Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: Cc1nc(C(=O)O)cn1C[C@@H](C)O
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C[C@@H](C)O
Yield: 45.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (1.059 mmol, 195 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.882 mmol, 246 mg) and using dry DMF (2 ml) as the solvent. After the reaction was finished, DCM was added and the reaction mixture was concentrated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 177.8 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.00-1.10 (m, 6H), 2.34 (s, 3H), 3.69-3.90 (m, 3H), 4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d, 1H), 7.91-7.96 (m, 1H), 8.00 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([O:8][C:9]1[C:10]([N:22]([CH2:34][CH2:35][CH3:36])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:19])([CH3:20])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2OCc2ccccc2)C(C)(C)CC=C3C)cc1
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1OCc1ccccc1)C(C)(C)CC=C2C
Yield: 65 %

Procedure:
Following General Procedure P ethyl 4-(3-benzyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 114, 0.030 g, 0.07 mmol) was reacted with propionaldehyde to afford 0.021 g (65%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[CH2:9][O:10][CH:11]([CH3:13])[CH3:12]>O1CCCC1>[CH:11]([O:10][CH2:9][O:4][CH2:3][CH2:2][CH2:1][OH:5])([CH3:13])[CH3:12]
Reactant: OCCCO
Reactant: CC(C)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OCOCCCO
Reaction time: 1 h

Procedure:
A solution of 1,3-propanediol (19.4 g, 255 mmol) in dry tetrahydrofuran (100 ml) under nitrogen at 0°-5° C. was treated with sodium hydride (2.04 g, 85 mmol) and stirred for 1 hour. Chloromethylisopropyl ether (9 g, 83 mmol) in dry tetrahydrofuran (15 ml) was added over 15 min. Stirring was continued for a further 2 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with dichloromethane:methanol (97:4) to give the title compound as a colourless oil. (5.3 g, 44%). νmax (Film) 3400, 2910, 2860, 2805, 2760, 1460, 1440, 1425, 1410 and 1380 cm-1 ; δH (CDCl3) 1.17 (3H, s, CH3), 1.20 (3H, s,CH3), 1.84 (2H, quintet, J=6 Hz CH2CH2CH2), 2.3 (1H, br s, D2O exchangeable OH), 3.72 (2H, t, J=6 Hz, CH2OCH2OCH(CH3)2) 3.76 (2H, t, J=6 Hz,CH2ON), 3.86 (1H, m, CH(CH3)2), 4.70 (2H, s, OCH2O).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8](C(C3C=CC=CC=3)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1>O1CCOCC1.[OH-].[K+]>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Brc1ccc2cc[nH]c2n1
Temperature: 25 °C

