Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:30]([C:32]1[C:37]([CH3:38])=[CH:36][C:35]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=1)#[N:31]>C(O)(C)(C)C.ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:42][S:39]([C:35]3[CH:36]=[C:37]([CH3:38])[C:32]([C:30]#[N:31])=[CH:33][C:34]=3[CH3:43])(=[O:40])=[O:41])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: Cc1cc(S(N)(=O)=O)c(C)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c(C)cc1C#N
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (2.5 g, 9.5 mmol, prepared as described in Example 1 Step C) in t-butanol (70 mL) and dichloromethane (70 mL) was added 4-(dimethylamino)pyridine (3.47 g, 28.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.54 g, 23.7 mmol). The reaction mixture was stirred for 15 min after which time 4-cyano-2,5-dimethylbenzenesulfonamide (1.85 g, 8.85 mmol) was added, and stirring was continued at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×100 mL), the organic phase was collected and dried over magnesium sulfate and then concentrated under reduced pressure to afford a solid. The solid was isolated by filtration, rinsed with diethyl ether, and recrystallized from hexane/ethyl acetate to afford 1.5 g of the title compound, a compound of the present invention, as a solid, m.p. 228-229° C. 1H NMR (CDCl3) δ 9.97 (br s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 2.71 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:7]([S:10][CH3:11])=[C:3]([C:1]#[N:2])[C:4]([NH2:6])=[O:5])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CCO
Product: CSC(Nc1cccc(Cl)c1)=C(C#N)C(N)=O
Yield: 57 %

Procedure:
Dissolved 7.00 g (2-cyano-3,3-bis(methylthio)acrylamide) in 125 mL of ethanol. Then added 4.348 mL (1.10 eq.) of 3-chloroaniline to the reaction vessel and stirred the reaction at 75° C. until starting amide was absent and confirmed by HPLC. Once complete (18 hrs), the reaction was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-2-cyano-3-(methylthio)acrylamide as an off white to light yellow powder. Product was allowed to dry under vacuum for 1 hr (6.0 g, 57% yield).
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[Cl:51][C:52]1[O:56][C:55]([CH:57]=O)=[CH:54][CH:53]=1>C(O)C>[Cl:51][C:52]1[O:56][C:55]([CH:57]2[C:5]3=[C:6]4[N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10](=[O:20])[C:11]4=[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[N:4]3[CH2:3][C@H:2]([CH2:24][OH:25])[O:1]2)=[CH:54][CH:53]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](CO)C3
Temperature: 100 °C

