(C(F)(F)F)c2)n1
Reactant: C1CSCN1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(C(F)(F)F)c2)n1)N1CCSC1

Procedure:
130 mg (0.26 mmol) of the compound of Example 47A is reacted analogously to the synthesis of the compound of Example 1 with 26 mg (0.29 mmol) of thiazolidine. 105 mg (71% of theory) of the title compound is obtained.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Cl:23][C:24]1[C:25]([C:31](Cl)=[O:32])=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1.O>[Cl:23][C:24]1[C:25]([C:31](=[O:32])[CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[C:19]([O:21][CH3:22])=[O:20])=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: O=C(Cl)c1ncc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)C(C(=O)c1ncc(Cl)cc1Cl)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
28.5 ml (28.5 mmol) of a 1 M solution of LiHMDS in hexane are added to 50 ml of THF at −78° C. A solution of 4.00 g (23.8 mmol) of methyl (2-fluorophenyl)acetate in 10 ml of THF is then added dropwise. The mixture is stirred at −78° C. for 1 h and then 6.00 g (28.5 mmol) of 3,5-dichloro-pyridine-2-carbonyl chloride are added in portions. After a further hour, the mixture is allowed to reach RT and saturated ammonium chloride solution is added dropwise. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. The residue after concentration in vacuo is purified by chromatography on silica gel (eluent: dichloromethane/methanol 50:1). 4.46 g (46% of theory) of the desired compound are obtained as a yellowish oil.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:26])C.[OH-].[Na+]>C(O)C.CO.O1CCCC1>[F:26][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)[CH:9]=[CH:10][C:5]=1[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)c(F)c3)cc21
Temperature: 70 °C
Yield: 27.1 %

Procedure:
A solution of 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen -2-ylethynyl)benzoic acid ethyl ester (Compound 9, 0.1 g, 0.274 mmol) in ethanol(4 mL), methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 1M aqueous sodium hydroxide solution and heated at 70° C. for 1 h. The volatiles were distilled off in vacuo and the residue was diluted with water and dilute hydrochloric acid and extracted with ethyl acetate (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid that was recrystallized from hot aqueous acetonitrile to afford the title compound (0.025 g, 27%).
Reaction SMILES: [OH-].[Na+].[NH:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([O-:7])=[O:6].[Na+].[Na+]>>[NH:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C([O-])CNCC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNCC(=O)O

Procedure:
One conventional processes for the preparation of PMIDA starts with iminodiacetic acid (IDA), and requires the involved preparation of that material from its alkali metal salt. More specifically, the IDA moiety is produced by the alkaline hydrolysis of iminodiacetonitrile (IDAN) or by the oxidative dehydrogenation of diethanolamine under alkaline conditions. If sodium hydroxide is used as the base, the product from either of these methods is an aqueous disodium iminodiacetate (DSIDA) solution. This solution is the feedstock used either directly for conversion to PMIDA or to produce IDA for subsequent conversion to PMIDA. In the second case, disodium IDA solution is typically acidified with sulfuric acid or other strong mineral acid and the resulting IDA is separated from sodium sulfate or sodium salt of the strong mineral acid by fractional crystallization. This isolation of IDA by fractional crystallization, which is described in U.S. Pat. No. 3,808,269, requires an evaporative crystallizer for crystallization of anhydrous sodium sulfate, a cooling crystallizer for crystallization of IDA, two centrifuges, solids conveying equipment, and a sodium sulfate dryer, and storage silos or bins for the isolated IDA and dry sodium sulfate. Mother liquors can be recycled but a portion must be purged to remove impurities. An economically and environmentally significant amount of IDA is lost in this purge stream.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]([NH2:21])=[O:20].[CH:22](N)=O>>[CH:7]([N:6]1[C:2]2[N:1]=[CH:22][NH:21][C:19](=[O:20])[C:3]=2[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[N:5]1)([CH3:9])[CH3:8]
Reactant: NC=O
Reactant: CC(C)n1nc(-c2cccc([N+](=O)[O-])c2)c(C(N)=O)c1N
Product: CC(C)n1nc(-c2cccc([N+](=O)[O-])c2)c2c(=O)[nH]cnc21
Temperature: 160 °C
Yield: 91 %

Procedure:
Compound 27 (1 g, 3.46 mmol) was added to formamide (1.167 mL, 29.3 mmol) and heated to 160° C. for 40 hours. Afterwards, the reaction mixture was allowed to cool to room temperature and diluted into ice cold water. The mixture was filtered and a solid was collected (943 mg, 91% yield): 1H NMR (400 MHz, DMSO) δ 12.37 (s, 1H), 9.32 (s, 1H), 8.81 (d, J=7.8, 1H), 8.23 (d, J=8.1, 1H), 8.13 (s, 1H), 7.75 (t, J=8.0, 1H), 5.06 (hept, J=6.6, 1H), 1.52 (d, J=6.7, 6H); 13C NMR (100 MHz, DMSO) δ 157.77, 152.48, 148.16, 148.06, 143.85, 133.58, 129.95, 123.05, 122.07, 103.02, 49.07, 21.74; [M+H]+ calculated for C14H13N5O3 300.1, found 300.0.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21](Br)[CH3:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>CS(C)=O>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(Br)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)C(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.8 %

