Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[CH2:7]([C:14]1[NH:19][C:18](=O)[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI>CN(C=O)C.C1COCC1>[CH2:7]([C:14]1[N:19]([CH3:18])[C:1](=[O:4])[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccnc(Cc2ccccc2)[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1c(Cc2ccccc2)nccc1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cs2CO3 (24.6 g, 75.7 mmol) was added to 2-benzyl-3H-pyrimidin-4-one (Step 1, 12.8 g) in DMF (80 mL) and THF (60 mL) at 0° C. After 10 min, MeI (4.3 mL, 68.8 mmol) was added, and the reaction was warmed to RT. After 3 h, the reaction was decanted, diluted with CH2Cl2, and washed with H2O, and aq. sat. NaCl solution. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Et2O and Hexane (1:1) were added and the solvent was evaporated to provide a brown solid. The solid was triturated with 30′ EtOAc/hexane to afford the title compound as a light brown solid. The filtrate was purified by chromatography with 0-5% MeOH/CHCl3 to afford additional compound. MS (ESI pos. ion) m/z: 201.0. (M+H). Calc'd for C12H12N2O: 200.09.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[H-].CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([CH2:4][OH:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (50 mg) in THF (1 mL) at -78° C. was added Diisobutylahminum hydride (0.534 mL, 1M/THF). After 1 hour at -78° C, the mixture was warmed to RT and 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 80/20/1 CH2Cl2 /MeOH/NH4OH) gave 28 mg of a solid. 1H NMR (300 MHz, CD3OD) δ 7.57 (t, 2H, J=7.5 Hz), 7.48 (t, 2H, J=7.5 Hz), 7.26 (s, 1H), 7.08-7.02 (AB quartet, 4H), 5.54 (s, 2H), 4.74 (s, 2H), 2.85 (q, 2H, J=7.5 Hz), 2.66 (s, 3H), 1.26 (t, 3H, J=7.5 Hz).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][F:14])(=O)=O)=CC=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:33])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][NH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[F:14][CH2:13][CH2:12][N:26]1[CH:27]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:23](=[O:33])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)cc(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
2-Fluoroethyl 4-methylbenzenesulfonate (1.00 g) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.00 g) and cesium carbonate (2.49 g) in DMF (9 ml) at room temperature. The reaction mixture was stirred at 80° C. for two hours. The reaction mixture was returned to room temperature and diluted by adding ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography [ethyl acetate:hexane:methanol=1:1:0->7:3:0->1:0:0->19:0:1 (v/v)] to give 0.35 g of the title compound as an oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:32]=[CH:31][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36]/[N:35]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:31][CH:32]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
In analogy to example 151, step 3, 3-{4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoylamino}-propionic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=460.3 [M−H]−.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10].[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>CN(C)C=O>[CH3:8][S:9]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:20])[CH2:16][CH2:17]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(NC(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (229.4 mg, 0.785 mmol, US20060014708) in N,N-dimethyl formamide (4.0 mL) was added TEA (101 mg, 1.004 mmol) and 1,1′-carbonyldiimidazole (Aldrich, 134 mg, 0.826 mmol). After it was stirred at rt for 2 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give imidazole-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (150.7 mg, 70.5%) which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][S:4]([CH2:7][CH:8]([NH:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])[C:9](=[O:26])[NH:10][CH:11]([C:14]([C:16]1[O:20][N:19]=[C:18](C2SC=CC=2)[N:17]=1)=[O:15])[CH2:12][CH3:13])(=[O:6])=[O:5].C1C=CC2N(O)N=NC=2C=1.N[C@@H](CC)C(C1ON=[C:53]([C:56](C)([CH3:58])[CH3:57])N=1)O>ClCCl>[C:56]([C:18]1[N:17]=[C:16]([CH:14]([OH:15])[CH:11]([NH:10][C:9]([CH:8]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])[CH2:7][S:4]([CH2:3][CH:2]([CH3:36])[CH3:1])(=[O:5])=[O:6])=[O:26])[CH2:12][CH3:13])[O:20][N:19]=1)([CH3:58])([CH3:57])[CH3:53]
Reactant: CC[C@H](N)C(O)c1nc(C(C)(C)C)no1
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(=O)c1nc(-c2cccs2)no1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(O)c1nc(C(C)(C)C)no1
Reaction time: 0.33 h
Yield: 104.7 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methylpolystyrene (0.526 g, 1 mmol, loading 1:9 mol/g) was suspended in dichloromethane (20 mL). 3-(2-methyl-propane-1-sulfonyl)-2-[(morpholine-4-carbonyl)-amino]-propionic acid (0.242 g, 0.6 mmol, reference Example 5) and HOBt (0.114 g, 0.85 mmol) were added and the reaction mixture was stirred for 20 minutes. (2S)-2-Amino-1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol (0.107 g, 0.5 mmol, Reference Example 6) was added and stirring continued for 5 hours. Silicycle Triamine (1.27 g, 5 mmol) was added and the mixture stirred for 15 hours. The reaction mixture was filtered under suction and the filtrate concentrated to give morpholine-4-carboxylic acid [1-{1-[(3-tert-butyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide (0.271 g), [LC/MS m/z=518 (M+H+)].
Reaction SMILES: NCCNC(=O)OCC1C=CC=CC=1.[N:15]([C:18](=[CH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2)[C:19]([O:21][CH3:22])=[O:20])=[N+]=[N-].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]1[C:24]2=[C:25]3[C:29]([CH:30]=[CH:31][C:32]2=[N:15][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[N:28][CH:27]=[CH:26]3
Reactant: COC(=O)C(=Cc1cccc2[nH]ccc12)N=[N+]=[N-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCNC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 338.3 %