Procedure:
(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)-methanone, 586 was dissolved in 20 mL of dioxane and 20 mL of 2M KOH (aq). This was stirred at ambient temperature until analysis indicated all of the starting material had been consumed (2 to 4 hours). The reaction was diluted with 50 mL of ethyl acetate and washed with 2×25 mL of NaHCO3 (aq. satd.) and 25 mL of brine. The organic layer was dried with sodium sulfate, evaporated and purified by column chromatography. Combined steps 2 and 3 gave approximately 65% overall yield.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][CH:21]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:21]1[CH:20]=[N:19][N:12]2[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)=[N:10][C:11]=12
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3nccc3n2)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of 5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.0 g, 15.1 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.40 g, 17.1 mmol) and drop wise a solution of iodine monochloride (2.77 g, 17.1 mmol) in acetic acid (10 mLl). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (up to 100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (6.49 g, 94%) as a yellow solid. MS (EI) 457.0 [(M)+]; mp 142° C.
Reaction SMILES: [C:1](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:5])[C:2]([CH3:4])=O.Cl.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30](=[NH:35])[O:31]C(C)C)=[CH:21]1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:4][C:2]1[C:1](=[O:5])[NH:31][C:30](=[O:35])[C:29]=1[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]([CH3:19])[CH:21]=1
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Reactant: CC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(c2cn(C)c3ccccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
A solution of 802 mg of pentafluorophenyl pyruvate in 20 ml of dichloromethane was added dropwise to a solution of 266 mg (1 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 808 mg (8 mmol) of triethylamine in 20 ml of dichloromethane. After completion of the addition, the mixture was stirred at room temperature for 18 hours. Then, 1.9 g (10 mmol) of p-toluenesulfonic acid were added and stirring was continued for 1 hour. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/dichloromethane (1:8) for the elution to give 24 mg(10% ) of 3-methyl-4-(1 -methyl-3-indolyl)- 1H-pyrrole-2,5-dione in the form of a yellow solid of melting point 181° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: CC(C)(C)OC(=O)NCCCCC(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
5-[1-(t-Butoxy)formamido]valeric acid is coupled with 5-aminosalicyclic acid to give 5-[5-(1-t-butoxyformamido)valeramido]salicylic acid, m.p. 181° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]=[C:14]=[S:15])[CH:7]=2)[CH2:3][CH2:2]1.[NH3:17]>CO>[CH:1]1([NH:4][C:5](=[O:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]([NH2:17])=[S:15])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N=C=S
Reactant: N
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A suspension of N-cyclopropyl-3-isothiocyanato-4-methyl-benzamide 3B (7.45 g) in a 7N solution of ammonia in methanol (40 mL) was stirred at room temperature for 1 hr. The mixture was concentrated, then redissolved in MeOH and reconcentrated to give the desired product as white solid (6.1 g, 60% for two steps).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6](Cl)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>N1C=CC=CC=1.O>[SH:4][C:3]1[N:5]=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:1][N:2]=1
Reactant: NNC(N)=S
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Sc1n[nH]c(-c2cccnc2)n1

Procedure:
To a solution of 19 g (0.200 mol) of thiosemicarbazide in 175 ml of dry pyridine, 29 g (0.200 mol) of nicotinoyl chloride was slowly added at 10° C. After reflux for 40 min. the reaction mixture was concentrated to half the original volume, 500 ml of water was added, and stored in the cold overnight. The precipitate formed was removed by filtration, and the filtrate was evaporated in vacuo. The resulting heavy, yellow oil was dissolved in 300 ml of water, and 64 g (0.600 mol) of sodium carbonate in 400 ml of water was added. After reflux for 4 h the solution was cooled and acidified with conc. hydrochloric acid to pH=4. The formed, colorless precipitate, 65, was isolated by filtration and dried in vacuo. Yield: 35 g (0.297 mol, 98%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:5]([O:7]CC)=[O:6].[H][H]>CO.[Pd]>[F:1][C:2]([F:16])([F:17])[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CCCCCCC(=CC(=O)OCC)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(=CC(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 112.5 %

Procedure:
13.78 g of ethyl 3-trifluoromethyl-2-nonenoate was dissolved in 138 ml of methanol, and 1.38 g of 5%-palladium/activated carbon was added thereto, followed by stirring for 4 hours at room temperature and normal pressure in a hydrogen atmosphere in a catalytic hydrogenation apparatus. After the reaction, the 5%-palladium/activated carbon was filtered out, and the remaining methanol solution was mixed with 24 ml, of water and 20 g of potassium hydroxide, followed by 2 hours of heat refluxing, distilling-off of methanol under a reduced pressure, acidification with addition of 6N-hydrochloric acid, and extraction with methylene chloride. The resultant methylene chloride solution was dried on sodium sulfate, followed by distilling-off of the solvent and purification by distillation (b.p.: 118.5°-119.7° C./20 mmHg), whereby 13.78 g of 3-trifluoromethylnonenoic acid was obtained. (Yield: 51.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:17]1[CH:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=1[CH3:11])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ccc(C)cc1
Product: Cc1ccc(C)c(C(=O)c2ccccc2Cl)c1
Reaction time: 4.5 h
Yield: 55 %

