Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1([CH3:17])[CH2:14][C:13](=O)[O:12][C:11]1=[O:16]>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:12])[CH2:14][C:10]([CH3:17])([CH3:9])[C:11]2=[O:16])=[N:6][CH:7]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Nc1ccc(I)cn1
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(c2ccc(I)cn2)C1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
5-iodopyridin-2-amine (1 g, 4.55 mmol) was dissolved in DMF (5 ml) and 3,3-dimethyldihydrofuran-2,5-dione (1.28 g, 10.0 mmol, 2.2 equiv.) was added at room temperature. The mixture was stirred for 3 hr at 150° C. The reaction mixture was evaporated to dryness and loaded directly to a silica gel column. The crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (1.3 g, 3.94 mmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=331.0 (M+H+).
Reaction SMILES: CO[C:3]1C(OC)=CC2C(C3C=CC=CC=3)=NNC(=O)CC=2[CH:20]=1.[S:23]1[C:27]([C:28]2[C:34]3[CH:35]=[C:36]([O:42][CH2:43][CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[CH:38][C:33]=3[CH2:32][C:31](=[O:45])[NH:30][N:29]=2)=[CH:26][C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]1=2>>[S:23]1[C:27]([C:28]2[C:34]3[CH:35]=[C:36]([O:42][CH2:43][CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[CH:38][C:33]=3[CH2:32][C:31](=[O:45])[N:30]([CH2:3][CH3:20])[N:29]=2)=[CH:26][C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]1=2
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Reactant: CCOc1cc2c(cc1OCC)C(c1cc3ccccc3s1)=NNC(=O)C2
Product: CCOc1cc2c(cc1OCC)C(c1cc3ccccc3s1)=NN(CC)C(=O)C2
Yield: 72 %

Procedure:
By replacing 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa in example IIIag by 1-(2-benzo[b]thienyl)-7,8-diethoxy-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIab and proceeding in the same manner, the abovenamed product is obtained. Yield: 72%. M: 100–103° C. 1H-NMR (200 MHz, CDCl3): d 1.26 (t, J=7.1, 3H, CH3), 1.44 (t, J=7.0, 3H, CH3), 1.52 (t, J=7.1, 3H, CH3), 3.29–3.56 (m, 2H, 5-CH2), 3.85–4.25 (m, 6H, 3×CH2CH3), 6.87 (s, 1H Ar), 7.15 (s, 1H Ar), 7.32–7.44 (m, 3H Ar), 7.71–7.89 (m, 2H Ar).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[C:36]([C:43]2[C:52]3[C:47](=[CH:48][C:49]([C:53](O)=[O:54])=[CH:50][CH:51]=3)[N:46]=[CH:45][CH:44]=2)=[C:37]2[CH2:42][CH2:41][CH2:40][N:38]2[N:39]=1>ClCCl>[CH:23]1([NH:28][C:53]([C:49]2[CH:48]=[C:47]3[C:52]([C:43]([C:36]4[C:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=5)=[N:39][N:38]5[CH2:40][CH2:41][CH2:42][C:37]=45)=[CH:44][CH:45]=[N:46]3)=[CH:51][CH:50]=2)=[O:54])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1CCCC1)c1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (53 mg, 0.30 mmol), HOBT, (24 mg, 0.28 mmol), cyclopentylamine (0.03 mL, 0.30 mmol), and 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid (90 mg, 0.25 mmol) in dichloromethane (1 mL) is stirred room temperature for 18 h. The mixture is concentrated in vacuo and the residue chromatographed on SiO2 to yield the title compound, 31 mg (31%,) as a white solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([O:26]CC)=[O:25])[CH:20]=1)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[K+].Cl>C(O)C.O>[CH:3]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=1)=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCC(=O)c1cc(C(=O)OCC)c[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCC=Cc1cc(C(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
Sodium borohydride (500 mg, 13 mmol) was added to an ethanol solution (100 ml) of 4.59 g (13 mmol) of ethyl 5-pentadecanoylpyrrole-3-carboxylate prepared in the same manner as in Synthetic Example 4. The mixture was stirred at room temperature for 16 hours. After a removal of the ethanol under reduced pressure, the mixture was treated with water, extracted with ether, washed with water and dried over anhydrous magnesium sulfate. A removal of the solvent under reduced pressure quantitatively gave an alcoholic compound. To the resulting product were added 3.53 g (63 mmol) of potassium hydroxide in ethanol (35 ml) and water (12 ml), and the mixture was heated under reflux for 5 days. The resulting mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/2) to obtain 2.33 g (60 % yield) of 5-(1-pentadecenyl)pyrrole-3-carboxylic acid, m.p. 90°-96° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>>[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:22][C:21]([C:20]2[N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:12](=[O:31])[C:13]3[C:18]([C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=3)=[O:23])[CH:33]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: OCc1cccnc1
Product: O=C(OCc1cccnc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and 3-pyridinemethanol. Colorless crystals (288 mg).
