Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=O.N1C=CC=CC=1.Cl.[O:21]([NH2:23])[CH3:22]>O>[CH3:22][O:21][N:23]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH3:13])=[C:2]([OH:1])[CH:3]=1
Reactant: CCCOc1ccc(C=O)cc1O
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCOc1ccc(C=NOC)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.9 %

Procedure:
An amount of 3-hydroxy-4-propoxybenzaldehyde (150 mg, 0.83 mmol) is added pyridine (4.0 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (101.2 mg, 1.2 mmol). The mixture is stirred at ambient temperature for 24 h, and 4 mL of water is added. After the solvents were evaporated, the residue is dissolved 8 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a yellow solid (210 mg). MS (ESI) m/z 210.5 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[S:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2sccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccsc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 57 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1

Procedure:
Potassium carbonate (1.7 g, 12.31 mmol) was added to a solution of 2-Chloro-5-nitropyridine (1.33 g, 8.38 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.57 g, 8.42 mmol) in dioxane (10 ml) then stirred at reflux for 4 hours. The reaction was cooled, and solvent evaporated. The residue was extracted with MeCl2 (100 ml) washed with H2O (50 ml), separated organic layer washed with brine (50 ml) dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding desired product as a pale yellow solid (2.3 g, 88%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[CH2:15])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:15][O:25]1)=[O:16])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCC1CCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCC2CCCCC2)CO1
Temperature: 0 °C

Procedure:
7.9 g of 5-cyclohexyl-2-methylenevaleric acid ethyl ester and 12.2 g of m-chloroperbenzoic acid in 100 ml of methylene chloride are boiled under reflux for 21 hours. The mixture is cooled to 0° C., the precipitate is filtered off and washed with 50 ml of methylene chloride and the combined filtrates are concentrated. The turbid, oily residue is dissolved in 60 ml of acetone and dilute sodium carbonate solution is added, while cooling with ice, until a pH value of 9 is reached. 100 ml of water are also added and the mixture is extracted with 3 times 100 ml of diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated and the oily residue is distilled. This gives 4.9 g of the title compound, bp 100°-108° C. at 0.02 mm Hg (2.7 Pa).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH:43]1([NH2:46])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:46][CH:43]3[CH2:45][CH2:44]3)=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: NC1CC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NC4CC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and cyclopropanamine
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[K+].C(OP([CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)(OCC)=O)C>CO>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:21]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([CH:1]=[O:10])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Reactant: O=Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C=Cc2ccc(C=O)cc2)cc1
Yield: 91 %

Procedure:
With stirring, cooling and blanketing with nitrogen, 6.7 g of terephthalaldehyde are added in portions to a mixture of 6.2 ml of aqueous potassium hydroxide solution 50% w/v and 40 ml of methanol, such that the temperature does not exceed 22° C. The resultant solution is then treated dropwise at 10° C. over 1/2 hour with a solution of 12.7 g of p-diethylphosphonomethylbenzonitrile (99.5%) in 10 ml of methanol, whereupon the reaction product soon precipitates. After stirring overnight at 10° C., the thick suspension is neutralised with 3 ml of glacial acetic acid, diluted with 40 ml of water, and filtered with suction. The filter residue is washed repeatedly with a 3:2 mixture of methanol/water and then with water until salt-free and dried under vacuum at 80° C., affording 10.6 g of 4-cyanostilbene-4'-aldehyde as a pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2].[OH:18]O>C1COCC1>[OH:18][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: OO
Reactant: CC[C@H](C)COc1ccc(B(O)O)cc1C#N
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc(O)cc1C#N

Procedure:
A mixture of compound 47 (3.00 g, 0.014 mol), hydrogen peroxide (30% w/v, 150 ml) and THF (200 ml) was heated under reflux for 3 h. The water /THF mixture was removed in vacuo and the oily residue was dissolved in diethyl either and washed with water. The ether was dried (MgSO4) and evaporated in vacuo to give a viscous, fawn oil.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([NH2:16])[CH:11]1[O:15][CH2:14][CH2:13][CH2:12]1>CO>[O:15]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:10][NH:16][CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: c1ccc(C2CO2)cc1
Reactant: NCC1CCCO1
Solvent: CO
Product: OC(CNCC1CCCO1)c1ccccc1
Temperature: 0 °C
Reaction time: 60 h
Yield: 33 %

