Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([O:22]CC)=[O:21])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)OCC)ccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)O)ccc2c1OCO2

Procedure:
To ethyl 2-(4-carbomethoxy-2-propylphenoxy)-3,4-methylenedioxyphenylacetate (Step A of Example 56) (2.04 g, 5.10 mmol) in MeOH (40 mL) was added 5 N NaOH (8 mL). The rapid reaction was followed immediately by TLC to monitor mono deesterification. The reaction was quenched with 9 N HCl (4.5 mL) after loss of the ethyl ester and before methyl ester saponification. A saturated solution of NaHCO3 was added to the reaction until it was basic and the MeOH was removed in vacuo. The residue was partitioned between Et2O and water collecting the product in the aqueous phase and removing impurities with the organic phase. The aqueous phase was then acidified with 9 N HCl (pH=1) and the product extracted into EtOAc. The solution was dried over MgSO4, filtered and the solvent removed. yield=1.78 g (4.78 mmol, 94%) rf=0.16 (80:10:1/CHCl3 :MeOH:NH4OH).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32](=[N:41][S:42]([CH3:45])(=[O:44])=[O:43])OOC3C=CC=CC=3)[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2].[CH3:46][NH:47][CH3:48]>>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32]([N:47]([CH3:48])[CH3:46])=[N:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CNC
Reactant: CCc1nc2c(C)cc(NC(=NS(C)(=O)=O)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCc1nc2c(C)cc(NC(=NS(C)(=O)=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 14b from 4'-[[2-ethyl-4-methyl-6-(2-phenoxy-3-methylsulphonyl-isoureido)-1H-benzimidazol -1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and dimethylamine.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C@@H:8]([F:21])[CH2:7]1)=[O:5])C.[OH-].[Li+].C(O)(=O)C>CO>[C:4]([OH:5])(=[O:3])[CH3:6].[F:21][C@@H:8]1[C@H:9]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N[C@H](C)c2ccccc2)[C@@H](F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](N[C@@H]1CC[C@@H](C(=O)O)C[C@@H]1F)c1ccccc1
Yield: 122.6 %

Procedure:
A solution of ester (c) (1.5 g) in methanol (50 mL) was treated with lithium hydroxide (630 mg). After 2 hours acetic acid (1 mL) was added and the mixture was evaporated to dryness. Chromatography on silica eluting with 1:9:90 (acetic acid:methanol:dichloromethane) afforded an oil (1.02 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:30])[CH:27]=4)[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Product: O=C(c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCOCC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from morpholine, (3-bromomethyl)-benzoate (commercially available) and (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C28H25ClN2O3: 472, observed (M+H)+: 473.2 1H NMR (400 MHz, MeOD-d4) δppm 2.15-2.27 (m, 2 H) 3.18-3.36 (m, 1 H) 3.47 (br. s., 4 H) 3.70 (br. s., 4 H) 5.11 (s, 2 H) 6.08 (d, J=7.58 Hz, 1 H) 6.71 (t, J=7.58 Hz, 1 H) 6.88 (d, J=8.08 Hz, 1 H) 7.01-7.12 (m, 1 H) 7.17-7.26 (m, 2 H) 7.25-7.40 (m, 4 H) 7.43-7.56 (m, 2 H).
Reaction SMILES: COC1C=CC(C(C)(C)C#N)=CC=1.[C:14]([C:16]1([C:19]2[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=2)[CH:24]=[O:25])[CH2:18][CH2:17]1)#[N:15]>>[C:14]([C:16]([C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[CH:24]=[O:25])([CH3:18])[CH3:17])#[N:15]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Agent: COc1ccc(C(C)(C)C#N)cc1
Product: COc1ccc(C(C)(C)C#N)cc1C=O

Procedure:
This compound was prepared from Compound 26 in the same manner of Compound 2.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:34])[NH:12][CH2:13][C:14]([N:16]([CH2:23][C:24]([N:26]([CH3:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:7]=[CH:8][CH:9]=1)[CH3:3]>[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:34])[NH:12][CH2:13][C:14]([N:16]([CH2:23][C:24]([N:26]([CH3:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Product: CC(=O)c1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2)c1
Yield: 46.6 %

