Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]([N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]([N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:11]
Reactant: CN(C(CO)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(C=O)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Yield: 93.4 %

Procedure:
Oxalyl cloride (0.51 g, 4.00 mmol) and dimethyl sulfoxide (0.63 g, 8.01 mmol) were dissolved in dichloromethane (10 ml) and the solution was cooled to −78° C. To the solution, a solution of (±)-1-hydroxymethyl-N-methyl-N-(4-phenoxybenzene-sulfonyl)-2-phthalimidoethylamine (1.70 g, 3.64 mmol), the product of (5) above, in dichloromethane (25 ml) was added dropwise with stirring and this was stirred for 30 minutes. Triethylamine (1.84 g, 18.2 mmol) was added dropwise to the mixture and this was stirred at room temperature for 2 hours. To the reaction mixture, ice-water was added and then this was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound (1.58 g, yield 93%) as a white amorphous solid.
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[CH2:7]([CH2:9][NH2:10])[OH:8].[CH2:11]=O.[OH-].[Na+]>C(O)(C)C.O>[N+:1]([C:4]([CH3:11])([CH3:6])[CH2:5][NH:10][CH2:9][CH2:7][OH:8])([O-:3])=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=O
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(CNCCO)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
607.8 g (6.55 mol) of 2-nitropropane and 100 ml of water are added to a solution of 450 g (7.40 mol) of ethanolamine in 1000 ml of isopropanol. The solution is stirred at room temperature and 225.4 g (7.5 mol) of paraformaldehyde and 7 ml of 20% aqueous solution of sodium hydroxide (% w/v) are added under stirring and maintaining the temperature at room temperature for 16 hours. The mixture is then heated to 50° C. with nitrogen being bubbled into the mixture to eliminate the formaldehyde in excess. The mixture obtained is used for the following reaction without any isolation of the product.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[N:47]1CC[O:50][CH2:49][CH2:48]1.NC(C[C:58]([F:61])([F:60])[F:59])CO>ClCCl.CN(C=O)C>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:47][CH:48]([CH2:49][OH:50])[C:58]([F:61])([F:60])[F:59])=[O:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(CO)CC(F)(F)F
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CN1CCOCC1
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
50 mg (0.16 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 55 mg (0.17 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 79 mg (0.79 mmol) of 4-methylmorpholine were initially charged in 1.0 ml of dichloromethane. After 10 min at RT, 28 mg (0.17 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were added and the mixture was stirred at room temperature overnight. 1 ml of DMF and 50 mg (0.39 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were then added, and the mixture was stirred at 50° C. for 8 h. Another 50 mg (0.39 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were added, and the mixture was stirred in a microwave at 80° C. for 0.5 h. Another 50 mg (0.39 mmol) of 2-amino-4,4,4-trifluorobutan-1-ol were then added, and the mixture was stirred in a microwave at 80° C. for 1 h. The reaction solution was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). All product-containing fractions were combined and concentrated. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. This gave 17 mg of the target compound (25% of theory, purity 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]12([C:31](O)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/1=[N:8]\[C:31]([C:21]12[CH2:30][CH:25]3[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]3)[CH2:28]1)[CH2:22]2)=[O:32])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: BrCCCOCc1ccccc1
Reactant: Cc1nc(N)sc1C
