Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.OS(O)(=O)=O.[CH2:26]1COCC1>CO.ClCCl>[C:10]([C:2]1[N:1]=[CH:6][CH:5]=[CH:4][C:3]=1[C:7]([O:9][CH3:26])=[O:8])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: C1CCOC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccnc1C(=O)c1ccccc1
Temperature: 21 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a suspension of 29.84 grams 2,3-pyridinedicarboxylic anhydride in 300 ml THF under an atmosphere of dry nitrogen was added dropwise 200 ml of a 1.0M solution of phenyl magnesium bromide at -78° C. After two hours the reaction mixture was warmed to 21° C. and stirred overnight. The mixture was then refluxed for 24 hours, cooled, treated with 220 ml 1N HCl, stirred one hour, and transferred to separatory funnel. The THF layer was dried over magnesium sulfate, filtered and concentrated under vacuum to give 44.26 grams crude material which was then dissolved in 400 ml anhydrous methanol. To this solution was carefully added 10 ml conc. H2SO4. The solution was then refluxed overnight under an atmosphere of nitrogen. The mixture was cooled and concentrated under vacuum, neutralized with saturated sodium carbonate solution, and extracted with dichloromethane. The mixture was then dried over magnesium sulfate, filtered and concentrated under vacuum to give 42.71 grams crude material. The crude material was dissolved with a minimum amount of dichloromethane and treated by silica gel [column chromatography, eluted with ethyl acetate/hexane (1:3)] to give 12.35 grams (26% yield) of the desired methyl 2-benzoylnicotinate as a white powder. Characteristic analytical data are as follows: mp 74° C.; TLC in 1:3 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ3.77 (s, 3H), 7.45-7.85 (m, 6H), 8.37 (dd, 1H, J=8.0, 1.6 Hz), 8.82 (dd, 1H, J=4.8, 1.5 Hz); mass spectrum (EI), m/e 421.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=O)[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a stirred solution of (1-carbamoyl-cyclopropyl)-carbamic acid tert-butyl ester (5.7 g, 28.4 mmol) in DMF (50 mL) was added cyanuric chloride (2.6 g, 14.2 mmol) and it was stirred at room temperature for 1 h before it was diluted with water (400 mL). The product precipitated and filtration gave (1-cyano-cyclopropyl)-carbamic acid tert-butyl ester (2.79 g, 53.9%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@@H:20]([C:32](O)=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:35]1([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][C@H:20]([C:32](=[O:33])[N:38]([CH:35]4[CH2:36][CH2:37]4)[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[Cl:47])[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(CNC2CC2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CCCP(=O)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred, ice-cooled mixture of (3R*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (233 mg, 0.5 mmol), cyclopropyl-(2,3-dichloro-benzyl)-amine (112 mg, 0.52 mmol) and N-ethyldiisopropylamine (685 μL, 4 mmol) in dimethylacetamide (3 mL), propylphosphonic anhydride solution (˜50% in DMF, 0.48 mL, ˜0.75 mmol) is added. The mixture is stirred for 14 h at RT. After evaporation of the solvent in vacuo, the residue is diluted with ethyl acetate and washed with a 10% aqueous K2CO3 solution and brine. The organic layer is dried over Na2SO4, evaporated in vacuo and the residue purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford (3R*,5R*)-3-tert-butoxycarbonylamino-5-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester as a colourless oil. tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.45 min. The product is dissolved in CH2Cl2/piperidine 4:1 (5 mL) and stirred for 1 h at RT. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 30 min, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a colourless resin. MS: 442.3/444.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.58 min.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:33])[NH:29][CH2:30][CH2:31]Br)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([O:27][C:28](=[O:33])[NH:29][CH2:30][CH2:31][N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)NCC2
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CCNC(=O)OC(C)(C)C)CC2
Temperature: 70 °C
Reaction time: 120 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (example A31, 1.05 g, 3.5 mmol) in THF (40 mL) is added (2-bromo-ethyl)-carbamic acid tert-butyl ester (example B1, 0.94 g, 4.2 mmol) and DIPEA. The reaction mixture is stirred at 70° C. in a sealed flask for 5 days. After cooling to rt, the reaction mixture is evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(CNCCCSc2ccncc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 84.3 %