Reaction SMILES: I[CH2:2][CH2:3][OH:4].[CH3:5][O:6][CH2:7][CH2:8][C@@H:9]1[NH:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]3[N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:21][C:20]=3[NH:19][C:18]3[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=3[N:16]=2)[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>C(O)C.C(OCC)(=O)C.O>[CH3:5][O:6][CH2:7][CH2:8][CH:9]1[CH2:10][N:11]([C:15]2[C:24]3[N:23]=[C:22]([C:25]([F:27])([F:28])[F:26])[S:21][C:20]=3[NH:19][C:18]3[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=3[N:16]=2)[CH2:12][CH2:13][N:14]1[CH2:2][CH2:3][OH:4]
Reactant: OCCI
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCC1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
Add 2-iodo-ethanol (0.44 mL, 2.55 mmol) to a slurry of (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.75 g, 1.82 mmol), and powdered potassium carbonate (1.26 g, 9.11 mmol) in absolute ethanol (7.5 mL) and heat to reflux. After an overnight period, cool, add saturated aqueous sodium chloride and ethyl acetate, and add deionized water to dissolve precipitated salt formed during the extraction. Extract aqueous phase with ethyl acetate (2×), and dry (sodium sulfate), filter, and concentrate organics under reduced pressure to an oil (0.564 g). Add absolute ethanol (8 mL), powdered potassium carbonate (0.62 g, 4.50 mmol), followed by 2-iodo-ethanol (0.098 mL, 1.26 mmol), and stir 15.5 hours at reflux. Add additional 2-iodo-ethanol (0.010 mL, 0.13 mmol), and stir at reflux. After 4 hours, cool to ambient temperature and add deionized water and ethyl acetate. Extract separated aqueous phase with ethyl acetate, and combine, dry (sodium sulfate), filter, and concentrate organics under reduced pressure to a residue (0.86 g). Purify the residue by flash chromatography, eluting with a gradient of solutions of 2M ammonia in methanol: ethyl acetate (1%-5% 2M ammonia in methanol in ethyl acetate) to give the title compound (0.213 g, 26%): mass spectrum (APCI, m/e): 456 (M+1); NMR (1H, 300 MHz, DMSO-d6) δ 8.45 (s, 1H), 6.96-6.81 (m, 3H), 6.71 (m, 1H), 4.38 (t, 1H, J=5.4 Hz), 3.54-3.06 (m, 11H), 2.71 (m, 2H), 2.55 (m, 1H), 2.41 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41].CCN(C(C)C)C(C)C.Cl[CH2:52][CH:53]1[CH2:55][O:54]1>CN(C=O)C>[Cl:40][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([N:1]3[CH2:55][CH:53]([OH:54])[CH2:52]3)[C@H:3]([OH:41])[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:20]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]2[N:18]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: ClCC1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N4CC(O)C4)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
(+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (29 mg, 0.046 mmol) was dissolved in DMF (1 ml) in a 4 ml vial. DIPEA (0.25 ml, 1.431 mmol) was added and the mixture warmed to 70° C. A solution of 2-(chloromethyl)oxirane (100 μl, 1.279 mmol) in DMF (1 ml) was added slowly. The reaction mixture was kept at 70° C. for 30 minutes. The crude reaction mixture was filtered through a MCX cartridge (Waters, 5 g adsorbent). The cartridge was washed with MeOH and the product eluted with a 1:1 mixture of (CH3CN+2 molar solution of NH3 in MeOH). Evaporation to dryness gave 30 mg of (+/−)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(3-hydroxyazetidin-1-yl)piperidin-1-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile. The crude was used “as is” in the following deprotection
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH:8]([CH2:13][N+]([O-])=O)[C:9]([F:12])([F:11])[F:10])[CH3:4].[O-:18]S([O-])(=O)=O.[Mg+2].[O-][Mn](=O)(=O)=O.[K+]>C1COCC1.O>[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH:8]([CH:13]=[O:18])[C:9]([F:12])([F:11])[F:10])[CH3:4]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])C(F)(F)F
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a 100 mL round-bottomed flask, KOH (356 mg, 5.45 mmol) was combined with H2O (50 ml) to give a colorless solution and cooled to 0° C. 4,4,4-Trifluoro-3-nitromethyl-butyric acid ethyl ester (1.25 g, 5.45 mmol) in 10 ml THF was added and the resulting reaction mixture was stirred for 20 min. This was followed by addition of MgSO4 (657 mg, 5.45 mmol) in 5 ml of H2O then by KMnO4 (862 mg, 5.45 mmol) in 30 ml of H2O. The resulting reaction mixture was stirred for 30 min, filtered through celite and the celite cake washed with CH2Cl2. The combined filtrate and washes were washed with brine, dried over Na2SO4, filtered and concentrated to afford 4,4,4-trifluoro-3-formyl-butyric acid ethyl ester as a liquid which was used without purification.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30](=O)[CH:31](Br)[CH2:32][CH3:33])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:39][C:40]([C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[CH3:52])=[S:41]>CCO>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[N:39]=[C:40]([C:42]4[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=4[CH3:52])[S:41][C:31]=3[CH2:32][CH3:33])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccc(C(N)=S)c(C)c1
