Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:5]([O:4][C:2]([NH:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(C(=O)O)CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of benzyl chloroformate (0.290 g, 1.1 mmol) in dioxane (2.5 cm3) was added dropwise to a solution of 1-aminocyclopentanecarboxylic acid (Fluka) (0.2 g, 1.54 mmol) and sodium carbonate (0.490 g, 4.64 mmol) in water (5 cm3) at 0° C. Stirring was continued at room temperature overnight and the reaction mixture washed with ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried (Na2SO4), filtered and the solvent removed to afford carbamate 21 (0.253 g, 62%) as an oil which solidified on standing. Carbamate 21 was shown to be a 70:30 mixture of conformers by 1H NMR analysis (the ratio was estimated from the integration of the resonances at δ 5.31 and 7.29-7.40, assigned to the N—H protons of the major and minor conformers, respectively): mp 70-80° C. (lit.1 82-86° C., ethyl acetate, petroleum ether); δH (400 MHz; CDCl3; Me4Si) 1.83 (4H, br s, 2× cyclopentyl-H2), 2.04 (2H, br s, cyclopentyl-H2), 2.20-2.40 (2H, m, cyclopentyl-H2), 5.13 (2H, br s, OCH2Ph), 5.31 (0.7H, br s, N—H) and 7.29-7.40 (5.3H, m, Ph and N—H*); δC (100 MHz; CDCl3) 24.6 (CH2, cyclopentyl-C), 37.5 (CH2, cyclopentyl-C), 66.0 (quat., cyclopentyl-C), 66.8 (CH2, OCH2Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 136.1 (quat, Ph), 155.8 (quat., NCO2) and 179.5 (quat., CO2H). * denotes resonance assigned to minor conformer.
Reaction SMILES: [N:1](OC)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[CH:24]=[C:23]([C:25](=[O:28])[CH2:26][CH3:27])[CH:22]=[CH:21][C:15]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18]>O1CCCC1.Cl.CCOCC>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[CH:24]=[C:23]([C:25](=[O:28])[C:26](=[N:1][OH:2])[CH3:27])[CH:22]=[CH:21][C:15]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CCC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Reactant: CON=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=NO)C(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 3 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
Methyl nitrite [prepared from sodium nitrite (1.4 g), methanol (0.9 ml) and sulfuric acid (0.7 ml) in water (2.3 ml)] was introduced into an ice-cooled mixture of 2'-(2,4-difluorophenylthio)-4'-propionylmethanesulfonanilide (2.54 g) in tetrahydrofuran (10 ml) and 12% hydrogen chloride in ether (10 ml). The mixture was stirred for 5 hours at 3° C. and evaporated. The residual solid was recrystallized from ethanol to give colorless crystals of 2'-(2,4-difluorophenylthio)-4'[2-(hydroxyimino)-1-oxopropyl]methanesulfonanilide (2.5 g).
Reaction SMILES: NCCCOC1C=CC(C(N2CCC([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])CC2)=O)=CC=1.C(=O)C1C=CC=CC=1.B.[Na]>CO>[NH:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:19]1=[O:20]
Reactant: NCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: B
Agent: [Na]
Solvent: O=Cc1ccccc1
Solvent: CO
Product: O=C1CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 201.7 %

Procedure:
A mixture of 1-{1-[4-(3-aminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.4 g), benzaldehyde (0.42 ml) and methanol (15 ml) is stirred at room temperature for 3 hours and cooled with ice. Thereto is added sodium boron hydride (0.21 g) and the mixture is stirred under ice cooling for 2 hours and then allowed to stand at room temperature overnight. The solvent is distilled off and water is added to the resulting residue and the mixture is extracted with ethyl acetate. The extract is washed successively with saturated sodium hydrogen carbonate, water and saline solution, dried with sodium sulfate and then the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: methanol:dichloromethane=1:100) to give 1-{1-[4-benzylaminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.02 g).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])[C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: O=C1CSC(=O)N1CCCOc1cccn2ccnc12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.17 g (4.0 mmol) of 3-[3-(imidazo[1,2-a]pyridin-8-yloxy)propyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 15 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 1.07 g (77.5%, light orange oily substance) of the desired product.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of the product of Step A (4.44 g, 22.1 mmol) in CH2Cl2 were added N,N-diisopropylethylamine (1.2 eq.), 4-dimethylaminopyridine (0.1 eq), and tert-butyldimethylsilyl chloride (1.2 eq). The reaction mixture was stirred for 1.5 hours at room temperature, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluted with 2.5% ethyl acetate/hexane to afford 5.0 g (71%) of the titled product.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:16])[C:6]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]>CC(O)=O.O>[CH2:1]([C:5]1[N:10]2[CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:16])[C:6]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)nc2n1C(C)C(=O)N2
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)nc2n1C(C)C(=O)N2
Yield: 76.6 %