Procedure:
A solution of 1 (47 mg, 0.06 mmol), 2 (40 mg, 0.078 mmol) and BOP (34.5 mg, 0.078 mmol) in DMF (3 ml) was treated with DIPEA (68 uL). The reaction mixture was stirred at 25° C. for 30 min. The solvent was removed and was further dried in high vacuo for 4 h. The solvent was removed under vacuo and the crude product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to give 3 (56 mg, 85%). MS: calcd for C56H54BrN9O8 (M+H) m/z 1060.33 found 1060.44.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[N:3]=1.[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])(=[O:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: OCC(F)(F)F
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(OCC(F)(F)F)c1cc2nc(Cl)c(Cl)nc2cc1Cl

Procedure:
To a stirred mixture of 470 g (1.42 mole) of 2,3,7-trichloro-6-quinoxalinesulfonyl chloride and 153 g (1.53 mole) of 2,2,2-trifluoroethanol in 3 liters of anhydrous tetrahydrofuran are added 183 g (1.42 mole) of N,N-diisopropylethylamine. The resulting mixture is heated under reflux with exclusion of moisture for 24 hours. The solvent is removed under reduced pressure to obtain a residue which is dispersed in one liter of diethyl ether. The resulting mixture is washed twice with 500 ml of water then dried over magnesium sulfate, and filtered. The filtrate obtained therefrom is evaporated to give crude product which is recrystallized first from cyclohexane and then from 2-propanol to give 112 g (20%) of nearly colorless crystals having a melting point of 142°-144°.
Reaction SMILES: [C:1]([CH:3]=[C:4]([CH:6]1[CH:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[CH:10]2[CH2:16][CH:7]1[CH2:8][CH2:9]2)[CH3:5])#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH2:3][CH:4]([CH:6]1[CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:10]2[CH2:16][CH:7]1[CH2:8][CH2:9]2)[CH3:5])#[N:2]
Reactant: [H][H]
Reactant: CC(C)=CC1C2CCC(C2)C1C(C)=CC#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CC1C2CCC(C2)C1C(C)CC#N
Reaction time: 5 h

Procedure:
A solution of 30.6 g (0.14 mole) of 2-(1-cyanoprop-1-en-2-yl)-3-(2-methylprop-1-en-1-yl)-bicyclo[2.2.1]heptane in 100 ml of ethyl acetate was stirred together with 800 mg of 10% palladium on carbon at 90° C. in a hydrogen atmosphere under 90 bar, until the pressure remained constant for 5 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[C:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:9][C:10]=1[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[C:8]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[NH:9][C:10]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Yield: 95.3 %

