Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:56])[N:7]([CH2:22][CH2:23][CH2:24][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:26][CH2:27][CH2:28][CH2:29][N:30]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:56])[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:22][CH2:23][CH2:24][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:26][CH2:27][CH2:28][CH2:29][N:30]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
The compound from Stage 2 above (1.49 g, 1.88 mmol, 1 eq) is refluxed in 50 mL of EtOH in the presence of hydrazine hydrate (0.5 mL, 16.1 mmol, 8.5 eq) for 6 hrs. The cooled medium is filtered, washed with EtOH, and evaporated. The residue is flash chromatographed on SiO2 (gradient elution pure CH2Cl2 up to 80:18:2 CH2Cl2:MeOH:NH4OH). After evaporation of the pure fractions, 1.09 g of a colorless oil is obtained (yield 88%). TLC SiO2 (90:9:1 CH2Cl2:MeOH:NH4OH) Rf=0.34. MS: m/z=660 (M-H+).
Reaction SMILES: C([O:4][C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=O)C.[Li+].[OH-]>CO>[CH3:17][C:5]([OH:4])([CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: CC(=O)OC(C)(C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
To a solution of 1,1-dimethyl-2-(4-nitrophenyl)ethyl acetate (52 mmol) in MeOH (50 ml) was added 4N-LiOH (40 ml) and the mixture was stirred at 50° C. for 2 h. After the solvent was removed, this mixture was diluted with water and extracted with EtOAc (4×50 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated. This crude was purified by SiO2 column chromatography developing with hexane/ethyl acetate (5/1) to give the title compound as yellow oil (3.3 g, 33%).
Reaction SMILES: C1(C)C(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=CC=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[O:16].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[O:16]1[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=[CH:12]1
Reactant: CCOC(=O)C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)c1cnco1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Toluenesulfonylmethyl isocyanide (TosMIc) (12.31 g, 1 wt, 1 eq) is dissolved in DCM (61.6 ml, 5 vols) at 0° C. under N2. In a separate vessel, ethyl glyoxalate (50 wt % solution in toluene, 20.6 g, 20.0 ml, 1.67 wt) is diluted with DCM (61.6 ml, 5 vols) under N2 and DBU (12.48 g, 12.35 ml, 1.3 eq, 1.01 wt) is added resulting in a purple solution. The second solution is added to the TosMIc solution over 1 hr, maintaining temperature at 0° C., then checked by HPLC for completion after a further 20 mins. The reaction is quenched by slow addition of 2M HCl (10 vols, 123 ml) and the DCM layer separated. The aqueous layer is re-extracted with DCM (5 vols, 61.6 ml), and the combined organics dried over Na2SO4, then evaporated on Buchi, 25° C., 100 mbar to remove DCM and toluene. Distilled at 12 mbar, jacket temperature 105° C., vapour temperature 60-80° C. to afford ethyl oxazole-5-carboxylate as a colourless oil.
Reaction SMILES: C1([O:6][C:7](=[O:41])[C@@H:8]([NH2:40])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[N:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])CCCC1.[OH-].[Li+]>C1COCC1.O>[NH2:40][C@@H:8]([CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:38][CH3:39])[C:7]([OH:41])=[O:6]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ncnc2cc1OCC[C@H](N)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ncnc2cc1OCC[C@H](N)C(=O)O
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a mixture of (S)-2-amino-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinazolin-7-yloxy]-butyric acid cyclopentyl ester (25 mg, 0.045 mmol) in THF/H2O (4 ml, 1:1) was added lithium hydroxide (5.4 mg, 0.225 mmol) and the mixture was stirred for 18 hours, acidified and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide the title compound as a white solid (8 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][C:25]([CH3:27])=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:25]([CH3:27])([CH3:24])[O:10][C:9]2=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2-(4-Bromophenyl)-2-hydroxyacetic acid (97 g; 0,42 mol) is dissolved in 200 ml of acetone and the solution is cooled to −10° C. At this temperature 23 ml of concentrated sulfuric acid are added dropwise. After the addition is complete the reaction mixture is stirred at −10° C. for further 30 minutes and is subsequently poured into a cooled (0° C.) solution of sodium carbonate (86 g; 0,81 mol) in 800 ml of water. The crystalline 5-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolan-4-one is filtered, washed with ice-cold water and dried in the high vacuum.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:28]=4)[CH:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:42][C:39]([F:40])([F:41])[CH2:38][O:37][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:43]([F:45])([F:46])[F:44])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.9 %

Procedure:
To a cooled and stirred solution of 3-(4-{4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-pyridin-2-yl)-benzenesulfonic acid tert-butylamide (0.21 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by crystallization (diethyl ether) yielded the title compound as an off-white solid (0.15 g, 77%). MS (ISP) 623.2 [(M+H)+]; mp 211° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.03 g) in acetone (50 ml) was added 6 N-hydrochloric acid (5 ml), and the mixture was stirred for 2 hours at room temperature. After adding water (30 ml), the reaction mixture was neutralized with an aqueous sodium bicarbonate solution and acetone was distilled off under reduced pressure. The resultant oily precipitates were extracted with ethyl acetate. The ethyl acetate extracts were washed with water, saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give reddish oil of crude diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.26 g), which was used in a succeeding reaction without further purification.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH:1]([N:4]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: ClCc1cccc2ccccc12
Reactant: CC(C)NCc1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 92 %