Reactant: CCC(Br)C(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CCO
Product: CCc1sc(-c2ccc(C(=O)OC)cc2C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutanoyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (25 mg, 0.040 mmol) and methyl 4-(aminocarbonothioyl)-3-methylbenzoate (16.87 mg, 0.081 mmol) in EtOH (450 μL) was heated at 70° C. overnight. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (Si, 1000 microns, Hex/EtOAc (80:20)) to afford methyl 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoate, as colorless oil. LCMS calc.=731.2; found=731.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H); 7.92 (d, J=8.1 Hz, 1H); 7.86 (d, J=8.0 Hz, 2H); 7.79 (s, 1H); 7.72 (d, J=7.9 Hz, 1H); 7.69 (s, 1H); 7.55 (d, J=7.9 Hz, 1H); 7.29 (s, 1H); 5.59 (d, J=8.0 Hz, 1H); 4.91 (d, J=15.7 Hz, 1H); 4.27 (d, J=15.7 Hz, 1H); 4.04-3.99 (m, 1H); 3.95 (s, 3H); 2.88-2.76 (m, 2H); 2.68 (s, 3H); 1.36 (t, J=7.5 Hz, 3H); 0.57 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:11])(=[O:10])[CH2:5][C@:4]([C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[F:21])([CH2:12][F:13])[N:3]=1.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:11])(=[O:10])[CH2:5][C@@:4]([CH2:12][F:13])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[N:3]=1
Reactant: CC1(C)C(N)=N[C@](CF)(c2cc(Br)ccc2F)CS1(=O)=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)C(N)=N[C@](CF)(c2ccccc2F)CS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of (S)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (3.22 g, 8.44 mmol) in ethanol (15 mL) and ethyl acetate (5 mL) was added sodium bicarbonate (138 mg, 1.69 mmol) and 10 wt % palladium on carbon (0.90 g, 8.44 mmol). The flask was evacuated and backfilled with hydrogen three times, and stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was rinsed with ethyl acetate and ethanol. The combined filtrates were concentrated in vacuo and the residue was redissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and evaporated to provide the title compound (2.49 g, 8.23 mmol) as an off-white solid. LC/MS (ESI+) m/z=303 (M+H).
Reaction SMILES: C(S)C.[H-].[Na+].[OH:6][CH:7]([C:9]1[CH:10]=[C:11]([S:23]([NH2:26])(=[O:25])=[O:24])[S:12][C:13]=1[S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[CH3:8].Cl>CN(C=O)C>[OH:6][CH:7]([C:9]1[CH:10]=[C:11]([S:23]([NH2:26])(=[O:25])=[O:24])[S:12][C:13]=1[S:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:8]
Reactant: COc1ccc(Sc2sc(S(N)(=O)=O)cc2C(C)O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CC(O)c1cc(S(N)(=O)=O)sc1Sc1ccc(O)cc1
Yield: 61 %

Procedure:
Ethanethiol (2.1 ml, 0.028 mol) was added dropwise over 10 minutes to a stirred suspension of 60% NaH in mineral oil (1.28 g, 0.032 mol) in DMF (30 ml) at ice bath temperature under nitrogen. After the sodium hydride had reacted, 4-(1-hydroxyethyl)-5-(4-methoxyphenylthio)thiophene-2-sulfonamide (1.0 g, 0.0029 mol) was added and the solution was stirred at steam bath temperature over night. The mixture was cooled in ice and acidified with 3N HCl (20 ml). The mixture was extracted with ethyl acetate and the extract was washed with saturated NaCl, saturated NaHCO3 and again with saturated NaCl. The extract was dried, filtered and concentrated in vacuo. The residual oil was washed with pet ether to remove the mineral oil and was purified by silica gel chromatography using 10% methanol in chloroform. The white solid product was obtained in 61% yield, mp. 133°-137° C. Purity and structure were confirmed by HPLC, C, H, N analysis and NMR.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][N:7]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[CH2:8][CH2:9][N:10]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[CH2:11][CH:6]2[C:4]([OH:5])=[O:3])(=[O:22])=[O:21])=[CH:28][CH:27]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)O)cc1
Yield: 55.9 %

Procedure:
