Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[CH:16]([CH2:26][C:27](OCC)=[O:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1.CO.Cl>C1(C)C=CC=CC=1>[CH:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[CH:16]([CH2:26][CH2:27][OH:28])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC1c2ccccc2CCc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCCC1c2ccccc2CCc2ccccc21
Temperature: 0 °C

Procedure:
1120 ml of a 20 percent (v/v) solution of diisobutylaluminum hydride in toluene are added dropwise over a period of 1 hour while cooling to a solution of 160.36 g of ethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetate in 1 l of dry toluene, cooled in ice-water and stirred under argon. The solution is subsequently stirred at room temperature for 16.5 hours, cautiously treated while cooling with 20 ml of dry methanol, stirred for an additional 30 minutes and finally acidified with 1.5 l of 3N hydrochloric acid while cooling well. The organic phase is separated and washed with 1 l of water and the acidic-aqueous phase is back-extracted twice more with 2 l of ether each time. After washing the ethereal extracts with 1 l of water, the organic phases are combined, dried over magnesium sulfate and evaporated. The residue is taken up twice in 200 ml of dry toluene each time, the solutions obtained being in each case again evaporated to dryness. There is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol in the form of an oil which crystallizes only slowly upon standing.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[OH:21])=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)=[O:21])=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33]
Reactant: COc1ccc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
Pyridinium chlorochromate (2.6 g, 12.2 mmol) and Celite (1 g) was added to a stirred solution of (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (2.6 g, 8.1 mmol) in CH2Cl2 (100 mL). The mixture was stirred for 4 h at room temperature then filtered through Celite. The filtrate was washed with water (2×40 mL), brine (40 mL) and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 95:5) to give (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone (2.0 g, 76%): 1H NMR (CDCl3) δ 8.29 (d, J=2 Hz, 1H), 8.07-8.03 (dd, J=2, 8 Hz, 1H), 7.34 (d, J=1 Hz, 1H), 7.35-7.26 (dd, J=2, 8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 4.06 (s, 3H), 3.98 (s, 3H), 3.95 (s, 3H); 13C NMR (CDCl3) δ 192.10, 155.48, 153.34, 149.29, 139.01, 135.57, 130.35, 129.49, 127.60, 124.94, 113.14, 111.98, 109.96, 56.86, 56.13, 56.07.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].[NH2:23][CH:24]1[CH2:26][CH2:25]1>CCO>[CH:24]1([NH:23][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:26][CH2:25]1
Reactant: Fc1ccccc1Cn1cnc2c(Cl)nc(C(F)(F)F)nc21
Reactant: NC1CC1
Solvent: CCO
Product: Fc1ccccc1Cn1cnc2c(NC3CC3)nc(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A mixture of 100 mg (0.30 mmol) of 6-chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine, 1 mL (14 mmol) of aminocyclopropane, and 5 mL of EtOH were stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2, washed with 2×5 mL H2O, 5 mL brine, dried (Na2SO4), and concentrated. Chromatography over silica gel using 33% EtOAc in hexanes as eluant provided 102 mg (97% yield) of the desired product. M.P. 118.5-119.0° C.; 1H NMR (CDCl3) δ 7.892 (s, 1H), 7.50-7.39 (m, 1H), 7.37-7.29 (m, 1H), 7.18-7.05 (m, 2H), 5.95 (bs, 1H), 5.44 (s, 2H), 0.94-0.91 (m, 2H), 0.65-0.64 (m, 2H).
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[Si:13]([O:20][C:21]1[C:22]([F:27])=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Reactant: N[C@@H](C[SeH])C(=O)O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1F
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 75 mL, 98 mmol) was added slowly at −78° C. to a solution of Intermediate 31, 1-(tert-Butyldimethylsilyl)oxy-2-fluorobenzene (20.1 g, 89 mmol) and TMEDA (14.8 mL, 98 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (7.5 mL, 98 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and the reaction mixture was stirred at RT for 30 min. The organic layer was separated. Aqueous layer was extracted with EtOAc (200 mL). The organic layers was washed with sat. NaHCO3, brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (16.7 g, 74%, 66 mmol) as a yellow oil. 1H NMR data (dmso-d6): 10.21 (s, 1H, CHO), 7.39-7.45 (m, 1H, H—Ar), 7.32-7.38 (m, 1H, H—Ar), 7.22-7.28 (m, 1H, H—Ar), 0.97 (s, 9H, t-Bu), 0.20 (s, 6H, 2CH3).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH3:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 20.8 g (0.17 mol) 1-acetylpiperazine in 50 ml tetrahydrofuran were added dropwise to a solution of 13 g of diketene (0.16 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 27.2 g (0.13 mol, 83% yield) of a colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[OH:14])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>C(O)=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:14])[OH:15])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O=CO
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 45 °C
Reaction time: 3.5 h

