Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:18]=[O:19])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3cc(CO)ccc3n2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COc1ccc(Oc2ccc3cc(C=O)ccc3n2)cc1
Yield: 98 %

Procedure:
To a CH2Cl2 (38 mL) solution of [2-(4-methoxyphenoxy)quinolin-6-yl]methanol (1.11 g) and iodobenzene diacetate (1.33 g) was added 2,2,6,6-tetramethyl-1-piperidinyloxy radical (61.0 mg), then the resultant mixture was stirred over night at room temperature. The reaction mixture was quenched by addition of saturated aqueous Na2S2O3 and NaHCO3, and extracted with CH2Cl2. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=10/1 to 5/1) to afford 2-(4-methoxyphenoxy)quinoline-6-carbaldehyde (1.08 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[C:19]([NH:1][C:2](=[S:12])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:20])[C:18]1[CH:17]=[CH:21][CH:13]=[CH:3][CH:4]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1c(N)sc2c1CC(C)(C)OC2
Product: COC(=O)c1c(NC(=S)NC(=O)c2ccccc2)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a combined mixture of methyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (ChemBridge, CAS 713111-73-0, 31 mg, 0.13 mmol, 1 equiv.) and PhCONCS (0.02 mL, 0.15 mmol, 1.2 equiv.) was added THF (0.7 mL). The resulting solution was stirred at 50° C. for 3 days. The solvent was then removed under reduced pressure and the crude product was triturated with hexanes, filtered, and rinsed with hexanes (4×5 mL). The product was further purified by preparatory HPLC (0-50% EtOAC:hexanes) and isolated as a white solid (38 mg, 72% yield). 1H NMR (400 MHz, CDCl3) δ 14.83 (s, 1H), 9.14 (s, 1H), 7.98 (dd, J=8.4, 1.2 Hz, 2H), 7.72-7.63 (m, 1H), 7.56 (dd, J=10.5, 4.8 Hz, 2H), 4.77 (t, J=1.5 Hz, 2H), 4.04 (s, 3H), 2.85 (s, 2H), 1.35 (s, 6H). LCMS retention time: 3.508 min; LCMS purity at 215 nm=96%. HRMS m/z calculated for C19H21N2O4S2 [M++1]: 405.0937. found 405.0942.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[CH:5]=1.C1COCC1.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: COC(=O)c1cccc(N2CCC3(CC2)OCCO3)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(N2CCC(=O)CC2)c1
Yield: 84.9 %

Procedure:
A solution of methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (3.85 g, 13.88 mmol) in 10% aqueous sulfuric acid (40 mL and THF (40 mL) was stirred at ambient temperature for 14 days. The reaction mixture was neutralized by cautious addition of NaHCO3 and simultaneously diluting with water. The aqueous mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as an oil (2.75 g, 85%) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10]C(C#N)=[C:6]([Br:12])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:15][C:16]([OH:18])=[O:17]>O.OS(O)(=O)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:15]([C:16]([OH:18])=[O:17])=[C:6]([Br:12])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc(C#N)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(C(=O)O)c(Br)c1

Procedure:
A solution of the product obtained in step 2 (0.5 g, 2.23 mmol) in AcOH (2.5 mL), H2O (2.5 mL) and concentrated H2SO4 (2.5 mL) was refluxed for 5 h. After cooling, the reaction mixture was adjusted with 10 N NaOH to pH=10 and washed with AcOEt. The aqueous layer was acidified with concentrated HCl to pH=1 and then extracted with AcOEt. The organic phase was washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The crude product was used in the following step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH:14]=O>C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:14]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN=Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a solution of t-butyl carbazate (4.99 g, 37.76 mmol) in ethyl acetate (10 mL) was added with stirring 3,5-difluorobenzaldehyde (5.50 g, 38.7 mmol) followed by hexanes (50 mL). Crystallization occurred and the resulting slurry was stirred at rt for 15 min, then cooled to 0° C. and held at that temperature for 45 min. The solids were filtered, rinsed with cold hexanes and dried in vacuo at 60° C. to afford the title compound as a solid (9.04 g, 93.3%): mp 196.4-196.8° C. (dec); 1H NMR (DMSO-d6) δ 11.16 (br s, 1 H), 7.96 (s, 1 H), 7.28 (m, 2 H), 7.21 (t, 1 H, J=2.2 Hz), 1.45 (s, 9 H); 13C NMR (DMSO-d6) δ 163.3 (dd, J=246.1, 13.5 Hz), 152.9, 141.2, 139.2 (t, J=9.6 Hz), 109.9 (dd, J=20.2, 5.8 Hz), 105.1 (t, J=25.9 Hz), 80.5, 28.7; IR (KBr mull) 3263, 2987, 1709, 1584, 1536 cm−1. A portion was recrystallized (ethyl acetate) for analysis. Anal. Calcd. for C12H14F2N2O2: C, 56.25; H, 5.51; F, 14.83; N, 10.93. Found: C, 56.11; H, 5.49; N, 10.86.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[I:15]I.C(O)(=O)C>CCOCC>[I:15][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C#CCCCCCCCC
Reactant: II
Agent: CC[Mg]Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCC#CI
Temperature: 15 °C
Yield: 90 %

