Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)(C)(C)C.CN1CCOCC1.ClC(O[CH2:55][CH:56]([CH3:58])[CH3:57])=O.[CH3:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([C:72](=[N:74][NH2:75])[NH2:73])=[CH:68][CH:67]=2)=[CH:62][CH:61]=1>O1CCOCC1.CN(C=O)C>[C:56]([CH:7]([N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]2[N:73]=[C:72]([C:69]3[CH:68]=[CH:67][C:66]([C:63]4[CH:64]=[CH:65][C:60]([CH3:59])=[CH:61][CH:62]=4)=[CH:71][CH:70]=3)[NH:74][N:75]=2)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:28])([F:30])[F:29])=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:43])([CH3:58])([CH3:57])[CH3:55]
Reactant: Cc1ccc(-c2ccc(C(N)=NN)cc2)cc1
Reactant: CC(C)COC(=O)Cl
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(Cc3ccc(-c4n[nH]c(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)C(C(=O)O)C(C)(C)C)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (216 mg, 0.360 mmol) in dioxane (4 mL) were added N-methylmorpholine (79.0 μl, 0.719 mmol) and isobutyl chloroformate (49.0 μl, 0.378 mmol). After stirring at room temperature for 1 h, the reaction mixture was added drop wise through a frit to a stirred solution of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazonamide INT-39 (89.0 mg, 0.396 mmol) in DMF (2 mL). After 30 min, the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to room temperature then poured onto water (50 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed successively with citric acid (10 mL, 0.1 M aqueous solution) and NaHCO3 (10 mL) then dried over MgSO4 and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and treated with TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h then concentrated and purified by preparative HPLC to afford 24 mg (9%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)benzyl)benzamido)acetic acid 361. LCMS-ESI (m/z) calculated for C41H34F3N5O5: 733; found 734 [M+H]+, tR=7.72 min (Method 9). 1H NMR (400 MHz, DMSO) δ 14.54 (s, 1H), 12.84 (s, 1H), 10.34 (s, 1H), 8.25-8.13 (m, 2H), 8.08 (d, J=7.9 Hz, 2H), 7.94-7.73 (m, 2H), 7.70-7.59 (m, 4H), 7.57-7.35 (m, 5H), 7.32 (d, J=7.9 Hz, 2H), 7.25-7.14 (m, 2H), 4.73 (s, 1H), 4.65 (s, 1H), 4.03 (s, 1H), 3.93 (s, 1H), 3.90-3.76 (m, 5H), 2.37 (s, 3H).
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.N1C=CC=CC=1.[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>O1CCCC1.C(OCC)(=O)C>[CH3:26][C:21]1[CH:20]=[C:19]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[CH:24]=[CH:23][C:22]=1[NH:25][C:34](=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: CCCC(=O)Cl
Reactant: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(NCc2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
To a solution of (4-amino-3-methylphenyl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (500 mg, 1.31 mmol) in dry tetrahydrofuran (10 mL) at 0° C. was added pyridine (159 mL, 1.97 mmol) followed by butyryl chloride (164 μL, 1.58 mmol) dropwise. After 5 minutes, the reaction mixture was allowed to warm to room temperature, and stirring was continued for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed with 2 N HCl, saturated aqueous sodium bicarbonate twice, and brine, and was then dried over magnesium sulfate. Solvents were evaporated in vacuo and the residue was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid. After 30 minutes at room temperature the mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (10 mL), the solution was washed twice with saturated aqueous sodium bicarbonate, twice with water, and was then dried over sodium sulfate. Evaporation of the solvents and recrystallization of the residue from ethyl acetate:heptane gave the title compound as a colorless solid (226 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([NH:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][N:5]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(N2Cc3c(NCc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A stirred