Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:9](=O)[CH2:10]Br)=[C:6]([CH3:8])[N:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1>CC(N(C)C)=O>[NH2:2][C:3]1[S:4][C:5]([C:9]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:10]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(N)sc1C(=O)CBr
Reactant: Cc1cccnc1N
Agent: Br
Solvent: CC(=O)N(C)C
Product: Cc1nc(N)sc1-c1cn2cccc(C)c2n1
Yield: 21.8 %

Procedure:
A solution of 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (9.5 g) and 2-amino-3-methylpyridine (9.7 g) in dimethylacetamide (100 ml) was heated at 85° C. to 88° C. for 5 hours and the reaction mixture was evaporated in vacuo. To the residue was added water and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The acidified solution was treated with charcoal and filtered. The filtrate was washed with ethyl acetate. The aqueous solution was adjusted to pH 9.0 with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(2-amino-4-methyl-5-thiazolyl)-8-methylimidazo[1,2-a]pyridine (1.6 g). mp 226° C. (dec.)
Reaction SMILES: [H-].[Na+].F[C:4]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].CS(CCO)(=O)=[O:15]>CN(C=O)C>[F:12][C:11]1[C:4]([OH:15])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CS(=O)(=O)CCO
Reactant: N#Cc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(F)c1O
Temperature: 25 °C

Procedure:
Sodium hydride was added to a DMF solution of 2,3-difluorobenzonitrile and 2-(methylsulfonyl)ethanol and the whole was stirred at room temperature to obtain 3-fluoro-2-hydroxybenzonitrile. FN: 136.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:16][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCC#CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCC#CCBr

Procedure:
1-Bromo-2-tridecyne (colorless oil) was prepared from 2-tridecyn-1-ol using the CBr4/triphenylphosphine mixture in dichloromethane to carry out the halogenation. 1-Bromo-2-tridecyne (colorless oil) was thus formed with a yield of 91%.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH2:44][C:43]2[C:38](=[C:39]([O:51]C)[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42]=2[O:45]C)[CH2:37]1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH2:44][C:43]2[C:42](=[O:45])[C:41]([O:47][CH3:48])=[C:40]([O:49][CH3:50])[C:39](=[O:51])[C:38]=2[CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1(CCCCCCCC(=O)O)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(CCCCCCCC(=O)O)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 68 %

Procedure:
A water (1 ml) solution of CAN (238 mg, 0.435 mmols) was dropwise added to an acetonitrile (2 ml) solution of 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoic acid (78.6 mg, 0.174 mmols) with cooling with ice and then stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to ethyl acetate only) to obtain the entitled compound (50 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21]COC)=[C:5]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][C:15]3=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>CO>[OH:21][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 4-(3,4-Dimethoxy-2-methoxymethoxy-phenyl)-indan-1-one (1.6 g, 4.87 mmol) in methanol (15 mL) at 0° C., was added concentrated hydrochloride acid (3 mL) and the resultant reaction mixture was stirred at 50° C. for 15 min. The reaction mixture was concentrated under reduced pressure and basified with aq sodium bicarbonate solution extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by washing with ether to afford the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH:16]([CH3:18])[CH3:15])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.7 %