Procedure:
A mixture of (R)-6-(2,3-dihydroxypropyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2) (806 mg, 2.320 mmol), bismuth triflate (305 mg, 0.464 mmol) and 5-chlorofuran-2-carbaldehyde (commercial) (333 mg, 2.55 mmol) in ethanol (13.6 mL) was heated under microwave irradiation at 100° C. for 25 mins. The mixture was evaporated under vacuum. The residue was partitioned between 0.1 M HCl (50 mL) and DCM (100 mL) and extracted with DCM (3×100 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-60% EtOAc/hexane afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1([C:16]2([C:19](OCC)=[O:20])[CH2:18][CH2:17]2)[CH:15]=[CH:14][N:13]=[CH:12]1.[Cl-].[NH4+]>ClCCl>[N:11]1([C:16]2([CH2:19][OH:20])[CH2:18][CH2:17]2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CCOC(=O)C1(n2ccnc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: OCC1(n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
Diisobutylaluminum hydride (1M in tetrahydrofuran, 8 mL, 8 mmol) was added dropwise to a solution of ethyl 1-(1H-imidazol-1-yl)cyclopropanecarboxylate (0.3 g, 1.6 mmol) in anhydrous dichloromethane (20 mL) at −78° C. The reaction mixture was warmed to room temperature and stirred at that temperature for 5 h. A saturated aqueous solution of ammonium chloride was added and the mixture was stirred for 30 min. The resulting solids were filtered through a pad of Celite and the filtrate was dried over sodium sulfate. The organics were concentrated under reduced pressure and the crude material was purified via column chromatography (100-200 mesh silica gel, 0-6% methanol in dichlormethane) to afford (1-(1H-imidazol-1-yl)cyclopropyl)methanol 0.15 g). MS (ES+APCI) (M+H) 139.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3Cl)[CH:16]=2)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[NH:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:16]=2)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(NC(=O)OC(C)(C)C)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-[1-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 492 (MH+); HPLC Rf: 5.23 min.; HPLC purity 96%.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[C:6](Br)[C:5](Br)=[C:4]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])[C:3]=1Br.BrBr.[Br-].[Na+].Br.Br([O-])(=O)=O.[Na+].Br>>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])=[CH:3][CH:2]=1
Reactant: CC(C)(c1ccc(O)cc1)c1c(Br)c(Br)c(O)c(Br)c1Br
Agent: Br
Agent: BrBr
Agent: [Br-]
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
A highly pure and colorless tetrabromobisphenol-A (TBBPA) possessing melting point in the range of 178-182° C. is prepared in yields of 50-70% in first batch and 90-100% when the spent organic layer is recycled. In this method, the corrosive liquid bromine is displaced by sodium bromide/hydrobromic acid as brominating agent. Further, sodium bromate is used as an oxidizing as well as brominating agent to utilize the hydrobromic acid that is produced during the bromination of bisphenol-A (BPA). The reaction is conducted at 10-15° C. in a mixture of methylene chloride-water or carbon tetrachloride-water in the presence of hydrochloric acid and sodium lauryl sulfate. The crystalline product settled at the bottom of the reaction vessel is filtered, washed, dried and weighed. The spent organic layer is recycled in subsequent batches to maximize the overall yield of product recovered directly as solid and to minimize generation of organic effluent.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13](=[O:29])[NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]([CH2:30][C:31](=[O:47])[NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:9]=1)(C)(C)C.Cl.O1CCOCC1>ClCCl>[CH2:22]([O:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[NH:14][C:13]([C:11]1[N:10]([CH2:30][C:31](=[O:47])[NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:9]=[C:8]([NH2:7])[CH:12]=1)=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Reaction time: 6 h
Yield: 96.7 %

Procedure:
To a solution of {5-(2-Benzyloxy-cyclohexylcarbamoyl)-1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazol-3-yl}-carbamic acid tert-butyl ester (0.5 gm) in 5 ml of dichloromethane was added 1 ml of 4N hydrochloric acid/dioxane. After stirring for 6 hours the mixture was evaporated to dryness to obtain 0.41 gm of title product as the hydrochloride salt. ESI M+1=560.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)=[O:13])=[CH:7][CH:6]=1)(=O)C.C(Cl)(=O)C>CO.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[NH2:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)=[O:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Temperature: 0 °C
Yield: 85 %

Procedure:
To a suspension of 0.6 g (1.43 mmol) of N-[6-(acetylamino)pyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.1, in 9 mL of anhydrous methanol, stirred at 0° C. under an inert atmosphere, are added dropwise 2.03 mL (28.54 mmol) of acetyl chloride. The reaction mixture is stirred at 0° C. for 30 minutes and then gradually brought to 70° C. and stirred for 48 hours. The reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 200 mL of saturated aqueous NaHCO3 solution and 200 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. 0.46 g of the expected product is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]CC)=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.C(O)C.O.[OH-].[Li+]>O>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cncnc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1cncnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of 0.6 g (3 mmol) of ethyl (4-chloro-5-pyrimidinyl)acetate from Step A above in 0.5 mL of water and 1.5 mL of ethanol was added 215 mg (5.11 mmol) of lithium hydroxide hydrate. The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to remove all volatiles. The residue was diluted with 7 mL of 2.0 M aqueous hydrogen chloride and then concentrated in vacuo to remove all volatiles to yield the title compound (0.43 g, 83%). 1H-NMR (500 MHz, CD3OD) δ: 8.88 (s, 1H), 8.70 (s, 1H), 3.96 (s, 2H). LC-MS: m/z (E/S) 173 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12

