Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].F[P-](F)(F)(F)(F)F.[CH:14]([N+:17]([CH:25]([CH3:27])[CH3:26])=[CH:18]N1CCCCC1)([CH3:16])[CH3:15].[C:28]([O:32][C:33]([N:35]1[C:39](=[O:40])[CH2:38][CH2:37][C@H:36]1[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1.C(OC(C)C)(=O)C>[C:28]([O:32][C:33]([N:35]1[C@H:36]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:46][CH:47]=2)[CH2:37]/[C:38](=[CH:18]\[N:17]([CH:14]([CH3:15])[CH3:16])[CH:25]([CH3:26])[CH3:27])/[C:39]1=[O:40])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)[N+](=CN1CCCCC1)C(C)C
Agent: CC(C)(C)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 M solution of potassium tert-butoxide in THF (11.7 ml) is added to diisopropyl(piperidin-1-ylmethylidene)ammonium hexafluorophosphate (5 g, prepared according to Example 12). The resulting mixture is then stirred for 1 h at 50° C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (1 g) is then added to the reaction and the resulting mixture is stirred for 1 h at room temperature. The mixture is diluted with isopropyl acetate and filtered through silica. The residue is concentrated in vacuo then purified by column chromatography (ethyl acetate) to give (R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Rf 0.55 (ethyl acetate). 1H NMR (DMSO-d6), 7.65-7.62 (2 H), 7.61-7.58 (2 H), 7.47-7.42 (2 H), 7.37-7.31 (1 H), 7.29-7.25 (2 H), 7.01 (1 H), 4.28-4.20 (1 H), 3.84-3.70 (2 H), 3.07-3.01 (1H), 2.82-2.73 (1 H), 2.71-2.63 (1 H) 2.49-2.44 (1 H), 1.49 (9 H), 1.13-1.08 (12 H).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.CO>ClCCl>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:26])([F:28])[F:27])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[CH:37][CH:38]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(N)cc2)ncc(N)c1=O)C(=O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-nitrophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was subjected to a procedure similar to that described in Example 6 to give a brown solid; chromatography solvent: methanol:dichloromethane (gradient, 5:95, 10:90); NMR (DMSO/D2O): 7.29 (s,1), 7.01 (d,2), 6.49 (d,2), 4.52 (m,2), 4.10 (d,2), 2.25 (m,1), 0.88 (d,3), 0.80 (d,3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@@:11]([NH:33]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)[C:10]1=[O:41]>ClCCl>[NH2:33][C@@:11]1([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:41]
Reactant: CN1CC[C@](CC#Cc2nccc(-c3ccc(C(F)(F)F)cc3)n2)(NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC[C@@](N)(CC#Cc2nccc(-c3ccc(C(F)(F)F)cc3)n2)C1=O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Trifluoroacetic acid (2 mL, 26.9 mmol) was added to a solution of tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 7) (555 mg, 1.17 mmol) in dichloromethane (10 mL) at 20° C. and the reaction was stirred for 1 hr. The reaction was quenched by the addition of sat. NaHCO3 and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford the (3S)-3-amino-1-methyl-3-[3-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (D8) (340 mg, 0.9082 mmol, 77.6% yield) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Cu]>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2](=[O:1])[CH:11]=1
Reactant: Cc1cc(O)nc2ccccc12
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 54.7 %