Procedure:
A mixture of styrene oxide (1.20 g, 0.010 mole) and tetrahydrofurfurylamine (4.05 g, 0.040 mole) was heated on a steam bath for 2 hours. After standing at ambient temperature for 60 hours the reaction mixture was dissolved in 10 ml of methanol and the solution poured into 120 ml of ice-water. The aqueous mixture was extracted with methylene chloride (50 ml). The extract was dried (over magnesium sulfate) and concentrated to give an oil which began to solidify within one hour. The material was triturated with petroleum ether to obtain 0.73 g of an off-white solid (33%). The solid was recrystallized from isooctane; m.p. 70°-72° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:12][O:11][C@@H:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H](COCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H](CO)N1C(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
Stir (2R,3S,5S)-5-benzyloxymethyl-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.65 g, 1.59 mmol) and 20% palladium hydroxide on carbon (0.65 g) in methanol (25 mL) under a hydrogen atmosphere at room temperature for 2 hours. Filter through Celite®, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the desired compound as an oil (471 mg 93.0%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([N:15]3C=CN=C3)=[S:14])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+]>C(O)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([NH2:15])=[S:14])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(Nc1nnc(-c2ccccc2)s1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=S)Nc1nnc(-c2ccccc2)s1
Temperature: 90 °C

Procedure:
1.0 g of the crude mixture with N-(5-phenyl-1,3,4-thiadiazole-2-yl)-1H-imidazole-1-carbothioamide was combined with 0.536 g (6.96 mmol) ammonium acetate in 4 ml ethanol. The reaction mixture was heated in the microwave (at 100 Watt) for 30 minutes at 90° C. After completion of the reaction, the solvent was distilled off under vacuum, and water was added to the residue formed. After extraction with CH2Cl2 and drying of the organic phase with magnesium sulfate, the product crystallized out of the organic solvent and, after filtration, was washed with diethylether. 0.52 g of the N-(5-phenyl-1,3,4-thiadiazole-2-yl)thiourea was obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:3][C:2]([CH3:4])([CH3:1])[C:5]([OH:7])=[O:6])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 2-methylalanine (CAN 62-57-7, 30.9 g, 0.3 mol) and sodium hydroxide (20 g, 0.5 mol) in water (500 mL) was added benzyl chloroformate (61.4 g, 0.36 mol) at ice-water bath temperature. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting solution was washed with ethyl acetate (2×80 mL), then the aqueous layer was adjusted to pH=2 with conc. hydrochloric acid and the solution was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude target compound (26 g, 36%) which was used directly for the next step without further purification; MS: m/e 238.0 [M+H]+.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C1COCC1.[F:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13]>>[F:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Cl
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: C=CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
To 1.6 M vinylmagnesium chloride in THF (200 mL, 0.32 mol) at −78° C. was added hexafluoroacetone (50 g, 0.31 mol) by cannula over a period of 3 h with stirring. The reaction mixture was allowed to warm to r.t. and stirred for an additional 2 h, then heated to 40° C. for an additional 1 h. The reaction mixture was quenched with aqueous NH4Cl solution. The mixture was diluted with pentane, filtered, and the organic phase was dried over MgSO4. Fractional distillation (12 inch Vigreux column) at 100-103° C. afforded the product 1,1,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol (mixture containing around 66 mol % THF) as a clear liquid (50 g). 1H NMR δ 5.20 (br, 1H), 5.70 (d, 1H), 5.92 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].[CH3:13]I.O>CC(C)=O>[CH3:13][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: CI
Reactant: Cc1nc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccccc2n1C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To 10 grams of 2-methyl benzimidazole (75 mM), crushed 25 grams of crushed KOH (450 mM) in 300 ml acetone, methyl iodide (15 grams, 105 mM) was added at a continuous drip for 0.5 hours, at room temperature. Following additional 0.5 hour, water was added, the reaction extracted with dichloromethane, evaporated and chromatographed on silica gel to yield 6 grams (54%) of 1,2-dimethyl benzimidazole as a white solid having a melting point of 102° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)nc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 74B (0.044 g, 0.068 mmol) in a mixture of THF (0.3 mL), methanol (0.2 mL), and aqueous HCl (0.4 mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: COc1ccc(Cl)c(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
Product: COc1ccc(Cl)c(-c2ccc(N)c(F)c2)c1
Yield: 67.4 %

