Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>C(#N)C.O.O>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:31]=3)[CH2:14][CH:13]=[CH:12][N:11]2[CH3:16])[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: CC1(C)OB(c2cccc(OCCC3CCCCC3)c2)OC1(C)C
Reactant: Cn1c(I)ccc1CC[C@]1(C)COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: COCCOC
Solvent: O
Product: CN1C=CCC1(CC[C@]1(C)COC(=O)N1)c1cccc(OCCC2CCCCC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.8 %

Procedure:
(4R)-4-Methyl-4-[2-(5-iodo-1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (0.3101 g, 0.92 mmol) obtained in Example (40a), 2-[3-(2-cyclohexylethyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4646 g, 1.41 mmol), dichlorobis(triphenylphopsphine)palladium(II) (63.1 mg, 0.09 mmol) and cesium carbonate (0.6006 g, 1.81 mmol) were suspended in a mixed solvent of dimethoxyethane (8 ml) and water (2 ml) and stirred at 80° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the crude product. Furthermore, the crude product thus obtained was purified using a preparative reversed phase HPLC column (Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (41.1 mg, yield: 11%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[ClH:26]>CO.O.[C].[Pd]>[ClH:26].[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]2[NH:16][C:15]1=[O:23]
Reactant: [H][H]
Reactant: O=C1NC2CCCCC2N1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NC2CCCCC2N1C1CCNCC1

Procedure:
In this reference example, a solution of 6.1 g of 1-benzyl-4-(octahydro-2H-benzimidazol-2-one-1-yl)-piperidine obtained in the same manner as that of Reference Example 18 and 1 g of 5% palladium carbon in 100 ml of methanol, 100 ml of water and 20 ml of 12 N hydrochloric acid is shaken in the atmosphere of hydrogen under 4 to 5 atmosphere in an autoclave. The shaking is ceased when the absorption of hydrogen has been completed. The reaction mixture is subjected to filtration to remove the catalyst and the filtrate is concentrated. The residue is mixed with 20 ml of isopropanol and stirred to crystallize the reaction product. The crystals are dried and recrystallized from ethanol to obtain 3.9 g of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[C:8]([Cl:14])[CH:7]=1)=[O:5].[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[Cl:14][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[C:3]([OH:15])=[O:2])[CH:11]=[CH:10][C:9]=1[S:12][CH3:13]
Reactant: COC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)C(=O)O)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid methyl ester (61.7 g, 252 mmol) in toluene (120 mL) was heated at 50° C. This heated solution was then treated dropwise with a 3M aqueous sodium hydroxide solution (105 mL, 313 mmol) via a dropping funnel, taking care to keep the temperature below 60° C. After the addition was complete, the reaction mixture was stirred at 50° C. for another 1.5 h, during which time, a yellow precipitate began to form. After this time, the heat was removed, and the warm solution was treated dropwise with concentrated hydrochloric acid (10.6 mL, 290 mmol). The resulting reaction mixture was allowed to cool to 25° C. and then was stirred at 25° C. for 16 h. The solid was filtered and then washed with water (50 mL) and toluene (50 mL). The solid was dried by suction for 1 h and then dried in a high vacuum desiccator to afford (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid (57.22 g, 98%) as a white solid: mp 166° C. (dec); FAB-HRMS m/e calcd for C9H7ClO3S (M+Na)+ 252.9702, found 252.9700.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:18])=[C:12]([Br:17])[C:13]([Cl:16])=[C:14]([Br:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:18])=[C:12]([Br:17])[C:13]([Cl:16])=[C:14]([Br:15])[C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)c(Br)c(Cl)c(Br)c2n1
Product: CC(C#N)(Cn1nc2c(Cl)c(Br)c(Cl)c(Br)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 57, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (100 mg). MS (ES): M/Z [M+H]=630. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.45 (d, J=13.3 Hz, 1H), 5.60 (d, J=13.0 Hz, 1H), 7.82-7.92 (m, 4H) and 8.90 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:20]1[CH:21]=[CH:22][C:23]2N(O)N=[N:26][C:24]=2[CH:25]=1.NC1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:26][C:24]1[CH:25]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: Nc1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1

