Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:16])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)c1cc(C(C)C)c(OC)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (331 mg, 2.4 mmol) in acetonitrile (10 ml) was treated with dimethyl sulphate (0.2 ml, 2.1 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (440 mg, 98%) as a colourless solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=1)(=O)=O.[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC>>[Cl:13][C:11]1[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([CH:29]=[CH2:30])[CH:12]=1
Reactant: Nc1nnc(-c2cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c2)c(-c2ccccc2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cc(Cl)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 11 %

Procedure:
6-(3-Chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 11%) was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (0.65 g, 1.51 mmol and tri-n-butyl(vinyl) tin (0.57 g, 1.81 mmol) according to the general procedure for Example 4.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](Cl)=[CH:13][C:12]=2Cl)=[CH:6][CH:5]=1)([O-])=O.COC1C=C(OC2C=CC(Cl)=CC=2Cl)C=CC=1[N+]([O-])=O.ClC1C=C(Cl)C=CC=1OC1C=CC([N+]([O-])=O)=C(C=1)C(OC)=O.FC(F)(F)C1C=CC(OC2C=CC(C(F)(F)F)=C([N+]([O-])=O)C=2)=CC=1[N+]([O-])=O.C(OC1C=C(OC2C=CC(C(F)(F)F)=CC=2Cl)C=CC=1[N+]([O-])=O)C.ClC1C=C(OC2C=CC([N+]([O-])=O)=C(C=2)C(O)=O)C=CC=1C(F)(F)F>>[C:11]1([O:10][C:7]2[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: CCOc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: COC(=O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: COc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Product: c1ccc(Oc2ccccc2)cc1

Procedure:
2,4-Dichlorophenyl 4-nitrophenyl ether (Nitrofen), 2,4,6-trichlorophenyl 4'-nitrophenyl ether (Chlornitrofen), 2,4-dichlorophenyl 3-methoxy-4-nitrophenyl ether (Chlomethoxynil), methyl 5-(2,4-dichlorophenoxy)-2-nitrobenzoate (Bifenox), 4-nitrophenyl α,α, -trifluoro-2-nitro-p-tolyl ether (Fluorodifen), 2-chloro-4-trifluoromethylphenyl 3-ethoxy-4-nitrophenyl ether (Oxygluorfen), 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-2-nitrobenzoic acid (Acifluorfen), etc.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][C:32]=3[CH3:33])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 4 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.39–7.23 (m, 12H), 7.14 (br, 1H), 7.08 (d, 1H, J=8.4 Hz), 6.90 (br, 1H), 4.91 (s, 1H), 3.41 (dd, 2H, J=6.4, 12.4 Hz), 2.95 (d, 2H, J=12.4 Hz), 2.66 (m, 1H), 2.47 (m, 1H), 2.40 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 2.03–1.97 (m, 2H), 1.74–1.62 (m, 6H), 1.22 (d, 6H, J=7.2 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>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.[Cu]I.C1COCC1>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccc2nsnc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc2nsnc12
Temperature: 45 °C
Reaction time: 20 h

Procedure:
4-Bromobenzo[c][1,2,5]thiadiazole (0.378 g, 1.76×10−3 mol), Pd(PPh3)4 (0.125 g, 1.68×10−4 mol), CuI (0.014 g, 7.4×10−5 mol), THF (20 ml), diisopropylamine (1.00 ml), and (trimethylsilyl)acetylene (1.00 ml, 7.1×10−3 mol) were added to a 50-ml Schlenk tube. N2 was bubbled through the mixture for 5 min, following which the reaction was stirred at 45° C. for 20 h. After cooling, the solvent was evaporated and the residue was chromatographed on silica gel using 1:1 hexanes:CHCl3 as the eluent. Yield=0.398 g (97.3% based on 0.378 g of 4-bromobenzothiadiazole). 1H NMR (500 MHz, CDCl3): δ 7.88 (m, 1H, Ph-H), 7.67 (m, 1H, Ph-H), 7.45 (m, 1H, Ph-H), 0.33 (s, 9H, —Si—CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:15])=[O:11]>>[OH:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:15])=[O:11]
