Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7]2)(=O)[CH3:2].O=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17]CC)=[O:16].O.[NH2:26][NH2:27].[OH-].[Na+].Cl>C(O)(C)C>[C:15]([C:14]1[C:20](=[O:22])[NH:26][N:27]=[C:1]([C:4]2[CH:12]=[CH:11][C:10]3[O:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH:2]=1)([OH:17])=[O:16]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Temperature: 120 °C
Reaction time: 39 h

Procedure:
5-Acetylcoumarane [Brown H. C., Inukai T., J. Am. Chem. Soc., 83 4825 (1961)] (5.0 g, 30.8 mmol) and diethyl ketomalonate (5.9 g, 33.9 mmol) were mixed together, and the mixture was stirred for 39 hours at 120° C. The reaction mixture was dissolved in isopropanol (100 mL), and hydrazine monohydrate (3.38 g, 67.5 mmol) was added to the resultant mixture, followed by stirring for six hours at 100° C. A 2-mol/L aqueous sodium hydroxide solution (7 mL) was added thereto, and the resultant mixture was stirred for four hours at 100° C. The reaction mixture was cooled on ice and acidified with concentrated hydrochloric acid. The formed precipitates were collected through filtration and thoroughly washed with water, followed by drying, to thereby yield 5.9 g of the title compound as a yellow powder (74.1%).
Reaction SMILES: I.[PH2](O)=O.[C:5]([C:10]1[NH:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH:14]=1)([O:7][CH2:8][CH3:9])=[O:6].[CH:17](=O)[CH2:18][CH3:19].N>O.C(O)(=O)C>[C:5]([C:10]1[NH:11][C:12]([CH3:16])=[C:13]([CH3:15])[C:14]=1[CH2:17][CH2:18][CH3:19])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC=O
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Agent: I
Agent: N
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: O
Product: CCCc1c(C(=O)OCC)[nH]c(C)c1C
Yield: 40 %

Procedure:
Hydriodic acid (d 1.95, 10 ml) was slowly added to 10 ml of stirred and cooled acetic acid; hypophosphorous acid (50%, 2 ml) was then added. 2-Carbethoxy-4,5-dimethylpyrrole (0.004 mol) was added to the mixture at room temperature followed by propionaldehyde (0.008 mol). The solution was stirred 21/2 h at ca. 25° C. then poured into 200 ml of water. This was made alkaline with ammonia, extracted with ether, and the ether was evaporated to leave the crude product. This was an oil which solidified after distillation (1 × 10-4 mm). It was recrystallized from aqueous ethanol, then from ethanol m.p. 101°-104° C. (lit. 102° C), yield 40%. ##STR68##
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH2:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[CH3:21][N:22]([CH:24]=O)[CH3:23]>>[CH3:21][N:22]([CH:24]=[N:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH3:23]
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)Cc1ccccc1N
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C=Nc1ccccc1CS(=O)(=O)N(C)C

Procedure:
Dimethylformamide (20 ml) was cooled under a nitrogen atmosphere to −40° C. in a dry ice-acetonitrile bath. Oxalyl chloride (2 ml) was added dropwise at such a rate as to maintain the temperature below −30° C. Upon completion of the addition, the suspension was allowed to rise to room temperature. After about an hour, 2-aminobenzyl-N,N-dimethylsulfonamide (0.630 g) dissolved in DMF (5 ml) was added with stirring and the reaction mixture was stirred at room temperature for 4 h. The solution was partitioned between 1% sodium hydroxide solution and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to afford C-[2-(dimethylamino-methyleneamino)-phenyl]-N,N-dimethyl-methanesulfonamide as an oil which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[C:16](O)(=[O:19])[C:17]#[CH:18]>C1CCCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:16](=[O:19])[C:17]#[CH:18])=[C:10]([F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1F
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1F

Procedure:
Prepared analogously to Example 1.1.b. from 4′-chloro-3-fluorobiphenyl-4-ylamine and propynoic acid. Yield: 0.16 g (43.7% of theory); C15H9ClFNO (M=273.69); calc.: molecular ion peak (M+H)+: 274/276; found: molecular ion peak (M+H)+: 274/276; Rf value: 0.3 (silica gel, cyclohexane/ethyl acetate (3:1)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH3:25])[CH:11]=1)[CH3:2].[ClH:34]>CCOC(C)=O.O1CCOCC1>[ClH:34].[ClH:34].[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.375 g, 0.8 mmol) in EtOAc (4 mL) was added 4N HCl in 1,4-dioxane (0.8 mL), and the reaction was stirred at 50° C. for 1 hour. Additional 4N HCl in 1,4-dioxane (0.8 mL) was added, and the reaction was stirred for 1 hour at 70° C. The mixture was concentrated to give [5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]([CH3:29])[CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH:27]([CH3:29])[CH3:28])[CH2:18]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl>CN(C=O)C.O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: N#Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2cccc(Cl)c2)cc1
Temperature: 0 °C

