Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17](O)=[O:18])=[C:4]([F:25])[CH:3]=1.[Na].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:22])([F:21])[F:23])[CH2:16][CH2:17][OH:18])=[C:4]([F:25])[CH:3]=1
Reactant: CC(C)Oc1cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc1Cl
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(NC(=O)CC(CCO)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 150 h
Yield: 39.2 %

Procedure:
To a solution of N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-3-(trifluoromethyl)glutaramic acid (4.32 g, 11.4 mmol) in 20 ml of tetrahydrofuran, (freshly distilled from sodium/benzophenone) was slowly added 10M borane-methyl sulfide complex (1.18 ml) via syringe. The temperature was maintained at 10°-20° C. with an ice bath while vigorous bubbling was evident. The mixture was allowed to warm slowly to room temperature and stirred 150 hrs while kept under nitrogen, heated to 55° C. for 6 hours, then cooled to room temperature and allowed to stand for 16 hours. The flask was cooled in an ice/water bath, then 7 ml of methanol (MeOH) were added slowly via addition funnel. The reaction mixture became too thick to continue stirring. It was allowed to warm slowly to room temperature, when the stir bar was again able to stir the mixture. The MeOH and THF were removed in vacuo (20-50 Torr) and the residue was flash chromatographed (2"×7" column, 3:1 hexanes/ethyl acetate, 75 ml fractions). Fractions 18-45 were combined and the solvent was removed in vacuo. The residue was dried in vacuo at 50° C. to yield 1.66 g (39% yield) of the pentanamide as a nearly colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.[CH3:18][C:19]([CH3:24])([CH2:22][NH2:23])[CH2:20][NH2:21]>[Cl-].[Na+].O>[Cl:17][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:19]([CH3:24])([CH3:18])[CH2:22][NH2:23])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: Clc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reactant: CC(C)(CN)CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1

Procedure:
A mixture of Example 61a (1.70 g, 6.44 mmol) and 2,2-dimethylpropane-1,3-diamine (10 mL) was heated in a Biotage microwave reactor at 160° C. for 25 minutes. The solution was diluted with 20% brine and washed with EtOAc (2×). The combined organic layers were washed with 20% brine, dried (MgSO4), filtered, and concentrated. The residue was triturated with EtOAc and diethyl ether. The solids were filtered, washed with ether, and dried to give 1.19 g of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 0.87 (s, 6H), 2.36 (s, 2H), 3.16 (d, J=6.10 Hz, 2H), 6.78-6.89 (m, 2H), 6.97 (d, J=1.02 Hz, 1H), 7.21 (dd, J=7.97, 4.58 Hz, 1H), 8.13 (s, 1H), 8.27-8.38 (m, 2H). MS (ESI+) m/z 329.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].C1(C)C(C)=CC=CC=1.C[Sn]([N:23]=[N+:24]=[N-:25])(C)C>CO>[Cl:10][C:3]1[CH:4]=[C:5]([C:6]2[NH:25][N:24]=[N:23][N:7]=2)[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: Nc1ccc(-c2nnn[nH]2)cc1Cl
Temperature: 135 °C
Reaction time: 8 h

Procedure:
The mixture consisting of 1.07 g of 4-amino-3-chlorobenzonitrile, 30 ml of xylene and 1.7 g of trimethyltin azide was stirred at 135° C. for 8 hours. After cooling, 25 ml of methanol were added, the mixture was stirred at room temperature for 30 minutes and the volatile constituents were removed on a rotary evaporator. On stirring, a solid precipitated out of the mixture obtained in this way, and was filtered off with suction and briefly dried under reduced pressure. This solid was dissolved in 1N sodium hydroxide solution and filtered, and the product was precipitated by acidifying with 2N hydrochloric acid, filtered off with suction and dried under reduced pressure.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][OH:13]>>[C:4]([O:13][CH3:12])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11]
Reactant: CO
Reactant: O=C1OC(=O)c2ccccc21
Product: COC(=O)c1ccccc1C(=O)O

