Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C#C.[CH3:7][O:8][CH:9]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[CH2:14][C:13]=2[CH:12]([O:20][CH3:21])[CH2:11][CH2:10]1>O1CCCC1>[CH3:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][C:15]([C:1]#[CH:2])([OH:19])[CH2:14][C:13]=2[C:12]([O:20][CH3:21])=[CH:11][CH:10]=1
Reactant: CC[Mg]Br
Reactant: COC1CCC(OC)C2=C1C=CC(=O)C2
Agent: C#C
Solvent: C1CCOC1
Product: C#CC1(O)CCc2c(OC)ccc(OC)c2C1

Procedure:
Acetylene, purified by passing it first through a dry ice acetone trap, then through concentrated sulfuric acid, was bubbled rapidly through freshly distilled tetrahydrofuran (20 ml) under nitrogen for one hour. Ethylmagnesium bromide (50 ml, 3.15 M in ether, 15.8 mmole) was added slowly. The temperature was maintained between 28°-33° C. by cooling with a water bath. After the complete addition of ethylmagnesium bromide, the passage of the acetylene gas was continued and 1,4-dimethoxy-6-tetralone (XIII) (1.03 g, 5 mmole) in dry tetrahydrofuran (5,0 ml) was added with stirring. After addition, the passage of the acetylene was continued for an extra one hour and the reaction mixture was left stirring at room temperature overnight. The reaction mixture was quenched with saturated oxalic acid and extracted with chloroform. The chloroform extract was washed well with water, dried over anhydrous magnesium sulfate, and evaporated to dryness. The oil residue was triturated with ether to give 1,4-dimethoxy-6-ethynyl-6-hydroxy-5,8-dihydro-(7H)naphthalene (XIV) as a white solid, m.p. 103°-105° C. (ethanol).
Reaction SMILES: C[O-].[Na+].Cl[Cu:5].[CH:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:12]3[N:44]=[C:43]4[N:45]=[C:36]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=54)[N:35]=[C:33]4[NH:34][C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=54)=[N:25][C:23]4=[N:24][C:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=54)=[N:15][C:14]=2[NH:13]3)[CH:11]=1>>[CH:6]1[CH:11]=[C:10]2[C:12]3[N:13]=[C:14]([C:9]2=[CH:8][CH:7]=1)[N:15]=[C:16]1[C:17]2[C:22]([C:23](=[N:24]1)[N:25]=[C:26]1[C:27]4[C:32]([C:33](=[N:34]1)[N:35]=[C:36]1[C:37]5[C:42]([C:43](=[N:45]1)[N:44]=3)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=[CH:19][CH:18]=2.[Cu:5]
Reactant: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Reactant: Cl[Cu]
Agent: C[O-]
Agent: [Na+]
Product: [Cu]
Product: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12

Procedure:
After the addition of sodium methoxide add 1.5 grams pigmentary mono-chloro-copper phthalocyanine. Finally raise the temperature to reflux and reflux 8 hours. After reflux, filter, wash with methanol and then water. The pigment is purified in the manner of Example 7 to give 28 grams of pigmentary alpha copper phthalocyanine.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>O.CO.O1CCCC1>[Cl:15][C:16]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A solution of sodium dithionite (14.0 g, 20.0 mM) and sodium carbonate (6.7 g) in 200 mL of water was slowly added to a solution of methyl 2-chloro-3-nitrobenzoate (6.0 g, 27.9 mM) in 40 mL methanol and 40 mL of tetrahydrofuran at 25° C. over 30 minutes. The mixture was stirred at room temperature for an additional 30 minutes, then extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 1.2 g (33%) of methyl 2-chloro-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
Reaction SMILES: [CH3:1][CH:2]([C:8]([OH:10])=[O:9])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Na+]>O>[CH2:15]([O:14][C:12]([NH:4][CH:3]([C:5]([OH:7])=[O:6])[CH:2]([CH3:1])[C:8]([OH:10])=[O:9])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)O)C(N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)C(NC(=O)OCc1ccccc1)C(=O)O
Yield: 100.8 %

Procedure:
Using a similar method to above 3-methyl-D,L-aspartic acid (10.0 g, 67 mmol), benzyl chloroformate (12 ml, 100 mmol) in 50% NaOH (16.7 g, 208 mmol) in water (125 ml) yielded N-benzyloxycarbonyl-3-methyl-D,L-aspartic acid 19.0g as a low melting solid. 1H NMR (90 MHz, CDCl3 /d6DMSO): δ1.1 (3,d), 2.9 (1,dt), 4.4 (1,m), 4.95 (2,s) 5.9 (1,bd) 7.2 (5,6) 7.9 (1,bs).
Reaction SMILES: O[CH2:2][C:3]#[N:4].[CH2:5]([NH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[CH2:5]([NH:17][CH2:2][C:3]#[N:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N#CCO
Reactant: CCCCCCCCCCCCN
Solvent: CO
Product: CCCCCCCCCCCCNCC#N
Reaction time: 16 h

