Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[N:32]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:34][CH:33]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid (1.25 g) in methanol (20 ml) were added 4-methanesulfonylbenzylamine hydrochloride (1.6 g) and triethylamine (2.5 ml), and the mixture was stirred at 50° C. for 18 hrs. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, and dried. The solvent was evaporated under reduced pressure. 4N Hydrochloric acid ethyl acetate solution (10 ml) was added to the residue, and the mixture was stirred at room temperature for 18 hrs. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound (1.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[OH-].[NH4+:15].II.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:15]
Reactant: [NH4+]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(C#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3-Methoxy-2-nitrobenzaldehyde (50.2 g, 277 mmol) was dissolved in THF (300 mL) and 28% aqueous ammonium hydroxide (1000 mL) and iodine (100.7 g, 396 mmol) were slowly added. The mixture was stirred 2 h at rt, then Na2SO3 (21 g, 166 mmol) was added and the mixture stirred vigorously for 20 min. The brown-colored mixture became colorless and a precipitate formed. The solid was collected by vacuum filtration, washed well with water and dried briefly under suction to give the title compound (43 g, 87%): 1H NMR (DMSO-d6) δ: 3.94 (3H, s), 7.64 (1H, dd), 7.75-7.78 (2H, m).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=[O:8]>>[CH2:1]([O:5][C:6](=[O:10])[C:7]([Cl:9])=[O:8])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CO
Product: CC(C)COC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutanol (191 μL, 2.1 mmol, 1.0 eq.) was added dropwise over 5 minutes to oxalyl chloride (350 μL, 4.14 mmol, 2.0 eq.) at 0° C., and the resulting mixture was stirred at room temperature for 2 hours. The excess oxalyl chloride was removed by rotary evaporation (40° C., 40 mmHg) and used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:28])[C:18]=2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Product: Cc1nc2c(N)nc3c(c2n1CCCCNC(=O)N1CCOCC1)CCCC3
Yield: 79.7 %

Procedure:
Using the general method of Example 143, 1-(4-aminobutyl)-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with 4-morpholinecarbonyl chloride (0.43 mL, 3.7 mmol) to provide 1.14 g of N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamide as an off white solid, m.p. 133.6-134.6° C. Analysis: Calculated for C20H30N6O2.1.1 H2O: % C, 59.12; % H, 7.99; % N, 20.68. Found: % C, 58.77; % H, 7.53; % N, 20.46.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[C:24]1([C@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:32][C@@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:31])=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: C[C@@H](NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2)c1ccccc1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and (1R)-1-phenylethylamine (43.4 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[(1R)-1-phenyl-1-ethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.8 mg).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[N:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1>[O-]CC.[Na+].C(O)C>[C:1]1([S:7][C:9]2[N:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1cnc(Sc2ccccc2)nc1
Yield: 70 %

Procedure:
A solution of thiophenol (60 mmol) in 0.43 M sodium ethoxide (150 ml) and a solution of 2,5-dichloropyrimidine (60 mmol) in absolute ethanol (90 ml) were mixed and heated under reflux for 2 h. The cold mixture was then filtered, the filtrate evaporated, the residual material dissolved in chloroform (150 ml), the chloroform solution washed with 2 M NaOH (2×15 ml) and water (15 ml) and the dried (MgSO4) solution evaporated leaving an oily material which crystallized in the cold; yield 70%, m.p. 47° C. (ligroin). 1H NMR (CDCl3): δ7.4(Ph), 8.33 (H-4, H-6).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[N+:16]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH2:1])([O-:18])=[O:17]
Reactant: [N-]=[N+]=NCCCCCOc1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCCCCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
To a solution of 1-(5-azido-pentyloxy)-3-nitro-benzene (3.12 g, 12.5 mmol) in 50 mL THF and 1 mL H2O was added triphenylphosphine (3.27 g, 12.5 mmol). The reaction mixture was stirred at room temperature for 48 hours and then was partitioned with ethyl acetate and water. The aqueous solution was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated to give a yellow liquid, which was purified by silica gel column chromatography to give 5-(3-nitro-phenoxy)-pentylamine (2.75 g, 12.3 mmol, 98%) as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:24]([O:23][CH2:22][CH2:21][N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:12])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred suspension of ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate (0.85 g, 3.33 mmol) in anhydrous N,N-dimethylformamide (8 mL) under nitrogen atmosphere was added in one portion sodium hydride (60% in mineral oil, 0.16 g, 4.00 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 h, and then (2-bromoethoxy)(tert-butyl)dimethylsilane (0.86 mL, 4.01 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h, and then partitioned between ethyl acetate (100 mL), water (35 mL) and brine (35 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-30% ethyl acetate in hexanes to afford the title compound as a colorless solid in 79% yield (1.09 g): 1H NMR (300 MHz, CDCl3) δ 6.13 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.85-3.69 (m, 6H), 3.41 (t, J=5.2 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H): MS (ES+) m/z 413.4 (M+1).
Reaction SMILES: S=[C:2]1[NH:7][C:6]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:5]=2[C:4](=[O:17])[NH:3]1>CO.[Ni]>[N:7]1[C:6]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:5]=2[C:4](=[O:17])[NH:3][CH:2]=1
Reactant: O=c1[nH]c(=S)[nH]c2c1CCCc1ccccc1-2
Agent: [Ni]
Solvent: CO
Product: O=c1[nH]cnc2c1CCCc1ccccc1-2