Procedure:
To a solution of 1.0 g (3.87 mmol) of 4-[3-(N-benzylamino)propylthio)-pyridine and 0.65 ml (4.64 mmol) of triethylamine in 25 ml of methylene chloride, 0.49 ml (4.64 mmol) of acetyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 980 mg of the desired compound (yield: 84.2%, yellow oil).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].ClN1[C:15](=[O:16])[CH2:14][CH2:13]C1=O.C(O)C#C.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:13]=[C:14]([CH2:15][OH:16])[O:9][N:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1ccccn1
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCc1cc(-c2ccccn2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of (E)-picolinaldehyde oxime (4 g) in N,N-dimethylformamide (20 mL) was treated with N-chlorosuccinimide (4.81 g) at 0° C., in portions. The mixture was stirred at 60° C. for 2 hours. The mixture was then cooled to 0° C. and treated with prop-2-yn-1-ol (7.59 mL) through a syringe. A solution of triethylamine (5.02 mL) in N,N-dimethylformamide (4 mL) was added slowly (30 minutes). The resulting mixture was stirred at 0° C. for 1 hour, and then at room temperature for 18 hs. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated in vacuo to a yellow oil and purified by column chromatography on silica gel (2-10% methanol in dichloromethane) to obtain the title compound (4.25 g) having the following physical data.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[C:9](Cl)(Cl)[CH:10]([OH:12])O.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[NH2:25])[NH:21][N:20]=[CH:19]2.Cl.[NH2:27][OH:28]>O.Cl>[OH:28]/[N:27]=[CH:9]/[C:10]([NH:25][C:24]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[CH:17][C:16]=1[CH3:15])=[O:12]
Reactant: NO
Reactant: Cc1cc2cn[nH]c2cc1N
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc2cn[nH]c2cc1NC(=O)/C=N/O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium sulphate (8.69 g, 61.15 mmol) in water (20 ml) was added chloralhydrate (0.62 g, 3.74 mmol) at ambient temperature. To the resulting clear solution was added a solution of 5-methyl-6-aminoindazol (0.5 g, 3.4 mmol, prepared as described in Eur. Pat. Appl. EP 040872) in 1N aqueous hydrochloric acid (3.7 ml). The resulting mixture turned cloudy and hydroxylamine hydrochloride (0.75 g, 10.9 mmol) was then added. The resulting reaction mixture was heated-up gradually from ambient temperature to 80° C. When the reaction mixture has reached an internal temperature of 80° C., it was stirred for an additional 30 min at 80° C. The reaction mixture was then cooled down to ambient temperature with an ice bath. The reaction mixture was filtrated. The filtercake was washed thoroughly with water and dried at 50° C. for 15 hours to afford the desired product as a brown powder of >95% purity according to HPLC. LC/MS: 219 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2CC(C)(C)C(C)(C)C2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2CC(C)(C)C(C)(C)C2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 70.1 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (35 mg, 0.084 mmol) was reacted with 2-chloro-6-methoxy-4-(3,3,4,4-tetramethylborolan-1-yl)phenol (42 mg, 0.150 mmol) to afford the desired product (29.1 mg, 70%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.30 (s, 1H), 8.07-7.99 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 4.00 (s, 3H), 3.54 (d, J=12.4 Hz, 2H), 3.22 (t, J=12.2 Hz, 2H), 2.59-2.50 (m, 1H), 2.43 (d, J=6.2 Hz, 2H), 2.35 (s, 6H), 2.01-1.83 (m, 3H), 1.67-1.53 (m, 2H), 1.35-1.27 (m, 2H), 1.27-1.19 (m, 2H); ESI MS m/z 494 [C28H32ClN3O3+H]+; HPLC 98.9% (AUC), tR=10.51 min.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([O:12][C:13](=[O:25])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH3:11].C([O-])([O-])=O.[K+].[K+]>>[CH2:10]([O:12][C:13](=[O:25])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:17]=1)=[O:15])[CH3:11]
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=O)c1cn(CCN2CCCCC2)c2ccccc12
Yield: 65.7 %