Procedure:
To a solution of 5×10-2 mole of 4-hydroxy benzonitrile (VIl) in 100 ml of DMF are added little by little 5×10-2 mole of NaH so as to obtain a temperature of 25° C. Then the solution is heated to 50° C. until the release of hydrogen ceases. After cooling to 0 ° C., 5×10-2 of 3-chloro benzyl chloride (VIII) is added little by little. The reaction mixture is heated to 40 ° C. for one hour then poured into 300 ml of iced water. The resultant solid is separated by filtration then recrystallized in an ethanol-water mixture, which leads to the expected compound.
Reaction SMILES: S(O[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.C1CCN2C(=NCCC2)CC1.C(Cl)Cl>CN(C=O)C>[N:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][CH:12]=[CH:13][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=CCC1
Temperature: 150 °C
Yield: 85 %

Procedure:
A mixture of tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (5.50 g, 15.40 mmol, 1 eq) and DBU (5.70 g, 31.00 mmol, 2 eq) in DMF (100 mL) was heated at 150° C. overnight and cooled to room temperature. To this, 100 mL of CH2Cl2 was added, and the mixture was washed with brine (20 mL×3) and water (30 mL×2). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) PE/EtOAc) to give the title compound as pale yellow oil (2.40 g, 85.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 184.1 (M+1).
Reaction SMILES: C([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(OC(C)(C)C)=O.[NH:21]1[C@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1.[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]>>[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39]([NH:8][C@@H:9]([C:18]([N:21]2[C@H:30]3[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: C1CC[C@H]2NCCC[C@@H]2C1
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Product: Nc1c(Cl)cc(S(=O)(=O)N[C@H](CCc2ccccc2)C(=O)N2CCC[C@@H]3CCCC[C@H]32)cc1Cl

Procedure:
4-amino-3,5-dichloro-N-{(1R)-1-[(trans)-octahydroquinolin-1(2H) -ylcarbonyl]-3-phenylpropyl}benzenesulfonamide is prepared from Boc-(D)-homo -phenylalanine, (±)-trans-decahydroquinoline, and 4-amino-3,5dichlorobenzene -sulfonyl chloride in the same manner that Example 1 is synthesized. ESI MS: Calc: 523.2; Found: 524.3 (M+H)+.
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]([C:29]([OH:31])=O)[NH2:28])=[O:21])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[B-](F)(F)(F)F.CN(C(O[N:46]1[C:51](=[O:52])[CH2:50][CH2:49][C:47]1=O)=[N+](C)C)C.[CH2:53]([O:60][C:61](=[O:68])[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][NH3+:67])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[C@@H:1]1([O:11][CH2:12][CH2:13][NH:46][C:51](=[O:52])[CH2:50][CH2:49][CH2:47][CH2:19][C:20]([NH:28][C@H:27]([C:29]([NH:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][C:61]([O:60][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:68])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15](=[O:32])[NH:14][CH2:13][CH2:12][O:11][C@@H:1]2[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])=[O:21])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: [NH3+]CCCCCC(=O)OCc1ccccc1
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](N)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)CCCCC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)NCCCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 40 mL vial was added N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (150 mg, 0.324 mmol) and DMF (5 mL). The solution was cooled to 0° C. To the above solution was added ML-4 (140 mg, 0.324 mmol) in DMF (2 mL) dropwise followed by the addition of TEA (45 μL, 0.324 mmol). The reaction mixture was warmed to rt and stirred for 1 h. To the resulting mixture was added TSTU (97 mg, 0.324 mmol) followed by the addition of TEA (45 μL, 0.324 mmol). The mixture was stirred at rt for 20 min. To the resulting mixture was added a solution of 6-(benzyloxy)-6-oxohexan-1-aminium 4-methylbenzenefulfonate (127 mg, 0.324 mmol) in DMF (1.0 mL). After stirring at rt for 18 hr, the mixture was concentrated. The residue was purified by flash chromatography to give the title compound. UPLC Method B: m/e=984.5469 [M+1]; Rt=3.37 min.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCN3C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCC(C)(C)c2cc(/C(C)=C/c3ccc(C(=O)O)cc3)ccc21
Reaction time: 48 h

