Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10]OC(OC)OC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][C:3]1[C:2]2[N:1]=[CH:10][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(OC)OC
Reactant: Cc1cccc(N)c1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2,3-diaminotoluene (1.00 g, 8.2 mmol) in CH2Cl2 (82 mL) was added trimethylorthoformate (4.5 mL, 41 mmol) and trifluoroacetic acid (0.32 mL, 4.1 mmol) and the mixture stirred at room temperature for 24 h after which the reaction mixture was diluted with CH2Cl2 (200 mL), and washed consecutively with saturated aqueous NaHCO3 (40 mL) and H2O (40 mL). The aqueous layers were reextracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated to a rusty brown solid (1.07 g, 97%). 1H NMR (300 MHz, CDCl3) δ 8.08 (s, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.23-7.18 (m, 1H), 7.10 (d, 1H, J=7.5. Hz), 2.64 (s, 3H).
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:29][C:28](=[O:30])[O:27][CH:26]3[O:31]CC3C=CC=CC=3)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1>CN1CCCC1=O.CCN(C(C)C)C(C)C>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:26]=[O:31])[CH2:29][C:28]([OH:30])=[O:27])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O=C(Cl)c1ccccc1
Product: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Yield: 30 %

Procedure:
Method 2. Synthesis of 213e. Following a similar procedure as method 1, resin 403 was acylated with 0.5M benzoyl chloride in N-methypyrrolidone (1 mL) and 1.6M DIEA in N-methypyrrolidone (0.35 mL) for 2 hr at rt. The acylation step was repeated. Cleavage of the aldehyde from the resin gave 214e (5.1 mg, 30%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:21]=1
Reactant: NNC(=O)c1cccc(Oc2ccccc2)c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 83 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-phenoxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 403 mg of the title compound (83%) as a yellow solid in 99.5% purity by HPLC (Rt: 6.58, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.CO.C[O-].[Na+].[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=[O:30])[CH:27]=2)[NH:22][N:21]=1>O>[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[O:30][CH:12]=[N:11][CH:10]=3)[CH:27]=2)[NH:22][N:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1n[nH]c2ccc(-c3cnco3)cc12
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a 150 mL round-bottom flask was added p-toluenesulfonylmethyl isocyanide (1.46 g, 7.5 mmol) and MeOH, followed by sodium methoxide (4.60 mL, 21.2 mmol) and a MeOH solution of 3-methyl-1H-indazole-5-carbaldehyde (1.00 g, 6.24 mmol) (prepared as described in WO 2007/124288). The solution was stirred at reflux for about 1 hour and followed by LCMS. Water was added (50 mL) and the MeOH was removed in vacuo. The suspension was cooled to 0° C. and the resulting precipitate was filtered and dried in the vacuum oven overnight to give 3-methyl-5-(oxazol-5-yl)-1H-indazole (1.01 g, 81% yield) as a tan powder. LCMS (API-ES) m/z (%): 200 (100%, M++H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([Cl:22])[CH:24]=3)[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(N2CCNCC2)cc1Cl
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(Cl)c3)CC2)c(OC)nc1C
Yield: 62 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chloro-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[CH2:17](O)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1>C1CCCCC1.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH2:17][CH:18]2[O:22][CH2:21][CH2:20][CH2:19]2)=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: OCC1CCCO1
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Agent: C
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Product: CC(C)=CCc1ccc(C(C)C(=O)OCC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of 21.8 g of 2-(p-prenylphenyl)propionic acid, 10.2 g of tetrahydrofurfuryl alcohol and 0.4 g of graphite bisulfate in 100 ml of cyclohexane was stirred at room temperature for 8 hours. The mixture was passed through a column of silica gel, and the solvent was evaporated to give 24.5 g of tetrahydrofurfuryl 2-(p-prenylphenyl)propionate. b.p. 135° C./0.08 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.C[CH:24](O)[C:25]([O-:27])=[O:26].[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:24][C:25]([O:27][CH3:29])=[O:26])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CC(O)C(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 726.9 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy) phenylacetic acid and 1 g of methylglycolate were dissolved in 50 ml of benzene. Then, 0.2 g of p-toluenesulfonic acid was added to the resulting solution, followed by heating under reflux for 3 hours. After completion of the reaction, 50 ml of ether was added. The resulting reaction mixture was washed with water according to the customary method and dehydrated with anhydrous sodium sulfate, and the solvent was distillend off under reduced pressure to obtain 3.4 g of methoxycarbonylmethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: CCOCC.C(C(C)=O)C.[CH3:11][C:12](O)([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:13][CH3:14]>O>[CH3:11][CH:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH:13]=[CH2:14]
Reactant: CCC(C)(O)Cc1ccc(C)cc1
Solvent: CCC(C)=O
Solvent: CCOCC
Solvent: O
Product: C=CC(C)Cc1ccc(C)cc1