Procedure:
A solution of Example 118A (170 mg, 0.7 mmol) in methanol (15 mL) was treated with Raney nickel (slurry in H2O, 1 spatula) and refluxed for 16 hours. The mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated under vacuum to provide the title compound. 1H NMR (CD3OD) δ 2.24 (t, 2H), 2.40 (t, 2H), 2.59 (t, 2H), 7.27-7.34 (m, 1H), 7.36-7.42 (m, 2H), 7.60-7.66 (m, 1H), 8.14-8.18 (m, 1H). MS (M+H)+ m/z 213
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:34][C:35]1[C:40]([Pb+3])=[C:39]([CH3:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:34][C:35]1[C:40]([CH:10]2[C:11](=[O:13])[CH2:12][CH:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH2:8][C:9]2=[O:14])=[C:39]([CH3:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=1
Reactant: O=C1CC(=O)CC(C2CCOCC2)C1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C

Procedure:
To a mixture of 5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione (196 mg; 1 mmol) and 4-dimethylaminopyridine (610 mg; 5 mmol) is added dry chloroform (4 ml) under an atmosphere of nitrogen, and the mixture is stirred at room temperature until all the solids are dissolved. To this solution is then added dry toluene (2 ml) and a solution of 3,5-dimethylbiphen-4-yllead triacetate (1.2 mmol) in chloroform. The reaction mixture is heated under reflux for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane (2×40 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(3,5-dimethylbiphen-4-yl)-5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc([N+](=O)[O-])cc5)cc4)cc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(N)cc5)cc4)cc3)cc2)cc1

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 25.00 g of 1,4-bis(4-(4-nitrophenylmethyl)phenylmethyl)benzene was dissolved in 400 milliliters of tetrahydrofuran, 2.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) was added and contacted with hydrogen gas while cooled with water at a normal pressure and then stirred. By recrystallizing the concentrate from a tetrahydrofuran solvent, 21.13 g of a diamino compound according to the invention, that is, 1,4-bis(4-(4-aminophenylmethyl)phenylmethyl)benzene was obtained. Melting point was from 177.9° to 179.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl>O.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)cc1NN
Reaction time: 0.75 h
Yield: 152.2 %

Procedure:
To a stirred suspension of 5-chloro-2-methylaniline (1.436 g, 10.14 mmol, 1. eq) in 10 mL water at 0° C. was added 10 mL concentrated hydrochloric acid. To this reaction mixture was added dropwise a solution of sodium nitrite (0.791 g, 11.5 mmol, 1.13 eq) in 5 mL water. The reaction mixture was stirred at 0° C. for 2 hours while tin chloride dihydrate (5.8826 g, 25.839 mmol, 2.55 eq), dissolved in 8 mL concentrated hydrochloric acid, was slowly added. Water was added as needed to maintain the stirring while solids formed. The reaction was kept at 0° C. for 45 minutes. The white solids were filtered and rinsed with two 50 mL portions of diethyl ether, then dried under vacuum to provide 1.49 g (76%) of (5-chloro-2-methylphenyl)hydrazine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.08 (s, 3H), 7.98 (s, 1H), 7.13 (d, 1H), 6.97 (s, 1H), 6.91 (d, 1H), 2.14 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:18]([S:25][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 2-bromothiazole-4-carboxylate (2.0 g, 8.40 mmol) in DMF (15 mL) was added K2CO3 (1.16 g, 8.40 mmol) followed by benzyl mercaptan (1.07 g, 8.40 mmol) in DMF (5 mL) over 20 min. Upon completion of addition, the reaction mixture was stirred at RT for 16 h. After this time, the reaction mixture was diluted with water and extracted in EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel chromatography (10% EtOAc in hexane) to provide ethyl 2-(benzylthio)thiazole-4-carboxylate (2.0 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.42 (s, 1H); 7.47-45 (m, 2H); 7.36-7.28 (m, 3H); 4.52 (s, 2H); 4.31 (q, 2H, J=7.2 Hz); 1.31 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9](O)=O)[CH:5]=[CH:4][N:3]=1.CS(Cl)(=O)=O.[NH3:17]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]#[N:17])[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: Cc1c(C(=O)O)ccnc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(C#N)ccnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chloro-3-methyl-4-pyridinecarboxylic acid (30 g; 174 mmol) was dissolved in pyridine (250 ml) and cooled to 0° C. Methanesulfonyl chloride (13.6 ml) was then added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. NH3 (gas) was added under pressure and the reaction mixture was stirred at room temperature for 1 h. After the reaction had reached completion, the excess NH3 was removed in vacuo. The reaction mixture was then cooled to 0° C., methanesulfonyl chloride (140 ml) was added and the reaction mixture stirred at room temperature overnight. The mixture was then poured into 0.1 M HCl (200 ml) at 0° C. (with care), and adjusted to pH=7 with 1 M NaOH. The reaction mixture was extracted with EtOAc (2×100 ml), washed with brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (Biotage flash purification system; gradient: EtOAc/heptane from 15/85 to 30/70). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 12.6 g of D1.
Reaction SMILES: [OH:1][C:2]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:19]=[C:18]([O:31][CH2:32][O:33][CH3:34])[C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:35]([O:1][C:2]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH2:28][O:29][CH3:30])[CH:19]=[C:18]([O:31][CH2:32][O:33][CH3:34])[C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
A liquid mixture of 13.75 g of the 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone, 40 ml of acetic anhydride and 40 ml of anhydrous pyridine was stirred at room temperature to effect a reaction. Then, the reaction mixture was added into 200 ml of a cooled saturated solution of sodium hydrogencarbonate and the mixture was stirred at 0° C. for 30 minutes. The mixture was extracted with 1500 ml of ether, and the ether layer was washed with water, shaken with a saturated aqueous solution of copper sulfate, washed with water, shaken with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the residue was subjected to the silica gel column chromatography (300 g of 230-400 mesh silica gel, n-hexane/ethyl acetate=4/1, 0.3 kg/cm2). Fractions of 100 ml were collected and the 35th to 37th fractions were combined to obtain 12.58 g (yield=84.0%) of 2'-acetoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[CH3:15][N:16]([CH3:17])[CH2:18][CH2:19][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 190 °C

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.29 mmol), dimethylamino ethyl chloride (0.37 g, 2.58 mmol) and potassium carbonate (0.534 g, 3.87 mmol) were dissolved in 3 mL of dry dimethylformamide. The reaction mixture was heated in a Biotage Initiator series microwave at 190° C. for 1 hour. The reaction mixture was poured into 300 mL of ethyl acetate and 50 of mL brine. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 7.76 (s, 1H); 7.72 (s, 1H); 4.22 (t, 2H); 2.94 (s, 3H); 2.86 (s, 3H); 2.74 (t, 2H); 1.29 (s, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[C:32](=[O:36])[N:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)=[CH:26][CH:27]=2)[CH:35]=[N:34]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ncn1-c1ccc(Cn2ccnn2)cc1
Product: C[C@@H](n1ncn(-c2ccc(Cn3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1H-1,2,3-triazol-1-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 29).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:3]\[CH2:4][CH2:5][S:6][CH2:7][P:8](=[O:15])([O:12]CC)[O:9]CC>C1(C)C=CC=CC=1>[CH3:1]/[C:2](/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:3]\[CH2:4][CH2:5][S:6][CH2:7][P:8](=[O:9])([OH:12])[OH:15]
Reactant: CCOP(=O)(CSCC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OCC
Solvent: Cc1ccccc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCSCP(=O)(O)O
Yield: 45.6 %

Procedure:
Diethyl [(E,E)-4,8,12-trimethyl-3,7,11 -tridecatrienyl]thiomethylphosphonate (0.256 g, 0.636 mmol) was deprotected in a similar fashion as that described in Step 2 of Example 2. The reaction mixture was added toluene (3 mL), then evaporated in vacuo. This process was repeated two more times. The final residue was treated with diluted hydrochloride acid (0.1N) at 0° C., then extracted with ethylacetate. The extract was washed with water the three time (3×10 ML). After drying and filtration, filtrate was concentrated in vacuo to give the title compound (0.1 g, 0.29 mmol, 45%) as a gum.