Procedure:
Ethyl 2-[1-(4-nitrobenzyl)-1H-indazol-3-yl]acetate (225 mg, 0.663 mmol) was dissolved in methanol (20 mL). 10% Pd/C(18 mg) was added, and reacted under hydrogen atmosphere for half an hour. TLC (petroleum ether:ethyl acetate=2:1) indicated that starting material disappeared. It was filtered to remove solid, rotate evaporated to dryness to remove the solvent, and the resulting solid was used for the next step directly.
Reaction SMILES: BrCCCC(C(=O)C)C(=O)C.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:25](=[O:29])[CH2:26][CH2:27]C)[C:20](=[O:24])[CH2:21][CH2:22]C>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:20](=[O:24])[CH2:21][CH3:22])[C:25](=[O:29])[CH2:26][CH3:27]
Reactant: CCCC(=O)C(CCCCCCBr)C(=O)CCC
Agent: CC(=O)C(CCCBr)C(C)=O
Product: CCC(=O)C(CCCCCCBr)C(=O)CC

Procedure:
By selecting the appropriate alkane dibromide and dione, there can be prepared 3-(3-bromopropyl)-2,4-pentanedione, 4-(6-bromohexyl)-2,2,6,6-tetramethyl-3,5-pentanedione, 5-(6-bromohexyl)-4,6-nonanedione, and the like.
Reaction SMILES: C([O:8][C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:25])[CH:22]=3)[CH:17]2[OH:26])[CH2:11][CH2:10]1)C1C=CC=CC=1.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>CCO>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[OH:8][C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:25])[CH:22]=3)[CH:17]2[OH:26])[CH2:11][CH2:10]1
Reactant: Cc1ccc(CC2(OCc3ccccc3)CCN(CC3Cc4cc(O)ccc4C3O)CC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: Cc1ccc(CC2(O)CCN(CC3Cc4cc(O)ccc4C3O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1RS,2RS) and (1RS, 2SR)-2-[4-benzyloxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-indan-1,5-diol (674 mg, 1.84 mmol) was taken up in EtOH (20 ml), fumaric acid (106 mg, 0.92 mmol) was added and the mixture stirred for 2 hr at RT, after evaporation of the solvent, (1RS,2RS) and (1RS, 2SR)-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-indan-1,5-diol fumaric acid salt was obtained as a white foam (0.78 g, quant.), MS m/e=368.2 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[I:5][C:6]1[CH:15]=[CH:14][N:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][NH:11]2.[OH-].[Na+]>S(=O)(=O)(O)O>[I:5][C:6]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:14][N:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][NH:11]2
Reactant: O=[N+]([O-])O
Reactant: Ic1ccnc2c1CCCN2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2c(c1I)CCCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Fuming nitric acid (0.5 mL, 10 mmol) was added a mixture of 5-iodo-1,2,3,4-tetrahydro-1,8-naphthyridine (1.0 g, 3.8 mmol) in sulfuric acid (10 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 30 min. The mixture was poured into ice-water and neutralized with 3 M aq. NaOH. The resulting solid precipitate was collected by filtration, washed with water and dried to give the sub-title compound (0.50 g, 43%). LCMS calc. for C8H9IN3O2(M+H)+: m/z=306.0. Found: 306.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 1-benzyl-3-methyl-piperidin-4-one (5.0 g, 24.6 mmol) in dry tetrahydrofuran (100 mL) and cool the resulting solution to 0° C. Add 1 mL-lithium tri-sec-butylborohydride (L-Selectride®) solution in tetrahydrofuran (29.6 mL, 29.6 mmol) dropwise over 30 min. After stirring at 0° C. for 1 hr., quench with water (50 mL), extract with ethyl acetate (2×100 mL), wash the combined organic layers with aqueous NaCl solution (100 mL), separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 5% (2M NH3/methanol)/methylene dichloride to obtain of the title compound as a mixture of enantiomers (3.84 g, 76%). 1H NMR (CDCl3): 7.25 (m, 5H), 3.8 (m, 1H), 3.5 (s, 2H), 2.4 (m, 3H), 2.2 (m, 1H), 1.9 (m, 1H), 1.8 (m, 2H), 0.95 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=O.N1C=CC=CC=1.C[CH:29]([C:33](Cl)=[O:34])[C:30](Cl)=[O:31].Cl>C(Cl)Cl>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[NH:1][C:30](=[O:31])[C:29]=2[CH2:33][OH:34])[CH:19]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1cc(Cl)ccc1O
Reactant: CC(C(=O)Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2cc(Cl)ccc2O)c1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-amino-5-(trifluoromethyl)phenyl](5-chloro-2-hydroxyphenyl)methanone (0.5 g, 1.58 mmol) and pyridine (0.25 mL, 3.17 mmol) in methylene chloride (15 mL), a solution of methyl malonyl chloride (0.34 mL, 3.17 mmol) in methylene chloride (10 mL) was added dropwise at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was acidified with 1N HCl and the organic layer was separated. It was then washed with saturated NaHCO3 twice, water, brine and dried (MgSO4). Evaporation of the solvent gave the title compound as a yellowish oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[NH:13][C:12]1=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Si](Cl)([C:26]([CH3:29])(C)[CH3:27])(C)C>O1CCCC1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[N:13]([CH2:15][C:17]([O:19][CH2:27][CH:26]=[CH2:29])=[O:18])[C:12]1=[O:20])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 143.4 %