Procedure:
The HF-catalyzed condensation of 2-chlorobenzoic acid with p-xylene was also investigated. Condensation was carried out at 60° C. for 4.5 hours. 2-chloro-2',5'-dimethylbenzophenone product was isolated in 55% yield. Upon repeating the reaction at 80° C. for 4.5 hours, the conversion was slightly increased to afford the product in 60% yield. The results appear to show that p-xylene is not as reactive as m-xylene in this reaction.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.S(Cl)(Cl)(=O)=O>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[S:5][CH:4]([C:17]2[CH:18]=[CH:19][C:14]([OH:20])=[CH:15][CH:16]=2)[C:3]1=[O:13]
Reactant: Cc1ccc2c(c1)SCC(=O)N2C
Reactant: Oc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)SC(c1ccc(O)cc1)C(=O)N2C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a stirred solution of 3,4-dihydro-4,7-dimethyl-3-oxo-2H-1,4-benzothiazine (11.0 g) in methylene chloride (50 ml), sulfuryl chloride (4.8 ml) is added under ice-cooling. After the addition, the mixture is stirred for 15 minutes under ice-cooling. Phenol (7.0 g) is added to the mixture, and the mixture is stirred for 45 minutes and concentrated in vacuo. Ether is added to the residue and the separated crystals are collected by filtration to give 11.3 g (69.4%) of the titled compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2/[CH:21]=[CH:20]/[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(CCC(C=Cc2ccccc2O)CCCCC#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1

Procedure:
A solution of 1.70 g (3.38 mmol, 75% pure) of methyl 4-{7-cyano-3-[2-(2-hydroxyphenyl)vinyl]-heptyl}benzoate in 20 ml of dry acetonitrile is mixed with 1.53 g (7.76 mmol) of 4-(tert-butyl)benzyl bromide and 1.4 g (10.13 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The resulting crude product is taken up on silica gel and purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 1700 mg (3.12 mmol, 96% purity, 92% of theory) of an oil are obtained.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)[CH:2]=1.[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN>C1COCC1>[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH:3][CH3:2])=[O:17]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cl)cc1N
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Carbonyl-1,1′-diimidazole (1.70 g) was added to 2-amino-4-chlorobenzoic acid (1.50 g) in THF (22.2 mL). After stirring overnight a solution of methylamine in THF (2M, 6.6 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) and then water (2×100 mL). The organics were extracted with 1 M HCl (4×25 mL, then 2×100 mL then 50 mL), the aqueous phase basified with potassium carbonate (˜50 g) and the organics discarded. The aqueous was then extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4, 10 g) and concentrated to give 2-amino-4-chloro-N-methylbenzamide (1.2 g, 74%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@H:17]([O:19][C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:16]([CH2:28][O:29][C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:15][C@H:11]1[S:12][CH2:13][CH3:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[CH2:1]([O:9][C@@H:10]1[CH2:18][C@H:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:16]([CH2:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:15][C@H:11]1[S:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C[C@H]1OC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCS[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C[C@H]1OCc1ccccc1