Procedure:
The procedure is analogous to that described in Example 84, but 1.4 g of (RS)-2-{2-{3-[3-(1-hydroxyethyl)phenyl]ureido}-N-phenylacetamido}-N-methyl-N-phenylacetamide and 4.7 g of manganese dioxide are used as the starting material. After recrystallization from ethyl acetate, 0.65 g of 2-{2-[3-(3-acetylphenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide melting at 170° C is obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[Cl:30][CH2:31]I>C1COCC1>[Cl:30][CH2:31][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCl)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.75 h
Yield: 51.4 %

Procedure:
To a solution of diisopropylamine (22.6 mL, 159 mmol) in anhydrous THF (140 mL) in an oven-dried round-bottomed flask was added n-BuLi (65.4 mL, 163 mmol, 2.50 M in hexanes) dropwise at 0° C. The solution was stirred for 45 minutes and 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (20 g, 80 mmol) in THF (60 mL) was added dropwise at 0° C. and the mixture was stirred at 0° C. for 1 hour. Chloroiodomethane (17.9 mL, 239 mmol) was added dropwise and the mixture was stirred for 1 h. The mixture was quenched with 250 mL of saturated aqueous NaHCO3 followed by extraction with ethyl acetate (3×250 mL). The combined organic layers were washed (brine, 250 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil that was purified by silica chromatography using a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) system to give 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (12 g, 52%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.10-2.17 (m, 4H), 2.97 (br s, 2H), 3.56 (s, 2H), 3.74 (s, 3H), 3.83 (br s, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:12])=[CH:10][CH:11]=1.[C:14]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].CCOC(C)=O>C(#N)C.N1C=CC=CC=1>[C:14]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:13][C:8]2[CH:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:11]=[CH:10][C:9]=2[NH2:12])=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(-c2nccs2)cc1N
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)Nc2cc(-c3nccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.7 %

Procedure:
To a stirred suspension of 222a (47 mg, 0.25 mmol) in acetonitrile (10 mL) and pyridine (20 uL) was added 4-acetamidobenzoyl chloride (49 mg, 0.25 mmol) in acetonitrile (1 mL) at 0° C. for 15 min. The reaction mixture was warmed up to room temperature and stirred for 4 hours, concentrated under reduced pressure. The crude was diluted in DCM and washed with NaHCO3 and brine. The organic layer was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1:3), then EtOAc (100%) to afford the title compounds 223 (3 mg, 4% yield) and 224a (5 mg, 5% yield).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:31]=[CH:30][C:20]([CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1.BrB(Br)Br>>[NH2:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[OH:2])=[CH:31][CH:30]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: NCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 71.7 %

Procedure:
Following General Procedure F, tert-Butyl 4-(8-Methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (70 mg, 0.16 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.96 mL, 0.96 mmol) to afford the desired product (37 mg, 60%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.28 (s, 1H), 8.25 (br s, 2H), 7.68 (d, J=5.4 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.17 (d, J=8.8 Hz, 1H), 5.92 (d, J=5.4 Hz, 1H), 4.18 (m, 2H); ESI MS m/z 323 [C18H14N2O2S+H]+; HPLC 98.3% (AUC), tR=10.74 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:28])([CH3:27])[C:9]2=[O:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.CC(C)=O.O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:12]=3[O:11][C:10]([CH3:27])([CH3:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide (1 g) in acetone (3 mL) was added dropwise an aqueous sodium hydroxide solution (0.18 g/3 mL) at 25° C., and the mixture was stirred at the same temperature for 90 minutes. To the reaction mixture was added dropwise concentrated hydrochloric acid/acetone/water (0.24 g/0.5 mL/0.35 mL) at 25° C., and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration, washed with a solution of acetone/water (1:1.6 mL), and then dried under reduced pressure at 50° C. to obtain the title compound (0.79 g) as Form A crystals (yield: 95%, purity: 100%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=O>>[CH2:11]([OH:12])[CH:9]1[O:10][C:2](=[O:1])[CH:3]([OH:4])[CH:5]([OH:6])[CH:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=O
Product: O=C1OC(CO)C(O)C(O)C1O

