Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc2[nH]nc(C)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2C1CCCCO1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (28.5 g), 3,4-dihydro-2H-pyran (23.7 mL) and p-toluenesulfonic acid monohydrate (6.8 g) in THF (800 mL) was stirred at r.t. until the reaction was complete. The mixture was poured into water (1.5 l) and extracted with ethyle acetate (600 mL). The organic phase was dried over magnesium sulfate and concentrated in a vacuo. The crude product was purified by silica gel chromatography (heptane/ethyl acetate gradient). 37.8 g (98%) of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].[ClH:21].O1CCOCC1>O1CCOCC1>[ClH:21].[C:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(C#N)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of O1-tert-butyl O4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (0.4 g, 1.41 mmol) in 1,4-dioxane (10 mL) was added HCl-dioxane (4 M, 5 mL) solution. The resulting mixture was stirred at rt for 30 minutes. After completion of reaction (by TLC), solvent was evaporated to obtain the product as a solid (0.28 g). MS: 183.27 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH:29]=O)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH2:33]([N:35]([CH2:36][CH3:37])[CH2:29][CH2:28][N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:31])([F:32])[F:1])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:24]=[N:25]1)[CH3:34]
Reactant: CCNCC
Reactant: O=CCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(CC)CCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 40 °C

Procedure:
To a reaction vial charged with 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol 150 (0.250 g, 0.540 mmol) was added 4 mL DCM to give a slurry. Next, Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 0.2522 g, 0.594 mmol) was added portion-wise and the reaction mixture was stirred at room temperature with LCMS monitor. Full conversion was seen after 30 minutes reaction time. The reaction mixture was diluted with water to give a white precipitate. This solid was collected by vacuum filtration, washed with EtOAc and dried on high vacuum to give the intermediate aldehyde, 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanal. To a suspension of the aldehyde (0.160 g, 0.347 mmol) and diethylamine (0.127 g, 1.74 mmol) in 1.0 ml of DCM was added acetic acid (0.0198 mL, 0.347 mmol) and the reaction mixture was heated at 40 C for 1 hour. Finally sodium cyanoborohydride (0.0350 g, 0.556 mmol) was added in portions. The reaction mixture was heated at 40° C. for 45 minutes with complete conversion to product as determined by LCMS. The cooled reaction mixture was diluted with DCM, washed with water and saline, and concentrated to a solid which was purified by RP-HPLC to give 484. MS: (ESI+)=518.2
Reaction SMILES: I[CH2:2][CH2:3][C:4]([C:7]([C:10]([S:13]([O:15][Na])=[O:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5].[OH-].[K+]>C(O)C>[CH2:2]=[CH:3][C:4]([C:7]([C:10]([S:13]([OH:15])=[O:14])([F:11])[F:12])([F:8])[F:9])([F:6])[F:5]
Reactant: O=S(O[Na])C(F)(F)C(F)(F)C(F)(F)CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CC(F)(F)C(F)(F)C(F)(F)S(=O)O
Temperature: 20 °C
Yield: 88.8 %

Procedure:
The above ICH2CH2(CF2)3SO2Na wet solid was dissolved in ethanol and treated with 8.7 g KOH (MW=56, 85%, 0.132 mol) at room temperature, then the mixture was reacted at 50° C. for 8 hrs to precipitate a solid (KI). The reaction mixture was cooled to 20° C. and filtered to remove solids. No significant change in 19F NMR was observed. The solvent was stripped and the resulting solid was acidified with 2N H2SO4 to a pH<2. The acidified solution was extracted with t-butylmethyl ether (three times, 100 mL each) and the combined ether solution was dried over MgSO4. Finally, the solution was filtered and the solvent was stripped to yield 21.5 g (MW=242, 88.8 mmol) desired semisolid product, CH2═CH(CF2)3SO2H, which is soluble in water. The structure of the product was confirmed by NMR analyses, 19F NMR, −115 (dxt, 2F, ═CHCF2-), −125 (txm, 2F), −127 (t, 2F, —CF2SO2H). 1H NMR, 4.4˜5.6 (m) ppm, indicating no more ICH2CH2— signal. The isolated yield is ˜88.8% from ICH2CH2CF2CF2CF2I.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:32])[CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:10][CH2:9]1)=[O:7])[CH3:4].[CH2:33](Br)[CH2:34][CH3:35]>CN(C)C=O>[CH2:3]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([O:32][CH2:33][CH2:34][CH3:35])[CH2:16][N:17]2[C:18]3[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=3[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=3)[CH2:12][CH2:13]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1CCN(CC(O)CN2c3ccccc3CCc3ccccc32)CC1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC(CN1CCC(C(=O)OCC)CC1)CN1c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
Sodium hydride (60% oil suspension, 0.108 g, 2.7 mmol) was added to a stirred solution of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxy-propyl)-4-piperidinecarboxylic acid ethyl ester (1.1 g, 2.7 mmol) in dry N,N-dimethylformamide (7.5 ml). Propylbromide (0.7 g, 5.68 mmol) was added dropwise to the ice-cooled stirred solution and the reaction mixture was left at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in toluene (20 ml), washed with water (3×10 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of toluene, ethyl acetate and triethylamine (35:6:1) as eluent to give 0.11 g (9%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-propoxypropyl)-4-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:14]2[N:15]=[C:11]([C:10]3[C:2]([CH3:1])=[N:3][N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=34)[S:12][C:13]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccc(F)cc1
Yield: 67.7 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (500 mg, 1.2 mmol) produced in Example 15-B(i), (4-fluorophenyl)boronic acid (480 mg, 3.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (75 mg, 0.091 mmol), cesium carbonate (700 mg, 2.2 mmol), water (2 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B(iii), the title compound (310 mg, 73%) was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2](/[CH:7]=[CH:8]\[CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[K+:22].C(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([O-:6])=[O:5].[K+:22]
Reactant: CC(C)=CCCC(C)C/C=C\C(C)=CC(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)CC=CC(C)=CC(=O)[O-]