Procedure:
To a solution of 0.1 g (0.265 mmol) of methyl 4[(E)-2-(N-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-methylvinyl]benzoate in 10 ml of dioxane was added, with stirring, 0.8 ml (1.6 mmol) of 2N sodium hydroxide, with the temperature maintained at 25° C. Stirring was continued for 48 hours, and then the reaction mixture was diluted with 25 ml of water. It was then acidified to pH 2 with 2N hydrochloric acid and extracted with dichloromethane. The combined extracts were dried using sodium sulfate and then evaporated in vacuo to give the title compound as a white solid. The solid was recrystallized from methanol-hexane to give 70 mg of the title compound, mp 200°-202° C.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][CH:11]1[C:34]([OH:36])=O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1.[CH3:70][O:71][C:72]1[CH:73]=[C:74]([CH:77]=[CH:78][CH:79]=1)[NH:75][CH3:76]>C1COCC1>[OH:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:24][OH:25])[O:12][CH:11]1[C:34]([N:75]([C:74]1[CH:77]=[CH:78][CH:79]=[C:72]([O:71][CH3:70])[CH:73]=1)[CH3:76])=[O:36]
Reactant: O=C(OC[C@H]1OC(C(=O)O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CNc1cccc(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: C1CCOC1
Product: COc1cccc(N(C)C(=O)C2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Reaction time: 16 h
Yield: 42.5 %

Procedure:
(3R,4R,5R)-3,4-Bis(benzoyloxy)-5-(benzoyloxymethyl)tetrahydrofuran-2-carboxylic acid (3,4,6-Tri-O-benzoyl-2,5-anhydro-D-allonic acid, 2 g, 4 mmol) was dissolved in anhydrous THF (40 mL) under argon. Triphenylphosphine (2.1 g, 8 mmol) was then added, and the resulting mixture was stirred until it was completely dissolved. Subsequently 2,2′-dipyridyldisulfide (1.8 g, 8 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, after which 3-methoxy-N-methylaniline (0.7 g, 5.6 mmol) was added and stirring was continued at room temperature for 16 hours. The solvent was evaporated to dryness, the residue was dissolved in chloroform (150 mL), the solution was washed twice with 0.1M NaOH solution (100 mL), twice with 0.2 M HCl solution (100 mL), once with saturated NaHCO3 solution (100 mL), and dried (Na2SO4). The solution was evaporated to dryness and the residue dissolved in 7M solution of ammonia in methanol (250 mL). The solution was stirred for 16 hours at room temperature and evaporated to dryness. The residue was dissolved in chloroform and applied to a column of silica gel. Elution with a mixture of chloroform-methanol (3:1) and evaporation of the appropriate fractions yielded the title compound as a colorless oil (0.51 g, 1.7 mmol, 42%): MS (ES) m/z 399 [M+H+C6H15N]+, 296 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)=[O:4].[BH4-].[Na+].[OH-].[Na+]>CO>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH:3]1[O:4][CH2:2]1
Reactant: O=C(CBr)C1COc2ccccc2O1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2c(c1)OCC(C1CO1)O2
Reaction time: 5 h

Procedure:
The starting material is prepared as follows: To the solution of 42 g of 2-(2-bromoacetyl)-1,4-benzodioxan in 360 ml of methanol, 12 g of sodium borohydride are added while stirring and keeping the temperature below 10°. After 5 hours, the mixture is cooled to 0° and 13.2 g of sodium hydroxide in 150 ml of methanol are added and the mixture kept at -15° overnight. It is poured onto ice, extracted with diethyl ether, the extract washed with saturated aqueous sodium chloride, dried and evaporated, to yield the 1,4-benzodioxan-2-yl-ethyleneoxide.
Reaction SMILES: [Cl-:1].[CH2:2]1[CH2:7][CH2:6][C:5]([CH2:12][NH2:13])([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1>>[CH2:2]1[CH2:3][CH2:4][C:5]([CH2:12][NH2:13])([CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1.[ClH:1]
Reactant: [Cl-]
Agent: NCC1(CC(=O)O)CCCCC1
Product: Cl