Procedure:
A process for producing hydrogen peroxide and 2-keto-D-gluconic acid, comprising, reacting D-glucose in aqueous solution with oxygen and glucose-1-oxidase to catalize oxidation of the first carbon of the D-glucose and produce D-glucono-δ-lactone, reacting the D-glucono-δ-lactone in aqueous solution with oxygen and pyranose-2-oxidase to catalyze oxidation of the second carbon of the D-glucono-δ-lactone and produce hydrogen peroxide, 2-keto-D-gluconic acid, and D-isoascorbic acid, and recovering the 2-keto-D-gluconic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:25]=2[N:26]=1>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:28]3[CH:29]=[CH:30][C:24]4[S:23][C:22]([CH3:21])=[N:26][C:25]=4[CH:27]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2s1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: Cc1nc2cc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)ccc2s1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (31 mg, 0.104 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (22 mg, 0.114 mmol), (R)-4-((R)-1-(3-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.28 was isolated, following column chromatography.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([B:19]([OH:22])[OH:20])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COB(OC)OC
Reactant: CON=C1CCc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CON=C1CCc2cc(B(O)O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
A solution of the product of Example 1 Step 1 (48.0 g, 0.2 mol) in tetrahydrofuran (1 L) at −78° C. under argon atmosphere was treated dropwise with n-butyl lithium (138 ml, 1.6M in hexanes, 0.22 mol). After stirring at −78° C. for 30 minutes trimethyl borate (49 ml, 0.44 mol) was added and the solution warmed to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo, acidified to pH1 with 5N hydrochloric acid and stirred at room temperature for 1 hour. The mixture was then basified with 40% sodium hydroxide and the solution washed three times with diethyl ether. The aqueous phase was re-acidified to pH 1 and the mixture was extracted five times with ethyl acetate. The organic extracts were combined washed with brine, dried and evaporated in vacuo. The residue was triturated with hexane, filtered, washed with hexane and then a small amount of ether to afford the title compound (23.6 g, 58%); MS(AP−) m/e 204 [M−H]−.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[S:21][C:20]=2[CH2:30][CH3:31])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[S:21][C:20]=2[CH2:30][CH3:31])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 35.8 %

Procedure:
To a mixture of methyl 4-[cyclohexyl(5-cyclohexyl-2-ethylthiophen-3-yl)methoxy]benzoate (560 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred with heating under reflux overnight. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (194 mg, 36%) as a colorless crystal.
Reaction SMILES: C([S:4][CH2:5][C:6]1([CH2:14][CH3:15])[CH2:11][O:10]C(C)(C)[O:8][CH2:7]1)(=O)C.Cl>[OH-].[Na+].CO>[OH:8][CH2:7][C:6]([CH2:11][OH:10])([CH2:14][CH3:15])[CH2:5][SH:4]
Reactant: CCC1(CSC(C)=O)COC(C)(C)OC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CO)(CO)CS
Reaction time: 4 h

Procedure:
and (iii) 5-Acetylthiomethyl-5-ethyl-2,2-dimethyl-1,3-dioxane (2.0 g.) was stirred at 20°, in 10% aqueous sodium hydroxide solution (2.0 ml.) in methanol (20 ml.), for 24 hours under nitrogen. The mixture was neutralized with concentrated hydrochloric acid (0.5 ml.). Dowex 50×8-200 ion exchange resin (H+ form) (1.0 g.) was added and the mixture was refluxed with stirring, under nitrogen, for 4 hours. The mixture was filtered and the filtrate was evaporated in vacuo. Toluene was added to the residue and the mixture was evaporated in vacuo. 2,2-Di-(hydroxymethyl)-butanethiol was obtained as a colourless oil and was used without further purification (1.0 g.)
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]4=[CH:25][S:26][CH:27]=[C:21]4[N:20]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[C:19]3=[O:34])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]4=[CH:25][S:26][CH:27]=[C:21]4[N:20]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:19]3=[O:34])[CH2:12][CH2:13]2)=[O:7])=[CH:35][CH:36]=1
Reactant: COC(=O)CCn1c(=O)n(CCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Solvent: CCOCC
Product: O=C(O)CCn1c(=O)n(CCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 86.8 %