Procedure:
To a 50 L 3-neck round-bottom reaction flask equipped with a mechanical stirrer, temperature probe, nitrogen inlet and cooling bath was added 4-amino-1-benzylpiperidine (2,000 g, 10.5 mol) and dichloromethane (20 L). Acetone (610.5 g, 10.5 mol) was added and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then cooled to 0° C. to 5° C. with an ice/methanol bath and sodium triacetoxyborohydride (2,673 g, 12.6 mol) was added while maintaining the temperature of the reaction mixture below 25° C. The cooling bath was then removed and the reaction mixture was stirred until less than 1% starting material was present by gas chromatograhy (GC) analysis (about 3 hours). Concentrated hydrochloric acid was added until the pH of the reaction mixture was 7 (about 500 mL). The resulting slurry was filtered through a polypropylene filter pad and the solids were washed with dichloromethane (2×2 L). The solids were saved for use after concentration of the filtrate. The filtrate was concentrated at 40° C. until no condensate remained. In a 40 L separatory funnel, the solids and distillation residue were dissolved in water (15 L) and concentrated hydrochloric acid was added until the pH of the solution was 3 (about 2.5 L). The aqueous layer was then washed with dichloromethane (2×2 L). The pH of the aqueous layer was adjusted to 11 to 12 with 50% aqueous sodium hydroxide solution (about 4.5 L) and this mixture was extracted with dichloromethane (5×3 L). The organic layers were combined, decolorized with charcoal (50 g) and dried over anhydrous magnesium sulfate (200 g). The solids were filtered off using a glass fiber filter pad and the filtrate was concentrated until no condensate remained to afford the title compound (2,336 g, 96% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4]([F:32])[CH:3]=1.[C:33]([C:35]1([O:50][CH3:51])[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][CH3:49])[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)#[CH:34].N1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:10]1([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:33][C:35]3([O:50][CH3:51])[CH2:40][CH2:39][CH:38]([CH:41]4[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][CH3:49])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[CH:3][C:4]=2[F:32])[CH2:11][CH2:12][CH:13]([CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH2:14][CH2:15]1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C#CC1(OC)CCC(C2CCC(CCC)CC2)CC1
Reactant: CCCCCC1CCC(C2CCC(C#Cc3ccc(Br)cc3F)(CCCCC)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: CCCCCC1CCC(C2CCC(C#Cc3ccc(C#CC4(OC)CCC(C5CCC(CCC)CC5)CC4)cc3F)(CCCCC)CC2)CC1