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CCCOCc2ccccc2)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, (3-bromo-propoxymethyl)-benzene and 1-adamantane carboxylic acid were processed as described in Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.57-1.73 (m, 6H) 1.79-1.85 (m, 6H) 1.91-1.96 (m, 3H) 1.96-2.04 (m, 2H) 2.12-2.17 (m, 3H) 2.18-2.22 (m, 3H) 3.51 (t, J=5.93 Hz, 2H) 4.20 (t, 2H) 4.46 (s, 2H) 7.25-7.38 (m, 5H); MS (ESI) m/z 439 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([F:35])[CH:22]=2)=[C:6]2[N:11]([C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:10]=[CH:9][N:8]=[C:7]2[NH2:20])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:20][C:7]1[C:6]2=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:35])[CH:22]=3)[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CC(=O)c1c(-c2ccc(NC(=O)OC(C)(C)C)c(F)c2)c2c(N)ncnn2c1CN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1c(-c2ccc(N)c(F)c2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of CH2Cl2 (50 mL) was added of tert-butyl {4-[6-acetyl-4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2 fluorophenyl}-carbamate (291 mg, 0.60 mmol) followed by trifluoroacetic acid (5 mL). The solution was allowed to stir for 30 min at rt. Aq saturated NaHCO3 was added to the solution until bubbling stopped. Additionally CH2Cl2 was added and the solution was then transferred to a separatory funnel. The organic layer was isolated while the aqueous layer was back extracted with CH2Cl2 (2×25 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated to dryness yielding 214 mg of the above compound as a white solid (0.56 mmol, yield 93%). 1H-NMR (DMSO-d6) δ 7.95 (s, 1H), 7.08 (dd, J=1.7 Hz, 10.3 Hz, 1H), 6.92 (dd, J=1.8 Hz, 7.9 Hz, 1H), 6.86 (t, J=8.7 Hz, 1H), 5.47 (s, 2H), 4.05 (s, 2H), 3.49 (m, 4H), 2.41 (m, 4H), 2.06 (s, 3H); MS [M+H]+=385.1; LCMS RT=1.16 min.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.Cl.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24]C=1>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:24]2[CH2:25][CH2:26][CH2:27][C:22]2=[O:9])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: c1ccccc1
Agent: Cl
Product: O=C1CCCC1=Cc1ccc(Br)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 4-bromobenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a recovery of 71.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14].[OH-:21].[K+].Cl>CO.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:13](=[O:15])[CH2:14][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[CH2:14][C:13]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[O:21]
Reactant: CC(=O)c1ccco1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(CC(=O)c2ccco2)CC(=O)c2ccco2)c(OC)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Following the general methods outlined by Weller and Luellen (see above), to a solution of 16.6 g (0.1 mole) of 2,4-dimethoxybenzaldehyde 1 and 20 ml (0.2 mole) of 2-acetylfuran 2 in 100 ml of methanol was added 5.5 g of potassium hydroxide previously dissolved in a small amount of methanol. The resulting mixture was heated to reflux and then stirred overnight at 55° C. The solution was then poured into water acidified with 1N HCl and extracted with CH2Cl2. The CH2Cl2 extracts were dried (Na2SO4) and the solvents removed at high vacuum. The resulting amber oil solidified on standing overnight affording 36.7 g of crude dione 3.
Reaction SMILES: [C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.[C@H:20]1([NH:57][C:58]2[N:66]=[C:65]([Cl:67])[N:64]=[C:63]3[C:59]=2[N:60]=[CH:61][N:62]3[C@H:68]2[C@H:72](CC([O-])=O)[C@@H:71]([CH2:77][C:78]([O-])=[O:79])[C@H](C3N=NN(CC)N=3)O2)[CH2:25][CH2:24][C@H:23]([NH:26][C:27]2[N:35]=[C:34]([Cl:36])[N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[C@H:37]2[C@H:41](CC([O-])=O)[C@@H:40]([CH2:46][C:47]([O-:49])=O)[C@H](C3N=NN(CC)N=3)O2)[CH2:22][CH2:21]1.N[C@H]1CC[C@H](N)CC1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:67][C:65]1[N:64]=[C:63]2[C:59]([N:60]=[CH:61][N:62]2[CH:68]2[CH2:72][CH2:71][CH2:77][CH2:78][O:79]2)=[C:58]([NH:57][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27]3[N:35]=[C:34]([Cl:36])[N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4[CH:37]3[CH2:41][CH2:40][CH2:46][CH2:47][O:49]3)[CH2:22][CH2:21]2)[N:66]=1
Reactant: CCn1nnc([C@@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(Cl)nc7c6ncn7[C@@H]6O[C@@H](c7nnn(CC)n7)[C@H](CC(=O)[O-])[C@H]6CC(=O)[O-])CC5)nc(Cl)nc43)[C@H](CC(=O)[O-])[C@H]2CC(=O)[O-])n1
Agent: N[C@H]1CC[C@H](N)CC1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1nc(N[C@H]2CC[C@H](Nc3nc(Cl)nc4c3ncn4C3CCCCO3)CC2)c2ncn(C3CCCCO3)c2n1
Temperature: 75 °C

Procedure:
A stirred suspension of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Intermediate 1 in WO03/080613) (1.14 kg) in n-butanol (1.7 L) was treated with trans-1,4-diaminocyclohexane (239.2 g) and di-iso-propylethylamine (2.5 L), then heated at 75° C. for 17 hours. The suspension was allowed to cool to ambient temperature, filtered, washed with n-butanol (2×2.3 L) and dried in vacuo at 60° C. to give the title compound (0.9 kg).