Procedure:
A solution of pyrrolidine-1,2(S)-dicarboxylic acid 1-t-butyl ester (50 g, 233 mmol), EDC (45 g, 233 mmol) and HOBT (12 g, 77.5 mmol) in 1500 ml of dichloromethane was cooled to 0° C. and aniline (21 ml, 233 mmol) was added dropwise over a period of 15 minutes. The mixture was stirred over night, evaporated and partitioned between ethyl acetate and 1N-HCl. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and evaporated. The crude solid was crystallized from diethyl ether. Yield: 104 g (quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:27])[C:25]#[CH:26])=[CH:20][CH:19]=1>O1CCOCC1.O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([OH:27])[C:25]#[C:26][CH2:15][N:11]2[CH2:10][CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:14])[CH2:13][CH2:12]2)=[CH:22][CH:23]=1
Reactant: C#CC(O)c1ccc(F)cc1
Reactant: C=O
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: O
Solvent: C1COCCO1
Product: OC(C#CCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 80 °C
Yield: 77 %

Procedure:
To a solution of 4-(p-chlorophenyl)-4-hydroxypiperidine (4.00 g) in a mixture of dioxane (30 ml), water (10 ml), and 37 % formalin (2.06 g), there were added a solution of 3-(p-fluorophenyl)-3-hydroxy-1-propyne (2.38 g) in dioxane (5 ml) and a solution of cupric sulfate pentahydrate (127 mg) in water (4 ml) under ice-cooling. The resulting mixture was heated at 80° C for 2 hours and, after cooling, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure and extracted with chloroform. The chloroform extracts were dried over magnesium sulfate. After evaporation of the solvent, the residual oil was chromatographed on silica gel to afford 1-[4-(p-fluorophenyl)-4-hydroxy-2-butynyl]-4-(p-chlorophenyl)-4-hydroxypiperidine (4.56 g) as white crystals, M.P. 145° - 146.2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2ccc(F)cc2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccc(F)cc2)c1

Procedure:
Using the same method as in Example 1-(ii), 4′-fluorobiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluorobiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 82%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](O)(=[O:25])C>CO>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]([O:25][CH3:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)c2nc(SCc3ccccc3)nn12

Procedure:
2-Benzylthio-5,8-dichloro[1,2,4]triazolo[1,5-a]pyridine (6.0 g, 0.019 mol) and 25 percent sodium methoxide in methanol (26.5 mL, 6.3 g, 0.116 mol) were combined in methanol and the mixture was heated to reflux for 2 hours. The mixture was then cooled, acidified with acetic acid, and concentrated by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the solution was washed with water and concentrated by evaporation under reduced pressure. The residue was triturated with hexane and the resulting solids were collected by filtration and dried to obtain 5.76 g (99 percent of theory) of the title compound as a light tan powder melting at 90°-91° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[O:35]C(=O)C)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[OH:35])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)nc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(N4CCOCC4)nc3)c2)=C(C)C1=O
Yield: 96.3 %