Procedure:
20.5 g Boc-Ile-Glu-Trp-Oh was dissolved in 150 ml formic acid, stirred for 3.5 h at 45° C. The solvent was evaporated under vacuum. 200 ml water was added to the residue and evaporation under vacuum was repeated. 300 ml isopropanol and 200 ml ether was added to the residue and allowed to stand for 10 h. The precipitate was then filtered and dried under vacuum. Yield: 15.3 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-pyridin-2-ylamine (5 g) in 96% aq H2SO4 (20 mL) at 0° C. was added a mixture solution of 70% aq HNO3 (2.5 mL) and 96% aq H2SO4 (10 mL) drop-wise. After the addition was completed, the mixture was stirred at room temperature for 2 h. The solution was poured onto ice/water and 6M aq. NaOH was added drop-wise to adjust pH to 9. Then the solid was filtered off, washed with water, and dried before it was purified by chromatography on alumina (eluent: pentane:EtOAc 2:1) to afford 4-chloro-3-nitro-pyridin-2-ylamine (1.2 g). 200 mg of this material was dissolved methanol (3 mL) and NaOMe (125 mg) was added before the mixture was stirred at 60° C. for 16 h. 37% aq HCl was added drop-wise to adjust pH to 6. The mixture was cooled to 0° C., and the precipitated solid was filtered off, washed with water, and dried to afford 4-methoxy-3-nitro-pyridin-2-ylamine (180 mg). This material was dissolved in methanol (20 mL) and treated with hydrogen gas (1 bar) in the presence of 10% palladium on charcoal at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 4-methoxy-pyridine-2,3-diamine (50 mg). This procedure was repeated to produce more material. In the next step, 4-methoxy-pyridine-2,3-diamine (6.8 g) was dissolved in ethanol (200 mL). To this solution was slowly added methyl pyruvate (4.9 mL) at room temperature, and the mixture was stirred at ambient temperature for 3 h before the volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: pentane:EtOAc 5:1 to 0:1) to give afford 8-methoxy-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (6.1 g). To a suspension of 3 g of this material in DMF (12 mL) was added PyBroP (7.65 g) followed by DBU (3.58 g). The mixture was stirred overnight before the precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-1-yloxy)-8-methoxy-2-methyl-pyrido[2,3-b]pyrazine (3.5 g). 1.5 g of this material was dissolved in a mixture of ethanol (10 mL) and DCM (60 mL). Hydrazine monohydrate (3.6 g) was added, and the mixture was stirred overnight at ambient temperature before the volatiles were removed in vacuo. The residual solid was triturated from ethanol, filtered off, washed with ethanol, and dried to afford (8-methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)-hydrazine IIe (0.9 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:7])[OH:6].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:6])[OH:7])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCC[PH](=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCC[PH](=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g of 3-aminopropylphosphinic acid in 200 ml of water is cooled to 5° , and the pH adjusted to 9.5 with 2 molar sodium hydroxide solution. To this mixture is added 6.8 g of benzyl chloroformate whilst maintaining the pH and temperature. After the addition is complete the mixture is stirred for 3 hours at pH 9.5 at room temperature and left to stand overnight. The mixture is then extracted with 100 ml of ether and the aqueous layer stirred at 5° with an equal volume of chloroform. The mixture is acidified to pH 2, the chloroform layer separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The oily product is triturated with ether to give a white solid, 3-(N-benzyloxycarbonylamino)propylphosphinic acid, m.p. 53-55°, 31P-NMR : δ=+36.6 ppm (CDCl3).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O-:18])=O)[C:3]1=[O:19].[Li+].[NH2:21][C:22]1[CH:23]=[C:24]2[C:38](=[CH:39][CH:40]=1)[CH2:37][C:26]1([O:31][C:30](=[O:32])[NH:29][C:28]3[N:33]=[CH:34][CH:35]=[CH:36][C:27]1=3)[CH2:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]([CH2:15][C:16]([NH:21][C:22]2[CH:23]=[C:24]3[C:38](=[CH:39][CH:40]=2)[CH2:37][C:26]2([O:31][C:30](=[O:32])[NH:29][C:28]4[N:33]=[CH:34][CH:35]=[CH:36][C:27]2=4)[CH2:25]3)=[O:18])[C:3]1=[O:19]
Reactant: Nc1ccc2c(c1)CC1(C2)OC(=O)Nc2ncccc21
Reactant: CC1C(=O)N(CC(=O)[O-])C(c2ccccc2)CN1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1C(=O)N(CC(=O)Nc2ccc3c(c2)CC2(C3)OC(=O)Nc3ncccc32)C(c2ccccc2)CN1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of lithium(3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl)acetate (30 mg, 0.11 mmol) [Wood et al. US 2007/0265225], 5-amino-1,3-dihydrospiro[indene-2,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one (Intermediate 2, 27 mg, 0.10 mmol) and HATU (42 mg, 0.11 mmol) in DMF (1 mL) is treated with N-methylmorpholine (0.036 mL, 0.33 mmol). The mixture is stirred at rt for 18 h and is then purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and lyophilized to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[Br:11][C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:11][C:12]1[C:13]([NH:19][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: COc1ccc(Cl)cc1I
Reactant: Cc1cnc(N)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: COc1ccc(Cl)cc1Nc1ncc(C)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
In a oven dried 50 mL round bottom flask were sequentially added 4-chloro-2-iodo-1-methoxybenzen (1.13 g, 4.2 mmol), 3-bromo-5-methylpyridin-2-amine (945 mg, 5.05 mmol), Pd2(dba)3 (192 mg, 0.21 mmol), xantphos (146 mg, 0.06 mmol) and NatBuO (605 mg, 6.3 mmol) at room temperature. The solid materials were kept under vacuum for 5 min. and then refilled with nitrogen. This process was repeated thrice before adding dry, degassed dioxane (10 mL). The heterogeneous mixture was stirred at room temperature for 15 min. and then at 100° C. for 1 h. Finally upon completion of the reaction, it was diluted with ether and filtered through a small pad of silica gel with several washings. All the washings and filtrate concentrated in vacuum and the crude residue was further purified by flash chromatography to provide title compound (1.16 g, 84%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccccn1
Reactant: NCc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1ccc(CNc2ccccn2)cn1
Temperature: 230 °C
Yield: 154.8 %

