Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=1>C(O)(=O)C>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=2)=[C:6]([Cl:20])[CH:5]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)nn(C)c1=O
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (93) (300 mg, 0.66 mmol) in glacial acetic acid was heated to 110° C. for 3 h. At this time, the reaction was cooled to 25° C. and was poured onto water (100 mL). This mixture was extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to a brown oil. Recrystallization from diethyl ether and hexanes followed by flash chromatography (Merck Silica gel 60, 230-400 mesh, 30:70 ethyl acetate/petroleum ether) afforded 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-2-methyl-2H-pyridazin-3-one (94) (148 mg, 69%) as an off-white solid; ES-HRMS m/e calcd for C15H17Cl2N3O (M+H)+ 326.0822, found 326.0822. Exact Mass=325.0749; Molecular Weight=326.2282.
Reaction SMILES: ClC1C=C(C=CC=1F)C1C(C2C=CC3C(=CC=C(C4N(C5CCCCC5)C5C=CC(C(O)=O)=CC=5N=4)C=3)N=2)=CC(OC)=CC=1.C[O:46][C:47]([C:49]1[CH:82]=[CH:81][C:52]2[N:53]([CH:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)[C:54]([C:56]3[CH:57]=[C:58]4[C:63](=[CH:64][CH:65]=3)[N:62]=[C:61]([C:66]3[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[CH:68][C:67]=3Br)[CH:60]=[CH:59]4)=[N:55][C:51]=2[CH:50]=1)=[O:48].[N+:83]([C:86]1[CH:91]=[CH:90][C:89](B(O)O)=[CH:88][CH:87]=1)([O-:85])=[O:84]>>[CH:75]1([N:53]2[C:52]3[CH:81]=[CH:82][C:49]([C:47]([OH:46])=[O:48])=[CH:50][C:51]=3[N:55]=[C:54]2[C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[N:62]=[C:61]([C:66]2[C:67]([C:89]4[CH:90]=[CH:91][C:86]([N+:83]([O-:85])=[O:84])=[CH:87][CH:88]=4)=[CH:68][CH:69]=[C:70]([O:72][CH3:73])[CH:71]=2)[CH:60]=[CH:59]3)[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80]1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 14.3 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-nitrophenylboronic acid (62 mg, 0.2625 mmol) to produce the title compound (15 mg, 14% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].I[CH2:24][CH:25]([CH3:27])[CH3:26]>C1COCC1>[CH3:24][CH:25]([CH3:27])[CH2:26][CH:11]1[CH2:12][CH2:13][N:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:14]
Reactant: O=C1CCCN1CCc1ccccc1
Reactant: CC(C)CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
A solution of 1-(2-phenylethyl)-2-pyrrolidinone (500 mg, 2.64 mmol) and THF (6 mL) is cooled to -78° C. Some precipitation occurred and 2 mL of THF is added. A solution of lithium diisopropylamide (LDA, 1.4 mL, 2.8 mmol, 2.0M in heptane/THF/ethylbenzene) is added and the mixture stirred at -78° C. for 40 minutes, giving a dark brown solution. To this solution is added 1-iodo-2-methylpropane (0.37 mL, 3.2 mmol). The solution is allowed to warm from -78° C. to 5° C. over 2.5 hours. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgSO4) and purification by column chromatography (20% EtOAc/hexane) to give 642 mg (99%) of the title compound as a white solid (mp 69°-71° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:16])[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>O1CCCC1>[Si:28]([O:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:16])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:15])[CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)CCC(O)c2c(CO)cccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCC(O)c2c(CO[Si](C)(C)C(C)(C)C)cccc2C1
Reaction time: 8 h

Procedure:
To a solution of 4-(hydroxymethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (18.87 g, 85.65 mmol), 4-N,N-dimethylaminopyridine (0.5 g) and triethylamine (14.3 ml, 103 mmol) in tetrahydrofuran (100 ml) was added tert-butyldimethylchlorosilane (14.2 g, 94.2 mmol) at room temperature, and the mixture was stirred as it was overnight. The reaction solution was poured into water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1-9/1) to give the objective substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17]N(C)C)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17][N:27]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)NC(=O)OCc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
36 g (129 mmol) of methyl 2-benzyloxycarbonylamino-3-dimethylaminoacrylate and 24.12 g (142 mmol) of diphenylamine were dissolved in 630 ml of isopropanol at 40° C. Subsequently, the solution was admixed with 17.4 ml of concentrated hydrochloric acid within 5 min and stirred at 40° C. for a further 30 min. The reaction solution was concentrated to 300 ml and admixed slowly with 300 ml of water. The crystallized product was filtered off with suction and dried at 40° C. under reduced pressure. Yield: 30.5 g (59% of theory) 1H NMR: 3.62 (s, 3H), 4.68 (s, 2H), 6.95-7.10 (m, 6H), 7.20-7.50 (m, 9H), 7.61 (s,1 H)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[NH:5][C:6]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]([C:10](N(OC)C)=[O:11])=[CH:8][N:7]=1)[CH3:2].[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C(Cl)Cl>[C:10]([C:9]1[C:16]([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:25])=[N:7][CH:8]=1)(=[O:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)N(C)OC)cn1
Reactant: Br[Mg]c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)c2ccccc2)cn1
Temperature: 25 °C
Yield: 82 %

