Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]([CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])#[N:2].[N:32]([Sn](C)(C)C)=[N+:33]=[N-:34]>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]([CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH2:3][C:1]1[NH:34][N:33]=[N:32][N:2]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](CC#N)CC(C)C)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](Cc3nnn[nH]3)CC(C)C)ccc21
Yield: 41.8 %

Procedure:
218 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyanomethyl-3-methyl-butyl)-amide and 124 mg of azidotrimethyltin in 10 ml of dry toluene were heated under Argon for 48 h. The precipitated crude product was isolated by suction and then dissolved in 10% aqueous sodium bicarbonate solution and filtered with addition of charcoal. The pH of the filtrated was adjusted to 5, and the precipitated product was isolated by suction, washed with water and dried in vacuo to obtain 100 mg (42%) of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1-(1H-tetrazol-5-ylmethyl)-butyl]-amide.
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:24]2[O:29]CCCO2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.[C:30](=[O:32])=[O:31].Cl>C1COCC1.C(OCC)C>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([CH:24]=[O:29])[CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[C:30]([OH:32])=[O:31]
Reactant: COc1cc(OC)cc(C2OCCCO2)c1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(OC)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous TMEDA (2.05 ml, 13.62 mmole) and 90 ml dry THF was cooled to -78° C. under an argon atmosphere. n-Butyllithium (11.35 ml of a 1.20M soln.) was added and after 15 minutes, 2-(3,5-dimethoxyphenyl)-1,3-dioxane (44) (FIG. 23) (3.05 g, 13.62 mmole) predissolved in 50 ml dry THF was added. The reaction was warmed to 0° C. and was stirred at that temperature for an additional 60 minutes (the solution turned from a blood red color to a dark brown color). The aryl lithium solution was then poured onto solid carbon dioxide covered with anhydrous diethyl ether. A white precipitate formed immediately. When the reaction warmed to room temperature, 15 ml of 10% HCl was added and the reaction was stirred overnight. The product was then extracted into chloroform. The organic layer was dried over MgSO4, and concentrated in vacuo to a white solid (1.311 g, 46%). The solid can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](OCC)=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([NH:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1NC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc(CO)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g, 64.4 mmol) in anhydrous THF (100 mL) was added LiAlH4 (6.1 g, 0.16 mol) in portions at 0° C. under N2 atmosphere. The reaction mixture was stirred an additional 30 min at RT and was quenched by the addition of water (6 mL) followed by aqueous 2 N NaOH (6 mL). The suspension was filtered and the filtrate was concentrated to give (4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol (13.5 g, 98% yield), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (s, 1 H), 6.37 (d, J=7.6 Hz, 1 H), 5.10 (t, J=5.6 Hz, 1 H), 4.28-4.20 (m, 3 H), 2.38 (s, 3 H), 1.13 (d, J=6.4 Hz, 6 H).