Reaction SMILES: C(CS[C:6](=[S:12])[S:7][CH2:8][C:9]([OH:11])=O)(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1[C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl.C(N(CC)C(C)C)(C)C.Cl>O1CCCC1>[S:33]([C:27]1[CH:26]=[CH:25][C:30]([CH2:31][N:32]2[C:9](=[O:11])[CH2:8][S:7][C:6]2=[S:12])=[CH:29][CH:28]=1)(=[O:34])(=[O:35])[NH2:36]
Reactant: O=C(O)CSC(=S)SCC(=O)O
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(CN2C(=O)CSC2=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of bis(carboxymethyl)trithiocarbonate (200 mg) in tetrahydrofuran (10 ml) was added carbonyldiimidazole (291 mg), and the mixture was stirred at room temperature. After 2 hr, to the reaction mixture were added homosulfamine hydrochloride (200 mg) and N,N-diisopropylethylamine (155 mg), and the mixture was stirred overnight at 70° C. 2N Hydrochloric acid (10 ml) was added thereto under ice cooling, the mixture was extracted twice with ethyl acetate (40 ml), and the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2:1) to give 3-(4-sulfamoylbenzyl)-2-thioxothiazolidin-4-one (189 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:15]=2)=[C:8]([O:39][CH3:40])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:41]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)=[C:8]([O:39][CH3:40])[CH:7]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO)cc2)c(OC)c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 3.9 g (6.44 mmol) of dibutyl[4-[2-[4-(tert-butyldiphenylsiloxymethyl)phenyl]vinyl]-3-methoxyphenyl]amine, and 20 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 2.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.28 g of a yellow liquid (yield: 96.4%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](OCC)=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[BH4-].CC[O:22]CC>>[C:1]([N:8]1[CH2:11][CH:10]([CH:12]([OH:22])[CH3:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOCC
Reactant: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Product: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 132 (0.96 g, 3.9 mmol) in ether (20 mL) at ambient temperature was treated with LiBH4 (0.34 g, 15.8 mmol) then heated to 55° C. After 45 min at 55° C., the cooled reaction was quenched with 5% KHSO4 (10 mL) and then diluted with EtOAc. The organic phase was washed with 5% KHSO4 and brine, dried (MgSO4), and concentrated to give 133 (0.79 g) as a colorless oil. Rf 0.46 (silica, EtOAc).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:33][C:34]([N:36]1[CH2:41][C@@H:40]([CH3:42])[N:39]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[CH2:38][C@@H:37]1[CH3:53])=[O:35]>CN(C)C=O.O1CCCC1.C(OCC)C>[CH3:53][C@H:37]1[CH2:38][N:39]([C:43]2[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=2)[C@H:40]([CH3:42])[CH2:41][N:36]1[C:34](=[O:35])[CH2:33][O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: C[C@@H]1CN(C(=O)CCl)[C@@H](C)CN1c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)CO[C@H]2CC[C@H](Nc3ccc([N+](=O)[O-])c(C(F)(F)F)c3)CC2)[C@@H](C)CN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (118 mg, 0.39 mmol, prepared in accordance with Example 5) was placed under an inert atmosphere, dissolved in dry dimethylformamide (2 mL). A molar solution of lithium bis(trimethylsilyl)-amide (774 μL, 0.77 mmol) was added to the resulting mixture. The mixture was then stirred for 15 min at room temperature. Afterward, a solution of 2-chloro-1-[trans-2,5-dimethyl-4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (130 mg, 0.39 mmol, prepared in accordance with Example 3) in tetrahydrofuran (1 mL) was added. The resulting mixture was stirred at room temperature until the conversion stopped. Next, the mixture was diluted with diethylether (10 mL). The mixture was then washed with water (5 mL), and then saturated aqueous sodium hydrogencarbonate (5 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product isolated was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (24 mg, 10% yield). The structure was confirmed using Protocol II-A. Calculated mass=603; observed mass=603; HPLC retention time=4.69 min.