Procedure:
Compound 83 (15 mg, 0.044 mmol) was dissolved in dry THF (0.8 mL) and this solution added to the phenyl magnesium bromide (1M, 0.2 mL, 0.20 mmol) at 0° C. The mixture was stirred and allowed to warm slowly to RT. The mixture was quenched with MeOH/HCl (2M) (1 mL:0.1 mL) then NH4Cl (sat.) added and the mixture diluted with water and EtOAc (pH of aqueous ˜7). The mixture was extracted into EtOAc and the organics combined and dried with brine then Na2SO4. The solvent was removed to afford 20 mg crude residue. This was dissolved in DCM (2 mL) and applied to a silica column, eluting with EtOAc/heptane, to afford Compound 112 (13 mg).).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:14][CH3:15])=[C:7](I)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2].[C:16]([C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1)#[CH:17]>CC#N.CCN(CC)CC.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>[CH3:15][O:14][C:6]1[C:7]([C:17]#[C:16][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=2)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: COc1ccc(I)c(OC)c1OC(C)=O
Reactant: C#Cc1cncn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2cncn2C)c(OC)c1OC(C)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a stirred solution of 3-acetoxy-2,4-dimethoxy-iodobenzene (250 mg, 0.776 mmol) and 5-ethynyl-1-methyl-1H-imidazole (100 mg, 1.09 mmol) in dry MeCN (3 ml) and dry NEt3 (1 ml) was added Pd(Ph3P)2Cl2 (20 mg, 3.7 mol %) and the reaction vessel was evacuated and backfilled with N2(g) three times. Copper (I) iodide (15 mg) was added and the reaction was heated to 60° C. and stirred overnight. The resulting dark solution was cooled, diluted with EtOAc and filtered through celite. The filtrate was concentrated onto silica-gel under reduced pressure and the solid residue was purified by flash chromatography (silica-gel, eluted with EtOAc) to give the product as a tan solid (130 mg, 56%). 1H-NMR (300 MHz, CDCl3) δ 7.45 (br s, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.30 (br s, 1H), 6.68 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH:19]([C:22]1[N:26]=[C:25]([C:27](O)=[O:28])[O:24][N:23]=1)([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[O:24][N:23]=[C:22]([CH:19]([CH3:21])[CH3:20])[N:26]=3)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC(C)c1noc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.33 g, 1.28 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid (0.2 g, 1.28 mmol), HOBt (0.26 g, 1.92 mmol), DIPEA (0.7 mL, 3.84 mmol) and EDCI (0.37 g, 1.92 mmol) using DMF (10 mL) as solvent. Yield 0.197 g. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 1.33 (d, 6H), 3.15 (m, 1H), 4.38 (m, 2H), 4.57 (m, 1H), 6.78 (d, 1H), 7.71 (d, 1H), 7.77 (m, 1H), 7.87 (dd, 1H), 8.02 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]3[CH2:46][CH2:45][N:44]([CH:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH2:49][CH2:48]3)=[O:22])[CH:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)c(C)c1
Reaction time: 1.5 h

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (74 mg, 0.21 mmol) is dissolved in THF (4 mL) and CDI (68 mg, 0.42 mmol) added. The resulting solution was stirred for 90 min prior to the addition of 1-(1-methylpiperidin-4-yl)piperazine (77 mg, 0.42 mmol). The reaction was stirred at ambient temperature for 18 h, concentrated in vacuo and a portion of the resulting crude product purified using prep method B to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[N:13]1([CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8]2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: C1CNCCNC1
Solvent: Cc1ccccc1
Product: Cl
Product: Clc1ccc2c(c1)CCC(N1CCCNCC1)C2
Yield: 71.6 %