Reaction SMILES: O.NN.[O:4]([N:11]1C(=O)C2[C:13](=CC=CC=2)[C:12]1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][C:33]3[N:37]4[N:38]=[C:39](C(=O)C)[CH:40]=[CH:41][C:36]4=[N:35][N:34]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.Cl>CO>[C:5]1([O:4]/[N:11]=[C:12](/[C:39]2[CH:40]=[CH:41][C:36]3[N:37]([C:33]([CH2:32][C:28]4[CH:27]=[C:26]5[C:31](=[CH:30][CH:29]=4)[N:22]=[CH:23][CH:24]=[CH:25]5)=[N:34][N:35]=3)[N:38]=2)\[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Oc1ccccc1
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: C/C(=N\Oc1ccccc1)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Hydrazine monohydrate (5.45 mg, 0.109 mmol) was added to a solution of 2-phenoxyisoindoline-1,3-dione (Organic Lett, 2001, 31, 139) (30.8 mg, 0.129 mmol) in 10 mL of MeOH. The solution was heated at reflux for 2 h and then cooled to rt. White precipitate was filtered off and 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 mmol) was added. The pH value of solution was adjusted to 5-6 with 1N HCl solution. The reaction solution was then stirred at it overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give 23 mg (59%) of the title compound as a white solid (TFA salt). 1H-NMR (400 MHz, CDCl3) δ ppm 9.23 (d, 1H), 8.68 (d, 1H), 8.53 (d, 1H), 8.15 (m, 3H), 8.04 d, 1H), 7.83 (m, 1H), 7.40 (t, 2H), 7.29 (m, 2H), 7.15 (t, 1H), 4.92 (s, 2H), 2.56 (s, 3H). LC-MS (method H): [MH]+=395.2, tR=2.42 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[O:20][CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:7][S:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2cccc(C)c2O)CCSCC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a suspension of 4-(2-hydroxy-3-methyl-benzoylamino)-tetrahydro-thiopyran-4-carboxylic acid methyl ester (27) (98 mg, 0.32 mmol), anhydrous Cs2CO3 (208 mg, 0.64 mmol), and KI (11 mg, 0.06 mmol) in DMF (5 mL) is added 2-bromopropane (150 μL, 1.6 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (80 g silica gel, gradient elution: 5-40% EtOAc in heptane) to give a pure product (28) as white solid (92 mg, 81%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30](O)=[O:31])=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:11][O:10][C:8]([C:4]1[C:3]([NH:2][C:30](=[O:31])[CH2:29][O:28][C:25]2[CH:24]=[CH:23][C:22]([Br:21])=[CH:27][N:26]=2)=[CH:7][S:6][CH:5]=1)=[O:9]
Reactant: COC(=O)c1cscc1N
Reactant: O=C(O)COc1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of methyl 4-amino-3-thiophenecarboxylate hydrochloride (500 mg, 2.58 mmol) in dimethylformamide (25 mL) was added N-ethyldiisopropylamine (2.26 mL, 12.9 mmol), (5-bromo-pyridin-2-yloxy)-acetic acid ([79674-66-1], 600 mg, 2.58 mmol) and HATU (1.24 g, 3.23 mmol). The reaction mixture was allowed to stir for 2 hours at room temperature. After such time, water was added, and precipitation was eased by ultrasonication. The precipitate was isolated by filtration and washed with a mixture of water and ethanol (3:1) to yield 4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (699 mg, 73%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Cl:11][C:12]1[N:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:13]=1[C:14]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[N:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:13]=1[C:14]([C:16](=[CH:22][NH:4][C:3]1[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[F:10])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)nc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1c(F)cc(F)cc1F)C(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 5 ml of a toluene solution containing 1.39 ml of 2,4,6-trifluoroaniline was added dropwise to 10 ml of a toluene solution containing 6.40 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-ethoxyacrylate and stirred overnight at room temperature. The solvent was distilled off then to the residue, ethanol was added. The resulting crystals were collected by filtration and