Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
3.59 g (19.08 mmol) of N-(tert-butoxycarbonyl)-1,4-diaminobutane was dissolved in 70 ml of triethylamine and 3.79 g (18.17 mmol) of 4-chloro-3-nitroquinoline was added thereto. The resulting mixture was heated at 70° C. and stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with water, and dried (MgSO4). The solvent was distilled off under reduced pressure. The resulting residue was triturated with diethel ether and collected by filtration to obtain 5.77 g (16.01 mmol) of 4-[4-(tert-butoxycarbonylamino)butylamino]-3-nitroquinoline shown below as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:17]=1)[C:7]([C:9]1([OH:16])[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)=[O:8].CC([O-])(C)C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:9]3([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]3)[C:7](=[O:8])[C:6]=2[CH:17]=1
Reactant: O=C1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)Oc1ccc(Br)cc1C2=O
Temperature: 100 °C
Yield: 41.3 %

Procedure:
To a solution of 4-(5-bromo-2-fluorobenzoyl)-4-hydroxycyclohexanone (1.0055 g, 3.19 mmol, 1.0 equiv) in THF (30 mL) was added 95% t-BuOK (0.3440 g, 2.91 mmol, 0.9 equiv) portionwise. The resulting mixture was heated at 100° C. for 1 h. The reaction mixture was then cooled with an ice bath and quenched with H2O, extracted with ethyl acetate, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.3889 g (41%) of 5-bromo-3H-spiro[benzofuran-2,1′-cyclohexane]-3,4′-dione as a white solid. LC-MS tR=1.58 min in 3 min chromatography, m/z 295, 297 (MH+); 1H NMR (400 MHz, CDCl3) δ 7.82-7.81 (m, 1H), 7.76-7.73 (m, 1H), 7.10-7.07 (m, 1H), 2.81-2.72 (m, 2H), 2.60-2.55 (m, 2H), 2.29-2.21 (m, 2H), 2.08-2.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 208.25, 200.80, 169.71, 140.99, 127.47, 121.58, 115.55, 114.81, 88.10, 36.68, 31.86.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:14]3[N:15]=[C:16]([NH2:25])[N:17]=[C:18]([C:19]4[O:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[C:13]=3[N:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=1.[CH2:26]([OH:31])[C:27]([F:30])([F:29])[F:28]>>[CH3:24][C:21]1[O:20][C:19]([C:18]2[C:13]3[N:12]=[N:11][N:10]([CH2:9][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][O:31][CH2:26][C:27]([F:30])([F:29])[F:28])[N:8]=4)[C:14]=3[N:15]=[C:16]([NH2:25])[N:17]=2)=[CH:23][CH:22]=1
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COCC(F)(F)F)n2)o1