Procedure:
To a 500 ml 3-neck round bottom flask is transferred an ethylmagnesium bromide solution, 100 ml of 3.0M in dried ether, 0.30 mole, under an argon atmosphere. The contents are cooled to about 0° to 3° C. in a solution of 1-decyne, 25 grams, 0.1808 mole, and 50 ml of dried ether are added dropwise into the reaction mixture over a period of 1.5 hours. Thereafter the mixture is warmed to 35°-38° C. and maintained at that temperature for an additional hour. The mixture is then cooled to about 15° C. and powdered iodine, 80 g., 0.315 mole, is slowly added through a solid addition funnel over a period of about 1.5 hours. The reaction is maintained at 30° C. for approximately 2.5 additional hours. In the meantime, an additional 150 ml of dried ether is added to limit the viscosity increase during the reaction. In the work-up process, 200-300 ml of ether are added and the contents hydrolyzed by slowly pouring them into two liters of cold, dilute acetic acid having a pH of about 1-2. The organic phase is extracted with ether and washed several times with 10 percent Na2S2O3 solution to remove the unreacted iodine. Washing continues until the organic phase exhibits a clear color. Following this, the phase is washed several times with water and dried over MgSO4. The solvent is removed by means of a rotary evaporator, and the oily crude product is purified by column chromatography, using silica gel absorbent and hexane as an eluent. The yield is about 90 percent based on 1-decyne used, of a pale yellow liquid, 43.0 grams, 0.1629 mole.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.CO[NH3+].[Cl-:46].N1C=CC=CC=1>C(O)C.ClCCl>[ClH:46].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1
Reactant: N#Cc1ccc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)nc1
Reactant: [Cl-]
Agent: CO[NH3+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cl
Product: N#Cc1ccc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(N)=N4)c2)nc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-cyano-pyridine-2-carboxamide (360 mg, 0.59 mmol) is dissolved in ethanol (10 mL) and dichloromethane (2 mL). 0-Methylhydroxylamine hydrochloride (504 mg, 5.91 mmol) and pyridine (478 μL, 5.91 mmol) are added and the reaction is stirred at room temperature over the weekend (70 hrs). The reaction is warmed to 60° C. and stirred for 24 hrs. The reaction is concentrated to give the crude product and purified via silica gel chromatography using a 0-10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.54 mL, 540 μmol) is added. The solvent is removed in vacuo to give the title compound (240 mg, 75%). ES/MS (m/e): 475 (M+H).
Reaction SMILES: CCCCCCCCCCCCCCCCCCSC1SC(=C2S[C:27]3[CH:29]=[C:30]([C:33]4[N:37]([O-])C(C)(C)C(C)(C)[N+]=4[O-])[CH:31]=[CH:32][C:26]=3S2)SC=1SCCCCCCCCCCCCCCCCCC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCCC1.O.NOS(O)(=O)=O.O1CCCC1>[C:30]1([CH3:33])[CH:31]=[CH:32][C:26]([C:29]2[CH:27]=[CH:26][CH:32]=[CH:31][C:30]=2[C:33]#[N:37])=[CH:27][CH:29]=1
Reactant: CCCCCCCCCCCCCCCCCCSC1=C(SCCCCCCCCCCCCCCCCCC)SC(=C2Sc3ccc(C4=[N+]([O-])C(C)(C)C(C)(C)N4[O-])cc3S2)S1
Agent: NOS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
1 molar equivalent of o-(p-tolyl)-N-cyclohexylbenzaldimine is dissolved in a 1/1 mixture of tetrahydrofuran/water and X molar equivalents of aminohydroxysulphonic acid are added. This mixture is maintained at a temperature T for 1 hour, which gives a mixture of OTBO/OTBN. This mixture is diluted in tetrahydrofuran, 10 molar equivalents of phosphorus pentoxide are then added and the mixture is allowed to react for a further 1 hour at room temperature.
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: CCC=C(C)C(O)CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC=C(C)C(CCCCC)OCCCC
Temperature: 80 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
20 g of 4-methyl-3-decen-5-ol dissolved in 100 ml of toluene are added dropwise at 80° C. over a period of 30 minutes to 6.2 g of a 55-60% sodium hydride dispersion in 100 ml of toluene. The mixture is stirred at 80° C. for 12 hours, then cooled to 50° C. and treated dropwise with a solution of 24.1 g of n-butyl bromide in 50 ml of toluene. The mixture is subsequently held at reflux temperature for 6 hours. For the working-up, the mixture is treated at room temperature with water, the organic layer is separated and washed neutral with water, dried and, after the addition of 0.2 g of potassium carbonate, fractionally distilled There are obtained 20.7 g of 5-butoxy-4 methyl-3-decene of boiling point 60° C./0.03 Torr, nD20 =1.4378. Odour: caramel-like, delicate, fatty-fruity.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C(O)(C(F)(F)F)=O.N.CO>C(Cl)Cl>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:16]=[C:15]([NH:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: CN(C)CCCNc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN(C)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(2-(3-(dimethylamino)propylamino)quinazolin-4-ylamino)piperidine-1-carboxylate (3.3 g, 7.71 mmol) in CH2Cl2 (20 ml) at 0° C. was added CF3COOH (4 ml, 53.9 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was then neutralized with 7 N NH3-MeOH. The resulting white solid was filtered away. The filtrate was concentrated and purified by silica gel column chromatography using 10% NH3 ca. 7 N MeOH in CH2Cl2 and 90% CH2Cl2 solution as eluent to obtain the title compound as a pure white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[O:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([C:35](O)=[O:36])[C:25]1=[O:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([C:35]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:36])[C:25]1=[O:26]
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1cc2ccccc2oc1=O
Yield: 72.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), coumarin-3-carboxylic acid (2.3 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.8 g, 71%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20]C(=O)OC(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[NH2:20][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:2]=1[Cl:1])[C:18]#[N:19].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CN1CCN(CCCc2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CCCc2cc(C#N)cc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)carbamate (49 mg, 0.125 mmol) was taken up in DCM (0.8 mL) and TFA (0.192 mL, 2.494 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material azeotroped 2× with toluene. The material was dried under vacuum overnight. 3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile, TFA (88 mg) was obtained as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[SH:17].C([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(OC(C)(C)C)=O>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[BrH:1].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[S:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: Cc1ccc(S)c(C)c1
Reactant: Brc1ccccc1I
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Br
Product: Cc1ccc(Sc2ccccc2N2CCNCC2)c(C)c1
Temperature: 100 °C
Yield: 35.7 %