Procedure:
The starting 1,2-dihydro-4-methyl- 1 -phenyl-2-quinolone (1) is prepared either by an Ullmann coupling according to a literature procedure (Wawzonek et al., supra.) or via the reaction of the corresponding diarylamine with dikctene followed by acid cyclization (Elderfield, supra). Thus 10.0 g (62.9 mmoles) of 2-hydroxy-4-methylquinoline is heated at reflux with 24.0 g (377 mmolcs) of copper powder, 8.68 g (62.9 mmoles) of potassium carbonate and 19.2 g (94 mmoles) of iodobenzene for 48 hours. The reaction is cooled to room temperature, partitioned between water and ethyl acetate, filtered, and the organic layer is dried over magnesium sulfate. The crude product is purified on a silica gel column, eluting with 1:1 ethyl acetate/hexanes to yield 8.1 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)=[N:6][CH:7]=1.[CH:18]1([C:21]2[N:22]=[C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][N:24]3[C:30]=2[CH3:31])[CH2:20][CH2:19]1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:26]4[CH:27]=[CH:28][C:23]5[N:24]([C:30]([CH3:31])=[C:21]([CH:18]6[CH2:20][CH2:19]6)[N:22]=5)[CH:25]=4)[C:11](=[O:17])[C:10]=3[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1c(C2CC2)nc2ccc(I)cn12
Reactant: O=c1[nH]ccc2oc(-c3ccc(Cl)cn3)cc12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc4oc(-c5ccc(Cl)cn5)cc4c3=O)cn12
Temperature: 220 °C
Yield: 2 %

Procedure:
A mixture of 2-(5-chloropyridin-2-yl)furo[3,2-c]pyridin-4(5H)-one (69.0 mg), 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (100 mg), N,N′-dimethylethylenediamine (0.030 mL), copper(I) iodide (53.3 mg), potassium carbonate (116 mg) and DMSO (3.0 mL) was heated at 220° C. for 1 hr under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate to give the title compound (2.30 mg) as a pale red solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:20]=1)=O.FC1C=C(C2OC3C=CC(CO)=CC=3N=2)C=CC=1>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([CH2:3][OH:2])=[CH:20][C:9]=3[N:10]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2oc(-c3ccc(F)cc3)nc2c1
Agent: OCc1ccc2oc(-c3cccc(F)c3)nc2c1
Product: OCc1ccc2oc(-c3ccc(F)cc3)nc2c1

Procedure:
Compound 74A was reacted in a manner analogous to Compound 69B to give the title product. MS m/z 244 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]1[SH:15])(=[O:3])C.C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26].O>CN(C)C=O>[CH3:23][N:24]1[C:25](=[O:26])[S:15][C:5]2=[N:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:8][N:4]2[C:1]1=[O:3]
Reactant: CN=C=O
Reactant: CC(=O)n1cc(-c2ccccc2)nc1S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)sc2nc(-c3ccccc3)cn2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.6 g (2.75 millimoles) of 1-acetyl-4-phenyl-2-mercaptoimidazole, and 1.0 ml of triethylamine was added to the solution. Then, 0.65 ml (10.9 millimoles) of methyl isocyanate was further added to the solution and the mixture was stirred at room temperature overnight. Then, 20 ml of water was added to the reaction mixture, and the mixture was stirred for 1 hour and the precipitated crystal was recovered by filtration to obtain 0.4 g (yield=56%) of intended 3-methyl-7-phenyl-1,3,5-thiadiazino[3,2-a]imidazole-2,4(3H)-dione (compound No.53).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[CH2:10][C:11](=[O:14])[CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=[O:17].[K+]>CO>[CH2:1]([NH:8][C:9](=[O:15])[CH2:10][C:11](=[O:14])[CH2:12][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)CC(=O)NCc1ccccc1
Reactant: O=C[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CO)CC(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
N-benzyl-4-bromo-3-oxobutanamide (compound B 50 g, 185.1 mmol) was dissolved in methanol (400 ml), and potassium formate (31.14 g, 370.2 mmol) was added. The resulting mixture was heated under reflux for 2 hours. Methanol was removed by distillation under reduced pressure; the residue was taken up into ethyl acetate (250 ml) under reflux, filtered hot, the filter cake washed with warm ethyl acetate (100 ml). The combined filtrate was cooled to −10° C., aged for 1.5 hours. The precipitate was collected, washed twice with cold ethyl acetate (2×25 ml), dried to give N-benzyl-4-hydroxy-3-oxobutanamide (18.2 g, 101 mmol, 38.8% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:27](O)=[O:28])[C:12]2[CH2:13][CH2:14][N:15]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:16](=[O:19])[C:17]=2[CH:18]=1)#[N:2].Cl.[NH2:31][C@@H:32]([CH2:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=1)[C@H:33]([OH:49])[CH2:34][NH:35][C:36]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)[CH2:38][CH2:37]1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[F:58][C:53]1[CH:52]=[C:51]([CH:56]=[C:55]([F:57])[CH:54]=1)[CH2:50][C@H:32]([NH:31][C:27]([C:11]1[C:12]2[CH2:13][CH2:14][N:15]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:16](=[O:19])[C:17]=2[CH:18]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:10]=1)=[O:28])[C@H:33]([OH:49])[CH2:34][NH:35][C:36]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=2)[CH2:38][CH2:37]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cc(-c3ccccc3C#N)cc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cc(-c3ccccc3C#N)cc2C1=O
Reaction time: 15 h