Procedure:
Prepared from 3-(6-bromomethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and trifluoroethanol by the method described in Example 32.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[C:4](=[O:12])[CH:3]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>COCCOC.C(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>[OH:13][C:14]([CH3:46])([CH3:47])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:7]=[CH:6][N:5]([CH:8]4[CH2:11][O:10][CH2:9]4)[C:4](=[O:12])[CH:3]=3)=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(Br)ccn1C1COC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccn(C3COC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pd(PPh3)4 (10 mg) was added to a solution of 4-bromo-1-(oxetan-3-yl)pyridin-2(1H)-one (14 mg) in 1,2-dimethoxyethane (6 mL) under nitrogen. The formed mixture was stirred at room temperature for 1 h prior to the addition of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (24 mg) in ethanol (2 mL) followed by saturated aqueous NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate (3×). The combined organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound. Yield: 14 mg (55% of theory); LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=445 [M-Me2CO+H]+; 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.12 (s, 3H), 1.45 (d, 3H), 2.10-2.30 (m, 4H), 2.35 (m, 1H), 2.72 (m, 1H), 4.70 (m, 2H), 5.09 (m, 2H), 5.63 (m, 1H), 5.71 (m, 1H), 6.43 (m, 1H), 6.61 (m, 1H), 6.98 (d, 2H), 7.28 (m, 7H), 7.61 (d, 1H).
Reaction SMILES: C1OC2C=CC(CCN)=CC=2O1.[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19](C2N=C(Cl)C3C=C(CC)SC=3N=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Agent: NCCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccccc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: OB(O)c1cccnc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4cccnc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and pyridine-3-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.58 min; Mass spectrum (ESI+): m/z=382 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[O:18][CH2:19][CH3:20])/[C:14]([O:16]C)=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:39])[C:28]([NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:29])[CH:22]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.CO.O.O.[OH-].[Li+]>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[O:18][CH2:19][CH3:20])/[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:39])[C:28]([NH:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:29])[CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1-c1cccc(N(C)C(=O)NCCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCCOc1cc(/C=C(\OCC)C(=O)O)ccc1-c1cccc(N(C)C(=O)NCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
40 mg (0.08 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]-2-ethoxyacrylate are placed in 0.5 mL of a 5/1/1 by volume mixture of tetrahydrofuran/methanol/water, 17 mg (0.4 mmol) of lithium hydroxide monohydrate are added and the reaction medium is stirred at room temperature for 18 hours. The reaction medium is acidified to pH 3 with acetic acid and then extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 85/15 and then 60/40 heptane/ethyl acetate mixture. 16 mg (34%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]-2-ethoxyacrylic acid are obtained.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Br:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:21][CH:20]([Br:19])[C:22]([F:25])([F:24])[F:23])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C=C(Br)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(C#N)(CC(Br)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 0.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile was dissolved in 6 ml of a solution (1 mol/L) of tetrabutylammonium fluoride in tetrahydrofuran and then cooled to 0° C. Thereto 1.1 g of 2-bromo-3,3,3-trifluoropropene dissolved in 3 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 8 hours and at 60° C. for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.02 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(2-bromo-3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (57)).
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:12][NH:13][CH3:14])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:15]1([C:11]2[C:3]3=[C:4]4[CH:10]=[CH:9][NH:8][C:5]4=[N:6][CH:7]=[C:2]3[N:13]([CH3:14])[N:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CNN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN1CCCC1=O
Product: Cn1nc(C2CCCCC2)c2c3cc[nH]c3ncc21
Temperature: 160 °C
Yield: 57.4 %

Procedure:
A mixture of 5-chloro-4-(cyclohexyl(2-methylhydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine (0.241 g, 0.829 mmol), sodium tert-butoxide (0.191 g, 1.99 mmol), palladium acetate (0.001 g, 0.0083 mmol) and (R)-1 [(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butyl phosphine (0.0046 g, 0.0083 mmol), was heated in NMP (3 mL) at about 160° C. for about 15 min in a Biotage microwave. Additional palladium acetate (0.001 g, 0.0083 mmol) and (R)-1[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butyl phosphine (0.0046 g, 0.0083 mmol) was added and the reaction mixture was heated at about 160° C. for about 30 min. The insoluble residue was removed by filtration through a Celite® pad and to the filtrate was purified by preparative RP-HPLC (Table 2, Method r) to provide 1-cyclohexyl-3-methyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as a white solid (0.121 g, 58%): LC/MS (Table 2, Method d) Rt=2.29 min; m/z: 255 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[K+].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:17]1)[CH3:12]
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Reactant: Sc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2ccccc2Cl)C1
Temperature: 25 °C

Procedure:
28 G. of 2-chlorothiophenol and a solution of 10.8 g. of 85% potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 50.6 g. of 3-bromo-4-ketocyclohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotovapor), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A forerun was collected at 100°-190° (1 mm), while a main fraction was collected at 190° -222° (1 mm). The yield of 3-(2-chlorophenylthio)-4-ketocyclohexaneacetic acid ethyl ester from the main fraction was 33.9 g., b.p. 205-215/0.7 mm.
Reaction SMILES: Cl[C:2]([CH2:10][Cl:11])([CH2:5][CH:6]([C:8]#[N:9])[CH3:7])[CH:3]=O.[ClH:12]>C(#N)C.Cl[Ni]Cl>[Cl:12][C:8]1[C:6]([CH3:7])=[CH:5][C:2]([CH2:10][Cl:11])=[CH:3][N:9]=1
Reactant: Cl
Reactant: CC(C#N)CC(Cl)(C=O)CCl
Agent: Cl[Ni]Cl
Solvent: CC#N
Product: Cc1cc(CCl)cnc1Cl

