Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH:7]([NH2:12])[CH2:8][CH2:9][CH2:10][CH3:11])C.Cl.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:18].[CH:31](=O)[CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:31][CH:32]1[CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22](=[O:29])[CH:21]([C:20]([O:19][CH2:17][CH3:18])=[O:30])[CH:4]2[N:12]1[CH:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH2:5]2
Reactant: CC=O
Reactant: CCCCC(N)CCC(OCC)OCC
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC1CCC2C(C(=O)OCC)C(=O)C(C(=O)OCC)C(C)N12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 434 g (2 (Mol) 4-amino-octanal diethyl-acetal in 2 liters of ethanol (water free) was brought to pH4 with 0.5 N hydrochloric acid. To this solution 404 g (2 Mol) diethyl-3-oxo- glutarate and 88 g (2 Mol) acetaldehyde were added. The reaction mixture was stirred during three days at room temperature and was then brought to pH7 to 8 by addition of sodium carbonate powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[C:12]2[SH:22])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Br)[CH3:30]>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][S:22][C:12]1[N:11]([CH2:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH:2]=2)[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[N:13]=1)[CH3:30]
Reactant: COc1ccc2c(c1)nc(S)n2Cc1csc2ccccc12
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1nc2cc(OC)ccc2n1Cc1csc2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 45.3 %

Procedure:
101 mg (0.30 mmol) of 1-((benzothiophene-3-yl)methyl)-5-methoxybenzimidazole-2-thiol were dissolved in 2 ml of dimethylformamide followed by the addition of 62 mg (0.45 mmol) of potassium carbonate and 53 mg (0.40 mmol) of 4-bromobutanoate ethyl ester and heating to 80° C. After 12 hours, the reaction solution was concentrated under reduced pressure and extracted with diethyl ether followed by washing twice with 10 ml of saturated brine and drying with magnesium sulfate. The solvent was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 60 mg (0.136 mmol) of 4-(1-((benzothiophene-3-yl)methyl)-5-methoxybenzimidazole-2-ylthio)butanoate ethyl ester (yield: 45%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]2[N:8]3[C:9]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:24][CH:23]=4)=[CH:21][C:7]=13)=[C:10]1[C:18](=[O:19])[O:17][C:15](=[O:16])[C:11]1=2)(=[O:3])[CH3:2].[CH3:36][NH:37][CH3:38]>>[C:1]([O:4][CH2:5][C:6]1[C:7]2[N:8]3[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=[O:16])=[C:10]([C:18](=[O:19])[N:37]([CH3:38])[CH3:36])[C:9]3=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=1)[CH:21]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2c3c(c4c(-c5ccc(OCc6ccccc6)cc5)cc1n24)C(=O)OC3=O
Reactant: CNC
Product: CC(=O)OCc1ccc2c(C(=O)O)c(C(=O)N(C)C)c3c(-c4ccc(OCc5ccccc5)cc4)cc1n23
Yield: 68 %

Procedure:
5-Acetoxymethyl-3-(4-benzyloxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid anhydride was reacted with dimethylamine by the general synthetic principles outlined in example 62, step 9, to afford 5-acetoxymethyl-3-(4-benzyloxyphenyl)-2-dimethylcarbamoylpyrrolo[2,1,5-cd]indolizine-1-carboxylic acid as crystals in 68% yield. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.22 (s, 3H); 2.72 (s, 3H); 3.08 (s, 3H); 5.20 (s, 2H); 5.70 (s, 2H); 7.19 (d, 2H); 7.32-7.53 (m, 5H); 7.82 (d, 2H); 7.89 (s, 1H); 8.02 (d, 1H); 8.32 (d, 1H); 12.78 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[NH2:10][C@H:11]([CH2:13][OH:14])[CH3:12].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:12][C@H:11]([NH:10][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:13][OH:14]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: C[C@H](N)CO
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)[C@@H]1CSC(=O)N1
Yield: 66.3 %

Procedure:
In 20 ml of dry tetrahydrofuran were dissolved 1.0 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 0.56 g of L-alaninol, 2.8 ml of triethylamine and 1.8 ml of diphenylphosphoryl azide were added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography employing ethyl acetate as an eluent and further purified by silica gel column chromatography employing dichloromethane-methanol (95:5) as an eluent to obtain 0.92 g of the desired compound as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Li+]>CS(C)=O>[N:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Li+]
Solvent: CS(C)=O
Product: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C