Procedure:
5-(2-Ethoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1c (24 g, 68.3 mmol) was dissolved in anhydrous ethanol (180 ml) under stirring, and added with palladium on activated carbon (2.44 g, 10%) to the solution. The resulting solution was stirred at room temperature overnight under a hydrogen atmosphere. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered to remove palladium on activated carbon, and washed with a little ethanol. The filtrate was concentrated under reduced pressure to obtain the title compound 5-(2-ethoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1d (23 g, yield 95%) as a white solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]#[CH:26])#C.Cl[C:28]1C=CC=C[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].CO>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([C:20]1[CH:19]=[CH:24][C:23]([C:28]#[CH:29])=[CH:22][CH:21]=1)#[CH:26]
Reactant: Clc1ccccc1
Reactant: C#Cc1ccccc1C#C
Agent: [Ni+2]
Agent: C(C#Cc1ccccc1)#Cc1ccccc1
Agent: CC(=O)/C=C(/C)[O-]
Solvent: c1ccccc1
Solvent: CO
Product: C#Cc1ccc(C#C)cc1
Reaction time: 1 h

Procedure:
A copolymer prepolymer of diphenylbutadiyne and p-diethynylbenzene was prepared in refluxing benzene solvent. The polymerization vessel was charged with 63 parts of diphenylbutadiyne, 2 parts of diethynylbenzene, 600 parts of benzene, and 2 parts of chlorobenzene. After heating to reflux, 2 parts of a catalyst mixture prepared by mixing 2 parts of nickel acetylacetonate and 4 parts of triphenylphosphine in 20 parts of benzene were added. After 1 hour, an additional 10 parts of diethynylbenzene was added. After 2 hours, 10 parts of diethynylbenzene and 2 parts of catalyst solution were added. After 3 hours, 20 parts of diethynylbenzene and 4 parts of catalyst solution were added. After a total reaction period of 7 hours, gas-liquid chromatographic analysis of the reaction mixture showed that 10% of each of the monomeric components remained. The solution was added to 5 times its volume of methanol, and 77 parts of the copolymer was precipitated. It has an acetylene content of 8.4% and an aromatic to olefin hydrogen ratio of 8:1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:9])[N+:7]=1[O-:8].[H-].[Na+].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)(Cl)Cl.O.CS(C)=O>[CH2:12]([O:19][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:9])[N+:7]=1[O-:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(Cl)[n+]1[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(OCc2ccccc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
0.80 g of 6-chloro-2-picoline 1-oxide was added to an alcoholate solution prepared from 0.33 g of 60% oily sodium hydride, 0.69 ml of benzyl alcohol and 5 ml of dimethyl sulfoxide. The mixture was stirred overnight at room temperature. 1N-HCl (1.7 ml) was added to the reaction mixture and then water and chloroform were added. The organic layer was separated, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 100 g; eluting solvent: chloroform/methanol=80/1→40/1) to give 0.64 g (yield 54%) of 6-benzyloxy-2-picoline 1-oxide.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.[O:26]=[C:27]([C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1)[CH2:28][CH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]#[CH:38])[CH2:32][C@@H:31]1[CH2:39][C:40]([O:42][CH3:43])=[O:41].C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:26]=[C:27]([C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1)[CH2:28][CH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]#[C:38][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH2:32][C@@H:31]1[CH2:39][C:40]([O:42][CH3:43])=[O:41]
Reactant: Ic1cccs1
Reactant: C#CCN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](CC(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reaction time: 0.17 h

Procedure:
0.263 g of triphenylphosphine and then 0.85 g of tetrakis(triphenylphosphine)palladium, 0.4 g of cuprous iodide, and 1.75 cm3 of 2-iodothiophene were added with stirring, at a temperature in the region of 20° C. and under an inert atmosphere, to a solution of 4.3 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[prop-2-ynyl]piperidine-3-acetate in 100 cm3 of acetonitrile. The mixture was stirred for 10 minutes and then 2.95 cm3 of triethylamine were added. After stirring for 48 hours at a temperature in the region of 20° C., the mixture was filtered through celite and the insoluble material was washed with 2 times 50 cm3 of acetonitrile. The filtrate was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 4.5 cm; silica volume 500 cm3), elution was carried out with pure ethyl acetate, and approximately 60-cm3 fractions were collected. The fractions corresponding to the expected product were combined. These fractions were concentrated under the above conditions. 4 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-acetate were obtained in the form of an oil with a yellow color.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([O:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>C(Cl)Cl>[CH2:72]([O:71][C:67]1[CH:66]=[C:65]([CH:70]=[CH:69][CH:68]=1)[CH2:64][C@H:50]([NH:49][C:11]([C:9]1[N:10]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[O:7][CH:8]=1)=[O:13])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1)[CH2:73][CH2:74][CH3:75]
Reactant: CCCCOc1cccc(C[C@H](N)[C@H](O)CNCc2cccc(CC)c2)c1
Reactant: CS(=O)(=O)Nc1nc(C(=O)O)co1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOc1cccc(C[C@H](NC(=O)c2coc(NS(C)(=O)=O)n2)[C@H](O)CNCc2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6 %