Procedure:
A mixture of 2-fluoropyridine (1.4 g, 15 mmol) and 6-chloro-3-pyridinemethanamine (2.55 g, 18 mmol) in N-methylpyrrolidinone (5 mL) was heated at 230° C. in a microwave reactor for 30 min. This reaction was repeated four times using the same amounts of starting materials for each repetition. All five of the reaction mixtures were then poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel using 10% ethyl acetate in hexanes as the eluent to provide the title compound as an oil (5.1 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([N+:19]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.[Ni]>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: [Ni]
Agent: N
Product: NC1CN(Cc2ccccc2)CC1c1ccccc1
Reaction time: 12 h

Procedure:
To a stirred solution of (3S and R, 4R and S)-1-benzyl-3-nitro-4-phenylpyrrolidine (100 g, 0.354 mol) in methanolic ammonia (1 L) was added Raney Ni (20 g) at room temperature in a 2.0 L hydrogenation flask. The reaction was hydrogenated at 100 psi for 12 h at room temperature. After completion of the reaction, the mixture was filtered through Celite and the filtrate was concentrated in vacuo to afford (3S and R, 4R and S)-1-benzyl-4-phenylpyrrolidin-3-amine, which was carried onto the next step without further purification. MS ESI calc'd. For C17H20N2 [M+1]+ 253. found 253.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C[N+]1([O-])CC[O:14]CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C@H:5]1[O:14][CH2:6]1
Reactant: C=Cc1cccc(Cl)c1
Reactant: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A round-bottom flask equipped with a overhead stirrer was charged with 3-chlorostyrene (1.00 g, 7.22×10−3 mol), CH2Cl2 (78 mL), (R,R)-4 (0.349 g, 3.61×10−4 mol), and NMO (4.22 g, 3.62×10−2 mol). The solution was cooled to −78° C. before solid M-CPBA (2.51 g, 1.46×10−2 mol) was added in portions over 1.5 minutes. The reaction was monitored by GC. Upon completion (3 h), the reaction was quenched by the addition of a solution of dimethyl sulfide (6 mL) in CH2Cl2 (25 mL) precooled to −78° C. The solution was stirred for an additional 10 minutes at −78° C. before removal of the cold bath and addition of 2N NaOH (20 mL) and CH2Cl2 (20 mL). The phases were separated and the aqueous layer was washed with CH2Cl2 (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Removal of the catalyst was effected by elution through a pad of SiO? (10 g) using pentane and CH2Cl2 (1:1). The eluent was concentrated in vacuo, and subsequent bulb-to-bulb distillation from CaH2 afforded (R)-3-chlorostyrene oxide (0.963 g, 86%) as a colorless liquid in 81% ee.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[N:3][CH:2]=1.[CH3:10]O>>[CH3:10][O:8][C:7]([C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)c1cncnc1
Product: COC(=O)c1cncnc1
Temperature: 25 °C
Yield: 77 %