Procedure:
2.1 g (0.01 mole) of N-(isopropyl)-4-t-butylbenzylamine was dissolved in 50 ml of dry dimethylformamide, and 1.6 g (0.015 mole) of anhydrous sodium carbonate was added. While the mixture was stirred at room temperature, 1.94 g (0.011 mole) of 1-(chloromethyl)-naphthalene was added. The mixture was reacted at 30° to 40° C. for 6 hours. Ice water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with water and then toluene was evaporated. The residue was chromatographed on a silica gel column and eluted with 5% ethyl acetate/n-hexane. The eluate was concentrated to give 3.17 g (yield 92%) of an oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C[Si]([C:14]#[CH:15])(C)C>C1COCC1.[Cu]I.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)#[CH:15]
Reactant: CSc1nccc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1ccnc(SC)n1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a solution of Pd(PPh3).CH2Cl2 (22 mg, 0.031 mmol) and PPh3 (17 mg, 0.065 mmol) in THF (200 mL), TEA (300 mL), and 4-Chloro-2-methylsulfanyl-pyrimidine (1.0 g, 6.75 mmol, 1 eq.) were added under argon. CuI (13 mg, 0.065 mmol) and trimethylsilylacetylene (725 mg, 7.25 mmol, 1.1 eq) were then added sequentially. The reaction mixture was heated at reflux for 8 h and cooled to rt. The precipitate was filtered off and washed with AcOEt. The filtrate solution was concentrated and the residue was diluted with DCM and 3 g of silica gel. The solvent was removed and the residue was loaded on silica column. The product was eluted with 10% AcOEt/hexanes to provide the desilylated product (540 mg, 3.6 mmol, 53%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(N2CCN(Cc3ccccn3)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of pyridine-2-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 8.52 (d, J=6.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.50-7.19 (m, 4H), 6.84 (dd, J=3.6 Hz, 1.0 Hz, 1H), 4.09-4.06 (m, 4H), 3.89 (br s, 2H), 2.51-2.41 (m, 4H) ppm. MS: m/z: 378 [M+H]+.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C@@H:15]([CH3:35])[C:16]([NH:18][CH:19]([C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[CH2:20][C:21]([O:23]CC)=[O:22])=[O:17])=[O:12])=[CH:6][CH:5]=1.[OH-].[Li+]>CO.O>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C@@H:15]([CH3:35])[C:16]([NH:18][CH:19]([C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(NC(=O)[C@H](C)CNC(=O)Nc1ccc(C=NN)cc1)c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](CNC(=O)Nc1ccc(C=NN)cc1)C(=O)NC(CC(=O)O)c1ccc2c(c1)OCO2
Yield: 71.8 %

Procedure:
A portion of ethyl β-[[2(R)-[[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]-amino]methylpropanoyl]amino]-1,3-benzodioxole-5-propanoate (0.18 g; 0.37 mmoles)) was then treated with 1N lithium hydroxide in methanol/water (1:1; 10 ml) for 15 min. The solvents were evaporated under reduced pressure and the residue was dissolved in water/acetonitrile. The crude product was purified by HPLC (C-18 DeltaPak column) using a gradient of acetonitrile/water/trifluoroacetic acid. Both diastereomers were separated and the desired fractions were lyophilized to give 121 mg of white solid (71% combined yield). FAB-MS: MH+ =456.3 (isomer 1) and 456.2 (isomer 2).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:7].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)[C@H:9]([CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:10]2)=[CH:16][CH:17]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1c[nH]c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Yield: 99.5 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)-4-(4-nitrobenzyl)-piperazine (360 mg), iron powder (360 mg), ammonium chloride (36 mg) and water (1.5 ml) in ethanol (6 ml) was heated under reflux for 40 minutes. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (10:1) to give (2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.34 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CN1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl-2,2-dimethyl-3-oxopropanoate (200 mg, 1.0 mmol) in DCM (30 mL) were added piperidine (0.10 mL, 1.1 mmol) and sodium triacetoxyborohydride (400 mg, 2.0 mmol). The reaction mixture was left to stir at rt for 16 h. The mixture was partitioned between DCM and water and treated with saturated NaHCO3. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification via silica gel chromatography (5% EtOAc in Hexane) afforded the title compound as a yellow oil. MS (ES+): m/z: 276.18 (100) [MH+]. HPLC: tr=1.97 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=1.17 (s, 6H), 1.28-1.37 (m, 2H), 1.40-1.46 (m, 4H), 2.34-2.36 (m, 4H), 2.44 (s, 2H), 5.09 (s, 2H), 7.25-7.34 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[CH2:18]([N:20]([CH2:28][CH3:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])[CH3:19]>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2([C:3]3[N:27]=[C:25]([NH:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:18][CH3:19])[CH2:28][CH3:29])[S:26][CH:2]=3)[CH2:8][CH2:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCN(CC)CCCNC(N)=S
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)CCCNc1nc(C2(c3ccc(Cl)cc3)CCC2)cs1
Temperature: 50 °C
Yield: 86.8 %

