Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH:16]S(O)(=O)=O.[N+]([O-])(O)=O>>[Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(Br)C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=C(O)C(Br)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
α-Bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then reacted with H2SO4 and HNO3 to produce α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). More specifically, α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q) is prepared from α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) by first charging an Erlen-Meyer flask with H2SO4. The flask is then cooled in an ice bath and 50% HNO3 is added to the flask. The solid α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then added to the mixture in portions which maintain the temperature under 28° C. The reaction is then heated to 60° C. with stirring until a clear solution is obtained. When the reaction is complete, it is cooled to and maintained at room temperature. Water is then added to quench the reaction. The resulting slurry is cooled in an ice bath and then filtered to obtain α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). See also Example 18 herein.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]2[C:7]3[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9](S)[C:8]=3[CH:15]=[CH:16][CH:17]=2)(=[O:4])=[O:3].[N:18]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][N:20]=[CH:19]1>C(O)C>[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:9]2[C:8]3[CH:15]=[CH:16][CH:17]=[C:6]4[C:7]=3[C:11](=[CH:12][CH:13]=[C:5]4[S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(S)=N2
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c3c(cccc13)C(NCCCn1ccnc1)=N2

Procedure:
The reaction of molecular equivalents of 6-methylsulfonylbenz(cd)indol-2-thiol, 3-(1H-imidazol-1-yl)propanamine, mercuric acetate, and sufficient refluxing ethanol to permit stirring, by the procedure of Example 55 gives the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[CH:30]=[CH:29][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:11]=1)[CH3:4].[OH-].[K+]>CO.O1CCOCC1>[OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[CH:30]=[CH:29][NH:28][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[N:11]=1)[CH3:4]
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N[C@H](C)CO)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N[C@H](C)CO)c4cc[nH]c4n3)cc2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
To a solution of (R)-1-(4-(4-(4-(1-hydroxypropan-2-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (25 mg, 0.044 mmol) in MeOH (1 mL) and dioxane (1 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. After being stirred at 60° C. for 3 h, it was concentrated in vacuo. The residue was acidified with HOAc (1 mL), then was purified by HPLC to give (R)-1-(4-(4-(4-(1-hydroxypropan-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (7 mg), MS 410.5 (M+H); UV 202.6, 267.5, 303.1 nm; and (R)-2-(2-(4-(piperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)propan-1-ol (3 mg), MS 368.5 (M+H); UV 229.6, 271.0, 301.9 nm.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][N:11]([CH3:18])[C:12](=[O:17])[CH2:13][C:14]([CH3:16])=O.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH3:4][C:3]1([CH3:5])[S:6][C:14]([CH2:13][C:12]([N:11]([CH3:18])[CH3:10])=[O:17])([CH3:16])[NH:1][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CC(=O)CC(=O)N(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CN(C)C(=O)CC1(C)NC(C(=O)O)C(C)(C)S1
Yield: 65.9 %

Procedure:
A suspension of 2.00 g (13.4 mmoles) of D-penicillamine and 1.73 g (13.4 mmoles) of N,N-dimethylacetoacetamide in 15 ml of dry benzene, and 0.6 g of anhydrous magnesium sulfate was refluxed for 3.5 hours under a stream of argon. The reaction mixture became clear and then the solvent was distilled off. The resulting residue was dissolved in hot methyl alcohol. Insolubles were removed by filtration and the solvent was again distilled off. The residue was crystallized from chloroform and further recrystallized from ethyl alcohol-ether to give 2.3 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=3[C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(=O)C>CO.[Pt](=O)=O>[CH2:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=3[C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cnccc23)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCNC3)CC1
Yield: 83.1 %

Procedure:
A solution of tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9.80 g, 21.56 mmol) in 50 mL MeOH was treated with acetic acid (1.234 ml, 21.56 mmol) and platinum(IV) oxide (Sigma-Aldrich, St. Louis, Mo., 0.979 g, 4.31 mmol) and was placed under 45 psi (4559.6 kpa) H2 overnight. The reaction mixture was filtered through a plug of diatomaceous earth and concentrated. The resulting residue was taken up in DCM, was washed with saturated NaHCO3 solution, the organics dried over MgSO4 and concentrated yielding tert-butyl 4-(2-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (8.21 g, 17.91 mmol).
Reaction SMILES: [CH3:1][O:2][N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:4](=[O:12])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.BrN1C(=O)CCC1=O>[CH3:1][O:2][N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Br:20])[C:4](=[O:12])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CON(C(=O)Oc1ccccc1)c1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CON(C(=O)Oc1ccccc1)c1ccccc1CBr
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A mixture of 324 g (1.3 mol) of phenyl N-methoxy-N-(2-methylphenyl)carbamate (Example 2b), 258 g (1.45 mol) of N-bromosuccinimide and 1 g of azoisobutyronitrile in 1 l of CCl4 is irradiated using a 300 W UV lamp for about 6 hours, whereby the reaction mixture is heated to boiling. 13 g of N-bromosuccinimide are then added and the mixture is irradiated for a further 8 hours. It is then cooled to room temperature and the precipitated succinimide is filtered off. The organic phase is then extracted with water, dried over MgSO4 and concentrated. The residue crystallizes and is stirred with cyclohexane. 300 g (68%) of the title compound are obtained as a beige solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:22]1(OC)[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC#N>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH:22]1[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1C1(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C