Procedure:
To a stirred suspension of 20 mmole of 4-bromomethyl-2'-cyanobiphenyl [P. E. Aldrich, M. E. Pierce, and J. J. V. Duncia, European Patent Application 291,969 (1988)] in 55 ml of dry DMSO was added 1.23 g (25 mmole) of freshly pulverized lithium azide, and the mixture was stirred at room temperature under N2. Within a few minutes virtually all of the solid had dissolved, accompanied by a mild exotherm, and this was followed immediately by precipitation of product. After 4 hours the solid was collected on a filter and washed with some methanol, then with a relatively large volume of H2O, and finally again with methanol. The solid was air-dried overnight and then dried further in a vacuum oven at 70° C. (<1 mm) to give white crystals, satisfactory purity by TLC (9:1 hexane-ethyl acetate) for use in the next step. From the combined filtrate and washes was recovered a less pure second crop (cream-colored crystals), which was also usable in the next step. Mass spectrum (FAB) m/e 235 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:16])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(Cl)cc1O
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4'-chloro-2'-hydroxyacetophenone (1.0 g) in dry DMF (5 ml) was added to a stirred mixture of sodium hydride (0.235 g, 60% dispersion) in dry DMF (5 ml) at 5° C. under nitrogen. After the addition the mixture was stirred at 0° C. for 15 minutes and then at ambient temperature for 1 hour. A solution of iodomethane (0.92 g) in dry DMF (5 ml) was added dropwise to the mixture whilst keeping the temperature below 10° C. The reaction mixture was stirred at ambient temperature for 5 hours and then left to stand for 16 hours. Potassium carbonate solution was added to basify the mixture and the product was extracted into dichloromethane. The combined extracts were dried and evaporated. The residue was dissolved in ether, washed with water, then dried and evaporated to give 4'-chloro-2'-methoxyacetophenone which was sufficiently pure for synthetic use in Example 17.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4]([CH3:23])[CH:3]=1.ClC1C=C(C)C=CC=1C(N(CC)CC)=O>>[ClH:1].[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][NH:14][CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Agent: CCN(CC)C(=O)c1ccc(C)cc1Cl
Product: Cc1cc(Cl)c2c(c1)[C@@H]1CNC[C@H]1NC2=O
Product: Cl

Procedure:
Following the procedure described in Example 23, Part K, (3aS,9bR)-tert-butyl 6-chloro-5-oxo-8-methyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the second eluting compound from Example 37, Part C, was converted into the title compound of Example 38 as an off-white solid. 1H NMR (DMSO-D6): δ 9.55 (broad s, 1H), 9.41 (broad s, 1H), 8.67 (s, 1H), 7.29 (s, 1H), 7.02 (s, 1H), 3.85-3.80 (m, 1H), 3.66-3.61 (m, 1H), 3.58-3.52 (m, 1H), 3.30-3.25 (m, 1H), 3.15-3.10 (m, 1H), 3.07-3.02 (m, 1H), 2.30 (s, 3H). LRMS (ESI): 237.1/239.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:13][CH:14](OCC)OCC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:4]2[S:9][CH:13]=[CH:14][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccccc1S
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc2ccsc12
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)benzenethiol (5.000 g, 0.028 mol) in acetone (50 mL) was added 2-bromo-1,1-diethoxyethane (6.08 g, 0.030 mol) and potassium carbonate (7.757 g, 0.056 mol). The resulting mixture was then stirred at 45° C. for 2 hours prior to removal of the solvent in vacuo and suspension of the residue in EtOAc. The inorganic salts were filtered off and the organic phase was concentrated to give crude product, which was used in next step without further purification. This residue was dissolved in toluene (50 mL), and to this solution was added PPA (10 g) and the resulting mixture stirred at 95-100° C. for 2 hours. The mixture was allowed to cool to rt, was poured into ice-water, then extracted with EtOAc (3×50 mL). The combined extracts were washed with aqueous sodium bicarbonate followed by brine, then dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield an oil. This was purified by column chromatography over silica gel eluting with hexane to give 7-trifluoromethyl-benzo[b]thiophene. 1H NMR (400 MHz, MeOD) δ ppm 7.49-7.57 (m, 2H), 7.70 (d, J=7.33 Hz, 1H), 7.74 (d, J=5.56 Hz, 1H) and 8.10 (d, J=8.08 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].CCOC(C)=O>CN(C=O)C>[N:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 6-(bromomethyl)nicotinate from Example G1 (2.0 g, 8.60 mmol) in DMF (15 ml) was added sodium azide (0.84 g, 12.9 mmol). The mixture was stirred at room temperature for 18 h. EtOAc (100 ml) was added and the mixture was washed with water (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80) to give a yellow gum; yield 1.55 g (93%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:1])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:18])[N:6]=1)=[O:4]
Reactant: CC(C)CNCC(C)C
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)N(CC(C)C)CC(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 19.4 mg diisobutylamine, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 65-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.29 min. (m/Z=402.3, 424.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:12](I)[CH3:13].[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH2:12][CH3:13])[C:10]#[N:11])[CH:16]=[CH2:15]
Reactant: CCI
Reactant: COc1cccc(CC#N)c1
Reactant: C=CCBr
Product: C=CCC(C#N)(CC)c1cccc(OC)c1
Yield: 46 %