Procedure:
is dissolved in chloride free demineralized water (375 ml) at 50 degrees. The solution is treated with charcoal at the same temperature and filtered through a bed of hyflo. The bed is washed with demineralized water (150 ml). The filtrate is cooled to 10 deg and neutralized with sodium lye (110 g of 50% w/w sodium hydroxide solution) with the temperature kept strictly below 15 degrees. The neutralized mixture is heated to 70-75 degrees over a period of 3 hours to get a clear solution, then cooled to 5-10 degrees over a period of 4 hours and kept at that temperature range for 1 hr and filtered (mother liquor A). The product is suck dried thoroughly to give moist gabapentin (about 195 g) having water content of 14%. This is dissolved in a mixture of methanol (570 ml) and water (60 ml) at about 70 degrees. The solution is treated with activated charcoal (5 g) and filtered through a bed of hyflo. The bed is washed with a mixture of methanol (80 ml) and water (16 ml). To the combined filtrates is added isopropanol (815 ml). The mixture is cooled to 0-5 degrees and maintained for 1 hr, when pure white gabapentin crystallizes out, the mixture is centrifuged; the product is spin-dried for 45 min (mother liquor B) and dried to yield gabapentin (125 g) with 1. Chloride 40 ppm, 2. Gabalactam, 0.01%, 3. Impurity with RF 0.5 relative to gabapentin NIL 4. Any other individual impurity less than 0.1% 5. Total impurities 0.032%
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15].[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1>>[ClH:1].[CH2:13]([NH:16][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:19]2[C:18]([CH3:17])=[CH:22][C:21]([CH3:23])=[N:20]2)[N:11]=1)[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: C=CCNc1nc(-n2nc(C)cc2C)nc2ccccc12
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, allylamine and 3,5-dimethylpyrazole. Mp. 211-212° C.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9](=[O:15])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH:6]=1.ClCC(O)COC1C2SC=CC=2C(=O)C2C=CC=CC=2C=1.CO.[CH3:44][C:45]1([CH3:52])[CH2:49][CH2:48][C:47]([CH3:51])([CH3:50])[NH:46]1>>[OH:1][CH:2]([CH2:20][N:46]1[C:47]([CH3:51])([CH3:50])[CH2:48][CH2:49][C:45]1([CH3:52])[CH3:44])[CH2:3][O:4][C:5]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9](=[O:15])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH:6]=1
Reactant: CC1(C)CCC(C)(C)N1
Reactant: O=c1c2ccccc2cc(OCC2CO2)c2sccc12
Agent: O=c1c2ccccc2cc(OCC(O)CCl)c2sccc12
Solvent: CO
Product: CC1(C)CCC(C)(C)N1CC(O)COc1cc2ccccc2c(=O)c2ccsc12

Procedure:
20.0 g of a mixture of 10-(2,3-epoxypropoxy)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one and 10-(3-chloro-2-hydroxypropoxy)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one are boiled at reflux in 65 ml of 2,2,5,5-tetramethylpyrrolidine and 200 ml of methanol for 5 hours. The reaction mixture is evaporated to dryness and the residue is taken up in 600 ml of chloroform and 150 ml of 3N caustic soda solution. The organic solution is separated and is washed thrice with 3N caustic soda solution. After washing neutral with water, the solution is dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on 600 g of silica gel with a mixture of chloroform containing 5% methanol to give the title compound in free base form. (M.Pt. 104° - 107° from isopropanol).
Reaction SMILES: [CH:1]1([N:6]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>N1C(C)=CC(C)=CC=1C>[CH:1]1([N:6]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([O:31][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(O)cc1OC
Reactant: O=C(c1ccc(Br)cc1)N(C1CCCC1)C1CCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N,N-dicyclopentyl amide (1.839 g, 5.47 mmol), 3,4-dimethoxy phenol (876 mg, 5.68 mmol) and cuprous oxide (413 mg, 2.89 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 179.95° C. (DSC).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)[CH:23]=[CH:22][N:21]=2)[CH:17]=[N:16][CH:15]=1.O>ClCCCl.C1COCC1>[N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:31][CH:32]=3)[CH:23]=[CH:22][N:21]=2)[CH:17]=[N:16][CH:15]=1
Reactant: CC(C)(C)C(N)=O
Reactant: Nc1ccc(Oc2ccnc(-c3cncnc3)c2)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3cncnc3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.048 g, 0.475 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.042 mL, 0.475 mmol), stirred at RT for 1 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, treated with a solution 5-((2-(pyrimidin-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.063 g, 0.237 mmol) and TEA (0.099 mL, 0.712 mmol) in THF (3 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-((5-((2-(pyrimidin-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (65 mg, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.44 (s, 1H), 9.41 (s, 2H), 9.24 (s, 1H), 8.62 (d, J=5.7 Hz, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.78 (dd, J=9.0, 2.9 Hz, 1H), 6.99 (dd, J=5.7, 2.4 Hz, 1H), 1.21 (s, 9H); MS (ESI) m/z: 393.2 (M+H+).