Procedure:
A solution of 2-chloro-1-[1-(4-chlorophenyl)cyclobutyl]ethanone (120 mg, 0.494 mmol) and sodium iodide (74 mg, 0.494 mmol) in acetone (2.5 mL) was stirred at room temperature for 5 minutes. Next (3-diethylaminopropyl)thiourea (94 mg, 0.494 mmol) was added. The resulting mixture was heated at 50° C. for 1 h. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (2×50 mL). The extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oil. The oil was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (90:10) to give 162 mg of N′-{4-[1-(4-chlorophenyl)cyclobutyl]thiazol-2-yl}-N,N-diethylpropane-1,3-diamine, 19, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 1.02 (t, 6H, J=7.2 Hz); 1.71-1.80 (m, 2H); 1.82-1.91 (m, 1H); 2.08-2.20 (m, 1H); 2.48-2.59 (m, 8H); 2.67-2.76 (m, 2H); 3.27 (t, 2H, J=6.3 Hz); 5.91 s (s, 1H); 6.17 (bs, 1H); 7.25 (s, 4H); 13C NMR (CDCl3, 75 MHz): δ 11.8, 16.9, 26.2, 34.3, 45.8, 47.1, 49.1, 51.9, 100.3, 128.2, 128.3, 131.5, 147.1, 159.8, 169.9.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(OC(N1CCN(C2[C:50]3[C:45](=[CH:46][C:47](F)=[C:48](F)[CH:49]=3)[N:44]=CN=2)CC1)=O)(C)(C)C>>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[N:11]1[CH2:12][CH2:13][N:8]([C:6]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([O:24][C:21]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)=[CH:49][CH:50]=2)=[O:7])[CH2:9][CH2:10]1
Reactant: COc1cc2nccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc(F)c(F)cc23)CC1
Product: COc1cc2nccc(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)c2cc1OC
Yield: 57 %

Procedure:
Substantially the same procedure as in Example 329 was repeated, except that 4-(6,7-dimethoxy-4-quinolyl)-1-piperazinecarboxylic acid tert-butyl ester obtained in Reference Example 17 was used in place of 4-(6,7-difluoro-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester, to give the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.19 mmol) in dichloromethane (1 mL) was added phenyl isocyanate (23 μL, 0.21 mmol). The mixture was stirred at room temperature 15 hours and the resulting precipitate collected by filtration to give a gray solid (62% yield). 1H-NMR (DMSO-d6): δ 11.01 (s, 1H), 7.60 (d, 1H), 7.45 (m, 2H), 7.33-7.23 (m, 4H), 7.17 (dd, 1H), 6.94 (m, 1H), 6.63 (d, 1H), 5.02 (m, 1H), 2.68 (m, 2H), 2.06 (m, 1H), 1.95-1.70 (m, 3H); MS m/z 384 (M−1).
Reaction SMILES: [OH:1][CH:2]1[CH2:14][CH2:13][C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[O:15]=[C:16]1[CH:20]=[C:19]([CH2:21]P(=O)(OC)OC)[CH2:18][O:17]1>>[OH:1][CH:2]1[CH2:14][CH2:13][C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[CH:21][C:19]3[CH2:18][O:17][C:16](=[O:15])[CH:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: O=CC1CCC2(CCC(O)CC2)CC1
Reactant: COP(=O)(CC1=CC(=O)OC1)OC
Product: O=C1C=C(C=CC2CCC3(CCC(O)CC3)CC2)CO1

Procedure:
Using the same reaction conditions described in Ex. 2 and 9-hydroxy-3-formyl-spiro[5.5]undecane (I-bc, Ex. 50) and dimethyl (2-oxo-[5H]-4-furyl)methylphosphonate (intermediate described in Ex. 2) as starting materials, the title compound (EZ)-9-hydroxy-3-(2-(2-oxo-[5H]-4-furyl)vinyl)-spiro-[5.5]undecane (I-ai) was obtained as an amorphous solid, identical to the one above described.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CS(C)=O.O>[CH2:17]([O:24][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 1.80 g, 45 mmol) was added to a solution of 4-fluoro-3-trifluoromethyl benzoic acid (4.162 g, 20 mmol) and benzyl alcohol (3.25 g, 30 mmol) in DMSO (50 mL). The mixture was stirred overnight at room temperature, poured into water (50 mL) and acidified with concentrated hydrochloric acid. The white precipitate was filtered off, dissolved in ethyl acetate (ca 50 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane. Yield: 4.252 g (72%). 1H-NMR (400 MHz, CDCl3) δ=5.37 (s, 2H), 7.32-7.48 (m, 6H), 8.12 (d, J=2.0 Hz, 1H), 8.18 (dd, J=8.6, 2.0 Hz, 1H), 13.16 (br s, 1H, —COOH). LRMS (FAB+): 91.1 (100), 297.1 (18, [M+H]+).