Procedure:
The procedures described in the portion of Example 1 which is concerned with the preparation of starting materials were repeated except that 3-methoxyphenylacetonitrile was alkylated in turn with ethyl iodide and allyl bromide. The 2-allyl-2-(3-methoxyphenyl)butyronitrile so obtained was treated with boron tribromide to give the required starting material in an overall yield of 46% as a gum.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9])([O-:16])=[O:15]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Trifluoromethoxybenzaldehyde (1.9 g, 10 mmol) was dissolved in concentrated sulfuric acid (8 mL) at 0 ° C. followed by dropwise addition of 70 % nitric acid (1,1 mL). The reaction mixture was stirred at 0 ° C. for 2 hours, then poured onto ice water and extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium bicarbonate solution , dried (sodium sulfate), filtered and evaporated. The residue was chromatographed on silica gel, eluting with 20 % ethyl acetate/hexane to provide 1.55.g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCN=[N+]=[N-]
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(2-bromoethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile (0.906 g; 2.49 mmol) and sodium azide (0.486 g; 7.48 mmol) in DMF (7 mL) was stirred at 70° C. for 4 hours and concentrated under reduced pressure. The residue was diluted in ethyl acetate, washed with brine, dried and concentrated under reduced pressure to yield 0.900 g (quantitative) of the title compound as a brown oil.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH2:9][C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[CH2:21]=[O:22]>C(OCC)C>[OH:22][CH2:21][C-:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][N:7]([CH3:8])[CH3:6].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: C=O
Reactant: CN(C)C[c-]1cccc1
Agent: [Fe+2]
Agent: [Li]CCCC
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: CN(C)Cc1ccc[c-]1CO
Reaction time: 3 h

Procedure:
n-Butyl lithium (Aldrich, 1.6 molar in diethyl ether, 5.14 ml, 8.24 mmol) is added to a solution of 1-dimethylaminomethyl ferrocene (Aldrich, 1.0 g, 4.12 mmol) in diethyl ether (20 mL) under argon. The reaction is stirred for 3 hours and developes a reddish colour. The solution is then cooled in a dry ice/acetone bath, calcined paraformaldehyde (0.247 g, 2 times excess) added and the resultant mixture stirred overnight at room temperature. The reaction is then quenched with water, extracted with diethyl ether, dried over MgSO4, and filtered over celite. The solvent is removed in vacuo to yield crude title compound. The crude product is applied to a neutral alumina column, which is eluted with petrol/diethyl ether (9:1 ratio) to remove the starting material, 1-dimethylaminomethyl ferrocene. The column is then eluted with substantially pure ethyl acetate to elute the title compound. The ethyl acetate is removed in vacuo, to yield the title compound as an orange oil/crystalline mass.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([O:1][C:24]2[N:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[N:23]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(O)cccc1C=Cc1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(C=Cc2ccccc2)cccc1Oc1nc(OC)cc(OC)n1
Yield: 54.2 %