Procedure:
102 g 2-bromo-iodobenzene (362 mmol) and 50 g 2,4-dimethylthiophenol (362 mmol) are dissolved in 1000 ml toluene. To this solution was added 81 g BOC-piperazine (434 mmol) followed by 2.08 g Pddba2 (1 mol %) and 4.51 g rac-BINAP (2 mol %). The mixture was purged with nitrogen for 5 minutes before adding a slurry of 87 g NaOBut (905 mmol) in 300 ml toluene. The suspension was heated to 100° C. under nitrogen overnight. A GCMS analysis showed full conversion into the intermediate product (1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene) and the temperature was increased to reflux (120° C.) for another 24 hours. A HPLC analysis showed full conversion into the intermediate (1-BOC-4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine). The reaction mixture was cooled on ice for one hour before filtering the mixture. The filter cake is washed with 2×200 ml toluene and to the combined filtrates was added 80 ml 48-wt % HBr (aq.) followed by heating to reflux for 18 hours after which full deprotection was detected by HPLC. The mixture was cooled on ice for 2 hours and filtrated. The brownish solid was dissolved in 1000 ml boiling H2O for 1 hour together with activated charcoal (25 g), filtered while hot and left to cool. The precipitate was collected by filtration and drying in vacuum at 40° C. overnight produced 49 g of 4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (36%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCC2C=CC(CO)=CC=2)C=CC=CC=1.[N:36]([C@H:39]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:40]([O-:42])=[O:41])=[C:37]=[O:38].[N-]=C=O.COC(=O)[C@H](CC1C=CC=CC=1)N>>[C:44]1([CH2:43][CH:39]([NH:36][C:37]([O:16][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:18][CH:17]=2)=[O:38])[C:40]([OH:42])=[O:41])[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(O)c1ccc(CCCc2ccccc2)cc1
Reactant: O=C=N[C@H](Cc1ccccc1)C(=O)[O-]
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: OCc1ccc(CCCc2ccccc2)cc1
Agent: [N-]=C=O
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(CCCc2ccccc2)cc1