Procedure:
To a solution of 6-chloro-2-tetralone (7.22 g) and homopiperazine (8.0 g) in 100 ml of toluene were added 10 g of 3A molecular sieves. The mixture was heated on the steam bath for 2 hours, the sieves were filtered off, and toluene was evaporated from the filtrate. The residue was dissolved in a mixture of 100 ml of THF and 30 ml of methanol. The resultant solution was cooled in an ice bath with stirring under nitrogen, 2.51 g of sodium cyanoborohydride were added, and, with stirring and cooling, gaseous HCl was added portionwise periodically until the solution remained acidic. After stirring overnight at room temperature, the solvents were evaporated, and the residue was partitioned between dilute hydrochloric acid and ether. The acidic aqueous layer was separated and made basic with sodium hydroxide. The oil which formed was extracted with ether. The ether solution was dried (MgSO4), and the ether was evaporated. The residue was dissolved in ethanol, and excess gaseous HCl was added to the solution The solvent was evaporated. The residue crystallized slowly from a mixture of ethanol and ether to obtain 3.22 g of the title compound. m.p. 181°-183° C.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[O:24][CH3:25])=[O:13])[C:9]([OH:26])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:27][N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.C(N(CC)CC)C>>[CH3:25][O:24][C:17]1[C:18]([O:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:26])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([S:35][C:32]2[CH:33]=[CH:34][C:29]([N:28]([CH3:36])[CH3:27])=[CH:30][CH:31]=2)[N:11]=1)=[O:13]
Reactant: CN(C)c1ccc(S)cc1
Reactant: COc1cccc(CNC(=O)c2nc(Br)c3cccnc3c2O)c1OC
Solvent: CCN(CC)CC
Product: COc1cccc(CNC(=O)c2nc(Sc3ccc(N(C)C)cc3)c3cccnc3c2O)c1OC
Temperature: 135 °C

Procedure:
Into a pressure reactor was placed 5-bromo-N-(2,3-dimethoxybenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.1 g, 0.24 mmol), 4-(dimethylamino)benzenethiol (0.147 g, 0.96 mmol) and triethylamine (0.363 g, 0.5 mL, 3.59 mmol). The vessel was purged with nitrogen gas, sealed and heated to 135° C. for 18 hours, after which time it was cooled and the excess triethylamine removed in vacuo. The residue was partitioned between EtOAc/water and extracted. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the solvent removed. The resulting glass was triturated with diethyl ether and filtered to yield N-(2,3-dimethoxybenzyl)-5-{[4-(dimethylamino)phenyl]thio}-8-hydroxy-1,6-naphthyridine-7-carboxamide as a solid.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][C:17]1=[O:31].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][C:17]1=[O:31]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)OC
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1C/C=C\CCCC(=O)OC
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A 50 mL round bottom flask was charged with nickel (II) chloride (273 mg, 2.10 mmol) and sodium borohydride (40 mg, 1.05 mmol), then 95% ethanol (2.0 mL) was added. The mixture immediately turned black. After 15 min at rt, ethylene diamine (0.23 mL, 3.36 mmol) was added. After another 15 min at rt, 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (152 mg, 0.42 mmol) in 95% ethanol (2.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the resulting residue by flash column chromatography (10→50% EtOAc/CH2Cl2, gradient) afforded 65 mg (43%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CO>[CH2:11]([NH:18][C:8]([C@H:5]1[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]1)=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CO
Product: O=C(NCc1ccccc1)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of cis-4-hydroxycyclohexanecarboxylic acid (1.0 g, 6.94 mmol), benzylamine (0.82 mL, 7.51 mmol) and HOAt (1.0 g, 7.35 mmol) in dichloromethane (50 mL) was added EDC free base (1.2 g, 7.73 mmol). The reaction was stirred overnight at room temperature, at which time it was washed with 1 N HCl, 1 N Na2CO3, brine, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-80 g, 0 to 4% MeOH in CH2Cl2) gave (cis)-N -benzyl-4-hydroxycyclohexanecarboxamide (1.0 g, 4.29 mmol, 61.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (t, J=5.81Hz, 1H), 7.26-7.38 (m, 2H), 7.11-7.27 (m, 3H), 4.31 (d, J=3.28 Hz, 1H), 4.25 (d, J=6.06 Hz, 2H), 3.76 (d, J=2.53 Hz, 1H), 2.08-2.22 (m, 1H), 1.73-1.89 (m, 2H), 1.56-1.69 (m, 2H), 1.33-1.49 (m, 4H). MS(ES) [M+H]+ 234.0.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH:18]([O:23][CH2:24][C:25]3([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:19]([O:21][CH3:22])=O)[CH:17]=1)[NH:14][N:13]=[CH:12]2.ClC1C=C2C(=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C(OC(C)(C)C)=O)CC3)COC)C=1)NN=C2>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH:18]([O:23][CH2:24][C:25]3([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH2:19][O:21][CH3:22])[CH:17]=1)[NH:14][N:13]=[CH:12]2
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: COCC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: COCC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12