Procedure:
Analogously to Example 4, 1.913 g of 4-(4-bromo-2-fluorophenylethynyl)-4,4′-dipentylbicyclohexyl are reacted with 0.997 g of 4-ethynyl-4-methoxy-4′-propylbicyclohexyl in the presence of 0.219 g of tetrakis(triphenylphosphine)palladium(0) and 5 ml of pyrrolidine, giving 4-[4-(4,4′-dipentylbicyclohexyl-4-ylethynyl)-3-fluorophenylethynyl]-4-methoxy-4′-propyl-bicyclohexyl (C 177 N (36) I, Δε −0.26, Δn −0.015).
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]([CH2:20][CH3:21])[C@H:4]([NH:12]C(=O)OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>O1CCOCC1>[ClH:1].[ClH:1].[NH2:12][C@@H:4]([C@@H:3]([OH:2])[CH2:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](O)[C@H](N)Cc1ccncc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
a solution of 50 cm3 of 4N hydrochloric acid in dioxane is added, with stirring and at a temperature in the region of 20° C., to a solution of 4 g of tert-butyl N-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)-butyl]carbamate in 50 cm3 of dioxane. The mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated under reduced pressure (1 kPa) at a temperature in the region of 60° C. 3.6 g of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride are obtained in the form of a white solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm) 0.92 (t, J=7.5 Hz: 3H); from 1.30 to 1.65 (mt: 2H); 3.13 (dd, J=14 and 9 Hz: 1H); 3.28 (dd, J=14 and 5 Hz: 1H); 3.52 (mt: 1H); 3.68 (mt: 1H); 8.11 (broad d, J=6.5 Hz: 2H); 8.25 (unresolved complex: 3H); 8.90 (broad d, J=6.5 Hz: 2H) ].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][N:10]2[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.25 g (7.8 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 1.5 g (7.76 mmol) of 6-fluoro-3-methoxycarbonyl-1H-indole in 40 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.5 hour, 1.29 g (7.8 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 6 hours, the reaction mixture is poured into 150 cm3 of water and extracted with 150 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a brown solid which is purified by silica gel chromatography [eluent: dichloromethane and then dichloromethane/ethyl acetate (90/10 by volume)]. After concentrating the fractions under reduced pressure, 1.5 g of 6-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 186° C.
Reaction SMILES: [H-].[Li+].[CH2:3]([C:5]1[N:6]=[C:7]([CH2:10][C:11]#[N:12])[S:8][CH:9]=1)[CH3:4].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]([C:10](=[C:7]2[NH:6][C:5]([CH2:3][CH3:4])=[CH:9][S:8]2)[C:11]#[N:12])[CH:17]=[CH:16][N:15]=1
Reactant: CCc1csc(CC#N)n1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1=CSC(=C(C#N)c2ccnc(Cl)n2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a suspension of LiH (699 mg, 87.90 mmol) in anhydrous THF was added dropwise a suspension of (4-ethyl-1,3-thiazol-2-yl)acetonitrile (6.69 g, 43.95 mmol) in THF (60 mL) and the suspension was stirred for 1 h at 0° C. A suspension of 2,4-dichloropyrimidine (7.2 g, 48.34 mmol) in THF (60 mL) was added dropwise to the pale red suspension at 0° C. and the resulting mixture was stirred at rt for 7 h. The reaction was quenched by addition water (10 mL) at 0° C. then the solution obtained was left overnight under stirring. The THF was removed under reduced pressure then 80 mL of water were added and the suspension was acidified with 1N HCl. The precipitate formed was filtered off and washed with water until neutral pH to afford 9.96 g of the title compound as a beige powder (Y=85.5%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[N+](C1C=CC([C:30]([O-])=[O:31])=CC=1)([O-])=O>ClCCl>[CH:30]([NH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:4]=1[C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)=[O:31]
Reactant: NCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=CNCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole (Example C-1) (8.04 g, 30 mmol) in 120 mL dichloromethane was added p-nitrophenylformate (6.01 g, 36 mmol) as a solid. The suspension was stirred for 24 h at room temperature and the solvents removed under reduced pressure. The residue was triturated with ether and filtered to obtain the desired 5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole derivative as a white solid: MS (M+H): 297 (base peak).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:21][C:22]#[CH:23]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][C:22]#[CH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To the degassed solution of piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 2.69 mmol) in acetonitrile (5 mL) was added Na2CO3 (0.854 g, 8.05 mmol) and mixture was stirred for 20 min. The suspension was heated to 50° C. and 3-bromo-propyne (448.65 μl, 4.03 mmol) was added. The solvent was evaporated and the residue was extracted with EtOAc and water. Organic layer was washed with NaCl and NaHCO3 (2×20 ml), dried over K2CO3 and evaporated in vacuum yielding 0.45 g of the title product as yellowish oil.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Li+].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1>O1CCCC1.O>[CH3:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium tert-butoxide (1M in hexanes, 178 mL, 0.178 mol) was added dropwise at room temperature to p-toluoyl chloride (25 g, 0.162 mol) in tetrahydrofuran (150 mL). The mixture was stirred at room temperature overnight and then diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and evaporated to give product as an oil which crystallized on standing (31 g, 98%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[NH2:6].[CH3:14][C:15]1([CH3:26])[O:20][C:19](=[O:21])[C:18](=[CH:22]OC)[C:17](=[O:25])[O:16]1>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[NH:6][CH:22]=[C:18]1[C:17](=[O:25])[O:16][C:15]([CH3:14])([CH3:26])[O:20][C:19]1=[O:21]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 50 °C
Yield: 96.4 %

Procedure:
3-Methoxy-4-methoxycarbonylaniline (14.15 g, 78 mmol) was suspended in isopropanol and heated at 50° C. 2,2-Dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (14.8 g, 80 mmol), (Montatsh. Chem. 1967, 98, 564), was then added in portions over 10 minutes and the mixture was heated at reflux for 30 minutes. The mixture was left to cool to ambient temperature overnight. The precipitate formed was collected by filtration, washed with isopropanol and dried under vacuum to give 5-((3-methoxy-4-methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.2 g, 96%).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]([Cl:23])[N:8]=1)C.O.[OH-].[K+].Cl>C(O)CO>[Cl:23][C:9]1[N:8]=[C:7]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:13][C:12]2=[CH:11][CH:10]=1
Reactant: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A solution of N-[6-chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (1.7 g, 0.00462 mole) in ethylene glycol (25 ml) was refluxed under nitrogen for two hours. To one-half of the solution (0.0023 mole) was added water (2 ml) and solid potassium hydroxide (0.20 g, 0.003515 mole) and the mixture was refluxed for an additional 15 minutes, poured into ice water (100 ml) and acidified with 3N hydrochloric acid solution. The resulting solid was collected by filtration, rinsed with water, dissolved in hot methanol and filtered hot. Addition of water to the cloud point and cooling to room temperature gave a solid which was collected by filtration, washed with water, and dried at 60° C. under high vacuum to give 0.4 g (54% yield) of title compound, mp>250° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:9][C:2]=1[O:1][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)#[N:5]
Reactant: N#Cc1ccc(Nc2nccs2)cc1O
Reactant: BrCc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Nc2nccs2)cc1OCc1nccs1