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Reactant: ClCc1cscn1
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1OCc1cscn1
Yield: 13 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 82, preparation of starting materials) to give the title compound as a white solid in 13% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.21 (s, 3H), 3.42 (dt, 1H), 3.71 (dt, 1H), 3.79 (d, 2H), 4.95 (m, 1H), 5.24 (s, 2H), 5.48 (t, 1H), 7.09 (d, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 7.54 (d, 1H), 7.62 (dd, 1H), 7.68 (t, 1H), 7.77 (d, 1H), 8.16 (t, 1H), 8.44 (s, 1H), 9.14 (d, 1H), 9.95 (s, 1H); Mass spectrum MH+ 480.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[N:17]([CH2:20][CH2:21][CH2:22][CH2:23]Br)=[N+:18]=[N-:19]>CCO>[C:2]([NH:5][C:6]([CH2:23][CH2:22][CH2:21][CH2:20][N:17]=[N+:18]=[N-:19])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: [N-]=[N+]=NCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCN=[N+]=[N-])(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 0.598 g (0.026 mol) sodium metal in 25 ml absolute EtOH, 5.65 g diethyl acetamidomalonate (0.026 mol) was added, following previously published procedures (Chenault, H. K. et al., 1989). The mixture was stirred for 30 min at room temperature. By dropwise addition, azidobutylbromide 1a (4.82 g, 0.027 mol) was added with stirring. The reaction mixture was stirred for 2 h at room temperature and refluxed for 6 h at 80° C. After cooling overnight, the reaction mixture was concentrated to dryness, and the residue was extracted with diethyl ether. The combined ether extracts were washed with water, sat. NaHCO3, water, and brine, and were dried over MgSO4 and then concentrated. Silica gel chromatography (Hex:EtOAc=1:1) gave a product (63%) as a clear, viscous oil. 1H NMR (300 MHz, CDCl3): δ 6.77 (1H, s), 4.24 (4H, q, J=6.9 Hz), 3.26 (2H, t, J=6.9 Hz), 2.31-2.37 (2H, m), 2.04 (3H, s), 1.59 (2H, p, J=7.5 Hz), 1.26 (6H, t, J=6 Hz), 1.16-1.27 (2H, m). ESI-MS m/e 315.
Reaction SMILES: C([O-])(=O)C.[K+].[CH2:6]([C:8]([CH2:13][CH2:14][CH:15]=[CH2:16])=[CH:9][C:10](O)=O)[CH3:7].C(OC(=O)C)(=O)C.COP([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(OC)=O.[Cl-].[Li+].N12CCCN=C1CCCCC2>O.C(#N)C.CC(N(C)C)=O>[CH2:6]([C:8]1[C@H:13]2[C@H:16]([CH2:15][C:14]2=[CH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:10][CH:9]=1)[CH3:7]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: C=CCCC(=CC(=O)O)CC
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC1=CC[C@H]2CC(=CC(=O)OC(C)(C)C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium acetate (2.56 g, 26.1 mmol) was added to a dimethylacetamide (25 mL) solution of 3-ethylhepta-2,6-dienoic acid (2.01 g, 13.0 mmol) and acetic anhydride (2.66 g, 26.1 mmol), and the mixture was stirred at room temperature for 1 hour and then stirred at 120° C. for 3 hours. The mixture was treated with an ice water solution, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was applied to column chromatography to obtain a pale yellow oil substance. The substance obtained here was added to an acetonitrile (40 mL) solution of tert-butyl dimethylphosphonoacetate (2.60 g, 16.6 mmol), lithium chloride (0.70 g, 16.6 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.60 g, 16.6 mmol) stirred in advance for 1 hour, and the mixture was further stirred for 3.5 hours. The mixture was treated with water, and volatile portions were then distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (2.20 g, 68%).