Procedure:
3-Phenyl-2-[4-(3-phenyl-propyl)-benzyloxycarbonylamino]-propionic acid 168, mp. 134.8-135.2° C. was prepared from 4-(3-phenyl-propyl)-benzoic acid (commercially available from Aldrich) followed by reduction to [4-(3-phenyl-propyl)-phenyl]-methanol, condensation with (R)-2-isocyanato-3-phenyl-propionate of formula 5 and hydrolysis as described for example in Example 1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].C(N(CC)CC)C.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:14](=[O:15])[O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#CCNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 88.5 %

Procedure:
N-Methylpropargylamine (600 mg, 8.70 mmol) and triethylamine (878 mg, 8.68 mmol) in dichloromethane (10 ml) were added dropwise, with ice cooling, to a stirred solution of 4-nitrophenyl chloroformate (1.75 g, 8.68 mmol) in dichloromethane (10 ml). The reaction was stirred at ice temperature for 3 hr. then the resulting solution purified by column chromatography on silica using 25% ethyl acetate in iso-hexane as eluent. Thus was obtained 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (1.80 g, 89%) as a colourless oil. Dimethylamine (3.0 ml of a 2.0M solution in THF, 6.0 mmol) and 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (600 mg, 2.56 mmol), in dichloromethane (7 ml) were stirred at room temperature for 6 days then the reaction solution purified by chromatography on silica using ethyl acetate as eluent to give N,N,N′-trimethyl-N′-prop-2-yn-1-ylurea (164 mg, 46%) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[OH:48][CH:49]1[CH2:52][NH:51][CH2:50]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:21]([N:51]2[CH2:52][CH:49]([OH:48])[CH2:50]2)=[O:22])[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:15]=1)#[N:2]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2C#N)c1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′-cyano-5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (90 mg, 0.29 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (120 mg, 0.61 mmol), 1-hydroxybenzotriazole hydrate (93 mg, 0.61 mmol), and methylene chloride (5 mL) were added 3-hydroxyazetidine hydrochloride (67 mg, 0.61 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol). The mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>CO>[NH2:11][C@@H:12]([CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: COC(=O)[C@@H](N)CN(c1ccccc1)c1ccccc1
Yield: 91 %

Procedure:
In order to eliminate the Z protecting group, 2.7 g (6.68 mmol) of the Z-protected derivative (4) were dissolved in 500 ml of methanol, and 100 mg of catalyst (10% Pd(OH)2—C) were supplied under a protective atmosphere of nitrogen. The inert gas was subsequently displaced with a large excess of hydrogen and the mixture was shaken for 2 h in the hydrogen atmosphere. In order to terminate the reaction, the catalyst was filtered off and the filtrate was concentrated. 1.65 g (yield: 91%) of methyl 2-amino-3-diphenylaminopropionate (5) were obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[C:7]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1nc(C=Cc2ccccc2)cc2ccccc12
Yield: 63.5 %

Procedure:
A solution of 7-bromo-1-chloroisoquinoline (200 mg, 0.80 mmol), styrene (94 mg, 0.90 mmol), tri-o-tolylphosphine (30 mg, 12 mol %), palladium (II) acetate (Pd(OAc)2) (10 mg, 5 mol %) and triethylamine (0.34 mL, 2.5 mmol) in DMF (0.75 mL) were placed in a MOS-2000™ (650 W) microwave and irradiated at full power for 7×40s (reaction monitored by TLC). The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over MgSO4, evaporated in vacuo and the residue was purified by column chromatography upon silica gel using hexanes-EtOAc (100:0 to 95:5) as eluant to give 1-chloro-(2-phenylethen-1-yl)isoquinoline (135 mg, 0.508 mmol) as a yellow solid.