Procedure:
The title compound (134 mg) was prepared from 4-bromo-2-fluoroaniline (150 mg, 0.79 mmol) and 2-chloro-5-methoxylphenylboronic acid (191 mg, 1.02 mmol) as a colourless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]([Sn:17]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])Cl)[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:23]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a solution of 2-bromopyridine (5 g, 31.65 mmol, 1.00 equiv) in freshly distilled THF (50 mL) was added n-BuLi (15.3 mL, 3.80 mmol, 1.20 equiv) dropwise at −78° C. under N2. After stirring for 30 min at this temperature, tributyl(chloro)stannane (12.5 g, 38.40 mmol, 1.21 equiv) was added via a syringe at −78° C. and stirred for additional 1 h. Then the reaction mixture was warmed to room temperature and stirred for another 2 h. The reaction was quenched by the addition of 50 mL of NH4Cl (sat), extracted with 3×100 mL of ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/20) to give 2-(tributylstannyl)pyridine (1.0 g) as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[OH-].[Na+].C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10]
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)=CCC/C(C)=C\CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
In 125 ml of anhydrous tetrahydrofuran was suspended 18 g of (E)-4-methyl-(-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The resulting mixture was stirred at -20° C. for one hour and to this was further added 8.4 g of (Z)-1,1-diethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared in Referential example 3) in 25 ml of anhydrous tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours and, after addition of ice-water, extracted with n-hexane, and from the extract was obtained an oil. The oil was treated with a sodium hydroxide solution and acetic acid and reduced with 150 mg of sodium borohydride in the same manner as in Example 13, yielding 3.0 g of a mixture of the (E,Z,Z) and (E,E,Z) isomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=2[CH3:23])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (6.00 g, 0.03508 mol) in CH2Cl2 (50 ml) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (5.65 g, 0.03157 mol), and N,N-diisopropylethylamine (15.1 ml, 0.0877 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 22.32 g, 0.07016 mol) is added via syringe and stirred at 60° C. After 3 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (8.70 g, 74%). Mass spectrum (m/z): 333.2 (M+1).
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[C:1]([C:3](=[CH:12][NH:21][C:20]1[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a warm solution of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (14.8 g) and ethanol is added p-chloroaniline (8.9 g) in ethanol. Precipitate appears instantaneously. The mixture is stirred at room temperature for one hour and filtered to yield α-cyano-β-(4-chloroanilino)-N-ethoxycarbonylacrylamide, m.p. 177°-183°.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH3:11].Cl.[NH:21]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:22]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[NH:21]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:22]([C:31]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
1.68 ml (12.0 mmol) of triethylamine are added to a suspension containing 2.58 g (12.0 mmol) of H-Val-OtBu.HCl and 4.62 g (11.0 mmol) of Z-Asp(OtBu)-OSu in 25 ml of dimethylformamide (DMF). The reaction mixture is left to stand overnight, then evaporated under reduced pressure. The residue is mixed with 50 ml of ethyl acetate and the suspension obtained is successively washed with 25 ml of water, 3 times with 25 ml of 1 mol/liter hydrochloric acid each, 3 times with 25 ml of 5% aqueous sodium hydrogenocarbonate each and finally with 25 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 4.3 g (81.7%) of oily Z-Asp(OtBu)-Val-OtBu protected dipeptide, Rf1 =0.85.
Reaction SMILES: [C:1]([CH:9]1[CH:14]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:12]=[CH:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)(=O)C>[C:2]1([C:1]2[N:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]3[C:9]=2[CH2:10][CH:11]=[CH:12][CH2:13]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1CC=CCC1C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Cn1c(-c2ccccc2)c2c(c1-c1ccccc1)CC=CC2

Procedure:
The procedure is as in Example 6, using as substrate 4,5-dibenzoylcyclohexene (Preparation 2) and as the reagent tert-butyl 2-aminoacetate in the presence of acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH3-]C#N.[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2
Reaction time: 1 h
Yield: 70.2 %

Procedure:
3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one (, from Step 2) (1-7 g, 4.1 mmol) was stirred in 26 mL of acetic acid and NaCNBH3 (0.27 g, 4.3 mmol) was added portionwise. The reaction was stirred for 1 hour. The reaction was diluted water, and washed 5 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (1.2 g, 71%): 1H NMR (300 MHz, DMSO-d6) δ 7.64 (app q, J=8.5 Hz, 1H), 7.34 (dt, J=9.5, 2.6 Hz, 1H), 7.17 (app t, J=8.5, 1H), 6.82 (s, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 6.42 (d, J=8.0 Hz, 1H), 5.48 (br s, 1H), 5.27 (s, 2H), 5.13 (s, 2H), 3.37 (t, J=8.3 Hz, 2H), 2.82 (t, J=8.3 Hz, 2H), 2.35 (s, 3H).