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.[N:13]([O-])=[O:14].[Na+]>O>[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[N:13]=[O:14]
Reactant: CC1NCCc2ccccc21
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1c2ccccc2CCN1N=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
21.5 g of 1-methyl-1,2,3,4-tetrahydro-isoquinolinehydrochloride (its preparation: Monatshefte, volume 53-54, 959 (1929) are dissolved in 50 cm3 water and to the solution a solution of 8.22 g of sodium nitrite in 25 cm3 water is added within 1 hour at 75° C. dropwise. The reaction mixture is cooled at 75° C. after stirring for 2 hours and it is extracted with 6×30 cm3 chloroform. The chloroform solution is washed with 50 cm3 water, dried and evaporated in vacuo. 19.2 g (93%) 1-methyl-2-nitroso-1,2,3,4-tetrahydro-isoquinoline are obtained as a brown oil which is used for the next step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>CCOCC>[N+:18]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3]2)([O-:20])=[O:19]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=C(O)C1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of indane-2-carboxylic Acid 9a (18.8 g) in ether (250 ml) was added to conc. sulfuric acid (300 ml) (temp.=3-13° C.). To this mixture, a solution of conc. nitric acid (4.4 ml) and conc. sulfuric acid (100 ml) was added (temp.=−1° C.). The mixture was stirred at 2-8° C. for 1 h, poured onto ice, and the aqueous phase was extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness in vacuo. The residue was crystallized from ether to give 5-nitroindane-2-carboxylic acid (6.0 g). The solid was dissolved in CH2Cl2 (100 ml) and DMF (1 ml). Thionyl chloride (8.4 ml) was added, and the solution was boiled under reflux for 5 hours. Evaporation in vacuo gave the title compound (8.6 g).
Reaction SMILES: O1CCCC1.[OH-].[Na+].C([O:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([Cl:39])[CH:32]=3)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:40]#[N:41])[CH:25]=3)[N:20]=2)[CH2:15][CH2:14]1)=[O:12])C.Cl>O.C(O)C>[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([Cl:39])[CH:32]=3)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:40]#[N:41])[CH:25]=3)[N:20]=2)[CH2:15][CH2:14]1)([OH:12])=[O:10]
Reactant: CCOC(=O)C1CCN(c2nc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2nc(N3CCC(C(=O)O)CC3)nc3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
30 ml of tetrahydrofuran, 30 ml of ethanol and 14 ml of a 1N aqueous solution of sodium hydroxide were added to 1.0 g of 2-(4-ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at room temperature for 16 hours and neutralized with 1N hydrochloric acid, followed by the addition of 100 ml of water. The crystals thus precipitated were recovered by filtration and recrystallized from tetrahydrofuran/ethanol/water to give 860 mg of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:18][CH:17]3[N:19]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]([CH2:14][C:15](=O)[C:16]3=[CH:33]O)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1.C(O)(=O)C>CCO>[Br:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:12][CH:13]3[N:19]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:17]([C:16]4[CH:33]=[N:3][NH:2][C:15]=4[CH2:14]3)[CH2:18]2)[CH:8]=[CH:9][CH:10]=1
Reactant: NN
Reactant: O=C1CC2CC(c3cccc(Br)c3)CC(C1=CO)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1C2Cc3[nH]ncc3C1CC(c1cccc(Br)c1)C2
Reaction time: 18 h

Procedure:
21% NaOEt (6 ml, 16.1 mmol) was added to a solution of 7-(3-Bromophenyl)-9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one (90) (2.28 g, 4.54 mmol) and ethyl formate (6 ml, 74.5 mmol) in THF (20 ml). The solution was placed into a preheated oil bath at 60° C. After stirring for 30 min, the solution was cooled to ambient temperature, diluted with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford 7-(3-bromophenyl)-2-(hydroxymethylene)-9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one. Hydrazine monohydrate (3 ml) was added to a solution of 7-(3-bromophenyl)-2-(hydroxymethylene)-9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one and glacial acetic acid (1 ml) in EtOH (20 ml). After stirring for 18 h, the solution was concentrated to afford compound 92.