Procedure:
In a flask of 500 ml provided with a magnetic stirrer, 4.56 gr of hydroxyacetonitrile (0.08 mol) were mixed at room temperature with 16.3 gr of dodecylamine (0.088 mol) in 250 ml of methanol. The mixture was allowed to stand for 16 hours at room temperature and methanol was evaporated. The obtained liquid was distilled under 10-2 mm Hg. The fraction distilling between 106° and 116° crystallizes after cooling.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.[C:27]12([CH2:37][NH2:38])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=[C:2]([NH:38][CH2:37][C:27]23[CH2:36][CH:31]4[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]4)[CH2:34]2)[CH2:28]3)[N:7]=1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(NCC34CC5CC(CC(C5)C3)C4)n2)cc1

Procedure:
To a solution of 4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and 1-(1-adamantyl)-methanamine (7.2 mg, 0.072 mmol). The mixture can be microwaved at 120 degrees for 20 minutes. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [OH:1][C:2]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[N:8]OC)[C:5]([OH:7])=[O:6].[H][H]>N.[C].[Rh]>[OH:1][C@@:2]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([OH:13])=[O:12])[CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[OH:1][C@:2]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([C:11]([OH:13])=[O:12])[CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CON=C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Agent: [Rh]
Agent: N
Product: N[C@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Product: N[C@H](C[C@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
0.264 g (0.824 mmol) of 4-hydroxy-4-(3-indolylmethyl)-2-methoxyiminoglutaric acid was dissolved in 10 ml of aqueous 28% ammonia. 0.18 g of 5% rhodium carbon (dry product) was added and the mixture stirred at a hydrogen pressure of 7.5 atmospheres for 18 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure, to obtain the residue. The resulting residue was analyzed by NMR, and a mixture of 0.115 g (0.395 mmol; yield, 48%) of (2S, 4S)/(2R, 4R)-4-hydroxy-4-(3-indolylmethyl)-2-aminoglutaric acid (monatin) and 0.065 g (0.223 mmol; yield, 27%) of (2S, 4R)/(2R, 4S)-4-hydroxy-4-(3-indolylmethyl)-2-aminoglutaric acid was found to have been generated.
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[F:10][C:11]1[CH:18]=[C:17]([N:19]([CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:30]4=[O:45])[CH2:20][C:21]#[CH:22])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].C([O-])(=[O:48])C.[Na+]>C(O)(=O)C.C(O)(C)(C)C>[F:10][C:11]1[CH:18]=[C:17]([N:19]([CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:43])[CH3:42])[C:30]4=[O:45])[CH2:20][C:21]#[CH:22])[CH:16]=[CH:15][C:12]=1[C:13]([OH:48])=[O:14]
Reactant: CC(=O)[O-]
Reactant: C#CCN(c1ccc(C=O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: C#CCN(c1ccc(C(=O)O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium chlorite (0.28 g) and sulphamic acid (0.24 g) were added portionwise to a stirred mixture of o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzaldehyde (0.47 g), 0.2M sodium acetate in acetic acid buffer (pH 4, 70 ml) and tert-butanol (70 ml). The mixture was stirred at ambient temperature for 24 hours. The mixture was partitioned between methylene chloride and a saturated aqueous sodium dihydrogen phosphate solution. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography to give o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid (0.41 g);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:19](Cl)(=[O:21])=[O:20])[C:5]([C:8]2[C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O>[C:23]1([S:19]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[S:15]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:17])=[O:16])(=[O:21])=[O:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1-c1ccc(Cl)cc1S(=O)(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=S(=O)(c1ccccc1)c1cc(Cl)ccc1-c1ccc(Cl)cc1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 154.8 %