Procedure:
Compound 25 (608 mg, 1.17 mmol) gave 364 mg substantially pure product (65%). [α]D=−11.8° (c=1, CHCl3); 1H NMR (CDCl3) 7.44-7.14 (m, 15H), 4.74 (d, 1H, J=11.6 Hz), 4.66-4.56 (m, 4H), 4.50 (d, 1H, J=9.4 Hz), 4.45 (d, 1H, J=11.4 Hz), 3.83 (d, 1H, J=10.7 Hz), 3.69 (dd, 1H, J=4.4, 10.7 Hz), 3.49 (m, 2H), 3.35 (m, 1H), 2.79 (m, 2H), 2.69 (m, H), 1.54 (m, 1H), 1.35 (t, 3H, J=7.3 Hz); 13C NMR (CDCl3): 138.8, 138.4, 135.8, 128.9, 128.7, 128.4, 128.2, 128.1, 127.4, 86.9, 81.3, 75.6, 73.8, 73.3, 72.5, 71.6, 69.8, 45.3, 36.7, 25.1, 20.3, 15.5; MS: calcd for C29H34O4SNa 501.2. found m/z 501.0 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CS(C)=O.[CH:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])[CH3:15]>O>[CH:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN(c2ccc(C#N)cn2)CC1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of 2-chloropyridine-5-carbonitrile (5.0 g, 36.1 mmol), DMSO (10 mL) and 1-isopropylpiperazine (10.7 mL, 75.8 mmol) was stirred under an atmosphere of nitrogen and heated on a 100° C. oil-bath for 3 h. The reaction mixture was allowed to cool, and then poured into cold water (500 mL). The solid was isolated by filtration, washed with water and dried to give 6.8 g (82%) of 6-(4-isopropylpiperazin-1-yl)nicotinonitrile.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1>C(O)C>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:11]2[CH2:12][CH:7]([C:5]3[O:4][N:3]=[C:2]([N:30]4[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]4)[N:6]=3)[CH2:8][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:10]2)=[CH:14][CH:15]=1)[CH3:20]
Reactant: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: O[C@@H]1CCNC1
Solvent: CCO
Product: CCc1ccc(C2CC(c3nc(N4CC[C@@H](O)C4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.191 mmol) of the oxadiazole from Example 25A in 1.20 ml of ethanol were added 333 mg (3.82 mmol) of (3R)-pyrrolidin-3-ol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure, dichloromethane was added and the mixture was washed with water. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 64.8 mg (70% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.Br.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)([O-:14])=[O:13]
Reactant: NCCSCc1ccon1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: Br
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
By the procedure of Example 8(i), 3-[(2-aminoethyl)thiomethyl]isoxazole (from the hydrobromide (3.7 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (3.5 g) to give 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene (3.6g) which, on reaction with methylamine by the procedure of Example 8(ii) gives the title product (3.0 g).
Reaction SMILES: CC(C)(OC([NH:7][CH:8]1[CH2:11][N:10]([C:12](=[O:20])[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:21])=O)C.CCOCC.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:7][CH:8]1[CH2:11][N:10]([C:12](=[O:20])[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:21]
Reactant: CCOC(=O)C=CC(=O)N1CC(NC(=O)OC(C)(C)C)C1=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=CC(=O)N1CC(N)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[1(E); 3S]-4-[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-oxo-1-azetidinyl]-4-oxo-2-butenoic acid, ethyl ester (2 g) was dissolved in 15 ml of trifluoroacetic acid and stirred for 15 minutes at 0° C. After adding ether, the title compound crystallized quantitatively from the solution as white crystals, melting point 138° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
In 50 mL of methanol, 6.77 g (21 mmol) of (3-nitro-5-(trifluoromethyl)phenyl)-(4-methylpiperazin-1-yl)methanone was dissolved, and 400 mg of 10% palladium carbon was added thereto and the mixture solution was stirred in an hydrogen atmosphere under normal pressures at room temperature for three hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and the residue was recrystallized from hexane and diethyl ether to obtain 6.14 g (quantitative) of a target product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([OH:36])=[O:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]=3[N:14]([CH2:33][C:34]([OH:36])=[O:35])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(O)CBr
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
To a solution of N-(4-chlorobenzyl)4-hydroxy-2-(3-hydroxy-1-propynyl)-thieno[2,3-b]pyridine-5-carboxamide (Example No. 5) (0.250 g) in DMF (3 mL) is added K2CO3 (0.278 g) and bromoacetic acid (0.279 g). The reaction is heated to 100° C. and stirred for 18 h. An additional 0.200 g of bromoacetic acid is added and the reaction is stirred for an additional 18 h. The reaction mixture is concentrated in vacuo, and the resulting residue is dissolved in 10% NaOH and washed with CH2Cl2. The aqueous layer is acidified with conc. HCl and the resulting precipitate is filtered. This material is recrystallized 3 times from methanol to yield 0.068 g (24%) of the title compound as a tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)#[N:2].[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][NH:16][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:10][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ccccc1N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccccc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5 (200 mg, 1.00 mmol), 1 (161 mg, 1.00 mmol), and acetic acid (300 mg, 5.00 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (66 mg, 1.05 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with three additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (12).