Procedure:
N-(6-Morpholinopyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.100 g, 0.187 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.089 g, 0.180 mmol, 96%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@H:12]1[C:45](=[O:46])[N:44]2[CH2:47][C@@H:41]([CH2:42][C@H:43]2[C:48]([O:50][CH3:51])=[O:49])[O:40][C:24]2=[N:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]([O:33][CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH2:52][C@H:16]2[O:15][C:14](=[O:53])[NH:13]1)([CH3:11])([CH3:10])[CH3:9].[I-].[K+].[CH3:56][O:57][CH2:58][CH2:59]Br>CN(C=O)C.C(N(CC)CC)C>[C:8]([C@H:12]1[C:45](=[O:46])[N:44]2[CH2:47][C@@H:41]([CH2:42][C@H:43]2[C:48]([O:50][CH3:51])=[O:49])[O:40][C:24]2=[N:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]([O:33][CH:34]3[CH2:39][CH2:38][N:37]([CH2:59][CH2:58][O:57][CH3:56])[CH2:36][CH2:35]3)=[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH2:52][C@H:16]2[O:15][C:14](=[O:53])[NH:13]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCNCC1)O2
Reactant: COCCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCC(Oc2c3c(nc4ccccc24)O[C@@H]2C[C@@H](C(=O)OC)N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]2C[C@H]2CCCCC3)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
The amine from Step 2 (70.9 mg) was dissolved in DMF (0.3 mL) and triethylamine (53 μl), potassium iodide (1.6 mg) and 2-bromoethyl methyl ether (20 μl) were added sequentially. The reaction mixture was stirred at 60° C. for 24 hours. The reaction mixture was then cooled to room temperature and quenched with a saturated solution of sodium bicarbonate. The mixture was extracted (3×) with ethyl acetate and the combined organics were dried with sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (ISCO, 0 to 10% methanol in DCM) gave the desired product (50.6 mg). LRMS (ES+) m/z 695.5 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[C:21](=[O:23])=[O:22]>O1CCCC1.CCCCCC>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[C:21]([OH:23])=[O:22]
Reactant: Clc1cncc(Cl)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)cncc1Cl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.96 ml (0.036 mole) of diisopropylamine in 200 ml of tetrahydrofuran at -65° C. under a nitrogen blanket was added dropwise 14.9 ml of 2.5M n-butyllithium in hexane while maintaining the above temperature. Twenty minutes subsequent to that addition, a solution 5.0 g (0.034 mole) of 3,5-dichloropyridine in 30 ml tetrahydrofuran at -60° to -70° C. was added. The reaction mixture was stirred at -70° C. for 1/2 hr, poured onto a large excess of dry ice and allowed to evaporate overnight at room temperature. The residue was taken up in 100 ml of dilute aqueous sodium hydroxide, washed with 3×30 ml of methylenechloride and filtered. The filtrate was acidified to ~pH 2 with dilute hydrochloric acid to precipitate out the product. After cooling, the precipitate was collected and recrystallized from ethyl acetate/hexane giving 1.9 g (29%) of white analytically pure crystals, m.p. 231-35° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:9]=[C:8]([C:24]([F:27])([F:26])[F:25])[CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]([C:24]([F:25])([F:26])[F:27])=[N:9]2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCNCC1
Temperature: 21 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 93 (1.014, 2.59 mmol) in CH2Cl2 (13 ml) was added TFA (3 ml, 38.9 mmol). The resulting solution was allowed to stir at 21° C. for 2 h. After the usual work-up, crude 94 was obtained as colorless oil. LRMS (ESI): calc. 291.3; found 292.2 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C([O-])(O)=O.[Na+]>C(#N)C>[Br:16][C:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)cc1F
Temperature: 23 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a solution of 3-fluoro-pyridin-2-ylamine (example C.29 step 2) (3 g, 26.8 mmol) in acetonitrile (50 mL) at 0° C. was added NBS (4.77 g, 26.8 mmol) and the mixture was stirred at 23° C. for 2 h. Poured on ice with sat. NaHCO3-sol., extracted thrice with AcOEt, dried over Na2SO4. Removal of the solvent in vacuum left a residue, which was purified by silica gel column chromatography with heptane/AcOEt 3:1 to give the title compound as a brown solid (3.1 g, 60%). MS (ISP) 191 [(M+H)+], 193 [(M+2+H)+].
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH2:6][CH2:5][CH:4](CO)[CH2:3][CH2:2]1.C1(=O)[O:17][CH2:16]CCCC1>>[C:1]1([CH2:9][OH:10])([CH2:16][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCC1CCC(CO)CC1
Reactant: O=C1CCCCCO1
Product: OCC1(CO)CCCCC1

Procedure:
Using a procedure similar to that for Experiment 1, various ratios of 1,4-cyclohexanedimethanol were reacted with ε-caprolactone. Table 1 gives the ratio of moles to viscosity and amount of unreacted cyclohexanedimethanol.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]([C:19]#[N:20])=[C:15](OC)[CH3:16])=[N:11][C:10]=2[CH:21]=1)(=O)=[O:4].[OH2:22].[NH2:23][NH2:24]>CO.Cl>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]3[C:15]([CH3:16])=[N:23][NH:24][C:19]=3[NH2:20])=[N:11][C:10]=2[CH:21]=1)(=[O:4])=[O:22]
Reactant: CNS(=O)(=O)c1ccc2sc(C(C#N)=C(C)OC)nc2c1
Reactant: NN
Reactant: O
Agent: Cl
Solvent: CO
Product: CNS(=O)(=O)c1ccc2sc(-c3c(C)n[nH]c3N)nc2c1
Yield: 43 %