Procedure:
Inside a glove box, a 125 mL round-bottom flask equipped with a stirring bar, reflux condenser, and gas inlet was charged with 4,4′-dichlorobiphenyl-2,2′-disulfonyl dichloride (15.4 g, 36.7 mmoles), benzene (25 mL, 280 mmoles), and anhydrous nitromethane (75 mL). Aluminum chloride (11 g, 81 mmoles) was added and the mixture stirred until dissolved under nitrogen. The solution was heated to 100° C. for 8 hours. The solution was cooled to room temperature and poured onto 200 g ice mixed with 100 mL hydrochloric acid. The mixture was extracted several times with dichloromethane. The organic extracts were washed with water, dried with sodium carbonate, filtered to give a dark solution. The solution was treated with decolorizing carbon and heated to a reflux, then filtered through filter aid, evaporated, and the solids dried at 150° C. in a vacuum oven for 8 hr to give 18.02 g (97% crude yield). The mixture was purified by column chromatography using silica gel and dichloromethane (Rf 0.28) to give 14.3 g (77% yield) of 2,2′-bis-benzenesulfonyl-4,4′-dichlorobiphenyl. The solids were recrystallized from xylenes to give 13.08 g (71%). 1H NMR (DMSO-d6): 6.96 (d, 8.2 Hz, 2H), 7.55 (bs, 4H), 7.56 (m, 8.1 Hz, 4H), 7.69 (m, 2H), 7.74 (dd, 8.2, 2.2 Hz, 2H), 8.13 (d, 2.2 Hz, 2H). 13C NMR (CDCl3): 128.42 (4CH), 129.14 (4CH), 129.58 (2CH), 132.21 (2CH), 133.84 (2CH), 134.13 (2CH), 134.68 (2C), 135.61 (2C), 140.42 (2C), 141.42 (2C). MS (M+H+): m/e 502.99 (100%), 504.99 (75%), exact mass for C24H17O4Cl2S2, 502.99 (100%), 504.99 (72.9%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][CH:20]=1)[O:17][C:13]1([CH2:16][CH2:15][CH2:14]1)[CH2:12][C:11]2=[O:21].N1([CH2:31][OH:32])C2C=CC=CC=2N=N1>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][CH:20]=1)[O:17][C:13]1([CH2:14][CH2:15][CH2:16]1)[C:12]([CH2:2][OH:4])([CH2:31][OH:32])[C:11]2=[O:21]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC2(CCC2)Oc2ccc(Br)cc21
Reactant: OCn1nnc2ccccc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2OC2(CCC2)C1(CO)CO
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
A solution of potassium tert-butoxide (441 mg, 3.93 mmol) in THF (5 mL) was added to a suspension of 6-bromospiro[chromene-2,1′-cyclobutan]-4(3H)-one (500 mg, 1.87 mmol) and 1H-benzotriazole-1-methanol (586 mg, 3.93 mmol) in THF (5 mL) over 10 minutes in a dry ice-acetone bath under an argon atmosphere. The mixture was stirred for 0.5 hours in an ice bath, and then diluted with EtOAc (10 mL). After stirring for 0.5 hours, the mixture was filtered off. The filtrate was washed with 0.2 M aqueous NaOH (two times), water and brine, dried over MgSO4 and silicagel, filtered off. The filtrate was evaporated to give crude 6-bromo-3,3-bis(hydroxymethyl)spiro[chromene-2,1′-cyclobutan]-4(3H)-one (641 mg).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN1CCC(Cc2ccccc2)CC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a solution of 4-benzyl-1-(3-hydroxypropyl)piperidine (1.0 g, 4.29 mmol) in CH2Cl2 (20 mL) were added TEA (1.2 mL, 8.57 mmol) and dropwise a solution of p-toluenesulfonyl chloride (1.22 g, 6.4 mmol) in CH2Cl2 (10 mL). The resulting solution was stirred at 25° C. for 2 h then diluted with CH2Cl2 (60 mL) and washed with NH4Cl (2×100 mL), dried and concentrated in vacuum to afford the crude intermediate, which was purified by trituration with EtOAc (10 mL) to give the title compound as a white solid (0.63g, 38%), mp 143-145° C. 1H-NMR (CDCl3): 1.2-1.45 (m, 2H), 1.65-1.85 (m, 3H), 2.319 (s, 3H), 2.502 (d, J=7.2 Hz, 2H), 2.6-2.8 (m, 2H), 3.338 (t, J=12.6 Hz, 2H), 3.875 (d, J=12.6, 2H), 4.277 (t, J=8.1 Hz, 2H), 4.421 (t, J=8.4 Hz, 2H), 7.064 (d, J=7.2 Hz, 2H), 7.122 (d, J=7.8 Hz, 2H), 7.15-7.30 (m, 3H), 7.76 (d, J=7.8 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[N:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[S:25][CH:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[N:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (65 mg), [4-(trifluoromethyl)-1,3-thiazol-2-yl]methanol (73 mg) and triphenylphosphine (156 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (140 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from 2-propanol-diisopropyl ether to give the title compound (42 mg).
Reaction SMILES: C(O)C.[Na].[CH2:5]([N:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25](OCC)(=[O:31])[C:26](OCC)=[O:27]>C(O)(=O)C>[CH2:5]([N:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:26]([OH:27])[C:25]([OH:31])=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1Cc1ccccc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Into a 20L three-necked flask, 2.7L of ethanol was put, and 139.2 g (6.05 moles) of small cuts of metallic sodium were gradually added thereto with stirring at room temperature. After the addition was completed, the mixture was stirred under reflux until the metallic sodium became dissolved completely. The mixture formed was cooled to room temperature, and 770.7 g (2.760 moles) of the diethyl N-benzyliminodiacetate and 405.8 g (2.775 moles) of diethyl oxalate were added thereto, which were then stirred under reflux for 8 hours. After the reaction was completed, the reaction product was left to cool, and its pH was adjusted to 5.5 by adding 4.5L of acetic acid. The precipitate formed was collected by filtration and washed with water. This precipitate was washed with acetone to obtain 532.8 g of diethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (yield: 57.9%), having a melting point of 143.5 to 145.0° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][N:4]3[C:3]([CH3:8])=[C:2]([Br:1])[C:6]([CH3:7])=[N:5]3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1n[nH]c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C)c1Br