Procedure:
To a stirred solution of 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylic acid (43) (100 mg, 0.5 mmol) and HATU (180 mg, 0.5 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (100 μL, 0.6 mmol). In a separate flask, N,N-diisopropylethylamine (200 μL, 1.2 mmol) was added to amine 48 (135 mg, 0.3 mmol) in methylene chloride (2 mL). This solution was added to the above solution containing the acid and the resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 93:7 to 90:10 methylene chloride/methanol) provided N-{(1S,2R)-1-(3-butoxybenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide (50a) (10 mg): mp 78–80° C.; IR (KBr) 2960, 1602, 1581, 1490, 1450 cm−1; 1H NMR (500 MHz, CD3OD) δ 7.67 (s, 1H), 7.34–7.09 (m, 5H), 6.82–6.68 (m, 3H), 4.18 (s, 2H), 4.07–4.05 (m, 1H), 3.90–3.84 (m, 3H), 3.23–3.16 (m, 2H), 3.04 (s, 3H), 3.04–3.01 (m, 1H), 2.75–2.64 (m, 3H), 1.69–1.66 (m, 2H), 1.46–1.42 (m, 2H), 1.21 (t, J=8 Hz, 3H), 0.94 (t, J=8 Hz, 3H); ESI-MS m/z 559 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>ClCCl.CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[N:6][CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NNc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred cold (0° C.) solution of 5.5 g of 5-bromo-pyridin-2-yl-hydrazine in 40 mL of dichloromethane, 30 mL of N,N-dimethylformamide, and 26 mL of N,N-diisopropylethylamine was added 3.1 ml of isobutyryl chloride dropwise. The mixture was stirred at 0° C. for 1 hour and a precipitate formed. The mixture was diluted with water and the solids were collected by filtration to give 5.9 g of isobutyric acid N′-(5-bromo-pyridin-2-yl)-hydrazide as a light yellow solid.
Reaction SMILES: [CH:1]1([NH2:16])[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[C:24]([NH:16][CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1c2c(nc3ccccc13)CCCC2N
Reactant: CCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NC1CCCc2nc3ccccc3c(N)c21
Reaction time: 0.08 h

Procedure:
To a chilled solution of 1,2,3,4-tetrahydro-1,9-acridinediamine (4.96 g) and triethylamine (3.6 ml) in 100 ml of tetrahydrofuran was added hexanoylchloride (3.6 ml). This was stirred for five minutes, then quenched into adilute NaOH solution. The aqueous phase was extracted with ethyl acetate (3x) and dried (MgSO4). The organics were concentrated to a semi-solid which was triturated with ethyl ether to give 3.32 g of a pale yellow powder, m.p. 205°-211° C. (dec.). This was recrystallized from methanol/water to give 2.54 g of a pale yellow powder,m.p. 214°-217° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:7]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([C:8]2([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: O=C1CCC(c2cc(F)ccc2C(F)(F)F)(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)C1(c2cc(F)ccc2C(F)(F)F)CCC(O)CC1

Procedure:
A 1 L 3-neck round bottom flask equipped with a nitrogen bubbler, thermocouple, stir bar and condenser was charged with 4-[5-fluoro-2-(trifluoromethyl)phenyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexanone (45 g, 96 mmol) in ethanol (464 ml). Next sodium borohydride (9.67 g, 256 mmol) was added and the reaction was stirred for 30 min. The reaction was quenched by adding HCl (200 ml, 2N) slowly over 10 minutes and then the reaction was poured into HCl (2 L, 2N) and extracted with ethyl acetate (3×1 L). The organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide 4-[5-fluoro-2-(trifluoromethyl)phenyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexanol.