Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[S:16][C:15]=2[NH2:22])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].FC1C=CC(CCl)=CC=1.[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>C(OCC)(=O)C.O1CCCC1>[C:19]([C:17]1[S:16][C:15]([NH:22][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([F:36])=[CH:38][CH:39]=2)=[C:14]([S:11](=[O:13])(=[O:12])[N:10]([CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:24])[CH3:23])[CH:18]=1)(=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(N)s1
Agent: Fc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(NC(=O)c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-acetyl-2-amino-thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 99) (120 mg) in ethyl acetate-tetrahydrofuran (4:1) (30 mL) was added an aqueous solution (10 mL) of 2N sodium hydroxide. After stirring vigorously at room temperature, 4-fluorobenzyl-chloride (51 mg) was added. After 30 minutes, an aqueous solution (10 mL) of 2N sodium hydroxide, then 4-fluorobenzoyl-chloride (100 mg) were added, and the solution was stirred for 30 minutes. In addition, an aqueous solution (10 mL) of 2N sodium hydroxide, then 4-fluorobenzoyl-chloride (100 mg) were added. After stirring for 30 minutes, extraction was carried out by adding ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. Purification was carried out by purification with silica gel column chromatography (hexane/ethyl acetate), and the title compound (59 mg) was obtained as yellow solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a solution of 3-bromo-5-fluorophenol (2.54 g, 0.013 mol) in DMF (12 mL) under a N2 atmosphere was added potassium carbonate (3.59 g, 0.026 mol) and the reaction was stirred for 20 min at RT. 2-Chloro-5-trifluoromethylpyridine (2.4 g, 0.013 mol) was added and the reaction mixture was refluxed at 110° C. overnight. Water was added and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give the title compound (4.28 g, 96%). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.96 (dd, J=2 Hz, J=8.5 Hz, 1H), 7.16-7.15 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.89-6.85 (m, 1H); m/z (337.9, M+ H+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[NH4+:13]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [NH4+]
Reactant: N#Cc1cccc(N=C=O)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-cyanophenyl isocyanate (1.0 g, 6.90 mmol) in THF (5 mL), ammonium hydroxide (1.7 mL, 13.8 mmol) was added. The reaction was stirred for 2 h at rt. The solvent was evaporated and the crude residue was redissolved in ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by flash column chromatography to 41A (0.37 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].Cl>O.CC(C)=O>[C:2]1([NH:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
N-phenylbenzamide (Structure II) is synthesized from aniline and benzoyl chloride using acetone as a reaction media and an aqueous solution of NaOH to neutralize the HCl generated. A 20 ml aqueous solution of NaOH (2.57 grams, 0.064 moles) and 6.0 grams (0.064 moles) of aniline are first added to a stirred 250 ml flask containing 75 ml of acetone. Benzoyl chloride (9.06 grams, 0.064 moles) is next added over a five minute period. This reaction mixture which now contains a white precipitate is stirred for 1.5 hours and then diluted with 50 ml of deionized water. This solution is next filtered and the filter cake obtained is sequentially washed with 50 ml of deionized water (two times) followed by 50 ml of methanol. The washed filter cake is recovered and DCS analysis of this product showed a sharp melting endotherm at 169° C. ##STR10##
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([N:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:32]=[C:31]([F:33])[C:28]([CH:29]=O)=[C:27]([F:34])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:35]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[CH:32]=[C:31]([F:33])[C:28](/[CH:29]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:27]([F:34])[CH:26]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To an ice-cooled solution of ethyl diethylphosphonoacetate (7.71 g, 34.4 mmol) in tetrahydrofuran (80 mL) was added sodium hydride (60% in oil, 1.38 g, 34.4 mmol) and the mixture was stirred for 30 min. A solution of 4-(dibenzylamino)-2,6-difluorobenzaldehyde (9.28 g, 27.5 mmol) synthesized according to the method described in European Journal of Medicinal Chemistry, 1999, vol. 34, pp. 137-151 in tetrahydrofuran (100 mL) was added dropwise. The mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3-hexane/ethyl acetate=60/40) to give the title compound (9.57 g, yield 85%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39]([O:41][C:42](=[O:67])[CH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]Br)[C:48]=1[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:40]>CC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([O:46][CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:67])[C:48]=3[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(O)cc(-c3ccc4c(c3)OCO4)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (400 mg) in a mixture of acetone and DMF (2:1, 3 mL) were added potassium carbonate (10 eq.) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.1 eq). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 4-(3-benzo[1,3]dioxol-5-yl-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (556 mg). The total amount of material from the previous step was dissolved in EtOH (3 mL), followed by addition of 10 M NaOH solution (10 eq.). The resulting reaction mixture was stirred at room temperature for 3 h. Then it was neutralized with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate. The crude material was concentrated under reduced pressure and redissolved in a mixture of TFA and dichloromethane (1:1, 2 mL) and stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the crude material was purified on reverse-phase HPLC to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:21][CH:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc2cc(OCc3ccccc3)ccc2c1
Yield: 25.6 %