washed with diethyl ether, to give ethyl 2,6-dichloro-5-fluoronicotinoyl-3-(2,4,6-trifluorophenyl)aminoacrylate. To 9 ml of a N,N-dimethylformamide solution containing 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl-3-(2,4,6-trifluorophenylamino)acrylate was added 0.63 g of potassium carbonate. The solution was stirred for 90 minutes at room temperature. The reaction solution was poured into ice water, the precipitated solid was collected by filtration and washed with ethanol and diethyl ether, to give 1.38 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:27])([CH3:26])[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CC(C)([O-])C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH3:26][C:8]1([CH3:27])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:11]([C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH2:14][CH2:13]2)[C:9]1=[O:10]
Reactant: Cc1ccc(N[C@H]2CC[C@H](NC(=O)C(C)(C)c3nccnc3Cl)CC2)nc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: Cc1ccc(N[C@H]2CC[C@H](N3C(=O)C(C)(C)c4nccnc43)CC2)nc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a glass microwave vial was added 2-(3-chloropyrazin-2-yl)-2-methyl-N-(trans-4-((5-methylpyridin-2-yl)amino)cyclohexyl)propanamide (0.2148 g, 0.554 mmol), RuPhos precatalyst (0.024 g, 0.033 mmol), and sodium tert-butoxide (0.106 g, 1.107 mmol) in dry dioxane (0.554 ml). The mixture was sealed and stirred at 80° C. for 3 hours. The mixture was allowed to cool to room temperature then the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 0% to 5% methanol in dichloromethane, to provide 7,7-dimethyl-5-(trans-4-((5-methylpyridin-2-yl)amino)cyclohexyl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.0178 g, 0.051 mmol, 9.15% yield). M+1: 324. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 1.50-1.72 (m, 3 H) 2.18 (s, 3 H) 2.23-2.35 (m, 2 H) 3.37-3.48 (m, 2 H) 4.36-4.46 (m, 1 H) 4.71-4.77 (m, 1 H) 5.27 (quin, J=8.90 Hz, 1 H) 6.26 (d, J=8.00 Hz, 1 H) 6.92-6.99 (m, 1 H) 7.42 (d, J=5.87 Hz, 1 H) 7.90-7.97 (m, 1 H) 8.15-8.20 (m, 1 H)
Reaction SMILES: Cl.[CH3:2][O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:6]([OH:8])=O.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[NH2:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][O:58][CH2:57]3)[CH2:54][S:55][C@H:50]12>CN(C=O)C.N1C=CC=CC=1>[CH3:2][O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:12][CH:13]=1)\[C:6]([NH:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][O:58][CH2:57]3)[CH2:54][S:55][C@H:50]12)=[O:8]
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)C1=C(C2CCOC2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C3CCOC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
2-(Z)-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (0.751 g) in DMF (5 ml) was treated with methanesulphonyl chloride (0.179 g, 0.121 ml) and diisopropylethylamine (0.404 g, 0.544 ml) as described in Example 1(g). This was then treated with t-butyl (6R,7R)-7-amino-3-[(RS)-tetrahydrofuran-3-yl]ceph-3-em-4-carboxylate (0.464 g) and pyridine (0.112 g, 0.114 ml) in DMF (5 ml). Following work up and purification by flash chromatography with 40, 50 and 60% ethyl acetate/hexane, the title compound was obtained as a yellow foam (0.874 g, 82%); νmax (CH2Cl2) 3398, 1783, 1731 (shoulder), 1718 and 1688 cm-1 ; δH (CDCl3) 1.53 (9H, s), 1.69-2.43 (3H, m's), 3.29 and 3.46 with 3.34 and 3.48 (2H, 2ABq's, J 17.7 and 17.7 Hz), 3.63-4.07 (6H, m's and s), 5.03 and 5.06 (1H, 2d's, J 4.8 and 4.8 Hz), 5.84-5.90 (1H, m), 6.73 and 6.74 (1H, 2s), 6.76 and 6.90 (1H, 2d's, J 8.7 and 8.7 Hz exchangeable with D2O), 7.02 (1H, br. s, exchangeable with D2O) and 7.31 (15H, s). [Mass spectrum: +ve ion (3NOBA, Na+) MNa+ (774)].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]([OH:12])[CH3:11].I[CH3:14]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]([O:12][CH3:14])[CH3:11]
Reactant: CC(O)c1ccncc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)c1ccncc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