The 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine-2-carboxylic acid ethyl ester (0.56 g, 1.18 mmol) was dissolved in THF/MeOH/H2O (3 mL each) and treated with lithium hydroxide monohydrate (0.099 g, 2.3 mmol). The reaction was heated at reflux overnight and then concentrated and acidified to pH 4 with acetic acid. The solution was extracted with methylene chloride and then washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.298 g (53%) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)- piperazine-2-carboxylic acid as a yellow powder. Electrospray Mass Spec 452.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:29][C:30](=[O:45])[C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1.CO.[OH-].[Li+]>O1CCCC1>[C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:22][C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:46])=[O:2])=[C:5]([NH:29][C:30](=[O:45])[C:31]3[CH:36]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:34]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:32]=3)[CH:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)ccc1C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 22 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[3,5-bis(trifluoromethyl)benzoyl]amino}benzoic acid methyl ester (0.25 g, 0.39 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.29 mL). The crude material was crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours. The product was isolated and then triturated with hexanes to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[3,5-bis(trifluoromethyl)benzoyl]amino}benzoic acid (0.054 g, 22%) as a white solid. mp=205-206° C. (dec). 1H NMR (500 MHz, DMSO-d6); δ 13.70 (bs, 1H), 12.70 (bs, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 8.32 (d, 2H), 8.00 (d, 1H), 7.67-7.64 (AA′BB′, 4H), 7.45 (t, 2H), 7.37 (t, 1H), 6.84 (d, 1H), 4.31 (t, 2H), 4.22 (t, 2H), 2.18 (m, 2H). Mass spec (MW 630.54); (ES+) m/z 630.96, (ES−) m/z 629.39. Elemental analysis; Calculated for C32H24F6N2O5: C, 60.96; H, 3.84; N, 4.44. Found: C, 60.10; H, 3.57; N, 4.18.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:38])[NH2:37])[CH:32]=3)[CH:27]=2)=[O:24])=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.C(OCC)C.[BrH:44].C(O)(=O)C>>[BrH:44].[BrH:44].[NH2:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:37])[NH2:38])[CH:32]=3)[CH:27]=2)=[O:24])=[CH:20][CH:19]=1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)OCc4ccccc4)s3)ccc2c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)s3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of a 30% HBr/acetic acid solution, was dissolved 1.0 g of 6-amidino-2-naphthyl 5-benzyloxycarbonylaminomethyl-thiophene-2-carboxylate methanesulfonate. The solution was stirred for 30 minutes at room temperature. Ethyl ether was added to the resulting solution. The precipitate was collected by filtration and recrystallized from a mixture of methanol and ethyl ether to obtain 800 mg of 6-amidino-2-naphthyl 5-aminomethyl-thiophene-2-carboxylate dihydrobromide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH3:36])[C:15](=O)[CH2:16][CH:17]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:18][C:19]([N:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>O1CCCC1>[CH2:23]([N:21]([CH3:22])[CH2:19][CH2:18][CH:17]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:16][CH2:15][N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(Cc1ccccc1)C(=O)CC(CC(=O)N(C)Cc1ccccc1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCC(CCN(C)Cc1ccccc1)N1CCCC1)Cc1ccccc1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
Under nitrogen, lithium aluminum hydride (0.44 g, 12 mmol) was added to a solution of N,N′-dibenzyl-N,N′-dimethyl-3-(1-pyrrolidinyl)glutaramide (1.16 g, 2.85 mmol) in anhydrous tetrahydrofuran (20 mL) stirred in an ice bath, and the mixture was stirred at 65° C. for 2 hours. Methanol (3.0 mL, 74 mmol) was added to the ice-cold reaction mixture, and the ice bath was removed. Water (2.0 mL), diethyl ether (150 mL) and anhydrous magnesium sulfate (15 g) were added, and the mixture was stirred at room temperature for 1 hour. Insoluble materials were removed by filtration through Celite, an the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield N,N′-dibenzyl-N,N′-dimethyl-3-(1-pyrrolidinyl)-1,5-pentanediamine as a colorless oil (917.3 mg, yield: 85%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7](O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(N)CO
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(N)COC(c1ccccc1)c1ccccc1
Yield: 69.3 %

Procedure:
A mixture of 2-amino-2-methylpropanol (89.1 g), benzhydrol (190 g) and para-toluenesulphonic acid monohydrate (200 g) in toluene (1200 ml) was heated under reflux in a Dean-Stark apparatus for four hours and evaporated. The residue was partitioned between ether and water and the organic layer was washed with water and extracted into 10% aqueous citric acid. The acidic extract was washed with ether, basified with solid sodium carbonate and extracted into ether. The organic extract was washed with water, dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (177 g, 69%) which was characterised by its 1H-n.m.r. spectrum.