Procedure:
Crude pyrimidine-5-carboxylic acid (2.4 g, 19.38 mmol) was suspended in 100 ml methanol in a round bottom flask fitted with a reflux condenser, drying tube, and a dropping funnel, and 2.8 ml thionyl chloride was added dropwise with stirring. The suspension was stirred and refluxed overnight; then cooled to room temperature and the solvents evaporated in vacuo. Ice cold water (50 ml) was added, basified to pH 8 (sat. NaHCO3), and extracted with chloroform (3×50 ml). The organics were dried (MgSO4), filtered and evaporated in vacuo to yield 2.07 g crude yellow crystals (77%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13](=[O:29])[N:14]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13](=[O:29])[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)O)c2=O)c1
Yield: 67 %

Procedure:
3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.24 g, 2.95 mmol), as prepared in the preceding step, was dissolved in methylene chloride (20 mL) and reacted with trifluoroacetic acid (8 mL) at ambient temperature for 2 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with pH 7 buffer and brine, dried over MgSO4, and filtered. Evaporation of the filtrate gave the title compound (0.72 g, 67%) as a light yellow solid. Mass spectrum (LCMS, ESI) calcd. for C17H20N2O5S: 365.4 (M+H). Found: 365.1.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH2:21]([NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:40]=[C:36]([C:37]([NH2:39])=[O:38])[C:35]([OH:41])=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([N:28]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:41])=[C:36]([C:37](=[O:38])[NH2:39])[CH:40]=1)[CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Reactant: c1ccc(-c2cc3ccccc3[nH]2)c(OCC2CO2)c1
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2-c2cc3ccccc3[nH]2)ccc1O

Procedure:
The starting compound is obtained in the following manner: (13a) A solution of 10.5 g of 2-[2-(2,3-epoxypropoxy)-phenyl]-indole and 10.2 g of 5-(2-benzylaminoethoxy)-salicylamide in 300 ml of isopropanol is reacted analogously to Example 4(c) and yields crude 1-[N-benzyl-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]]-3-[2-(indol-2-yl)-phenoxy]-2-propanol in the form of an orange resin that is further processed in that form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.[H-].[Na+]>CCOCC.CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,4-Dichlorophenylacetonitrile (10.00 g, 53.8 mmol) and bis(2-bromoethyl)ether (12.5 g, 53.8 mmol) were dissolved in ether and added dropwise via addition funnel to a suspension of NaH (60% dispersion in mineral oil; 6.45 g, 161 mmol) in 1-methylpyrrolidone (108 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and was then allowed to warm to ambient temperature. The reaction was then quenched with water. 5N HCl was added, and the reaction mixture was diluted with 200 mL of diethyl ether, added to a separatory funnel, washed 2 times with 100 mL of ether, separated, dried over Na2SO4, and concentrated in vacuo to give the purified title compound (7.97 g) after flash chromatography.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[C:11]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[N:34]>ClCCl>[C:19]([C:11]1[CH:10]=[C:9]([Cl:8])[CH:14]=[CH:13][C:12]=1[S:15]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28]#[N:27])(=[O:17])=[O:16])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CCCCCCN
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
15 ml of redistilled triethylamine are added to 15.7 g of 4-chloro-2-benzoylbenzenesulphonyl chloride in 100 ml of anhydrous dichloromethane, and 5.6 g of 6-aminocapronitrile in 20 ml of dichloromethane are then added dropwise at 0° C.