Procedure:
A mixture of 1.2 g (4.7 mmol) of methyl 2-hydroxy-6-styrylbenzoate, 1.02 g (4.7 mmol) of 4,6-dimethoxy-2-methylsulphonyl-pyrimidine, 0.8 g (5.7 mmol) of potassium carbonate and 50 ml of acetonitrile is heated under reflux for 15 hours and then concentrated. The residue is shaken with methylene chloride/water, and the organic phase is dried with sodium sulphate and filtered. The filtrate is concentrated and the residue is purified by column chromatography (silica gel; hexane/ethyl acetate, 10:1). 1.0 g (54% of theory) of methyl 2-styryl-6-(4,6-di-methoxy-pyrimidin-2-yl-oxy)-benzoate is obtained as an amorphous product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.I[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: CC(C)CI
Reactant: OCCNCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN(CCO)Cc1ccc(Cl)nc1
Yield: 80.6 %

Procedure:
A stirred mixture of 2.0 grams (0.007 mole) of 2-{[(6-chloro(3-pyridyl))methyl]amino}ethan-1-ol (known compound), 1.29 gram (0.007 mole) of 1-iodo-2-methylpropane and 0.9 gram (0.007 mole) if diisopropylethylamine in 50 mL of acetonitrile was heated at reflux for 16 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and hexanes. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.37 grams of 2-{[(6-chloro(3-pyridyl))methyl](2-methylpropyl)amino}ethan-1-ol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC(OCC)[CH:5]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[CH2:6][CH3:7])C.[NH:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[NH2:23].[C:40]([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[O:13]=[C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:18])[N:8]1[CH2:5][CH2:6][CH2:7][CH:40]=[N:23][NH:22][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:31])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(OCC)C(CC)N1C(=O)c2ccccc2C1=O
Reactant: NNc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCCC=NNc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Finely-divided phthalimidobutyraldehyde diethyl acetal (0.5 g) was added to a stirred solution of 4-hydrazino-N-phenyl-benzenesulphonamide (0.5 g) in 25% aqueous acetic acid (50 ml). After 30 min, the solution was basified (Na2CO3) and extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give an oil which was purified by flash chromatography eluted with ether to give the title compound as a solid (0.3 g) m.p. 126°-129°.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4](O)=[O:5].[H-].[Na+].C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4]([Cl:24])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(C)=CCCC(C)CC=CC(C)=CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(C)=CCCC(C)CC=CC(C)=CC(=O)Cl
Reaction time: 1 h

Procedure:
One gram of 3,7,11-trimethyltrideca-2,4,10-trienoic acid in 30 ml. of benzene and one mol of sodium hydride is stirred about two hours and then a slight excess of oxalyl chloride is added at about 0° and stirred for one hour. The product is worked up by removal of solvent in vacuo and extraction with pentane to yield 3,7,11-trimethyltrideca-2,4,10-trienoyl chloride.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:31])([CH3:30])[C:14]([O:16][CH:17]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[CH3:18])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:30][C:13]([CH3:12])([CH3:31])[C:14]([O:16][CH:17]([O:19][C:20]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:21])[CH3:18])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.1 g, 7 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 2,2-dimethylpropanoate (1.1 g, 3.8 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 21 (200 mg, 16% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.86-0.99 (m, 2H), 1.14 (s, 9H), 1.21-1.39 (br. m, 3H), 1.42 (d, J=5.2 Hz, 3H), 1.71-1.74 (m, 2H), 1.89-1.91 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.81-2.89 (m, 2H), 6.64 (q, J=5.6 Hz, 1H), 7.49 (t, J=6.0 Hz, 1H), 12.01 (br. s, 1H). MS (ESI) m/z 352.16 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[I-].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N1C2C(=CC=C(F)C=2)N(C(=O)C2C=CC(OC)=CC=2)[C@H](CC)C1=O)C1C=CC=CC=1>>[CH2:27]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([F:23])[CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Agent: CC[C@@H]1C(=O)N(Cc2ccccc2)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Agent: [I-]
Agent: [K+]
Product: CC[C@@H]1C(=O)N(Cc2ccccc2)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Yield: 85 %

Procedure:
(3R)-3-Ethyl-7-fluoro-4-(3-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 4) was treated with potassium iodide (5 eq) and benzyl bromide according to the procedure for the preparation of (3R)-1-benzyl-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 2) to yield (3R)-1-benzyl-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (85%).