Reaction SMILES: [Cl:1][CH2:2][P:3]([CH2:6]Cl)(=[O:5])[OH:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[ClH:1].[CH2:8]([NH:15][CH2:2][P:3]([CH2:6][NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])[OH:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=P(O)(CCl)CCl
Reactant: NCc1ccccc1
Product: Cl
Product: O=P(O)(CNCc1ccccc1)CNCc1ccccc1
Temperature: 115 °C

Procedure:
12 g (74 mmol) of bis(chloromethyl)phosphinic acid are added slowly to 80 g of benzylamine at room temperature while stirring, during which the temperature increases slightly. The mixture is then heated at 115° C. for 24 h. Excess benzylamine is removed by distillation in vacuo, and the white residue is dissolved in 150 ml of distilled water, filtered and mixed with 30 mi of concentrated HCl and stirred at room temperature for 1 h. The white precipitate is filtered off with suction, washed with water and dried over P2O5. Yield: 20 g (79%); m.p.: 254° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)=[CH:4][CH:3]=1.[S:14]1[CH:18]=[C:17](C=O)[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]1=2.[CH2:25](O)C(N)(CO)CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[S:14]1[CH:18]=[C:17]([N:13]([CH3:25])[C@H:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9]2)[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]1=2
Reactant: NC(CO)(CO)CO
Reactant: O=Cc1csc2ccccc12
Reactant: N[C@H]1CCN(c2ccc(F)nc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(c1csc2ccccc12)[C@H]1CCN(c2ccc(F)nc2)C1
Temperature: 25 °C

Procedure:
Mix an aliquot (1 mL) of a 0.25 M solution of (S)-[1-(6-fluoropyridin-3-yl)-pyrrolidin-3-yl]-amine (0.25 mmol) in toluene, an aliquot (1 mL) of a 1.0 M solution of benzo[b]thiophene-3-carboxaldehyde (1.0 mmol) in toluene and add a single activated 4 Å molecular sieve. Stir the reactants at room temperature in air. After 16 h add PS-Trisamine (1.5 mmol) and another single activated 4 Å molecular sieve. Stir the reactants at room temperature in air. After 24 h filter the reaction solution to remove the PS-Trisamine, and add an aliquot (2 mL) of a 0.25 M solution of sodium borohydride (0.5 mmol) in ethanol. Stir the reactants at room temperature in air. After 48 h add methanol (2 mL) to the reactants and agitate vigorously. Remove the excess reactants by ion-exchange chromatography using a 5 g SCX-2 cartridge (0.5 mmol/g SO3H) by wetting it with one column volume of methanol. Apply the mixture to the cartridge and allow it to percolate through the stationary phase (under gravity) into a vial. Wash the cartridge with one column volume of methanol such that these washings also pass into the vial. Replace with a second vial and elute with 3.5N ammonia in methanol (10 mL). Evaporate the solvents from the ammonia washings on a heating block under a stream of nitrogen to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.98 (2H, m), 7.57 (1H, s), 7.39-7.42 (1H, m), 7.35-7.39 (2H, m), 7.08-7.13 (1H, m), 6.96 (1H, dd, J=8.93, 3.30 Hz), 4.01 (2H, s), 3.43-3.50 (2H, m), 3.20-3.27 (1H, m), 3.17 (1H, d, J=5.14 Hz), 3.07-3.13 (1H, m), 2.10-2.18 (1H, m), 1.87-1.95 (1H, m), MS (ES): m/z=328 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[N:24]=[C:23]4[N:25]([CH2:28][C:29]5[C:34]([F:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=5[Cl:37])[N:26]=[N:27][C:22]4=[CH:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[ClH:37].[Cl:37][C:30]1[C:31]([F:36])=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[CH2:28][N:25]1[C:23]2=[N:24][C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)=[CH:20][CH:21]=[C:22]2[N:27]=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4nnn(Cc5c(F)ccc(F)c5Cl)c4n3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cl
Product: Fc1ccc(F)c(Cn2nnc3ccc(-c4cnn(C5CCNCC5)c4)nc32)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of Example 166 (0.240 g, 0.453 mmol) in dichloromethane (3 ml) cooled to 0° C., (0.1 ml) was added and warmed to RT. After 2 h, the reaction mixture was poured in ice water and pH was adjusted to call with 10% NaOH solution and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The residue was dissolved in THF (1 ml), ether saturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was filtered and washed with ether and dried under vacuum to afford the title compound as an off-white solid (0.090 g, 43%). M.P.: 85-87° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz); 8.48 (d, J=1.5 Hz, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.60 (dt, J=13.8, 4.8 Hz, 1H), 7.45 (dt, J=13.4, 4.2 Hz, 1H), 6.01 (s, 2H), 4.29 (m, 1H), 3.07 (d, J=12.4 Hz, 2H), 2.63 (m, 2H), 1.98 (m, 2H), 1.85 (m, 2H). MS (m/z):: 429.69 (M+−HCl).