mixture of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (518 mg, 2.0 mmol) and benzaldehyde (0.21 ml, 2.0 mmol) in methanol (20 ml) was heated to reflux for 5 h. The solvent was removed in vacuo to give a solid. The solid was re-dissolved in acetic acid (20 ml). The stirred solution was heated to reflux for 1 h, and was then allowed to cool to room temperature. To the stirred solution was added sodium borohydride (90 mg, 2.3 mmol) and stirring continued at room temperature for 18 h. The resulting suspension was filtered and washed with acetic acid (10 ml) and ether (20 ml) to give 3-{1-oxo-4-[benzylamino]isoindolin-2-yl}piperidine-2,6-dione as an off-white solid (420 mg, 60% yield): mp, 257-259° C.; 1H NMR (DMSO-d6) δ 2.01-2.07 (m, 1H, CHH), 2.23-2.30 (m, 1H, CHH), 2.49-2.65 (m, 1H, CHH), 2.85-3.00 (m, 1H, CHH), 4.19 (d, J=17 Hz, 1H, CHH), 4.31 (d, J=17 Hz, 1H, CHH), 4.39 (d, J=5.7 Hz, 2H, CH2), 5.12 (dd, J=5.1, 13 Hz, 1H, NCH), 6.37 (t, J=5.9 Hz, 1H, NH), 6.62 (d, J=8.0 Hz, 1H, Ar), 6.91 (d, J=7.3 Hz, 1H, Ar), 7.19-7.40 (m, 6H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.79, 31.25, 45.79, 46.09, 51.56, 110.32, 112.34, 126.72, 127.05, 128.32, 129.07, 132.08, 139.72, 143.33, 168.82, 171.22, 172.90; Anal Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03. Found C, 68.73; H, 5.41; N, 12.04.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](CO)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:46]([Br:49])(Br)Br>C(Cl)Cl>[Br:49][CH2:46][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CO)cc3)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CBr)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.5 g of 4'-(trans-4-pentylcyclohexyl)-4-biphenylmethanol and 2.9 g of triphenylphosphine in 150 ml of absolute methylene chloride was placed at -20° C. in a sulphonation flask while gassing with argon and treated portionwise within 10 minutes with 3.8 g of solid tetrabromomethane. Partially undissolved educt thereby dissolved slowly. The mixture was stirred for a further 2 hours while warming to room temperature. The mixture was subsequently concentrated on a rotary evaporator and the crystalline residue was suspended in 300 ml of warm hexane, freed by filtration from precipitated triphenylphosphine oxide (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.7 bar) of the residue on silica gel with toluene as the eluant gave 3.39 g (82%) of 4-(bromomethyl)-4'-(trans-4-pentylcyclohexyl)biphenyl as colourless crystals. This material was used in the following step without further purification. Rf value of the product [petroleum ether/ethyl acetate (97:3)]: 0.47.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21](N)=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([OH:34])(C)C.C(O)=O>O>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([OH:22])=[O:34])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)nn1
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A mixture of 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxamide (61.7 g), sodium hydroxide (28 g) and isopropanol (400 ml) was heated at reflux for 1 hour. The mixture was cooled to 70° C. and water (800 ml) was added over 30 minutes. The mixture was acidified to pH 3-4 with a solution of formic acid (41.5 ml) in water (200 ml) over 30 minutes, at 25°-30° C. The mixture was cooled to 10° C., the produce filtered off, washed with water and dried to give 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (60.2 g, 97.2% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:7][S:8]([C:11]1[CH:12]=[N:13][C:14](Cl)=[C:15]([Br:17])[CH:16]=1)(=[O:10])=[O:9])([CH2:5][OH:6])[CH3:4].[CH3:19][O-:20].[Na+].Cl>CO>[OH:1][CH2:2][C:3]([NH:7][S:8]([C:11]1[CH:12]=[N:13][C:14]([O:20][CH3:19])=[C:15]([Br:17])[CH:16]=1)(=[O:10])=[O:9])([CH2:5][OH:6])[CH3:4]
Reactant: C[O-]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncc(S(=O)(=O)NC(C)(CO)CO)cc1Br
Yield: 39.4 %