Procedure:
4 grams of 2-chloro-2-chloromethyl-4-cyano-4-methylbutyraldehyde dissolved in 30 mL of acetonitrile is pumped concomitantly with anhydrous HCl into a pre-heated (180°-230° C.) flow reactor packed with NiCl2 -impregnated clay. Short path distillation gives 2-chloro-3-methyl-5-chloromethylpyridine as a liquid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:27])=[CH:9][C:8]=1[CH3:28])C.[Li+].[OH-]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[S:19][C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:29][CH2:30][CH3:31])[C:4]([OH:32])=[O:3])=[C:8]([CH3:28])[CH:9]=3)=[C:16]([CH3:27])[N:17]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(Cl)cc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3ccc(Cl)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].Br[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>ClCCl.O>[CH2:1]([O:5][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:2][C:3]#[CH:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C#CCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C#CCCOCC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Stir a mixture of but-3-yn-1-ol (6.00 g; 85.60 mmol), tetrabutylammonium sulfate (2.07 g; 8.54 mmol) and sodium hydroxide (40% wt/wt; 150 mL) in dichloromethane (150 mL) at 0° C. Add tert-butyl bromoacetate (19.34 mL; 128.40 mmol) dropwise and stir the mixture for 2.5 hours at room temperature. Dilute the reaction mixture with dichloromethane (200 mL) and water (100 mL), separate the layers, and further extract the aqueous layer with dichloromethane (2×100 mL). Wash the combined organic layers with brine (100 mL), dry over anhydrous sodium sulfate, and concentrate to afford the crude title compound as a brown oil (11.93 g). Purify the oil by silica gel column chromatography, eluting with hexane:ethyl acetate (0% to 10% mixtures) to give the title compound (11.35 g; 72%) as a colorless oil. 1H NMR (CDCl3) δ 1.48 (s, 9H), 2.00 (m, 1H), 2.52 (m, 2H), 3.67 (m, 2H), 4.01 (bs, 2H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-].[CH:8]([C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=O)=O.[H-].[Na+].C(O)(=O)C>CN(C)C=O.O>[O:14]=[C:12]1[C:11]2[C:10](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[NH:1]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: COC(=O)c1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2ccccc2c(=O)[nH]1
Reaction time: 5 h

Procedure:
A solution of methyl isocyanoacetate (4.20 mL, 46.2 mmol) and methyl 2-formylbenzoate (6.90 g, 42.0 mmol) in 30 mL of N,N-dimethylformamide was added dropwise to a suspension of sodium hydride (1.21 g, 50.4 mmol) in 20 mL of N,N-dimethylformamide. After 5 hr, the mixture was treated with 10% aqueous acetic acid and water and extracted 2× with ethyl acetate. The combined organic extracts were washed 3× with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from 1:10 ethyl acetate:hexanes to provide methyl 1-oxo-1,2-dihydroisoquinoline-3-carboxylate.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.C(Cl)(=O)[C:24]([Cl:26])=O.CN(C)C=O.Cl.O1CCOCC1>C(Cl)Cl>[CH2:16]([C@H:5]([CH2:4][C:1]([CH2:24][Cl:26])=[O:3])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
The resultant acid from Example 23 (500 mg, 1.68 mmol) in CH2Cl2 (8 ml) at 0° C. was treated with oxalyl chloride (0.160 ml, 1.83 mmol) and dimethylformamide (0.0065 ml). After 2 h at 0° C., the solvent was evaporated and the residue was dissolved in ether (6 ml), cooled to 0° C. and treated with an ether solution of CH2N2. After 2 h at 0° C. the solvent was evaporated and the residue was dissolved in ether (6 ml), cooled to -10° C., and treated with 4.0M HCl/ dioxane (0.6 ml, 2.4 mmol). After 1 h the solvent was evaporated and the residue was chromatographed on silica gel with 10% ethyl acetate in hexane to afford 476.8 mg (83%) of a colorless oil. 1H NMR (CDCl3) δ7.08-7.40 (m,10H), 5.12 (d,1H), 5.08 (d,1H), 4.02 (s,2H), 3.30 (m,1H), 3.10 (dd,1H), 2.97 (dd,1H), 2.78 (dd,1H), 2.55 (dd,1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[CH2:13](O)[CH2:14][OH:15].P(=O)(O)(O)O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:14]1[O:15][CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3][CH2:2][Cl:1])[O:8][CH2:13]1
Reactant: OCCO
Reactant: O=Cc1ccccc1OCCCl
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: ClCCOc1ccccc1C1OCCO1
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of 46.5 g of 2-(2-chloroethyloxy)benzaldehyde and 33.2 g of ethylene glycol in 500 ml of benzene in added 0.5 ml of 85% phosphoric acid, and the mixture is refluxed with stirring for about 18 hours while removing the produced water. After the reaction, the reaction mixture is cooled with ice and is made alkaline with saturated sodium bicarbonate solution to separate into two layers. The benzene layer is taken, washed with saturated saline solution, dried and then distilled to remove the solvent. The crude product thus obtained is distilled to give 56 g of 2-(2-chloroethyloxy)benzaldehyde ethyleneacetal (yield: 97%) as a colorless oil. b.p. 130°-135° C./0.3 mmHg.
Reaction SMILES: [OH:1][CH:2]([C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+]>[O-2].[O-2].[Mn+4].O>[NH2:11][C:9]1[S:10][C:6]([C:2](=[O:1])[C:3]([OH:5])=[O:4])=[CH:7][N:8]=1
Reactant: Nc1ncc(C(O)C(=O)O)s1
Agent: [Mn+4]
Agent: N=c1[nH]cc(C(O)C(=O)O)s1
Agent: [Na+]
Solvent: O
Product: Nc1ncc(C(=O)C(=O)O)s1
Reaction time: 5 h