Procedure:
Protocol T was followed using 4-Bromo-3,5-dimethyl-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.95–7.1 (m, 2H), 6.84–6.92 (dd, 2H), 4.90 (s, 2H), 3.62–3.82 (m, 4H), 3.02–3.12 (m, 4H), 2.24–2.34 (d, 6H). 13C NMR (400 MHz, CDCl3): 165, 158.4, 156.6, 150.6, 146.8, 141.4, 119, 115.6, 115.2, 52.6, 51.6, 50.4, 45.2, 42.2, 14.8, 12.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].Br[C:14]#[N:15]>C(O)C.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[NH:12][C:14]([NH2:15])=[N:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: N#CBr
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2[nH]c(N)nc2c1
Temperature: 25 °C

Procedure:
3.4 g (20.5 mmol) of methyl 3,4-diaminobenzoate was dissolved in a mixture of 50 mL of ethanol and 10 mL of H2O. To this stirring solution 2.6 g (24.5 mmol) of BrCN was added in one portion, and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 10 mL, then washed with ethyl acetate (20 mL). The EtOAc layer was extracted with water (20 mL). The combined water extracts were neutralized with saturated NaHCO3 solution to ˜pH 8, and the resulting suspension was extracted with EtOAc (50 mL). The organic layer was washed with water and brine solution, dried with Na2SO4, and evaporated to give 2-amino-1H-benzoimidazole-5-carboxylic acid methyl ester, which was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[F:9].C([O:12][C:13]([Sn])=[CH2:14])C.Cl.C1C[O:20][CH2:19][CH2:18]1>>[C:19]([C:5]1[CH:6]=[CH:7][C:2]([C:13](=[O:12])[CH3:14])=[C:3]([F:9])[CH:4]=1)(=[O:20])[CH3:18]
Reactant: C=C([Sn])OCC
Reactant: C1CCOC1
Reactant: Fc1cc(Br)ccc1Br
Agent: Cl
Product: CC(=O)c1ccc(C(C)=O)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Into a 100 mL single neck flask were placed 1,4-dibromo-2-fluorobenzene (2.35 g, 9.2 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.645 g, 0.92 mmol), tributyt (1-ethoxyvinyl)tin (10 g, 27.7 mmol), in THF (50 mL), and the mixture was heated at reflux while stirring for 18 hours. The reaction was cooled to room temperature and poured into 5N HCl (20 mL). The product was extracted with EtOAc and the organic layer was separated and washed twice with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 90:10 to provide the intermediate title compound, 1-(4-acetyl-2-fluorophenyl)ethan-1-one, (1.65 g, 100%) as a solid. Electron spray M.S. 180.9 (M*)
Reaction SMILES: [CH:1]([NH:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)([CH3:3])[CH3:2].CN1CCOCC1.[ClH:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH2:31][NH2:32])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:29][CH2:30][CH2:31][NH:32][C:6](=[O:8])[C@@H:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:24][CH:23]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](NC(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
A suspension of (S)-2-isopropylamino-4-methyl-pentanoic acid (433 mg, 2.50 mmol), N-methylmorpholine (0.275 mL, 2.50 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (750 mg, 2.52 mmol) in dry DMF (12 mL) was treated with Triton® B (2.27 mL, 4.99 mmol, 40 wt percent solution in methanol, Aldrich, Milwaukee, Wis.), a clear solution was obtained and cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.940 g, 2.50 mmol) was then added. After stirring at 0° C. for 90 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 100 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (100 mL), brine (100 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 368 mg (35%) of the pure titled compound as a white foam: mp 100-103° C.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[ClH:18].[C:1]1([C:7]2[S:8][N:14]3[CH:13]=[CH:12][N:11]=[C:10]3[N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: S=C(Nc1ncc[nH]1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: c1ccc(-c2nc3nccn3s2)cc1

Procedure:
To a solution of 0.4 g. of 2-phenylthiocarbonylaminoimidazole [(IV), R = phenyl] in 20 ml. of chloroform there is added dropwise, at 20°-25°C., a solution of 0.165 ml. of sulfuryl chloride in 5 ml. of chloroform. After two hours the precipitate which forms is filtered, dissolved in methanol, and precipitated from ether to yield 2-phenyl-1,2,4-thiadiazolo-[2,3-a]-imidazole hydrochloride.