Procedure:
To a solution of 5-Bromo-6-chloro-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (550 mg, 2 mmol) in MeOH (5 mL) was added a solution of sodium methoxide (c=5.4 mol/L in MeOH, 10 mmol) at rt for 48 h. The reaction mixture was poured into a 1N solution of HCl and was extracted with 2 portions of EtOAc, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (heptane/EtOAc, 1:1) to give the title compound (0.28 g, 51%) as a white solid. MS (ISN) 353.1 [(M−H)−], 355.1 [(M+2-H)−].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O-:14].[Na+]>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:14][CH3:13])=[N:7]2
Reactant: C[O-]
Reactant: Clc1ccc2c(Br)cccc2n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(Br)cccc2n1
Temperature: 25 °C

Procedure:
To a suspension of 5-bromo-2-chloroquinoline (2.81 g, 11.6 mmol) in MeOH (25 mL) was added sodium methoxide (30% w/w in MeOH, 10.4 mL, 54.7 mmol). The mixture was refluxed for 3 hours, allowed to cool to room temperature, diluted with water, then extracted with EtOAc. The combined extracts were washed with water then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.36 (d, J=9.1 Hz, 1H); 7.81 (d, J=8.4 Hz, 1H); 7.63 (dd, J=7.6, 1.1 Hz, 1H); 7.46 (t, 1H, J=7.9 Hz); 6.98 (d, J=9.1 Hz, 1H); 4.08 (s, 3H); LC1 1.85 min. (M+H) 238.
Reaction SMILES: [Si](OC[C@@H](N)C(C)=C)(C(C)(C)C)(C)[CH3:2].BrCC(N(OC)C)=O.[Si:23]([O:30][CH2:31][C@@H:32]([N:35]([CH2:43][C:44]([N:46]([O:48][CH3:49])[CH3:47])=[O:45])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[CH2:34])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>>[Si:23]([O:30][CH2:31][C@@H:32]([N:35]([CH2:43][C:44]([N:46]([O:48][CH3:49])[CH3:47])=[O:45])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[C:33]([CH3:2])=[CH2:34])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: C=C(C)[C@H](N)CO[Si](C)(C)C(C)(C)C
Agent: CON(C)C(=O)CBr
Product: C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Yield: 39 %

Procedure:
The title compound was prepared from (S)-1-(tert-butyldimethylsilyloxy)-3-methylbut-3-en-2-amine (Intermediate 187, 5.57 g, 25.86 mmol) and 2-bromo-N-methoxy-N-methylacetamide (Intermediate 4, 4.28 g, 23.53 mmol) following the procedure described for Intermediate 5. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as a colorless oil (4.24 g, 39%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:16])=[C:5]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1)=O.[C:17](#[N:21])[CH2:18][C:19]#N.[F-].[K+].Cl.C([OH:27])C>>[C:17]([C:18]1[C:19](=[O:27])[O:16][C:4]2[C:3]([CH:1]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])#[N:21]
Reactant: CCO
Reactant: O=Cc1cccc(OCCCC(=O)O)c1O
Reactant: N#CCC#N
Agent: Cl
Agent: [F-]
Agent: [K+]
Product: N#Cc1cc2cccc(OCCCC(=O)O)c2oc1=O
Reaction time: 0.03 h

Procedure:
In 25 ml of ethanol was dissolved 4.3 g of 4-(3-formyl-2-hydroxyphenyloxy)butyric acid and 1.35 g of malononitrile, to which 3 ml of an aqueous solution containing 0.12 g of potassium fluoride was added at 40° C. and the mixture was vigorously stirred for 2 minutes. Then 5 ml of concentrated hydrochloric acid was added and the mixture was stirred for 3 minutes, followed by ice-cooling. A precipitate was filtered and recrystallized to give a desired compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8]OS(C)(=O)=O)[CH2:5][CH:4]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2].[N-:21]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1.O>[NH2:21][CH2:8][CH:6]1[CH2:5][CH:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:3]([CH2:1][CH3:2])[CH2:7]1
Reactant: CCC1CC(COS(C)(=O)=O)CC1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCC1CC(CN)CC1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 46.5 %

Procedure:
To a solution of tert-butyl 2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295 g, 0.964 mmol) in DMF (5 mL) was added sodium azide (0.313 g, 4.82 mmol). The reaction was heated at about 50° C. for about 16 h and then cooled to about 15-20° C. Water (40 mL) was added to the reaction mixture. The aqueous solution was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a dark brown oil. The brown oil was dissolved in THF (6.5 mL) and water (3.5 mL). Triphenylphosphine (0.316 g, 1.205 mmol) was added. The reaction mixture was stirred at about 25° C. for about 15 h. The organic solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (20 mL). The organic phase was concd under reduced pressure. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-20% (20% (7 N ammonium in MeOH) in MeOH)) in DCM to give tert-butyl 4-(aminomethyl)-2-ethylcyclopentanecarboxylate (0.102 g, 46%) as a brown oil: LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 228 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1CC=O)[CH3:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=C(C)C=[O:33])C=CC=CC=1.[C:47]1([CH3:53])[CH:52]=CC=[CH:49][CH:48]=1>>[CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:4]=1[CH2:49][CH:48]=[C:47]([CH3:53])[CH:52]=[O:33])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Reaction time: 15 h
Yield: 77 %