Procedure:
A solution of 0.2 g of 5-butyl-3-methyl-6-[[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)]biphenyl-4-yl]methyl]imidazo[1,2-a]pyrimidin-2,7-dione in 6 ml of AcOH and 2 ml of H2O is stirred at room temperature for 5 h, then is evaporated under reduced pressure. The residue is taken up into H2O, adjusted to pH 8 with diluted NaOH and extracted with AcOet. The aqueous phase is acidified to pH 5 with AcOH, to separate a solid which is filtered off and washed with H2O, to obtain 0.1 g of a white solid (80% yield, m.p=192°-194° C. dec.).
Reaction SMILES: COC(COCCCCCCCCCCCCCCCCCC)CS.[CH3:26][O:27][CH:28]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:29][OH:30].[CH:51]1[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>N1C=CC=CC=1>[C:54]1([S:57]([O:30][CH2:29][CH:28]([O:27][CH3:26])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])(=[O:59])=[O:58])[CH:55]=[CH:56][CH:51]=[CH:52][CH:53]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OC
Agent: CCCCCCCCCCCCCCCCCCOCC(CS)OC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COS(=O)(=O)c1ccccc1)OC

Procedure:
The 2-methoxy-3-octadecyloxy-1-propanethiol used as starting material is prepared in the following manner: 2-methoxy-3-octadecyloxy-1-propanol is reacted with benzenesulfochloride in anhydrous pyridine to give 2-methoxy-3-octadecyloxy-1-propanol benzene-sulfonate, (oil). This is then reacted with thiorea in butanol to give the isothiuronium salt which is saponified with potassium hydroxide solution and the thiol liberated with hydrochloric acid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=O.[Na+].[CH3:28][N:29]([CH3:39])[C:30](=[O:38])[CH2:31][N:32]1[C:36]([SH:37])=[N:35][N:34]=[N:33]1.[2H]C([2H])([2H])C(C([2H])([2H])[2H])=O>C(O)C>[S:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:16][C:14]([NH:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:24]([OH:26])=[O:25])=[C:6]([CH2:5][S:37][C:36]3[N:32]([CH2:31][C:30](=[O:38])[N:29]([CH3:28])[CH3:39])[N:33]=[N:34][N:35]=3)[CH2:23][S:22][C@H:9]12)=[O:15]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CN(C)C(=O)Cn1nnnc1S
Agent: [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H]
Agent: [Na+]
Solvent: CCO
Product: CN(C)C(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 44.1 %

Procedure:
Prepared from sodium cephalothin and N,N-dimethyl-5-mercapto-1H-tetrazol-1-ylacetamide as described in example 12(b) in 44.1% yield; t.l.c. (SiO2 ; B.A.W; 12:3:5) Rf=0.35; λmax (95% ethanol) 271 nm (ε 8,390); δ(free acid) [(CD3)2CO] 2.33 and 3.27 (6H, 2×s -N(CH3)2), 3.85 (2H,s, C2 methylene), 4.00 (2H,s, --CH2CO--), 4.47 (2H,bs, --CH2S--), 5.20 (1H,d, J 5 Hz, C6 proton), 5.55 (2H,s, --CH2CON(CH3)2), 5.97 (1H,dd, J 5 and 9 Hz, C7 proton), 6.9-8.0 (4H,m, thienyl protons and --CO2H), 8.29 (1H,d, J 9 Hz, --CONH--).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:29][CH3:30])[CH:9]([C:17]1[NH:18][C:19](=[O:28])[C:20]([OH:27])=[C:21]([C:23]([O:25]C)=O)[N:22]=1)[CH2:10][CH2:11][C@H:12]([O:15][CH3:16])[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:29]([N:8]([CH:9]([C:17]1[NH:18][C:19](=[O:28])[C:20]([OH:27])=[C:21]([C:23]([NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)=[O:25])[N:22]=1)[CH2:10][CH2:11][C@H:12]([O:15][CH3:16])[CH2:13][OH:14])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH3:30]
Reactant: NCc1ccc(F)cc1
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)[nH]1
Temperature: 80 °C