Procedure:
1.18 g of sodium hydride (60% and oily) was suspended in 20 ml of dimethyl sulfoxide, and 3.9 g of dimethyl malonate was added dropwise thereto under ice cooling. After the addition, the temperature of the reaction solution was elevated to room temperature, and 3.4 g of 1-(4-nitrophenyl)ethyl bromide synthesized in the above-mentioned section (1) was added thereto, followed by stirring at room temperature for 20 hours in an atmosphere which was shielded from light. The resulting reaction mixture was poured into 1N hydrochloric acid slowly, and the solution was then extracted twice with 50 ml of ether. Extracts were joined together, washed with water and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The solution was then evaporated to dryness, thereby obtaining 3.9 g of dimethyl 1-(4-nitrophenyl)ethylmalonate in an oily state.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH:27]1([O:33][CH2:34][CH2:35]O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:35][CH2:34][O:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the tosylate prepared from 2-(cyclohexyloxy)ethanol (1.49 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (diethyl ether-hexane; 1:1) to provide 0.9 g of pure 4-[[2-(cyclohexyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH:9]O>>[O:9]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:1]12
Reactant: OO
Reactant: C1=CCCCCCC1
Product: C1CCCC2OC2CC1
Reaction time: 24 h

Procedure:
The solid mixed phase after extraction in Example 1 was dried under reduced pressure for about 12 hours. 0.110 g (1.00 mmol) of cyclooctene was added to the solid mixed phase after drying under reduced pressure, and stirred well. Further, 0.10 mL (0.90 mmol) of 31% aqueous hydrogen peroxide was added and stirred well. Then, the mixture was allowed to stand still at 25° C. for 24 hours. Thereafter, a colorless solid of epoxycyclooctane was obtained in the same manner as in Example 1. The epoxide yield was 83%.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH:8]([C:16]([OH:18])=[O:17])[CH2:7]2.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH:8]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:7]2
Reactant: OCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(C(=O)O)NC2
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)CC(C(=O)OCc1ccccc1)NC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, hydrochloride (S-form) and 600 ml of benzyl alcohol was saturated with hydrogen chloride gas. The temperature rose to 45° C. The mixture was stirred at room temperature for three days. A relatively small amount of solid was filtered off and the filtrate was treated with ca 2-liters of ether to precipitate crude product; wt 37.5 g; yield, 83%. Purification was effected by treatment with excess saturated sodium bicarbonate, extraction of base into ethyl acetate and precipitation of hydrochloride salt with HCl gas. Recrystallization from methanol-ether gave pure product; mp 255°-260° C.; [α]D 23=-81.3° (1.0% MeOH); tlc (20% MeOH-CHCl3 /SiO2) one spot Rf 0.8.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([C:11]1[CH:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:13]1[C:14]([S:16][CH3:17])=[CH:15][C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:12]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CSc1cc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 62 %

Procedure:
Dimethylcarbamoyl chloride (10.7 g, 9.1 ml) was added to a solution of 3-t-butyl-5-(methylthio)pyrazole (17.0 g) and pyridine (8 ml) in benzene (100 ml). The reaction mixture was refluxed (at 80°) for 24 hours, allowed to cool, and washed with water (50 ml), 2 N HCl, (25 ml) and water again (50 ml). The organic layer was dried, and evaporated to give an oil which soon crystallised. Recrystallisation from petrol afforded 1-(dimethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole, 15.1 g, 62% yield, of melting point 58°-60°.
Reaction SMILES: N1([C:10]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)=[O:11])C2C=CC=CC=2N=N1.Cl>C1COCC1>[I:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:10]([C:12]2[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=2)=[O:11])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(I)cc1)n1nnc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C(C(=O)c1ccc(I)cc1)c1ccc(I)cc1
Reaction time: 0.08 h
Yield: 31.6 %

Procedure:
Under N2, benzotriazol-1-yl-(4-iodo-phenyl)-methanone (JYC-II-056-A) (3.5 g, 10.0 mmol) dissolved in 40 mL of anhydrous THF was added to a THF solution of SmI2 (221 mL of 0.1 M solution in THF, 22.1 mmol) at room temperature. The resulting mixture turned yellow brown in 5 min. HCl (2M, 65 mL) was added and the mixture was extracted with diethyl ether several times. The combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was washed with MeOH to give a yellow solid (0.73 g, 31.5%). 1H NMR (300 MHz, CDCl3, δ): 7.88 (d, J=8.5 Hz, 4H), 7.64 (dt, J=8.8 Hz, 4H). HRMS-EI (m/z): [M]+ calcd for C14H8I2O2, 461.86138; found, 461.86180.