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10][CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1C(C)(C)O[SiH2]C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 4-hydroxy-2-(t-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (192.15 mg, 0.58 mmol) was dissolved in anhydrous DCM and triethylamine (176.07 mg, 1.74 mmol, 0.24 mL) was added under argon. The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (73.08 mg, 0.64 mmol, 0.05 mL) was added via syringe. The reaction was stiffed at 0° C. for 30 min and then allowed to warm to room temp and stir for 12 h. The reaction was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane-ethyl acetate) Yield 220.94 mg. 1H NMR (CDCl3, 300 MHz): δ 0.05 (m, 6H), 0.89 (s, 9H), 1.46 (s, 9H), 2.20-2.43 (m, 2H), 3.04 (s, 3H), 3.48-3.92 (m, 4H), 3.93-4.10 (m, 1H), 5.31 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH3:23])[C:15](=[O:24])[CH2:14][N:13]=1.CC(C)([O-])C.[K+].[N:31](OCCC(C)C)=[O:32].O>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(O)(=O)C>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH3:23])[C:15](=[O:24])[C:14](=[N:31][OH:32])[N:13]=1
Reactant: COc1cc(C)cc(OC)c1C1=NCC(=O)N(C)c2ccccc21
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(OC)c1-c1nc(=NO)c(=O)n(C)c2ccccc12
Temperature: -20 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
To a suspension of 9 g of 1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one in 300 ml of toluene are added portionwise, with cooling to -20° C., 7.8 g of potassium tert-butoxide, then the temperature is allowed to rise slowly to 0° C. over 35 minutes, the mixture is cooled to -20° C. and 3.9 g of isoamyl nitrite in 50 ml of toluene are added dropwise. The reaction mixture is then stirred at 0° C. for 90 minutes, followed successively by pouring of the reaction mixture into water, adjustment of the pH to 4 with acetic acid, extraction with ethyl acetate, washing of the organic phase with water, drying over sodium sulphate and evaporation to dryness. The residue is crystallized from isopropyl ether, filtered and dried to give beige crystals melting at 150° C.; Yield=76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: COc1cc(C(=O)CC(Cc2ccc(NC(=O)OCc3ccccc3)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Yield: 69.5 %

Procedure:
Following the procedure described in Example 154, treatment of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (80 mg, 0.18 mmol) with benzyl chloroformate (0.039 mL, 0.27 mmol) provided 72 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-carbobenzyloxy)aminophenyl)ethylamide as a foam.
Reaction SMILES: [Na].[Br-:2].C(OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN([CH:38]([CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])CC1)(C)(C)C.Br.N1(CC(OC(C)(C)C)=O)CCNCCN(CC(OC(C)(C)C)=O)CCN(CC(OC(C)(C)C)=O)CC1.[OH-].[Na+]>C(OCC)C.C(OCC)(=O)C>[Br:2][CH:38]([CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(C(CCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: [Br-]
Agent: Br
Agent: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(Br)CCC(=O)OCc1ccccc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Synthesis of Sodium (5-benzyl 1-tert-butyl 2-(4,7,10-tris(2-tert- butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioate bromide, Compound XIV. 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, tri-t-butyl ester hydrobromide, 10.0 g (0.0168 mole), was stirred with aqueous sodium hydroxide, 0.1N 150 mL, and diethyl ether, 150 mL. When the entire solid had dissolved, the organic phase was collected and the aqueous phase washed with diethyl ether, 3×50 mL. The combined organic extracts were washed with 1×50 mL saturated aqueous sodium chloride, dried with magnesium sulfate, filtered and evaporated, under reduced pressure, to an oil, 8.8g (0.0171 mole as the free base). The oil was dissolved in acetonitrile, 100 mL. To this solution was added sodium bicarbonate, 1.51 g (0.0180 mole). The mixture was warmed to 30° C. A solution of 5-benzyl, 1-tert-butyl 2-bromopentandioate, 8.02 g (0.0180 mole), in acetonitrile, 40 mL, was added dropwise and the mixture was stirred overnight under argon. The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give a clear colorless oil. The oil was dissolved in diethyl ether, 100 mL, with stirring. The product began crystallizing after a few minutes. After stirring for ca. 1 hr, the product was collected by filtration, washed with fresh ether and vacuum dried. NMR analysis revealed the solid, 9.3g, consisted of a mixture of Na-DO3A-tris (tert-butyl ester) bromide and the desired product. The solid was recrystallized twice from minimal ethyl acetate, ca.,100 mL ea., giving very pure product. The yield was 2.7 g, 18% based on starting 5-benzyl, 1-tern-butyl 2-bromopentandioate. Anal. Calc. As the monohydrate % C, 55.25; H, 7.44; N, 6.08; Br, 9.08; Na, 3.68. Found C, 55.32; H, 7.96; N, 6.14; Br, 8.76; Na. 2.52. The NMR is consistent with the structure. Crystal suitable for x-ray analysis were grown from ethyl acetate.