Procedure:
The general procedure 1 was then followed using 1-(2-chloroethyl)piperidine (10 mmol, 1.5 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (7 mmol, 1.5 g) and K2CO3 (10.9 mmol, 1.5 g). The purification was achieved by column chromatography (petrol-ether:ethylacetate:diethylamine 8:1:1) to yield ethyl-2-{1-[2-(piperidin-1-yl)ethyl]-1H-indol-3-yl}2-oxoacetate (4.6 mmol, 66%) as an pale yellow oil. IR {tilde over (ν)} [cm−1]=2936; 2857; 1730; 1638. EI-MS m/z (rel. int.)=328 (18.99%; M+•). 1H NMR (300 MHz, CDCl3) 8.43 (m; 2H; indole-H); 7.35 (m; 3H; indole-H); 4.40 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.25 (t; 3J=6.8 Hz; 2H; indole-CH2CH2N); 2.72 (t; 3J=6.8 Hz; 2H; indole-CH2CH2N); 2.43 (m; 4H; piperidin-CH2 (C-2+6)); 1.57 (m; 4H; piperidin-CH2 (C-3+5)); 1.43 (m; 5H; piperidin-CH2 (C-4)+OCH2CH3).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH:18]([O:21][CH3:22])OC)[N:11]=[C:10]([NH:23][CH2:24][CH2:25][CH2:26][CH:27](OC)[O:28][CH3:29])[N:9]=1>C(Cl)Cl>[CH3:29][O:28][CH:27]1[CH2:26][CH2:25][CH2:24][N:23]1[C:10]1[N:11]=[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH:18]2[O:21][CH3:22])[N:13]=[C:8]([N:7]2[CH2:6][CH2:5][CH2:4][CH:3]2[O:2][CH3:1])[N:9]=1
Reactant: COC(CCCNc1nc(NCCCC(OC)OC)nc(NCCCC(OC)OC)n1)OC
Solvent: ClCCl
Product: COC1CCCN1c1nc(N2CCCC2OC)nc(N2CCCC2OC)n1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A mixture of strongly acidic AMBERLYST® 15 ion-exchange resin (6.6 g), a product of Rohm and Haas Company, Philadelphia, Pa., and methylene chloride (20 ml) in a 100 ml flask equipped with a magnetic stirrer, condenser and nitrogen inlet was stirred for 5 minutes and thereafter, the solvent was removed by decanting. A solution of the 2,4,6-tris-(4,4-dimethoxybutylamino)-1,3,5-triazine of Example 1 (6.1 g, 0.0129 mole) in methylene chloride (120 ml) was then added in one portion to the flask and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The ion exchange resin was then filtered and the volatiles removed under reduced pressure to give 2,4,6-tris-(2-methoxypyrrolidinyl)-1,3,5-triazine (2.7 g, 56% isolated yield) as a glassy solid. The structure of the product was confirmed by nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analysis: 1H NMR (δ): 5.6 (m, 1 H, --NCHOCH3); 3.8-3.2 (m, 5H, --OCH3 and --NCH2); 2.2-1.6 (m, 4H, --CH2 --); 13C NMR (ppm): 165, 88, 56, 46, 32, 22; MS (m/e, MH): 379.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:2]1[O:1][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1Cc2ccccc2O1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2ccccc2o1
Reaction time: 5 h

Procedure:
A solution of 2-coumaranone (5.0 g, 37 mmol) and methyl(triphenylphosphoranylideneacetate) (13.5 g, 40 mmol) in toluene (70 mL) was heated to reflux for 25 hours. More toluene was added (10 mL), and after a further 5 hours, more methyl(triphenylphosphoranylideneacetate) (0.5 g, 1.5 mmol). After another 19 hours, a further 1.0 g (3.0 mmol) was added, and after a further 21 hours, the solvent was removed in vacuo. Column chromatography (heptane:ethyl acetate 4:1) gave the product as a brown oil, 28 mmol, 75%.
Reaction SMILES: [CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[C:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10](Cl)=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].CN(C)[CH:25]=[O:26]>[Cu]>[NH2:17][C:9]1[CH:8]=[C:7]([C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH:20]([CH3:22])[CH3:21])=[O:6])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]=1[C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:26][CH3:25])=[O:6])=[CH:8][CH:9]=1.[CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[C:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([O:26][CH3:25])=[O:6])=[CH:8][CH:9]=2)=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1)C(C)C
Reactant: CN(C)C=O
Agent: [Cu]
Product: COC(=O)c1ccc(-c2c(N)cc(C(=O)N(C(C)C)C(C)C)cc2[N+](=O)[O-])cc1
Product: COC(=O)c1ccc(-c2c([N+](=O)[O-])cc(C(=O)N(C(C)C)C(C)C)cc2[N+](=O)[O-])cc1