Procedure:
To a suspension of 2-(1-cyano-2-methoxypropenyl)benzothiazole-5-sulfonic acid methylamide (120 mg, 0.37 mmol) in 4 mL of methanol, was added hydrazine hydrate (20 μL). The mixture was heated to reflux for 5 hrs and then 1 drop of conc. hydrochloric acid was added to the reaction mixture. The mixture was refluxed for an additional 5 min and was then allowed to cool. The volume of solvent was reduced under reduced pressure and a solid formed. The solid was isolated by filtration and was washed with methanol and then water and dried to yield 51 mg (43%) of the title compound as a cream coloured powder. MS (m/z, ES+): 324.0 (M+1,100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.FC(F)(F)[C:14](O)=[O:15].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>O>[CH:14]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[C:3]([O:2][CH3:1])=[O:11])=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Methyl-4-hydroxybenzoate (4.56 g, 30 mmol) was mixed with trifluoroacetic acid (24 ml) and hexamethylenetetramine (8.41 g, 60 mmol) (Duff reaction). The reaction medium was heated to 80° C. for three hours and cooled to 0° C., followed by successive addition of 15 ml of 50% sulfuric acid and 90 ml of demineralized water. After stirring for one hour at room temperature, the medium was extracted with ethyl ether, washed with water, dried over magnesium sulfate and filtered, and the solvents were evaporated off. The product was purified by passage through a column of silica and was eluted with dichloromethane. After evaporation of the solvents, 1.92 g of a crystallized white solid are obtained, equivalent to a yield of 36%. Its properties were as follows:
Reaction SMILES: [ClH:1].[F:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](C(F)(F)F)=[CH:16][C:15]=1[CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:1])[CH:17]=[CH:16][C:15]=1[CH2:24][S:25]([NH:5][CH2:4][CH2:3][F:2])(=[O:27])=[O:26]
Reactant: Cl
Reactant: NCCF
Reactant: O=S(=O)(Cl)Cc1cc(C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccc(Cl)cc1Cl)NCCF
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.1 %

Procedure:
To a suspension of 2-fluoroethylamine hydrochloride (0.287 g) in dichloro-methane (4 ml) was added triethylamine (0.4 ml) followed by (2,4-dichloro-phenyl)-methanesulfonyl chloride (Example 1.2) (0.25 g). The reaction mixture was stirred at ambient temperature for 3 hours then left to stand at ambient temperature for 16 hours. Dichloromethane (20 ml) was added to the reaction mixture and the mixture was washed with water (20 ml). The phases were separated and the organic layer was dried over magnesium sulfate and concentrated to give C-(2,4-dichloro-phenyl)-N-(2-fluoro-ethyl)-methanesulfonamide (15 mg) (60% pure). 1H-NMR (400 MHz, CDCl3): 7.47-7.51 (m, 2H), 7.29-7.32 (dd, 1H), 4.77 (bs, 1H), 4.49 (s, 2H), 4.51-4.53 (m, 1H), 4.39-4.42 (m, 1H), 3.33-3.36 (m, 1H), 3.27-3.29 (m, 1H) ppm.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[CH:12]2)=[N:9][CH:10]=1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([Br:1])[CH2:12]2)=[N:9][CH:10]=1
Reactant: BrBr
Reactant: O=c1cc(C(F)(F)F)ncn1-c1ccc(C(F)(F)F)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C(C(F)(F)F)N(Br)CN1c1ccc(C(F)(F)F)cn1
Reaction time: 16 h

Procedure:
Bromine (0.15 ml) was added in one portion to a suspension of 1-(5-trifluoromethyl-2-pyridyl)-4-trifluoromethylpyrimidin-6-one (compound No. 2 in Table I) (0.5 g) and sodium acetate trihydrate (1.1 g) in acetic acid (4.8 ml). After stirring for 16 hours, the solvent, was removed under reduced pressure, and the residue was poured into water and aqueous sodium bicarbonate solution. Rigourous extraction into diethylether followed by drying over magnesium sulphate and removal of the solvent under reduced pressure, gave 1-(5-trifluoromethyl-2-pyridyl)-3-bromo-4-trifluoromethylpyrimidin-6-one as a pale yellow solid (m.p. 142-143° C.). The compound showed (CDC13) 8.90 (1H,s), 8.80 (1H,s), 8.2 (1H,dg), 8.16 (1H,d).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH:30]=O)=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:8])=[O:7])=[CH:2]1.Cl.[CH3:41][NH:42][CH3:43].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH2:30][N:42]([CH3:43])[CH3:41])=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:7])=[O:8])=[CH:2]1
Reactant: CNC
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN(C)C)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Yield: 45.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.219 g, 0.385 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with dimethylamine hydrochloride (0.630 g, 7.70 mmol), triethylamine (1.10 mL, 7.70 mmol), acetic acid (0.441 mL, 7.70 mmol) and sodium triacetoxyborohydride (0.245 g, 1.16 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (0.104 g, 45%).