Procedure:
Methanol (300 ml) was added in a single portion to 148 g (1.00 mole) of phthalic anhydride and the resulting suspension was stirred and heated at reflux for 36 hours; solution occurred during heating. The solvent was removed and the product was recrystallized from a mixture of ethyl acetate and hexane to afford 114.6 g of the title compound (Lit.: Beilstein, 9 797-m.p. 82.5°-84°).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]1[CH2:26][CH:25]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:24]=[CH:23]1)([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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:39]#[N:40].[Na+]>CN(C)C=O>[C:1]([O:20][CH2:21][CH:22]1[CH2:26][CH:25]([CH2:27][C:39]#[N:40])[CH:24]=[CH:23]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2C=CC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1C=CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
To a stirred solution of compound from Step 2, toluene-4-sulfonic acid 4-trityloxymethyl-cyclopent-2-enylmethyl ester (21.3 g, 40.59 mmol) in dimethylformamide (150 mL) was added sodium cyanide (3.58 g, 73.18 mmol) at room temperature and the reaction was stirred at 70° C. for 48 h. After cooling, the reaction mixture was extracted with ethyl acetate (2×250 mL), washed with water (2×100 mL), brine (50 mL) and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was purified on a silica gel column using ethyl acetate in hexanes (0 to 30%), which afforded 14.96 g (97.1%) of desired product, (4-trityloxymethyl-cyclopent-2-enyl)-acetonitrile, as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].C(N(CC)CC)C>ClCCl>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2ccccc2OC)cc1
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24 mmol) and 2-methoxyaniline (3.0 g, 24 mmol) in dichloromethane (24 mL) at 0° C. was added triethylamine (3.4 mL, 24 mmol) over 10 minutes. The ice bath was removed, and the mixture was stirred for 16 hr. The mixture was diluted with dichloromethane (100 mL) and the combined solution was washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and evaporated, and the crude product was purified by silica gel chromatography (15-60% EtOAc/Hex). Product-containing fractions were pooled, evaporated, and dried under high vacuum to yield 5.3 g (44%) of the product as a tan-colored oil: 1H-NMR (CDCl3) δ 7.70-7.67 (d, 2H), 7.53-7.50 (d, 1H), 7.05-6.99 (m, 2H), 6.91-6.83 (m, 3H), 6.73 (d, 1H), 3.80 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1.[ClH:19]>C(#N)C>[Cl:19][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1
Reactant: Nc1nc2c(Cl)cccc2s1
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Clc1nc2c(Cl)cccc2s1
Temperature: 65 °C

Procedure:
Anhydrous CuCl2 (Aldrich, 4.37 g, 32.5 mmol), t-butyl nitrite (Aldrich, 4.83 mL, 40.6 mmol) and anhydrous acetonitrile (EM, 50 mL) were added to a 3-necked round-bottomed flask equipped with a reflux condenser, an additional funnel and a gas outlet tube. The mixture was warmed to 65° C. and a suspension of 2-amino-4-chlorobenzothiazole in 50 mL of acetonitrile. During the addition, the reaction mixture tuned to black and gas evolved. After gas evolution is complete, the reaction was allowed to reach room temperature. The reaction mixture was poured to 300 mL of 20% aqueous HCl, extracted 3× with EtOAc (400 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography with 60% CH2Cl2/hexanes to give 4.8 g of product. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, J=8.1, 1.0 Hz, 1H), 7.68 (dd, J=7.9, 1.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]12([C:27]([O:15][CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([F:16])[F:1])=[O:28])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
In 60 g of methylene chloride were dissolved 9 g of ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate, prepared in Synthesis Example 1-4, and 9.5 g of 1-adamantanecarbonyl chloride. Under ice cooling, a mixture of 6 g of triethylamine, 0.5 g of 4-dimethylaminopyridine and 20 g of methylene chloride was added dropwise to the solution. The reaction solution was aged overnight, after which it was quenched with 5 wt % hydrochloric acid, washed with water, and concentrated. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. There was obtained 15 g of the target compound, 2-ethoxycarbonyl-2,2-difluoro-1-phenylethyl 1-adamantanecarboxylate as colorless oily matter (yield 68%).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)=[O:13]>[Mo](=O)(=O)=O.C1CCCCC1>[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:5][CH:1]2[CH2:4][CH2:20][CH2:15][CH2:16][CH2:3]2)[C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:16][C:17]([CH3:24])([CH3:23])[N:18]([O:5][CH:1]2[CH2:4][CH2:11][CH2:10][CH2:9][CH2:3]2)[C:19]([CH3:22])([CH3:21])[CH2:20]1)=[O:13]
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 137.6 %