Procedure:
(3S,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-2-azetidinone (6 g) is dissolved in tetrahydrofuran (250 ml), and thereto is added 60% sodium hydride (0.796 g) at 10° C., and the mixture is stirred at 20° C. for 20 minutes. To the mixture is added t-butyldimethylsilyl chloride (3 g) at 10° C., and the mixture is stirred for 10 minutes, and concentrated under reduced pressure to the quarter volume thereof. The concentrated mixture is stirred at 20° C. for 20 minutes, and thereto is added a mixture of bromoacetic acid allyl ester (3.56 g) and tetrahydrofuran (190 ml), and further added thereto dropwise 1M solution (20 ml) of sodium bis(trimethylsilyl)amide in tetrahydrofuran at -50° C. The mixture is warmed to 20° C. over a period of 30 minutes, and concentrated under reduced pressure to a quarter volume thereof. The concentrated mixture is stirred at 20° C. for 2 hours, and thereto is added tetrahydrofuran (190 ml), and further added dropwise a solution of potassium carbonate (2.8 g) in water (40 ml) at 10° C. The mixture is stirred at 20° C. for 15 minutes. To the mixture is added diluted hydrochloric acid [hydrochloric acid (4.2 g) in water (8 ml)] at 10° C., and thereto is added 1N hydrochloric acid (18 ml) under ice-cooling. The mixture is allowed to stand, and the organic layer is collected. The aqueous layer is extracted with chloroform, and the organic layers are combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform→chloroform:methanol=98:2) to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-1-(allyloxycarbonylmethyl)-2-azetidinone (5.7 g) as oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:8]=1)=O.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[OH:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(O)c2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-hydroxyphenyl)-1H-pyridazin-4-one (A-17) and naphthalen-1-yl-hydrazine according to the method described for example 91. MS: M=381.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH3:22]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[2-[N-(4-Fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([C@H:4]1[C:8]2=[N:9][CH:10]=[C:11]([N:14]([CH2:25][CH:26]=[CH2:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:12](=[O:13])[N:7]2[C@H:6]([C:28]([OH:30])=[O:29])[CH2:5]1)[CH:2]=[CH2:3].[CH2:31](N(C1C(=O)N2[C@H](C(N(C(OC(C)(C)C)=O)C3C=CC=CC=3)=O)CC(CC=C)(CC=C)C2=NC=1)C(=O)OCC1C=CC=CC=1)[CH:32]=[CH2:33]>>[CH2:1]([C:4]1([CH2:33][CH:32]=[CH2:31])[C:8]2=[N:9][CH:10]=[C:11]([N:14]([CH2:25][CH:26]=[CH2:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:12](=[O:13])[N:7]2[C@H:6]([C:28]([OH:30])=[O:29])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@@H](C(=O)O)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)CC2(CC=C)CC=C
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)CC2(CC=C)CC=C
Yield: 76 %

Procedure:
According to the procedure for the preparation of 28d, 29c (372 mg, 0.595 mmol) afforded 202 mg (76%) of 29d. MS (ESI) 450.4 (M+H+), 448.2 (M−H+).