Procedure:
was obtained from 0.77 mol of metallic magnesium and 0.59 mol of p-methyl benzyl chloride. To this was added 0.6 mol of an ether solution of methyl ethyl ketone. After thorough reaction, a large excess of water was added to hydrolyze the reaction product. The resulting 3-methyl-4-(p-tolyl)-3-butanol was passed through a reaction tube packed with active alumina at 200° to 300°C. to afford the desired 3-methyl-4-(p-tolyl) butene almost quantitatively.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[NH:13][CH2:14][CH2:15][NH2:16]>C(O)C>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([CH3:4])[C:6]=1[N:13]1[CH2:14][CH2:15][N:16]=[C:2]1[NH2:1]
Reactant: N#CBr
Reactant: Cc1cc(C)c(NCCN)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(N2CCN=C2N)c(C)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A solution of cyanogen bromide (1.8 g, 18.5 mmol) in anhydrous ethanol (3 mL) was added at 0° C. to a solution of N1-(2,4,6-trimethyl-phenyl)-ethane-1,2-diamine (3.0 g, 16.9 mmol) in anhydrous ethanol (9 mL) under nitrogen. The reaction mixture was warmed up to room temperature for 10 min, then was heated at 155° C. for 40 min with a flow of nitrogen to remove ethanol. Upon cooling to r.t., the resulting solids were transferred to a separatory funnel via dichloromethane (70 mL), and washed sequentially with 1 N sodium hydroxide (2×35 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate and solvents were removed in vacuo to afford the title compound as a pale white solid (3.08 g, 90% yield). The solids were used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+]([C:13]1[CH:14]=C(S([O-])(=O)=O)C=C[CH:18]=1)([O-])=O.[Na+].S(=O)(=O)(O)O>OCC(CO)O>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]2[C:3]=1[CH:18]=[CH:13][CH:14]=[N:1]2
Reactant: Cc1ccc(O)cc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Product: Cc1ccc(O)c2cccnc12
Yield: 5.8 %

Procedure:
Following the same procedure as in Example 23-(a), reaction and treatment were carried out using 3.9 g of 3-amino-4-methylphenol, 7 ml of glycerol, 8.7 g of sodium m-nitrobezene sulfonate and 29 ml of a 80% aqueous sulfuric acid solution in order to obtain 290 mg of 5-hydroxy-8-methylquinoline.
Reaction SMILES: O.[C:2]1([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].[CH3:19]O>C(OC(=O)C)C>[C:2]1([C:8]2[NH:9][CH:10]=[C:11]([C:13]([O:15][CH3:19])=[O:14])[N:12]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c(-c2ccccc2)n1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c[nH]c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
2-Phenyl-1H-imidazole-4-carboxylic acid mono hydrate (2.00 g) was suspended in methanol (30 mL) and concentrated hydrochloric acid (10.0 mL) was added and the reaction mixture heated at reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethylacetate and the aqueous basified with 1 N sodium hydroxide. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound. The title compound was used without further purification, having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([F:12])[C:8]([O:13][CH3:14])=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5].COC(C1C2N=C(N)[NH:25][C:24]=2C=CC=1)=O.BrC#N>CO>[NH2:25][C:24]1[NH:11][C:10]2[C:9]([F:12])=[C:8]([O:13][CH3:14])[C:7]([F:15])=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: COc1c(F)c(N)c(N)c(C(=O)O)c1F
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: N#CBr
Solvent: CO
Product: COc1c(F)c(C(=O)O)c2nc(N)[nH]c2c1F

Procedure:
1.2 g (5.5 mmol) of 2,3-diamino-4,6-difluoro-5-methoxy-benzoic acid was subjected to a similar cyclization condition as illustrated in intermediate A by using 1.7 g (16.5 mmol) of BrCN in methanol to produce 2-amino-5,7-difluoro-6-methoxy-1H-benzoimidazole-4-carboxylic acid. LCMS: 244 (M+1)+.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[Br-].[Na+].CN1CCCC1=O.C([Br:22])C>O>[CH:1]([CH:3]([Br:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: CCBr
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CC(Br)c1ccccc1
Yield: 73 %

Procedure:
Vinylbenzyl chloride (50.60 g, 0.33 mol, 60:40 mixture of p,m isomers), sodium bromide (6.86 g, 6.67×10−2 mol), N-methylpyrrolidone (300 ml, passed through a short column of basic alumina), ethyl bromide (260 g), and 3-t-butyl-4-hydroxy-5-methyl phenyl sulfide (1.00 g, 2.79×10−3 mol) were combined in a 1 liter round bottomed flask fitted with a reflux condenser and a nitrogen inlet and the mixture was heated at reflux for 72 hours at which point the reaction was found to have proceeded to >95% conversion by gas chromatography. The reaction mixture was poured into 1 liter of water and extracted twice with 300 ml of diethyl ether. The combined ether layers were extracted twice with 1 liter of water, dried over MgSO4, and the solvents were stripped by rotary evaporation to yield yellowish oil. The crude product was purified by vacuum distillation to afford 47.5 g of product (53.1% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[C:9]=1[OH:10])[C:5]#[N:6].C(O)(=O)C.[N:16]([O-:18])=[O:17].[Na+].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]=1[OH:10])[C:5]#[N:6]
Reactant: O=N[O-]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 116.2 %