Procedure:
A two-phase mixture of 70% aqueous t-butyl hydroperoxide (103.9 g, 807 mmol), cyclohexane (200 ml) and sodium chloride (15 g) is shaken in a separatory funnel. The organic phase is dried over magnesium sulfate, filtered, and added to 40.0 g (101 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) succinate. Molybdenum trioxide (2.0 g) is added, and the mixture is refluxed for one hour. Water is collected in a Dean-Stark trap. The entire reaction mixture is then transferred to a Fischer-Porter bottle and heated at 140° C. for 6 hours. Additional t-butyl hydroperoxide (90%, 10.1 g, 101 mmol) is added and heating is resumed for another 4 hours. The colorless reaction mixture is filtered, concentrated, and dissolved in heptane (200 ml). The heptane solution is passed through a short column of silica gel with heptane. Subsequent evaporation affords an oil which is crystallized from ethanol to yield 41.2 g (69%) of a white powder, m.p. 122°-6° C.
Reaction SMILES: O1CCCCC1ONC([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:26](=[O:32])[CH2:27][NH:28][C:29]([NH2:31])=[O:30])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[C:41]([OH:48])(=[O:47])CNC(N)=O>>[OH:48][C:41]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:26](=[O:32])[CH2:27][NH:28][C:29]([NH2:31])=[O:30])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:47]
Reactant: NC(=O)NCC(=O)O
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CNC(N)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CNC(N)=O)[C@H](C/C=C/c1ccccc1)C(=O)O

Procedure:
The (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2-ureidoacetyl)valerohydrazide used as the starting material was prepared in a manner analogous to Example 11 using hydantoic acid in place of N-acetyl-glycine.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[C:3]1=[O:26].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:4]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:3]1=[O:26]
Reactant: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2CN(C)C(=O)C23CCCNC3)cc1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a stirred solution of tert-butyl 2-methyl-1-oxo-4-p-tolyl-2,7-diazaspiro[4.5]decane-7-carboxylate (270 mg, 0.753 mmol) in DCM (5 ml) at 5° C. was added TFA (870 ul, 11.30 mmol) and the reaction mixture was left to stir at 5-10° C. for 1 hr. The reaction mixture was added to 2M NaOH (5 ml) and extracted with DCM (3×5 ml). The organics were combined, washed with brine (5 ml), dried (MgSO4) and concentrated to give the crude product as a white solid (176 mg).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>[OH-].[NH4+]>[C:3]1([C:2]2[NH:9][C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1O
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc(-c2nc3c([nH]2)CCCC3)cc1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
To a solution of 6.3 g benzamidine hydrochloride in 60 mL ammonium hydroxide was added 4.6 g 2-hydroxycyclohexanone. The reaction mixture was heated to 90° C. for 7 hours in a sealed tube. On cooling to room temperature the crystals formed were collected by filtration and after drying yielded 3.0 g 2-phenyl-4,5,6,7,-tetrahydrobenzimidazole (Compound 136), m.p. 300-301° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O.O1CCOC[CH2:32]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:32])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: C1COCCO1
Reactant: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)O)cn2c1=O
Solvent: O=S(Cl)Cl
Product: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)OC)cn2c1=O