Procedure:
Added to a solution of 171 mg of 7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 2 cm3 of anhydrous dimethylformamide and under an argon atmosphere are 0.198 cm3 of triethylamine and 207 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride, then 71 mg of 1-hydroxy-7-azabenzotriazole and 100.5 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring for 15 h at a temperature close to 20° C. 50 cm3 of water and 50 cm3 of ethyl acetate are added to the reaction medium. After decanting, the organic phase is washed with 50 cm3 of a saturated aqueous solution of ammonium chloride, two lots of 20 cm3 of water, then 20 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residual solution (around 3 cm3) is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 268 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][CH3:20])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:19]([N:8]([C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=2)[CH:7]=[CH:6][CH:5]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH3:20]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCNC(=O)N(CC)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
135 mg (5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 800 mg (2.34 mmol, 1 eq) of 1-(3-bromophenyl)-1-ethyl-3-heptylurea and 460 mg (3.0 mmol, 1.3 eq) of 4-formylphenylboronic acid in 10 mL of a mixture of dimethylformamide and of 2M potassium phosphate solution (8/2). The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 740 mg of 1-ethyl-1-(4′-formylbiphenyl-3-yl)-3-heptylurea are obtained in oil form. Yield=86%
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:21]1>>[CH3:26][C@H:24]1[CH2:23][N:22]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=2)[CH2:21][C@@H:20]([CH3:19])[N:25]1[S:14]([C:12]1[CH:11]=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:2])=[O:18])[C:6]=2[CH:13]=1)(=[O:16])=[O:15]
Reactant: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1
Reactant: COC(=O)Cc1csc2ccc(S(=O)(=O)Cl)cc12
Product: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1ccc2scc(CC(=O)O)c2c1

Procedure:
The compound {5-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-acetic acid was synthesized according to the procedure in Example 37 using (5-chlorosulfonyl-benzo[b]thiophen-3-yl)-acetic acid methyl ester and cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine from Example 95, Step 1. 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.96 (d, 1H), 7.88-7.80 (m, 2H), 7.57 (d, 2H), 7.28 (d, 2H), 4.60-4.50 (m, 2H), 4.36 (s, 2H), 3.97 (s, 2H), 3.38-3.28 (m, 2H), 2.74-2.64 (m, 2H), 1.55 (d, 6H); LCMS 542.9 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:19]3[C:27]([O:28][CH:29]([F:31])[F:30])=[CH:26][C:25]([CH3:32])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([NH:12]S(C(C)(C)C)=O)[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(NS(C(C)(C)C)=O)C)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl>>[NH2:12][C:10]([C:19]1[C:27]([O:28][CH:29]([F:31])[F:30])=[CH:26][C:25]([CH3:32])=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([C:8]1[NH:7][C:6]2[CH:48]=[CH:49][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: Cc1cc(OC(F)F)c(C(C)(NS(=O)C(C)(C)C)c2nc3cc(C#N)ccc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: Cc1cc(OC(F)F)c(C(C)(NS(=O)C(C)(C)C)c2nc3ccc(C#N)cc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: Cl
Product: Cc1cc(OC(F)F)c(C(C)(N)c2nc3cc(C#N)ccc3[nH]2)c2ccn(C(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (306 mg, 0.427 mmol) was added HCl (1.25M in MeOH, 1.7 mL, 2.137 mmol) and the solution was stirred at room temperature for 90 minutes. The reaction mixture was then concentrated, diluted with sat. aq. NaHCO3, the aqueous layer was extracted with EtOAc, and the organic extract was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 482.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: NC(CO)CO
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NC(CO)CO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.0 g of 2-amino-1,3-propanediol are boiled under reflux for 3 h in 8 ml of ethanol. The crystals precipitating on cooling are recrystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazol-1-yl]-N-(2-hydroxy-1-hydroxymethylethyl)acetamide remains as colorless less crystals of m.p. 212-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[NH:9]2)=[CH:5][C:4]=1[C:25]([NH2:27])=[O:26].[H-].[Na+].Cl.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35]Cl)[CH3:32].O>CN(C=O)C>[CH2:31]([N:33]([CH2:37][CH2:38][N:9]1[C:10]2[C:6](=[CH:5][C:4]([C:25]([NH2:27])=[O:26])=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[C:8]1[N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH2:34][CH3:35])[CH3:32]
Reactant: CCN(CC)CCCl
Reactant: COc1cc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2cc1C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCn1c(N2CCC(Cc3ccccc3)CC2)cc2cc(C(N)=O)c(OC)cc21
Reaction time: 18 h
Yield: 55.2 %