Procedure:
Prepared according to the method described in Example 24b) from 6-(benzyloxy)-2-naphthol (2.2 g; Chem. Ber., (1965) 98, 1233), (±)-α-(chloromethyl)-3-pyridinepropanol (1.89 g; from Example 24a) above) and sodium hydroxide (0.8 g) in ethanol (30 ml) and water (10 ml) with heating at reflux for 6 hours to give the title compound as a solid (0.9 g).
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[S:25][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])[CH:17]=[CH2:18]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:16]([N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[S:25][C:26]([C:12]2[C:13]3[N:14]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])[CH:17]=[CH2:18]
Reactant: CC(C)(C)Nc1nc2c(Cl)ncnc2s1
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)(C)C)nc23)cc1-c1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of tert-Butyl-(7-chlorothiazolo[5,4-d]pyrimidin-2-yl)-amine (1.00 g, 4.12 mmol), 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole (1.71 g, 2.75 mmol) and DMF (23 mL) was stirred and degassed with vacuum. The atmosphere was replaced with nitrogen and then bis(triphenylphosphine)palladium(II) chloride (96.4 mg, 0.137 mmol) was added to the mixture. The orange solution was heated at 100° C. for 3 hours and the mixture was allowed to cool to rt. Column chromatography was performed to yield the title compound (1.12 g, 75%) as a pale yellow solid. LCMS: (FA) ES+ 541, 543. 1H NMR (400 MHz, d6-DMSO) δ; 8.73 (bs, 1H), 8.65 (bs, 1H), 8.56 (bs, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.5, 2.5 Hz, 1H), 7.21 (d, J=1.3 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.05 (d, J=1.3 Hz, 1H), 5.64-5.55 (m, 1H), 5.06-5.03 (m, 1H), 4.84-4.79 (m, 1H), 4.31-4.27 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O-:26])=[O:25].[K+].ClC1C=CC=CC=1CC([O-])=O.[K+]>CS(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C([O-])Cc1ccccc1Br
Reactant: Nc1c(Cl)cccc1Cl
Agent: O=C([O-])Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
The same procedure as in Example 1 given in Japanese Pat. No. 374/1980 was employed using 3.10 g of 2,6-dichloroaniline, 0.10 g of cuprous bromide, 2.80 g of potassium carbonate and 10 ml of dimethyl sulfoxide except that potassium o-bromophenylacetate was replaced with 4.17 g of potassium o-chlorophenylacetate. o-(2,6-Dichloroanilino)phenylacetic acid was not obtained at all.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:36]3[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 150 °C

Procedure:
370 mg (0.81 mmol) of 3-ethyl 1-(4-nitrophenyl) 5-(4-ethylphenyl)piperidine-1,3-dicarboxylate, 245 mg (2.42 mmol) of 4-hydroxypiperidine and 112 mg (0.81 mmol) of potassium carbonate were added to 9 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 15 min. For work-up, water was added and the reaction solution was extracted with ethyl acetate. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC. Yield: 208 mg (66% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([CH:9]1[CH2:13][C:12]([O:14]CC)=[CH:11][C:10]1=O)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(O)=O>C(O)C>[C:1]([O:5][C:6]([C:7]1[C:9]2[CH2:13][C:12](=[O:14])[CH2:11][C:10]=2[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1)=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC1=CC(=O)C(C(=O)C(=O)OC(C)(C)C)C1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nn(Cc2ccccc2)c2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of the intermediate from step A (2.15 g, 8.45 mmol) in ethanol (100 mL) was added benzyl hydrazine hydrochloride (1.8 g, 9.22 mmol) and HOAc (10 mL). The reaction mixture was stirred at room temperature for 16 hours and then refluxed at 70° C. for 30 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 30% ethyl acetate-hexanes to give the desired product (1.64 g) a brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].CN(C=O)C.[CH:16]([NH:18][NH2:19])=O.[H-].[Na+]>O>[N:19]1[N:18]=[CH:16][N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:10][C:9]=12
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)sc1nncn12
Temperature: 160 °C

Procedure:
Five grams (30.0 mmoles) of o-chlorophenylisothiocyanate were dissolved in 50 ml. of dry DMF. A solution of 1.8 g. (30.0 mmoles) of formylhydrazine in 50 ml. of dry DMF was added dropwise rapidly to the stirred reaction mixture. The temperature of the reaction rose to about 45° C. The temperature was maintained between 60° C. and 100° C. for 24 hours. Thirty millimoles, 1.5 g., of sodium hydride as a 50% mineral oil suspension was added to the reaction mixture. The reaction was completed by heating at reflux temperature (160° C) for about 185 hours. The cooled mixture was poured into water. The aqueous mixture was extracted with n-hexane to remove mineral oil. The product was extracted with ethyl acetate. The ethyl acetate extract was washed (water), dried (MgSO4) and evaporated in vacuo to a residual oil. the oil was covered with dry ether an the product crystallized upon standing. The yield of s-triazolo[3,4-b]benzothiazole, m.p. about 175°-176° C., was 200 mg.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CC(O)(C)C>[CH3:15][C:2]1[NH:22][C:16]2[C:21]([C:3]=1[S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: NNc1ccccc1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2ccccc2c1Sc1cccc(CC(=O)O)c1
Temperature: 70 °C