Sodium hydride (60% in mineral oil, 148 mg, 3.71 mmol) was added to a solution of 1-(3-bromopyridin-4-yl)ethanol (500 mg, 2.475 mmol) in DMF (12 mL) at 0° C. After 10 min, iodomethane (1.237 mL, 2.475 mmol) was added dropwise and the resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (ethyl acetate-heptane, v/v, 0-30%) to give 418 mg of the title compound. 1HNMR (CDCl3, 400.3 MHz) δ 1.42 (d, J=6.4 Hz, 3H), 3.30 (s, 3H), 4.64 (q. J=0.4 Hz, 1H), 7.58 (s, 1H), 8.56 (s, 1H), 8.70 9s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]([C:15](=[O:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[C:11]([O:22][CH2:23][CH:24]=[CH2:25])[C:6]=1[NH:7][C:8](=[O:10])[CH3:9])[CH:2]=[CH2:3].C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]([CH:15]([OH:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[C:11]([O:22][CH2:23][CH:24]=[CH2:25])[C:6]=1[NH:7][C:8](=[O:10])[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(=O)CS(C)(=O)=O)cc(OCC=C)c1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(C(O)CS(C)(=O)=O)cc(OCC=C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.7 g. of 2',6'-bis(allyloxy)-4'-[(methylsulfonyl)-acetyl]acetanilide in 20 ml. of ethanol and 20 ml. of water was treated with a solution of 0.40 g. of sodium borohydride in 5 ml. of water. There was also added 0.1 g. of sodium hydroxide. The mixture was stirred for 3 hours at room temperature and evaporated to dryness. The residue was taken up in water, removed by filtration under vacuum, dried and recrystallized from ethyl acetate/petroleum ether, whereby there was obtained 2',6'-bis(allyloxy)-4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-acetanilide having a melting point of 162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:23]([NH2:25])=[O:24].[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe].CO>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:23]([NH2:25])=[O:24])[CH:5]=3)[N:10]=[CH:9][CH:8]=2)=[N:15][CH:16]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cn3)c2cc1C(N)=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1C(N)=O
Yield: 72.2 %

Procedure:
7-Methoxy-4-((5-nitro-2-pyridyl)oxy)-6-quinolinecarboxamide (93.0 mg, 273 mmol), iron powder (76.0 mg, 1.36 mmol) and ammonium chloride (146 mg, 2.73 mmol) were heated and stirred in ethanol (4 ml)-water (1 ml) at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in an ethyl acetate-tetrahydrofuran mixed solvent. After washing the organic layer with water and saturated saline and drying over anhydrous magnesium sulfate, the drying agent was filtered out and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=20:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (61.0 mg, 197 mmol, 72%) as yellow crystals.
Reaction SMILES: [O:1]1C[C:2]21[CH:8]1[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]1)[CH2:4]2.B>O1CCCC1.[Cl-].[Na+].O>[N:5]12[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6]1)[C:2](=[O:1])[CH2:4]2
Reactant: C1CN2CCC1C1(CO1)C2
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2 mmol) and a dispersion of sodium hydride (60% in oil, 3.00 g, 75.0 mmol) in anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen for 30 minutes. Quinuclidin-3-one (II) (7.05 g, 56.3 mmol) was then added as a solid portionwise, and the resulting mixture was stirred at 65–70° C. under nitrogen for 1 hour. The reaction mixture was cooled, water was added (200 ml), and the resulting solution was extracted with chloroform (3×200 ml). The chloroform extracts were combined, and back-extracted with water (4×200 ml). The chloroform layer was then dried (MgSO4), filtered, and evaporated under reduced pressure to afford spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (6.51 g, 46.8 mmol, 83%) as a clear, colorless liquid. To a stirred solution of spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (5.3 g, 38.1 mmol) in anhydrous tetrahydrofuran (100 ml) at 0° C. was added dropwise a solution of borane in tetrahydrofuran (1.0 M, 38.1 ml, 38.1 mmol), and resulting solution was stirred at 0° C. under nitrogen for 30 minutes. Brine (100 ml) was added cautiously to the reaction solution, and the resulting aqueous mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (II) (4.3 g, 28.1 mmol, 74%) as a white solid: electrospray MS 152 ([M−H]+, 15).