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-hydroxy-4-(thiazol-2-ylamino)benzonitrile (70 mg, 0.32 mmol) and Cs2CO3 (105 mg, 0.32 mmol) in acetone (4.4 mL) was treated with 2-bromomethylthiazole (57 mg, 0.32 mmol) at RT. Reaction control by TLC showed full conversion after 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/6) in 8 yield (8 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH2:17]([N:19](NCCC)[CH2:20][CH3:21])[CH3:18]>C(O)C>[C:8]([C:7]1[C:2]([NH:3][CH2:2][CH2:7][CH2:6][N:19]([CH2:17][CH3:18])[CH2:20][CH3:21])=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: CCCNN(CC)CC
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Solvent: CCO
Product: CCN(CC)CCCNc1ncc(-c2cc[n+]([O-])cc2)cc1C#N

Procedure:
A mixture of 1 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide and 1.35 g diethylamino-1-propylamine in 50 ml ethanol is refluxed for 4 hours. Subsequently, the mixture is concentrated under vacuum and the oil remaining behind is crystallized first from ethanol/diethyl ether and subsequently from methanol. Yield: 1.3 g (90.9% of the theoretical yield), with a melting point of 132° C.-133° C.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[N:16]=[C:15]([C:36]([OH:38])=[O:37])[CH:14]=1)[CH2:10][CH2:11][CH3:12].[F:39][C:40]([F:44])([F:43])[CH2:41]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>ClCCl.C(N(CC)CC)C>[CH2:9]([C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:21][CH:20]=2)[N:16]=[C:15]([C:36]([O:38][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:37])[CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: OCC(F)(F)F
Reactant: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1cc(C(=O)OCC(F)(F)F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
N-Chlorosuccinimide (400 mg) was added to a stirred solution of 5-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrazole-3-carboxylic acid (682 mg), triethylamine (1.2 g), 2,2,2-trifluoroethanol (248 mg) and triphenylphosphine (891 mg) in dichloromethane (30 ml) by cooling with an ice-bath. After stirring for 15 minutes, triphenylphosphine (262 mg) and N-chlorosuccinimide (133 mg) were added and the mixture was stirred for 30 minutes. After addition of 2N-hydrochloric acid (15 ml) and stirring at room temperature for 30 minutes, the mixture was allowed to separate into layers. The organic layer was washed with water, dried, and concentrated to dryness to give a syrup, which was then purified by column chromatography on silica gel, to give a yellow syrup (460 mg, 58%).
Reaction SMILES: [NH2:1][OH:2].[CH:3]1([O:8][C:9]2[C:10]([O:27][CH3:28])=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16](=[O:19])[CH:15]=[C:14]3[NH:20][CH2:21][C:22](OCC)=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4]1>C(O)C>[CH:3]1([O:8][C:9]2[C:10]([O:27][CH3:28])=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16](=[O:19])[CH:15]=[C:14]3[NH:20][CH2:21][C:22]([NH:1][OH:2])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NO
Reactant: CCOC(=O)CNc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Solvent: CCO
Product: COc1ccc2c(NCC(=O)NO)cc(=O)oc2c1OC1CCCC1
Reaction time: 6 h

Procedure:
Hydroxylamine (0.5 mL, 50% water, 8.2 mmol) was added to a solution of ethyl 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetate (40 mg, 0.11 mmol, Example 8) and ethanol (0.5 mL) and stirred vigorously. After 6 h, the precipitate was filtered, washed with 65% ethanol (2 mL), and dried to give 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)-N-hydroxyacetamide: 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.97 (s, 1H), 7.93 (t, 1H), 7.71 (d, 1H), 7.07 (d, 1H), 4.90 (s, 1H), 4.80 (m, 1H), 3.86 (s, 3H), 3.77 (d, 2H), 1.90-1.46 (m, 8H); MS (ESI): 348.9.