Procedure:
To a solution of methyl 2-{(4S)-1-[(tert-butoxycarbonyl)(ethyl)amino]-5-hydroxy-4-methoxypentyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (48 g, 112 mmol) in MeOH (1118 mL) was added 4-fluoro-benzylamine (28 g, 224 mmol) and triethylamine (31.2 mL, 224 mmol). The resulting mixture was sealed and heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with 10% citric acid (˜100 mL), and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was dissolved in acetonitrile and concentrated under reduced pressure (3×) to remove MeOH. The residue was dried under high vacuum for 2 days and used in the next reaction without purification. LC-MS: 523.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:28]2[O:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:29][CH3:30])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:28]2[O:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:29][CH3:30])=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)OCCO1
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)OCCO1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (53 mg, 0.33 mmol) with compound 518 (74 mg, 0.25 mmol) in THF (1.5 mL) in the presence of LiHMDS (0.75 mL, 0.75 mmol) afforded compound 126 as a white solid material after purification by column chromatography (60-80% EtOAc in light petroleum). LC-MS: RT=3.63 min.; m/z 426.18, 428.16 (M+H)+. 1H NMR (DMSO-d6): δ 8.64 (2H, s), 7.39 (1H, d, J 8.8), 6.86 (1H, d, J 8.9), 4.60 (2H, s), 4.34 (2H, s), 4.17 (2H, s), 3.97 (4H, s), 3.84 (3H, s).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH:21]([CH3:23])[CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)Sc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 10.6 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-isopropylthiopyridine (1.40 g, 7.9 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.24 g, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26].O>O1CCCC1>[C:11]([C:10]1[C:14]([CH3:15])=[C:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[C:25](=[O:26])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)(=[O:13])[CH3:12]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(=O)C(=NNc1cccc(Cl)c1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(-c2cccs2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Pentan-2,3,4-trione 3-(3-chlorophenylhydrazone) (2.39 g) was added to a suspension of 66% sodium hydride (0.77 g) in anhydrous tetrahydrofuran (40 ml) under ice cooling, followed by stirring at room temperature for 30 minutes. Then, a solution of 2-thiopheneacetyl chloride (1.77 g) in anhydrous tetrahydrofuran (10 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), and the resulting crude crystals were washed with hexane to obtain 6-acetyl-2-(3-chlorophenyl)-5-methyl-4-(2-thienyl)-3(2H)-pyridazinone (2.19 g) (Compound No. 1-97).
Reaction SMILES: [C:1]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][OH:20]>C[O-].[Na+]>[OH:20][CH2:19][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:17][CH3:16])=[O:18]
Reactant: CO
Reactant: O=C1CCCCCCCCCCCCCCCO1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CCCCCCCCCCCCCCCO
Temperature: 60 °C
Yield: 90.2 %

Procedure:
76.3 gm of 16-hexadecanolide and 0.29 gm of 28% sodium methoxide solution were dissolved into 250 gm of methanol, and the solution was heated at 60° C. for 60 hours while stirring. The reaction mixture was cooled to deposit crystals. The crystals were collected by filtration, washed, and dried to obtain 77.5 gm of methyl 16-hydroxyhexadecanoate (yield: 90.2%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([NH2:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C)C=O>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([NH:71][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:18])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1COc2ccc(C(=O)c3ccccc3C(=O)NCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 211.7 %

Procedure:
To a solution of 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)carbonylbenzoic acid (100 mg, 033 mmol) in N,N-dimethylformamide (2.00 mL) was added N-methylmorpholine (0.14 mL 1.32 mmol) followed by addition of HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.33 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of benzylamine (36 uL, 0.33 mmol). The reaction mixture was then heated to 60° C. for 18 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate the organic layer was washed with brine, 1.0 M aq. hydrochloric acid, brine, saturated aq. sodium-hydrogencarbonate and brine. The organic layer was separated dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford the title compound (0.27 g, 80%). MS (EI) for C23H18N2O4: 387 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=O)=[CH:4][CH:3]=1.[NH2:25][NH2:26].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C#Cc2ccc(Cl)cc2)CC1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(Cl)cc3)n[nH]2)CC1
Temperature: 75 °C

Procedure:
To a solution of tert-butyl 4-[3-(4-chlorophenyl)prop-2-ynoyl]piperidine-1-carboxylate (5.28 g, 15.18 mmol) in ethanol (160 mL) was added hydrazine (0.953 mL, 30.4 mmol) and triethylamine (4.23 mL, 30 4 mmol). The mixture was heated at 75° C. for 3 h. The solvent was evaporated under reduced pressure, and dried under vacuum to give INTERMEDIATE 1. LC-MS m/z 362.19 [M+H]+, 306.14 [M−56+H]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[CH3:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1C
Temperature: 23 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (850 mg, 0.002 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (287 mg, 0.012 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (720 mg, 88%) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:30]#[C:29][CH2:28][OH:31])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: C#CCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as off-white solid, MS: 333(M).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3C[CH2:12]3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>CN1C(=O)CCC1>[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[N:7]3[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:6]3[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:23])[CH3:24])=[CH:18][CH:17]=3)[CH:3]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Reactant: CC(=O)N1CCCNCC1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCN(C(C)=O)CC3)n2n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and N-acetylhomopiperazine (59 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAc to give the titled compound (50 mg, 51% yield) as an off-white solid. ESI-MS: m/z 465 (M+H)+.