Procedure:
Prepared according to the procedure used to prepare methyl 2-(5-chloro-1H-indazol-7-yl)-2-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)acetate trifluoroacetic acid salt using tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. 1H-NMR (CD3OD, 500 MHz) δ 8.48 (s, 0.1H), 8.03 (s, 0.8H), 7.88 (s, 0.1H), 7.70 (m, 0.8H), 7.42 (m, 2H), 6.90-7.40 (m, 3H), 4.77 (m, 1H), 3.87 (m, 0.3H), 3.68 (m, 1H), 3.40-3.63 (m, 4.8H), 2.40-3.00 (m, 7H), 2.12 (m, 2H). Mass spec.: 432.26 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:21]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)(C)C.ClCCCl.C(Cl)Cl>[ClH:1].[O:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]4([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC1(C#Cc2ccc3ncnc(Cl)c3c2)CCOCC1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: Cl
Product: OC1(C#Cc2ccc3ncnc(Nc4ccc(Oc5ccccc5)cc4)c3c2)CCOCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A mixture of 4-(4-Chloro-quinazolin-6-ylethynyl)-tetrahydro-pyran-4-ol (43 mg, 0.15 mmol) and 4-phenoxyaniline (28 mg, 0.15 mmol) in 2 mL of t-BuOH/1,2-dichloroethane (1:1) was heated at 90° C. with stirring in a reaction vial for 1 hour. The reaction was cooled, diluted with CH2Cl2 and the product was collected by filtration to provide 52 mg (73%) of 32 as a yellow solid: 1H NMR (CD3OD) δ 1.86 (m, 2H), 2.02 (m, 2H), 3.74 (m, 2H), 3.92 (m, 2H), 7.05 (m, 4H), 7.15 (t, J=7.6 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H), 7.69 (d, J=6.8Hz, 2H), 7.81 (d, J=7.2Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 8.75 (s, 2H); HPLC: 6.36 min.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([NH:7][CH2:8][C:9]1[N:14]=[C:13]([C:15]#N)[CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH3:5].[OH2:17]>O1CCCC1>[C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][NH:7][C:4](=[O:6])[CH3:5])[N:14]=1)(=[O:17])[CH3:1]
Reactant: O
Reactant: C[Mg]Br
Reactant: CC(=O)NCc1cccc(C#N)n1
Solvent: C1CCOC1
Product: CC(=O)NCc1cccc(C(C)=O)n1

Procedure:
An ethereal solution of methyl magnesium bromide (3 mol/l) (17.6 ml) was added dropwise to a solution of 6-(acetylaminomethyl)-2-pyridinecarbonitrile (3.70 g) in tetrahydrofuran (60 ml) at 5 to 10° C. with stirring. After the mixture was stirred for two hours at the same temperature, cold water (15 ml) was dropped to the mixture under ice-cooling and evaporated in vacuo. The residue was mixed with water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography by eluting with a mixture of ethyl acetate and methanol (50:1) to give 2-acetyl-6-(acetylaminomethyl)pyridine (2.70 g).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[S:37]1([CH2:43][CH2:42][CH:41]([NH:44][NH2:45])[CH2:40]1)(=[O:39])=[O:38].Cl>O1CCCC1.O>[S:37]1([CH2:43][CH2:42][CH:41]([NH:44][N:45]=[CH:1][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C:25](=[O:36])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[CH2:40]1)(=[O:39])=[O:38]
Reactant: NNC1CCS(=O)(=O)C1
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=NNC3CCS(=O)(=O)C3)CS[C@H]12
Reaction time: 5 h
Yield: 73 %

Procedure:
To a solution of diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solution of (sulfolane-3-yl) hydrazine (70 mg) and 1.5 equivalents of hydrochloric acid in water (3 ml), and the mixture is kept at room temperature 5 hours. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 3-(sulfolan-3-ylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (142 mg). m.p. 117°-125° C. Yield: 76%. IR: νmaxNujol 3275, 1785, 1715, 1675, 1530cm-1.