Procedure:
To a 5-l, 3-neck round-bottom flask fitted with a thermocouple, stirring paddle, and nitrogen line were added 3,5-dibromo-4-hydroxybenzonitrile (95 g) and glacial acetic acid (3.3 l). Sodium nitrite (120 g) was then added in small portions. The mixture was heated to 50° C. and stirred overnight at this temperature. The mixture was then allowed to cool and poured into a large extractor containing water (10 l). ethyl acetate (10 l) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (4 l) and the combined organic layers were washed with water and brine, and then dried over magnesium sulfate and concentrated in vacuo to provide 96.9 g of the desired product. Mass spectrum (ESI) 243.0 (M+).
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:13](Cl)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1sccc1Oc1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2Oc2ccccc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfonamide was prepared from 3-phenoxythiophene-2-sulfonyl chloride aand 5-amino-4-bromo-3-methylisoxazole using the method described in Example 1. The product was recrystallized from acetonitrile/H2O to give a solid m.p. 121°-123° C., 61% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:4].[OH-].[Li+]>C1COCC1.CCO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:4]
Reactant: CCOC(=O)CCCC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(CCCC(=O)O)C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3-(1-Cyclohexyl-4-ethoxycarbonyl-butylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (40 mg, 0.09 mmol, 1.0 equiv) in THF (0.4 mL), EtOH (0.2 mL), water (0.4 mL) was added lithium hydroxide (18.9 mg, 0.45 mmol, 5.0 equiv). The resulting mixture was stirred at 50° C. for 2 hours, after which the organic solvent was removed under vacuum. The resulted solution was neutralized by addition of 1.0 N HCl aq. solution until pH=6. The mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated to product 30 mg (yield 83%).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]([N:32]1[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]1[C:38]#[N:39])=[O:31]>C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:29][C:30]([N:32]3[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]3[C:38]#[N:39])=[O:31])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reaction time: 4 h
Yield: 79.6 %

Procedure:
2-Tetrahydropyranyl 4-aminobicyclo[2,2,2]octane-1-carboxylate (62.9 mg) was suspended in acetonitrile (1 mL). To this suspension, diisopropylethylamine (47 μL) was added. With the solution chilled in an ice bath, (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (53.1 mg) in acetonitrile (0.8 mL) was added and the mixture was stirred for 4 hours. Subsequently, the reaction mixture was concentrated, and ethyl acetate and water were added to dissolve the residue. To this solution, an aqueous sodium bicarbonate solution was added to make the solution basic and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=10:1) to obtain (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2,2,2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (73.3 mg).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[C:4]1=2.[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.C(Cl)(Cl)Cl.CC(O)C>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:4]2[S:3][CH:7]=[CH:6][C:5]=2[CH:8]=[CH:9][CH:10]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccccc1-c1cccc2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCOc1ccccc1-c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Add sodium hydride (424 mg, 18 mmol) to a solution of 2-benzo[b]thiophen-7-yl-phenol (1 g, 4.4 mmol) in 10 mL of DMF. Stir the mixture at RT for 1 h and add (2-bromo-ethyl)-carbamic acid tert-butyl ester (2 g, 8.9 mmol). Continue to stir the reaction mixture for another 4 h at RT. Dilute the mixture with chloroform-IPA (3:1, 100 mL). Wash the organic phase with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify the residue by column chromatography (20% ethyl acetate in hexane) to give the title compound as a pale yellow solid (1.4 g, 86%). MS (ES) m/z 392 [M+Na]+.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>>[C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:22][CH3:23])=[O:2]
Reactant: CCC(CCCCCC1=CCCC1=O)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CC)CCCCCC1=CCCC1=O

Procedure:
Treatment of 2-(6-carboxyoctyl)-2-cyclopentone (Example 131) with thionyl chloride and then treatment of the acid chloride with ethanol in the manner described in Example 456 gives an amber oil. The oil is placed on a magnesia-silica gel column and eluted with 3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122°C. (0.06 mm).
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O>C1(C)C=CC=CC=1>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][N:14]1[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]1=[O:8]
Reactant: COC(CN)OC
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CN1C(=O)C(C)=C(C)C1=O)OC

Procedure:
84 g (0.66 mol) of dimethylmaleic anhydride are dissolved in 150 ml of toluene, and 70 g (0.66 mol) of aminoacetaldehyde dimethyl acetal are added. The solution is heated to the boil, and the water formed is separated off by means of a water separator. When the reaction is complete, the solvent is removed by distillation, and the residue is distilled, giving 127 g (90% of theory) of the product of boiling point 160° C. at 0.03 mbar which is a single product according to TLC and GC. NMR data: 2.97 (s) 6- methyl protons, 3.34 ppm (s) 6 methoxy protons, 3.61 ppm (d) 2 methyl protons, 4.66 ppm (t) 1 acetal proton.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([O:15][C:16]1[N:17]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][CH:36]=2)[C:18](=[O:33])[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([O:15][C:16]1[N:17]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[NH:3][C:4](=[O:7])[O:5][N:48]=3)=[CH:39][CH:40]=2)[C:18](=[O:33])[C:19]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:27][CH:28]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCOc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.77 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[2-ethoxy-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.53 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.39 g, 66%) as a colorless solid.