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=O)[CH:14]=1)([O-:9])=[O:8].C(N(CC)CC)C.[CH:26]([NH2:29])([CH3:28])[CH3:27]>CN(C=O)C.ClCCl.C1COCC1>[CH:26]([NH:29][C:16](=[O:18])[CH2:15][N:13]1[CH:14]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[N:12]1)([CH3:28])[CH3:27]
Reactant: O=C(O)Cn1cc([N+](=O)[O-])cn1
Reactant: CC(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)Cn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
Oxalyl chloride (29.6 g, 234 mmol) and DMF (several drops) were added to a stirred mixture of 2-(4-nitro-1H-pyrazol-1-yl)acetic acid (20 g, 117 mmol) in dichloromethane (200 mL) and stirred at room temperature for 5 h. The solvent was then removed in vacuo and the residue was diluted with THF (100 mL). This solution was added to a stirred solution of triethylamine (23.7 g, 234 mmol) and iso-propylamine (10.4 g, 176 mmol) in THF (200 mL) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue diluted with 1M hydrochloric acid to pH <4. The solid was filtered, washed with 1M hydrochloric acid and dried in a vacuum oven to afford N-isopropyl-2-(4-nitro-1H-pyrazol-1-yl)acetamide as a yellow solid (18 g, 84.8 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C.C(Cl)Cl>O1CCCC1>[C:26]([NH:1][C:2]1[C:3]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CN1CCN(c2cccc3ccc(Nc4ncccc4N)cc23)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccnc1Nc1ccc2cccc(N3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
The title compound was prepared following the procedure of example 30 from the product of example 29 (0.25 g, 0.75 mmol), acetyl chloride (0.045 mL, 0.80 mmol) and triethylamine (0.11 mL, 0.803 mmol) in tetrahydrofuran (8 mL) with stirring at room temperature for 3 hours. The product was isolated by flash chromatography and recrystallization from methylene chloride to yield 0.18g (64%) of the title compound: mp 110°-114° C. (dec.). 1H NMR (DMSOd6) δ 9.47 (s, 1H), 8.65 (d, J=1.5 Hz, 1H), 8.35(s, 1H), 8.03 (dd, J=1.5, 5 Hz, 1H), 7.77-7.70 (m, 2H), 7.53 (dd, J=2, 9 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.22 (t, J=8 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.88 (dd, J=5, 8 Hz, 1H), 3.07 (br s, 4H), 2.63 (br s, 4H), 2.29 (s, 3H), 2.14 (s, 3H). HRMS m/e calculated for C22H25N5O: 375.2054. Observed m/e: 375.2023.
Reaction SMILES: C([O:3][C:4](=[O:48])[C@H:5]([OH:47])[CH2:6][NH:7][C:8](=[O:46])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[F:27][C:26]([F:28])([F:29])[C:24]1[CH:25]=[C:20]([NH:19][C:17](=[O:18])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]([NH:7][CH2:6][C@@H:5]([OH:47])[C:4]([OH:48])=[O:3])=[O:46])=[CH:14][CH:13]=2)[C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[CH:21]=[C:22]([C:30]([F:32])([F:33])[F:31])[CH:23]=1
Reactant: CCOC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC[C@@H](O)C(=O)O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
(R)-3-{4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl] benzoyl-amino}-2-hydroxypropionic acid ethyl ester (0.26 g, 0.38 mmol) was dissolved in ethanol (96%, 15 mL) and added sodium hydroxide (4 N, 0.57 mL, 2.3 mmol). After stirring at 25 OC for 1 hour the mixture was evaporated in vacuo, and the residue was added water (30 mL) and acidified with hydrochloric acid (4 N, 0.62 mL). The aqueous phase was extracted twice with ethyl acetate (25 mL and 10 mL) and the combined organic phases were washed with saturated sodium chloride:water (1:1), dried (magnesium sulphate) and concentrated in vacuo to afford 0.21 g of the title compound.