Procedure:
To a solution of 0.5 g. of trans/cis 3,7,11-trimethyldodeca-2,4,10-trienoic acid in 15 ml. of benzene is added with stirring an equivalent amount of potassium bicarbonate. The mixture is stirred until the evolution of carbon dioxide ceases and then evaporated to yield potassium 3,7,11-trimethyldodeca-2,4,10-trienoate.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[C:27]([I:41])=[C:28]([CH2:34][CH:35]([CH2:39][CH3:40])[C:36]([OH:38])=[O:37])[C:29]([I:33])=[CH:30][C:31]=1[I:32])=[O:24])=[O:16]>CC(N(C)C)=O>[CH2:39]([CH:35]([CH2:34][C:28]1[C:29]([I:33])=[CH:30][C:31]([I:32])=[C:26]([NH:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15](=[O:16])[CH2:14][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:27]=1[I:41])[C:36]([OH:38])=[O:37])[CH3:40]
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CCl)c1I)C(=O)O
Reactant: C1CNCCNCCNCCN1
Solvent: CC(=O)N(C)C
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN2CCNCCNCCNCC2)c1I)C(=O)O
Yield: 58.8 %

Procedure:
According to the procedure described in Example 5, 171.3 g of 1,4,7,10-tetraazacyclododecane (1,00 mol) in 500 ml of DMA are reacted with 190 g of 3-[[6-[(chloroacetyl) amino]-1-oxohexyl]amino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid (prepared according to the procedure described in Example 2) (0,25 mol) in 250 ml of DMA. 155 g of α-ethyl-2,4,6-triiodo-3-[[1-oxo-6-[(1,4,7,10-tetraazacyclododec-1-yl-acetyl)amino]hexyl]amino]benzenepropanoic acid (0.147 mol) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[N:7]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:6]=2[CH:28]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[N:7]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:6]=2[CH:28]=1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCNC2)nc2ccc(Cl)cc21

Procedure:
((R)-tert-Butyl 3-(6-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (32C) (0.135 mmol, 0.055 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The reaction was then concentrated and dried in-vacuo affording (R)-6-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (32D) as a tan oil that was used directly in the next step without further purification. ESI-MS: m/z 308.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([CH3:8])[N:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([CH:22]=[O:23])[N:4]([CH3:8])[N:3]=1
Reactant: Cn1nc(Br)nc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nc(Br)nc1C=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To a solution of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (500 mg, 2.08 mmol, Eq: 1.00) in tetrahydrofuran (5 ml) was added dropwise at −45° C. under argon atmosphere n-butyllithium 1.6 M in hexane (1.56 ml, 2.49 mmol, Eq: 1.2). The resulting mixture was stirred for 30 minutes at −45° C. and was then cooled to −70° C. Then dimethyl formamide (197 mg, 209 μl, 2.7 mmol, Eq: 1.3) was added dropwise. After 15 minutes the cooling bath was removed and the mixture was allowed to reach 25° C. The mixture was stirred for additional 2 hours at 25° C. The mixture was poured on water and extracted twice with ethyl acetate, the organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtrated and evaporated, affording 5-bromo-2-methyl-2H-[1,2,4]triazole-3-carbaldehyde (218 mg/55.3%) as an orange semi solid. MS: m/e=189 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH:14]1[C:27]2[C:26](=O)[C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:26]3[C:25](=[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]4=[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:27]4=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(N)c1cccc(Br)c1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1cccc(-c2cnc3c4ccccc4c4ccccc4c3n2)c1

Procedure:
First, into a 500-mL three-neck flask were put 2.5 g of 1-(3-bromophenyl)ethane-1,2-diamine, 0.62 g of potassium hydroxide, and 200 mL of dry ethanol, and the atmosphere in the flask was replaced with nitrogen. A reaction container was heated, the reacted solution was refluxed for two hours, 2.1 g of 9,10-phenanthrenequinone was added thereto, and the mixture was refluxed for nine hours. Then, the obtained mixture was subjected to suction filtration, and washed with ethanol, thereby obtaining 2-(3-bromophenyl)dibenzo[f,h]quinoxaline (a yellow white solid, a collection rate of 70%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1OCc1ccccc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-phenylmethoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.11 (2H, s), 5.27 (2H, s), 5.74 (1H, d, J=2.0 Hz), 6.98-7.00 (2H, m), 7.33-7.39 (7H, m), 7.55 (1H, d, J=2.0 Hz), 7.99 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C23H17ClN4O2, 417. Found, 417.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:15])=[O:16])[CH2:19][CH2:20]1
Reactant: O=S(=O)(CC1CC1)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Diethylcarbamoyl chloride (1.55 ml; 11.8 mmol) was added to cyclopropylmethyl 1,2,4-triazol-3-yl sulfone (2.07 g; 11.1 mmol) in dry pyridine (10 ml) under dry nitrogen. The resulting solution was stirred at room temperature overnight. The resulting mixture was poured into cold 2M hydrochloric acid (40 ml) and the cloudy solution extracted into ethyl acetate (3×50 ml). The extracts were combined, washed with saturated brine (50 ml), dried (Na2SO4), filtered and evaporated to afford 3-(cyclopropylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (3.10 g; 98%) as white crystals, m.p. 68°-74° C., (Found, C: 46.23; H: 6.24; N: 19.60; S: 11.29. C11H18N4O3S requires C: 46.14; H: 6.34; N: 19.57; S: 11.20%) NMR - d(CDC13; 60 MHz) 0.2-0.9 (4H, m), 0.9-1.5 (7H, m), 3.3 (2H, d, J= 7 Hz), 3.6 (4H, q, J=7 Hz) and 8.9 (1H, s). IR vmax (CHCl3) 3040, 1710, 1440, 1340, 1270, 1180, 1150, 1030, 870 and 635 cm-1.
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=[CH:11]N=1)([C:3]1NC=CN=1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].N1CCCCC1>C(OCC)(=O)C>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:9]2[CH2:8][CH2:1][CH2:3][CH2:11][CH2:10]2)=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)N1CCCCC1
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A 5-L flask was charged with ethyl acetate (2.3 L) and carbonyl diimidazole (500.0 g, 2.48 mol) to which 4-chloro-3-nitrobenzoic acid (402.5 g, 2.48 mol) was added in portions over 1 hour. The solution was stirred for an additional 1.5 hours. Piperidine (222.2 g, 2.60 mol) was added dropwise over 2 hours and the resulting solution was stirred for an additional 4 hours. The reaction mixture was washed sequentially, twice with 6N HCl solution (600 mL), twice with saturated NaHCO3 (250 mL), and finally with saturated NaCl (250 mL). The organic solution was dried over anhydrous Na2SO4 and filtered, and the solvent was removed in vacuo to yield 646 g (97%) of 4-chloro-3-nitrobenzoyl-piperidine as a yellow crystalline solid with m.p. =76—78 ° C. IR: 1633, 1535, and 1440 cm31 1. 1H NMR (500 MHz, CDCl3): δ 7.92 (1H, d, J 1.5 Hz), 7.60 (1H, d, J=8.1 Hz), 7.56 (1H, dd, J═8.1 and 1.5 Hz), 3.70 (2H, br s), 3.35 (2H, br s), 1.70 (4H, br s), and 1.56 ppm (2H, br s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:14]C=NC=2C(O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1N=C(N)C=CC=1.FC1C=C(N)C=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ncsc1Nc1cc(F)cc(F)c1
Agent: Cc1cccc(N)n1
Agent: Nc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(N=C=S)c1

Procedure:
The title compound, MS (ISP): m/e=347.5 (M+H+), was prepared as for example 1, steps A to C. Step A was performed using 1,3-difluoro-5-isothiocyanato-benzene and yielded 5-(3,5-difluoro-phenylamino)-thiazole-4-carboxylic acid ethyl ester. This was hydrolized in step B to 5-(3,5-difluoro-phenylamino)-thiazole-4-carboxylic acid, which was reacted with 6-methyl-pyridin-2-ylamine in step C. 1,3-Difluoro-5-isothiocyanato-benzene was prepared as in example 96, starting from 3,5-difluoro-phenylamine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=O.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25].F.B(F)(F)F.[C:31](=[O:34])(O)[O-].[Na+]>O>[CH3:4][C:3]1[CH:2]=[C:1]([CH:10]=[C:9]([CH3:8])[C:31]=1[OH:34])[C:11]([C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:14](=[O:16])[C:22]3[CH:21]=[C:20]([CH3:24])[C:19]([OH:25])=[C:18]([CH3:17])[CH:23]=3)[CH:1]=2)[CH:6]=1)=[O:13]
Reactant: O=C([O-])O
Reactant: Cc1cccc(C)c1O
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: F
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)c2ccc3cc(C(=O)c4cc(C)c(O)c(C)c4)ccc3c2)cc(C)c1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
2,6-Naphthalenedicarboxylic acid (108 g, 0.50 mole) and 2,6-dimethylphenol (122 g, 1.00 mole) were charged to a one-liter Hastalloy C® shaker tube. The tube was cooled and charged with hydrogen fluoride (400 g) and boron trifluoride (150 g). It was then heated to 50° C. and shaken for 4 hr at 50° C. The tube was cooled and vented, and the contents, a red solid in a red solution, was allowed to evaporate in the hood. The resulting red solid was stirred in 2 l. of water, warmed, and isolated by filtration of the warm solution. The precipitate was stirred with 2 l. of water, warmed, and neutralized with sodium bicarbonate. The warm mixture was filtered and the precipitate was washed with water, then methanol, and air dried. There was obtained 192.5 g (91%) of crude 2,6-bis(3,5-dimethyl-4-hydroxybenzoyl)naphthalene as an orange powder. 2,6-Bis(4-acetoxy-3,5-dimethylbenzoyl)naphthalene, the diacetate of the above diol was prepared in a manner generally similar to that of Example 2. It had a m.p. (differential scanning calorimetry) of 302° C., and its elemental analysis is consistent with the formula C32H28O6.
Reaction SMILES: C([CH:3]([C:13]1[C:18]([N:19]([CH3:21])[CH3:20])=[C:17]([O:22][CH3:23])[N:16]=[C:15]([O:24][CH3:25])[N:14]=1)[C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8])#N.[H-].[Na+].CN(C=[O:32])C>>[CH3:20][N:19]([CH3:21])[C:18]1[C:13]([C:3]([C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=2)[C:7]#[N:8])=[O:32])=[N:14][C:15]([O:24][CH3:25])=[N:16][C:17]=1[O:22][CH3:23]
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(N(C)C)c(C(C#N)c2cc(C)cc(C#N)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(N(C)C)c(C(=O)c2cc(C)cc(C#N)c2)n1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 3-[cyano-(5-dimethylamino-2,6-dimethoxy-pyrimidin-4-yl)-methyl]-5-methyl-benzonitrile (0.0872 g, 0.258 mmol) in DMF (1.0 mL) was added 60% sodium hydride (0.0114 g, 0.284 mmol) and stirred for 30 min. Oxygen was bubbled into reaction mixture overnight. The reaction was quenched with saturated ammonium chloride solution. The pH was adjusted to ˜6.0 with 1N HCl and mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), dried (MgSO4) and concentrated to give a yellow solid (0.0834 g, 99%). 1H NMR (300 MHz, CDCl3): δ 7.91 (s, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 4.08 (s, 3H), 3.93 (s, 3H), 2.53 (s, 6H), 2.44 (s, 3H). Mass spectrum: 327.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][CH:19]([C:24]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])C(OC)=O)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(O)(=O)C.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][CH2:19][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(CC(C(=O)OC)C(=O)c3ncccc3C)co2)cc1OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A 0.8 g quantity or methyl 2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionate obtained in Example 180 was added to a mixture of 5 ml acetic acid and 1.5 ml of concentrated hydrochloric acid, and the resulting mixture was stirred at 110° C. for 4 hours. After cooling the obtained solution to room temperature, 30 ml of ethyl acetate and 30 ml of saturated sodium hydrogen carbonate solution were gradually added thereto with stirring, and stirring was further continued. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:1), and further recrystallized from ethyl acetate/n-hexane to give 0.28 g of white powdery 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.[Si](C#N)(C)(C)C.[N:33]1([C:38](N2C=CN=C2)=[O:39])C=CN=[CH:34]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:22]([C:21]4[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=4)[CH2:34][NH:33][C:38]3=[O:39])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1cccc(F)c1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: O=C1NCC(c2cccc(F)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 3-fluorobenzaldehyde (0.496 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.979 mL, 7.02 mmol), di-(imidazol-1-yl)methanone (0.621, 3.83 mmol) as described in method 2.