Procedure:
2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (1,2 g) was reacted with thionyl chloride (0.6 ml) in dioxane (12 ml) at reflux temperature for 1 hour, then the mixture was evaporated to dryness in vacuo. The residue was reacted with excess methanol at 50° C. for 30 minutes, then the solution was concentrated in vacuo and the residue diluted with ice water. Filtration of the precipitate gave 1.2 g of 2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine7-carboxylic acid, methyl ester, m.p. 190°-193° C. By proceeding analogously the following compounds were prepared:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:37][C:36]([OH:38])=[C:35]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[N:8]=3)[C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47]
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitril from Example A(147) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.17–1.59 (m, 8H), 1.59–1.62 (m, 2H)), 1.62 (s, 6H), 1.82–2.01 (m, 2H), 2.19 (s, 3H), 2.38–2.65 (m, 3H), 3.55 (d, J=16 Hz, 1H), 3.65 (d, J=16 Hz, 1H), 7.15–7.32 (m. 3H), 8.53 (d, J=2.3 Hz, 1H), 8.82 (s, 1H), 10.7 (s, 1H). C29H32ClN5O3: C, 65.22; H, 6.04; N, 13.11. Found: C, 65.15; H, 5.99; N, 13.10. MS (ESI): 535.2(M+H+).
Reaction SMILES: C([Al])C.[CH:4]([OH:7])([CH3:6])[CH3:5].[C-:8]#[N:9].[CH2:10]([Al+:12][CH2:13][CH3:14])[CH3:11]>C1COCC1>[Al:12]([C:8]#[N:9])([CH2:13][CH3:14])[CH2:10][CH3:11].[CH3:5][CH:4]([OH:7])[CH3:6]
Reactant: [C-]#N
Reactant: CC[Al+]CC
Agent: CC[Al]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC[Al](C#N)CC

Procedure:
The sulfinimine-mediated asymmetric synthesis involves addition of ethylaluminium cyanoisopropoxide generated in situ by addition of isopropanol (i-PrOH) to diethylaluminium cyanide (Et2AlCN) to the compound VIIa. Thus treatment of compound VIIa (1.0 mmol) at −78° C. in THF with 1.5/1.0 equiv of Et2AlCN/i-PrOH gave amino nitrile VIII in good yield (50-70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
The solution of ethyl 2-(4-aminophenyl)acetate (500 mg, 2.79 mmol) and triethylamine (0.58 mL, 4.18 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (0.24 mL, 3.07 mmol) dropwise at room temperature and stirred overnight. The mixture was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound. LC-MS: m/z (M+H)=258.3
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C([Li])CCC.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:29][N:18]([CH3:17])[CH2:19][CH2:20][C:21]([OH:22])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccccc1C
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1CC(O)(CCN(C)C)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 40.0 g. (0.28 mole) of o-methyl-N-methyl benzamide and 250 ml. of anhydrous tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 360 ml. of 1.6 M. n-butyllithium (0.616 mole) in hexane is added dropwise for about 1 hour maintaining the temperature below 8° C. The resulting red dilithio salt (compound VIII) is stirred at 5° C. for 1 additional hour and the reaction flask is then immersed in a dry-ice acetone bath and cooled to an internal temperature of -30° C. To the cold reaction mixture a solution of 49.7 g. (0.28 mole) 3-dimethylaminopropiophenone in 140 ml. anhydrous tetrahydrofuran is added dropwise in ca. 45 minutes maintaining the temperature between -30° C. and -20° C. The resulting reaction mixture is stirred at -25° C. for 1 hour, allowed to warm to -10° C. in ca. 1 hour, and then treated with 200 ml. of saturated aqueous ammonium chloride while maintaining the temperature below 0° C. The resulting solid is filtered, washed thoroughly with water and recrystallized from methylene chloride-ether (1:1) to give 2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide; m.p. 139.5 to 140.5° C.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(Br)=CC=2)C)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:26]>CN(C=O)C.Cl[Cu].Cl[Pd]Cl>[O:26]=[C:2]([CH3:3])[CH2:1][C:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1
Reactant: O
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Product: CC(=O)CC1(c2ccccc2)CCNC(=O)O1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (20 g, 50 mmol) and CuCl (12.4 g, 125 mmol) in dry DMF (50 mL) was added H2O (12 mL) and PdCl2 (2.66 g, 15 mmol) at 0˜−5° C. After addition, the mixture was allowed to warm to rt gradually for 48 h under O2. After TLC showing the stating material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography to give (S)-3-(S)-1-(4-bromo-phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (12 g, 58%).