Procedure:
The above ester (1.6 g, 3.1 mmol) was hydrolyzed to its corresponding carboxylic acid as described in Example 1. There was obtained 1.35 g (86.7%) of 3-[3-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoic acid after trituration with ether.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[C:14]([CH3:22])=[C:15]([N:19]=[C:20]=[S:21])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:22])=[C:15]([N:19]=[C:20]2[N:8]([CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10][S:21]2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(Cl)cccc1N=C=S
Reactant: ClCC[NH2+]CC1CCCC1
Agent: [Cl-]
Product: Cc1c(Cl)cccc1N=C1SCCN1CC1CCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:15][O:16][C:17](=[O:25])/[C:18](/[N+:23]#[C-:24])=[CH:19]/N(C)C.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:15][O:16][C:17]([C:18]1[N:23]=[CH:24][N:12]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([CH2:6][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:8][CH:9]=2)[CH:19]=1)=[O:25]
Reactant: NCc1ccc(Cn2cccn2)cc1
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OC
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-Pyrazol-1-ylmethyl-benzylamine (550 mg, 2.5 mmol), (Z)-methyl-3-(dimethylamino)-2-isocyanoacrylate (380 mg, 2.5 mmol) and DIPEA (1.3 mL, 7.4 mmol) in 20 mL nBuOH was heated to 120° C. for 16 h. The mixture was concentrated in vacuo and the crude product was used in the next step without further purification. LCMS (method A) RtA=1.210 min; [M+H]+=297.0.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24]Br)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:29])C.[K+].Cl.C(Cl)Cl>C(O)(=O)C>[CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24][OH:29])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CO)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 112.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (16 g, 36.3 mmol) and potassium acetate (8.90 g, 91 mmol) in acetic acid (130 ml) was heated to 110-115° C. (slow reflux visible) and stirred for 1 hour (complete by HPLC). Cooled, acetic acid (80 ml) removed under reduced pressure, the residue distributed between DCM (120 ml) and water (120 ml). The organic phase was washed with water, evaporated to half of the volume, diluted with 2-propanol (65.0 ml), the rest of DCM removed. Water (18.20 ml) was added followed by concentrated hydrochloric acid (2.102 ml, 25.4 mmol), residual DCM was distilled off at atmospheric pressure until head temperature reached 77° C., then stirred under reflux for 3 hours. Diluted with water (65 ml), 2-propanol removed at 60° C./180 mbar, to the biphasic residue EA (80 ml) was added followed by sodium bicarbonate with stirring until evolution of gas stopped. The organic phase was dried (MgSO4), evaporated to dryness to give N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide (13.2 g, 34.9 mmol, 96% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]CCO[Si](C(C)(C)C)(C)C)[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Si:35]([O:52][CH2:53][CH2:54][CH2:55]Br)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[Na+]>>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH2:55][CH2:54][CH2:53][O:52][Si:35]([C:48]([CH3:49])([CH3:51])[CH3:50])([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](OCCCBr)(c1ccccc1)c1ccccc1
Reactant: CNc1ccc(-c2cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: CNc1ccc(-c2cc3ccc(OCCCO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3s2)cc1
Yield: 69.1 %

Procedure:
2-[4-(N-Monomethylamino)phenyl]-6-hydroxybenzothiophene (115, 150 mg, 0.59 mmol) and potassium carbonate (122 mg, 0.89 mmol) were dissolved in dimethylacetimide (10 mL), and 3-(t-butyldiphenylsilyloxy)propyl bromide (TBDMSO-CH2CH2CH2Br) (444 mg, 1.18 mmol) was added. The reaction mixture was reacted at 90° C. for 6 hours. To the reaction mixture was added an aqueous solution of sodium chloride and organic compounds were extracted with ethyl acetate. The recovered organic solution was washed with a brine solution and dried over sodium sulfate. Purification was performed by column chromatography to give 2-[4-(N-monomethylamino)phenyl]-6-[3-(t-butyldiphenylsilyloxy)propoxy]benzothiophene (120, 225 mg, 69%) as a yellow solid.