Procedure:
A mixture of 2-hydroxy-2-(2-amino-1,3-thiazol-5-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid, (0.92 g.) and water (10 ml.) was adjusted to pH 7 to 7.5 with a 10% sodium hydroxide aqueous solution, and to the mixture was added manganese dioxide (1.74 g.) and then the mixture was stirred for 5 hours at 50° to 60° C. After the reaction, manganese dioxide was filtered off and then washed with a small amount of water. The filtrate and washing were combined together, adjusted to pH 1 with concentrated hydrochloric acid and then stirred for 15 minutes under ice-cooling. The precipitates were collected by filtration, washed with water and then dried to give 2-(2-amino-1,3-thiazol-5-yl)glyoxylic acid, which can be represented as 2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)glyoxylic acid, (0.53 g.), mp. 185° to 250° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12](=[O:14])[CH3:13])[CH:5]=1.[Br:16]Br>C(O)(=O)C.Br>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12](=[O:14])[CH2:13][Br:16])[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(C(C)=O)c1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC)c(C(=O)CBr)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
3-Acetyl-4-methoxy-benzoic acid methyl ester (T. Nagano et al., J. Am. Chem. Soc. 75 (1953), 6237-6238) (1.25 g) was dissolved in a mixture of acetic acid (7 ml) and hydrobromic acid (3 ml), the solution was cooled in an ice bath, and bromine (0.961 g) added. The mixture was allowed to slowly warm to room temperature and react for 2 h. Then the mixture was evaporated to dryness in vacuo, the residue was partitioned between EA and a saturated aqueous sodium hydrogencarbonate solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. Upon stirring with a mixture of EA and HEP, part of the title compound crystallized and was filtered off. The filtrate was evaporated to dryness and the residue purified by preparative RP HPLC (water/ACN gradient). Altogether, 1.18 g of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1>CO.[Pd]>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1cccc(N)c1
Reaction time: 15 h
Yield: 84.5 %

Procedure:
The compound (1.0 g, 6.08 mmol) prepared in step 1 was dissolved in methanol (25 ml) and added with 10%-palladium (Pd) (100 mg). The mixture was hydrogenated for 15 hours at room temperature under hydrogen gas. Once the reaction was completed, 10%-palladium (Pd) was removed by using celite-filter and the filtrate was concentrated to dryness. The residue was then purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (700 mg, yield: 90%, colorless liquid).