Procedure:
To a solution of crude compound 23 (7.14 g 14.4 mmol) in CH2Cl2/CH3CN (75 mL/75 mL) were added triethylsilane (4.6 mL, 28.9 mmol) and boron trifluoride diethyl etherate (3.6 mL, 28.9 mmol) at −55° C. The mixture was allowed to slowly warm to 0° C. To a mixture was added aq. saturated NaHCO3 solution (75 mL) to quench the reaction and the mixture was evaporated in vacuo to remove CH2Cl2 and CH3CN. The mixture was extracted with EtOAc (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude (3R,4R,5S,6R)-2-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (24, 6.36 g) was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[CH2:11](O)[CH2:12]O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:10][CH2:12][CH2:11][O:9]1
Reactant: OCCO
Reactant: Nc1ccccc1B(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccccc1B1OCCO1
Reaction time: 0.33 h

Procedure:
To a solution of o-aminophenylboronic acid (13.7 g, 100 mmoles) in dichloromethane (200 ml) is added ethylene glycol (6.30 g, 102 mmoles). The solution is shaken for 20 minutes, and then stirred over solid sodium sulfate. Removal of the volatiles affords ethylene o-aminophenylboronate. To a flame dried three neck round bottom flask equipped with septum, stopper and gas inlet, is added ethylene o-aminophenylboronate (0.36 g, 2.20 mmoles) in dry dimethylformamide (10 ml). To this solution is added Z-Gly-Ala (0.62 g, 2.21 mmoles), triethylamine (0.62 ml, 4.45 mmoles), and finally diethyl cyanophosphonate (0.37 ml, 2.44 mmoles). After stirring the reaction at room temperature for 17 hours, the DMF is removed under reduced pressure. The remaining residue is dissolved in ethyl acetate, and washed sequentially with 10% HCl, saturated sodium bicarbonate, and brine. After drying the organic phase over magnesium sulfate, the salts are removed by filtration and filtrate concentrated in vacuum to leave (0.63 g) of Z-Gly-Ala-o- aminophenylboronic acid. This compound can be used "as is" in the present invention, or the benzyloxycarbonyl (Z) group can be removed by hydrogenolysis (see first step of Example 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](Cl)([Cl:12])=[O:11]>>[Cl:12][C:10]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: OCc1cccc(Cl)c1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)OCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 3-chlorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C1(C)C=CC=CC=1.[ClH:20]>O>[Cl:20][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 5 h

Procedure:
Five grams (0.028 mole) of a commercially available D-glucose was added to a three-necked flask equipped with a condenser and a stirrer, and dissolved in 5 ml of water. Thirty milli-liters of toluene was further added and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride (about 12 g) was passed through the mixture at room temperature for 30 minutes with thorough stirring. Stirring was further continued at 45° C. for 5 hours. The reaction solution containing a small amount of humud was diluted with a little water and filtered through Celite while being washed with a small amount of toluene. The toluene layer was neutralized with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. Thus, about 1.0 g (theoretical yield 4.01 g) of 5-chloromethylfurfural was obtained as a crude product of pale brown color.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[CH3:52][O:53][C:54](=[O:65])[CH2:55][CH:56]([NH2:64])[C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:64][CH:56]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[CH2:55][C:54]([O:53][CH3:52])=[O:65])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)CC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 63.7 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (84 mg, 0.22 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (72.3 mg, 0.20 mmol), 3-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride (50 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.104 mL, 0.60 mmol) in N-methyl-2-pyrrolidinone (1.5 mL) at 20° C. under argon. The resulting solution was stirred for 5 h. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (71.0 mg, 63.8%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[NH2:19])=[S:7])=[O:4].[CH:20](O)=[O:21]>O>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]=1[NH:19][CH:20]=[O:21])=[S:7])=[O:4]
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c(N)c1
Reactant: O=CO
Solvent: O
Product: CCCCc1ccc(NC(=S)NC(=O)OC)c(NC=O)c1
Yield: 73.2 %