Procedure:
[3-(2-Oxo-propylsulfanyl)-phenyl]-acetic acid (0.200 g, 1.12 mmol) was dissolved in t-BuOH (5 mL) then phenylhydrazine (121 μL, 1.232 mmol) was added followed by HCl (1.232 mL, 1.0M in ether). The reaction was heated to 70° C. for 1 hour then cooled and submitted to aqueous workup to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=[C:11]([N:21](C)[C:22](=O)C)[N:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:28][NH2:29]>CCO>[CH3:22][NH:21][C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH2:2])=[N:28][NH:29]3)=[CH:8][CH:7]=2)[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:12]=1
Reactant: CC(=O)N(C)c1nc(-c2ccc(C#N)c(F)c2)cc(N2CCCCC2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCCC2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
In a 25 mL sealable tube were combined N-[4-(4-cyano-3-fluorophenyl)-6-(1-piperidinyl)-2-pyrimidinyl]-N-methylacetamide (0.04 g, 0.11 mmol) and hydrazine monohydrate (0.11 mL, 2.21 mmol) in EtOH (10 mL). The tube was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting oil was dissolved in EtOH (3 mL) followed by the addition of water (6 mL). Since no solid was observed (a yellow oil was formed), the mixture was concentrated to dryness. The resulting oil was diluted with CH3CN (2 mL) and sonicated. The resulting yellow solid was filtered, washed with CH3CN (1 mL) and dried to afford the title compound (18 mg, 48%). LC-MS (ES) m/z=324 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 1.68 (m, 2H), 2.92 (d, J=4.3 Hz, 3H), 3.84 (bs, 4H), 5.54 (bs, 2H), 6.81 (bs, 1H), 7.21 (bs, 1H), 7.40 (bs, 1H), 7.76 (bs, 1H), 7.85 (d, J=8.3 Hz, 1H), 11.83 (bs, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8](=[O:43])[C@@H:9]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1.Br[C:45]1[CH:46]=[C:47]2[CH2:53][N:52]([CH3:54])[C:51](=[O:55])[C:48]2=[N:49][CH:50]=1>O.C(#N)C>[NH2:7][C:8](=[O:43])[C@@H:9]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:45]2[CH:46]=[C:47]3[CH2:53][N:52]([CH3:54])[C:51](=[O:55])[C:48]3=[N:49][CH:50]=2)=[CH:13][CH:12]=1
Reactant: CN1Cc2cc(Br)cnc2C1=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1Cc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cnc2C1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
Potassium carbonate (176 mg) in water (2 mL) was added to (S)-tert-butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 329 mg), 3-bromo-6-methyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (Example 32, step (ii), 144 mg) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg) in degassed acetonitrile (12 mL) at 20° C. under nitrogen. The resulting solution was stirred at 80° C. for 90 min. The reaction mixture was cooled and filtered and the filtrate diluted with ethyl acetate, and washed with water. The aqueous was then extracted with dichloromethane and the combined organics dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with methanol/ethyl:acetate (15:85 to 25:75). Pure fractions were evaporated to dryness to afford the sub-titled compound (278 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].C1(C)C(C)=CC=CC=1>[Cl-].[Cl-].[Zn+2].O>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: OCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1ccc(C2OCCO2)cc1

Procedure:
8.2 g (0.05 mol) of methyl 4-formylbenzoate, 25 ml of ethylene glycol, 3.5 g of ZnCl2 and 200 ml of xylene are introduced into a round-bottomed flask. The mixture is heated to reflux and the water formed is separated after settling has taken place, the organic phase is evaporated to dryness, the reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 10.4 g (100%) of the expected product are collected in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:27])[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:29]>O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:27])[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cccn(C)c2=O)cc1

Procedure:
A solution of N-[(1,1-dimethylethoxyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (60 mg, 0.155 mmol) in 4 N HCl in dioxane (4 mL) was stirred for 2 hr and was concentrated. The residue was triturated with several portions of ether to give 4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (55 mg, quant) as a white powder. LRMS-Electrospray: m/z positive ion 573 (2M+H) 328 (M+H+CH3CN) 319 (M+H+CH3OH) 287 (M+H). HRMS: Obs. Mass 287.1396. Calcd. Mass 287.1396 (M+H)