Procedure:
[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde (90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-propionaldehyde (72.9 mg, 0.23 mmol) in toluene (3 mL) were heated at 100° C. After 15 hours, a second portion of 2-(triphenyl-phosphanylidene)-propionaldehyde (33 mg, 0.11 mmol) was added and the reaction mixture was heated for additional 9 hours. The toluene was removed in vacuo, and the residue was purified by silica gel chromatography to provide 77.6 mg (77%) of the desired product as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ=0.03 (s, 9H), 1.15 (t, J=7.5 Hz, 3H), 1.21 (m, 2H), 1.93 (s, 3H), 2.21 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 3.82 (d, J=6.9 Hz, 2H), 4.34 (m, 2H), 5.18 (s, 2H), 6.38 (m, 1H), 9.35 (s, 1H) ppm.
Reaction SMILES: [CH3:1][C:2](=[N:10][O:11][CH2:12][C:13]#N)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[Na].ClC1C=CC(C(=N[OH:26])C)=CC=1.ClCC#N.Cl.CN(C)[CH:34]=[O:35]>C(OC(C)C)(C)C.CO>[CH3:34][O:35][C:13](=[O:26])[CH2:12][O:11][N:10]=[C:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: CC(=NOCC#N)c1ccc(Cl)cc1
Reactant: CC(=NO)c1ccc(Cl)cc1
Agent: Cl
Agent: N#CCCl
Agent: [Na]
Solvent: CO
Solvent: CC(C)OC(C)C
Product: COC(=O)CON=C(C)c1ccc(Cl)cc1

Procedure:
Of the (α-methyl-4-chlorobenzylidene amino)oxy acetonitrile (melting point 57° C.-58.5° C.) which was obtained by reacting the sodium salt of 4'-chloroacetophenone oxime, with chloroacetonitrile in dimethylformamide, an amount of 11.3 g was dissolved in diisopropyl ether in which 1.94 g of hydrogen chloride and 1.73 g of methanol had also been dissolved. The solution was diluted with 25 ml of diisopropyl ether and subsequently stirred over night. Then the precipitate was drawn off, washed with absolute ether and dried in a vacuum. The resulting hydrochloride of methyl (α-methyl-4-chlorobenzylidene amino)oxy acetimidate melted at 95° C. with decomposition. After this substance had been dissolved in water, the superscribed ester separated out from the solution. It was extracted with ether and distilled in a vacuum. Boiling point at a pressure of 0.1 mm: 130° C.-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(Br)cc(F)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1=Cc2cc(F)cc(Br)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 48.4 g (199 mmol) of 4-bromo-6-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.0 g (84%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Br:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Br:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Brc1cc(Br)c2c(c1)CCN2
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 165° C.; 1H NMR (300 MHz, CDCl3): δ 7.49 (d, J=1.8 Hz, 1 H), 7.29 (d, J=1.8 Hz, 1 H), 7.02 (s, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 4.06 (app. q, J=8.0 Hz, 1 H), 3.15 (t, J=8.1 Hz, 2 H), 1.99–1.74 (m, 2 H), 1.11–0.99 (m, 1 H), 0.94 (t, J=7.5 Hz, 3 H), 0.88–0.73 (m, 1 H), 0.57–0.46 (m, 2 H), 0.39–0.27 (m, 1 H); HRMS (CI) calcd for C18H19N3OBr2Cl (M+H)+: 485.9583; found m/z 485.9604.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si]([C:11]#[N:12])(C)(C)C.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:1]1([C:11]#[N:12])[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCC1
Reactant: C[Si](C)(C)C#N
Reactant: NCc1ccccc1
Product: N#CC1(NCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
7 g of cyclopentanone are solubilized in 10 mL of benzylamine. The reaction mixture is stirred for 30 mins under argon and at RT. 12.75 mL of TMSCN are added dropwise and then stirred for 1 h. They are dry evaporated. They are purified by flash chromatography on silica gel (heptane/EtOAc 99:1, to heptane/EtOAc 65:35). 14.15 g (yield=85%) of 1-(benzylamino)cyclopentanecarbonitrile are obtained as a colorless oil.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3]C.[N+:6](/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)([O-:8])=[O:7].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:3][C@@H:2]([C@H:10]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:9][N+:6]([O-:8])=[O:7])[CH:1]=[O:5]
Reactant: O=[N+]([O-])/C=C/c1cccc2ccccc12
Reactant: CCCC=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1cccc2ccccc12

Procedure:
The title compound was prepared from butyraldehyde and (E)-1-(2-nitrovinyl)naphthalene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AD-H column at 220 nm (2-propanol:hexane=0.8:99.2), 1.0 mL/min; major enantiomer tmajor=43.3 min, minor enantiomer tminor=37.6 min. [α]D20=−21.1 (c=2.4, CHCl3).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:22])=O)=[CH:18][CH:17]=1)[CH3:15]>>[ClH:22].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:20]([C:19]3[CH:23]=[CH:24][C:16]([CH2:14][CH3:15])=[CH:17][CH:18]=3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Product: CCc1ccc(-c2nc(C3CCN(C(C)C)CC3)no2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 4-ethylbenzoyl chloride.