Procedure:
1-Methoxycarbonyl-3-(2-amino-4-n-butylphenyl)thiourea (15.0 g; 0.053 mole) and formic acid (18.4 g; 0.4 mole) were mixed together at laboratory temperature and the mixture was refluxed for forty minutes. The hot clear solution was then poured into water, and the solid which separated was filtered off, washed with water, dried and crystallised from 2-ethoxyethanol to give 1-methoxycarbonyl-3-(4-n-butyl-2-formamidophenyl)thiourea (12.0 g), m.p. 182°-183° C. (with decomposition).
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[F:47][C:48]1[C:53]([F:54])=[C:52]([C:55]([F:58])([F:57])[F:56])[CH:51]=[CH:50][C:49]=1[C:59]1[S:63][C:62]([CH2:64]O)=[C:61]([CH3:66])[CH:60]=1>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:64][C:62]2[S:63][C:59]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:57])[F:58])=[C:53]([F:54])[C:48]=3[F:47])=[CH:60][C:61]=2[CH3:66])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(OCc2sc(-c3ccc(C(F)(F)F)c(F)c3F)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate 7) and {5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol (intermediate 122).
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:12][P:13]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[OH:14])=[O:10])C1C=CC=CC=1>O.[Pd]>[CH2:16]([P:13]([CH2:12][CH:11]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:9]([OH:10])=[O:8])([OH:15])=[O:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CCC(CP(=O)(O)CCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCC(CP(=O)(O)CCc1ccccc1)C(=O)O
Yield: 115.7 %

Procedure:
2,4-Di(benzyloxycarbonyl)butyl(phenethyl)-phosphinic acid (1.1 g, 2.2 mmol) in 20 mL of water containing 120 mg of 10% Pd/C was hydrogenated at 40 psi overnight. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.8 g (114%) of 2-[(phenethylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=CH2CH2Ph) as a white solid.
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:10][CH2:9][CH:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:26]([C:25]1[CH:29]=[C:21]([CH3:20])[CH:22]=[CH:23][C:24]=1[N:30]1[N:34]=[CH:33][CH:32]=[N:31]1)=[O:27]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: OCC1NCC2CCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CO)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the carbamate above in DCM was added TFA (1:1 v/v). The reaction was stirred at rt for 30 min before being concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHCO3, brine, dried (MgSO4), and concentrated to afford (octahydrocyclopenta[c]pyrrol-1-yl)methanol as a pale yellow oil. To a solution of (octahydrocyclopenta[c]pyrrol-1-yl)methanol (1 equiv.) from the previous step in DMF was added DIPEA (2 equiv.) followed by 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.5 equiv.) and HATU (2 equiv.). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1 M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound as a clear oil. MS (ESI) 326 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cccc(C(C)(C)C#N)c4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
To a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3 ml) was added DMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (92 mg, 0.33 mmol) described in Example 278A. The reaction mixture was stirred at rt for 24 h. Concentration under reduced pressure gave a residue which was triturated with anhydrous diethyl ether to afford 1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (64.1 mg, 43%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.67 (s, 6H), 3.99 (s, 6H), 7.11 (d, J=6.6 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.30-7.45 (m, 5H), 7.53 (d, J=8.1 Hz, 1H), 7.66 (s, 1H), 7.84 (s, 1H), 8.70 (s, 1H), 8.91 (d, J=6.6 Hz, 2H); LC-MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.CS(OCCC1C=CC=CC=1)(=O)=O.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[CH2:52]([N:51]([CH3:50])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:53][CH2:54][CH3:55]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: CCCCNC
Agent: CS(=O)(=O)OCCc1ccccc1
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1

Procedure:
This was synthesized by using 4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate instead of 44643-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methylbutylamine in place of piperidine as described in general procedure 2 to afford N-(4-(2-(butyl(methyl)amino)ethyl)phenyl)-6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine 1H NMR 400 MHz (CDCl3) δ 13.14 (s, 1H), 10.31 (br s, 1H), 8.42-8.36 (m, 1H), 8.0 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.62-7.5 (m, 2H), 7.39-7.27 (m, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.09-7.06 (m, 1H), 6.92-6.8 (m, 1H), 4.33 (t, J=6.3 Hz, 1H), 3.58-2.9 (m, 8H), 2.85 (s, 3H), 1.84-1.68 (m, 2H), 1.5-1.35 (m, 2H), 0.98 (t, J=7.4 Hz, 2H). LCMS m/e 531 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:10][CH:9]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Yield: 132.2 %

Procedure:
A solution of 2.0 g (5.35 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate in 100 ml of ethanol was treated with 200 mg of palladium/charcoal (Type E101R) and hydrogenated at room temperature for 1 hour. Subsequently, the catalyst was filtered off and rinsed with ethanol. The filtrate was evaporated under reduced pressure and the light grey residue (1.97 g) was combined with those from three analogous hydrogenation batches (total 3.08 g). For purification, the crude product was chromatographed on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent and thereafter crystallized from ethyl acetate/hexane. There were obtained 2.67 g (87% of theory) of tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate as colourless crystals; MS: 378 (M+H)+.