Procedure:
1.67 g of the amide of Stage A, 1.39 g of methyl iodo benzoate (Preparation 7), 2.5 g of copper and 4 ml of dimethylformamide were mixed together in an autoclave at 200° C. for 90 minutes. After evaporation of the dimethyl-formamide, extraction was carried out with methylene chloride, followed by concentration under reduced pressure and purification by chromatography on silica, eluting with a cyclohexane/ethyl acetate mixture (7/3) to obtain 337.5 mg of Product A and 766 mg of Product B.
Reaction SMILES: C(N(CC)C(C)C)C.[CH2:9]([C@:16]1([CH3:22])[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[CH2:9]([C@:16]1([CH3:22])[CH2:21][N:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH3:27])=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)Cl
Reactant: C[C@@]1(Cc2ccccc2)CNCCN1
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)OC)[C@](C)(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Diethylisopropylamine (0.98 ml, 5.0 mmol) was added to a stirring solution of (R)-2-benzyl-2-methylpiperazine (0.38 g, 2.0 mmol) and methyl chloroformate (0.41 g, 0.35 ml, 2.8 mmol) in CH2Cl2 (20 ml). After stirring at ambient temperature for 2 h, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, CH2Cl2 to 40% EtOAc in CH2Cl2) to afford pure product (0.28 g, 34% yield over the two steps). MS (ESI) 307 (M+H).
Reaction SMILES: [CH2:1](OC(=O)C(C(OC)P(CC1C=CC([N+]([O-])=O)=CC=1)=O)CC(C)C)C1C=CC=CC=1.[N+:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([O-])=O.[CH2:42]([O:49][C:50]([CH:52]([CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:53][PH:54](=[O:56])[OH:55])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)C.O.Cl.[Fe]>[CH2:42]([O:49][C:50](=[O:51])[CH:52]([CH2:53][PH:54]([O:55][CH2:1][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([NH2:31])=[CH:35][CH:36]=1)=[O:56])[CH2:57][CH:58]([CH3:60])[CH3:59])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COC(C(CC(C)C)C(=O)OCc1ccccc1)[PH](=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CC(C[PH](=O)O)C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)CC(C[PH](=O)OCCc1ccc(N)cc1)C(=O)OCc1ccccc1
Yield: 53 %

Procedure:
2-[Methoxy(4-nitrobenzyl) phosphinoylmethyl]-4-methylpentanoic acid benzyl ester (prepared from 4-nitrobenzyl bromide and (2-benzyloxycarbonyl4-methylpentyl)phosphinic acid by the procedure described in Example 1/Step B) (900 mg, 2.08 mmole) in a mixture of ethanol (25 ml) and water (6 ml) was treated with concentrated hydrochloric acid (3 drops) and iron powder (1.14 grams, 20 mmole) at reflux. After 2 hours the cooled mixture was filtered through diatomaceous earth. The filtrate was concentrated and the residue chromatographed (ethyl acetate) to give 444 mg (53%) of 2-[(4-Aminobenzyl) methoxyphosphinoylmethyl]-4-methylpentanoic acid benzyl ester as a yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(COC)OC>[C:5]1([C:11]2[N:1]=[N:2][NH:3][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Nc1cc(-c2[nH]nnc2-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 79 %

Procedure:
Add sodium azide (0.13 g) to a solution of 1-phenyl-2-(3-(isopropylamino)-4-nitrophenyl)acetylene (0.56 g) in dimethoxyethane (5 mL). Heat to reflux for 2 hours. Cool to room temperature. Add 1N hydrochloric acid (10 mL), extract with ethyl acetate (20 mL), and wash with saturated aqueous sodium chloride (2×10 mL). Dry organic phase over sodium sulfate and concentrate under reduced pressure. Subject the reside to silica gel chromatography, eluting with 1:1 ethyl acetate:hexane to provide the desired compound as a yellow solid (0.51 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:38][C:39]#[C:40][C:41]1[S:42][CH:43]=[CH:44][CH:45]=1)[CH2:9][CH2:10][N:11]([CH:35]([CH3:37])[CH3:36])[C:12](=[O:34])[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:27][CH:28]([CH3:30])[CH3:29])=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]1C(O)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].O>C(OC(=O)C)(=O)C>[CH:35]([N:11]1[C:12](=[O:34])[C:13]2[N:15]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[C:19]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:18][C:17]=4[C:16]3=[C:40]([C:41]3[S:42][CH:43]=[CH:44][CH:45]=3)[C:39]=2[CH2:38][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]1)([CH3:36])[CH3:37]
Reactant: COc1cc2c(cc1OC(C)C)C(C(=O)O)N(C(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C)CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 580 mg of 14c and 1 g of anhydrous sodium acetate in 8 ml of acetic anhydride was heated at 100° C. for 45 min. The reaction mixture was cooled and 25 ml of water was added and stirring prolonged for 1 h. The product crystallized from the reaction mixture and was filtered, washed with water and dried in vacuo, to give 420 mg of 14d as white crystalline material; Mp 205-206° C.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:13].[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:15][CH3:16]>>[N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH:13][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Nc1nc2c(s1)CCc1sccc1-2
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc3c(s2)CCc2sccc2-3)cc1

Procedure:
The title compound was prepared from 4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-amine (105 mg, synthesized according to METHOD I from 4-keto-4,5,6,7-tetrahydrothianaphthene) and 4-n-propylbenzenesulfonyl chloride (111 mg) as described in the synthetic METHOD A to give a white powder (18 mg) with a purity >90%: MS-ES (neg) m/z 389.3.