Procedure:
0.3 g (0.862 mmol) of 6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide was dissolved in 20 mL dry DMF. It was cooled in an ice-bath and reacted with 0.12 g NaH (3 mmol, 60% suspension). 0.172 mg (1 mmol) of 2-(diethylamino)-ethylchloride hydrochloride was added and the mixture was stirred for 18 h. The reaction mixture was poured in to water and extracted with dichloromethane (3×75 mL). The combined extract was washed again with water, dried over anhydrous MgSO4, evaporated and purified by silica gel chromatography on a chromatotron using CH2Cl2-Methanol (95:5) to yield 0.22 g of the desired product. It was converted to the HCl salt and lyophilized, M+ 448.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](Cl)=[O:10])([O-:3])=[O:2].[N+:15]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].N1C=CC=CC=1>CC(C)=O>[N+:15]([C:18]1[CH:19]=[C:20]([O:24][C:9](=[O:10])[CH:8]=[CH:7][C:6]2[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 90.2 %

Procedure:
64.5 g (0.3 mole) of 3-nitrocinnamoyl chloride and 300 g of acetone were placed in a reaction vessel and stirred at 50° C. under a nitrogen current. 41.73 g (0.3 mole) of 3-nitrophenol, 60 g of pyridine, and 300 g of acetone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction mixtures were stirred under a nitrogen current for 2 hours. After the reaction, the solid obtained by concentrating the solution was washed by water and dried. 85 g of light yellow colored needle-like crystals ((3-nitrophenyl)-3-cinnamate) was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCCc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CCCBr)cc1
Yield: 95 %

Procedure:
3-(4-Chlorophenyl)-1-propanol (1.00 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.66 g) and N-bromosuccinimide (1.11 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 6 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.30 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4].[CH3:14][C:15]([CH3:18])([NH2:17])[CH3:16].[S:19](=[O:23])(=[O:22])([OH:21])[OH:20].O>CC(O)C>[S:19]([OH:23])([OH:22])(=[O:21])=[O:20].[CH3:14][C:15]([NH:17][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4])([CH3:18])[CH3:16].[CH3:14][C:15]([NH:17][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4])([CH3:18])[CH3:16]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(C(=O)CBr)ccc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)NCC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
5-(Bromoacetyl)-2-hydroxybenzaldehyde (10 g) is suspended in 2-propanol (60 ml) under an inert atmosphere and cooled to 0°. To the stirring slurry is added 1,1-dimethylethanamine (13 ml) and the reaction mixture permitted to warm to room temperature and stir for 50 minutes. The solution is then treated with a mixture of concentrated sulfuric acid (3.5 ml), 2-propanol (6.5 ml) and deionized water (5 ml). The reaction mixture is stirred for a further 18 hours whereupon the title compound (10.2 g) is isolated by filtration and dried in vacuo at 50°.