Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][CH2:6][C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:8]([CH3:11])[CH2:9][CH3:10].[C:21]1([CH:31]=O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH2:6][C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[C@@H:8]([CH3:11])[CH2:9][CH3:10])[CH2:31][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC[C@H](C)[C@@H](CNCC(=O)OC)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]glycine methyl ester (2.00 g, 6.97 mmol) was dissolved in 1,2-dichloroethane (56 ml) and 3A molecular sieves were added followed by 1-naphthaldehyde (1.89 ml, 13.9 mmol) and sodium triacetoxyborohydride (6.65 g, 31.4 mmol). The mixture was stirred at ambient temperature for 16 h, filtered and evaporated in vacuo. The residue was partitioned between EtOAc (100 ml) and sat. aq. NaHCO3 (25 ml). The aqueous layer was extracted with EtOAc (3×50 ml). The organic extracts were combined, dried (Na2SO4), filtered, and evaporated in vacuo to afford a residue which was purified by chromatography (SiO2, 15-33% ethyl acetate in hexanes) to afford the title compound as an oil.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:11]=1.BrCBr>CN(C)C=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:1][N:17]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:12]=2[CH:11]=1)=[O:30]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Agent: [K+]
Solvent: BrCBr
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CO2
Temperature: 80 °C
Yield: 99.3 %

Procedure:
Potassium carbonate (3.87 g, 28.0 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (2.08 g, 5.59 mmol) and dibromomethane (2.92 g, 16.5 mmol) in N,N-dimethylformamide (35 mL), and the suspension was heated at 80° C. for 48 h, then the reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 3-(5-chloro-2-methoxybenzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid methyl ester (2.13 g, 99%). White solid, MS (ISP)=384.1 (M+H)+.
Reaction SMILES: [F-].[K+].N#N.I[C:6]1[N:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].N>CN(C=O)C.CN1CCCC1=O.[Cu]I.CC(OC)(C)C>[CH3:12][C:9]1[N:8]=[N:7][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(I)nn1
Agent: [Cu]I
Agent: N
Agent: N#N
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 35 %

Procedure:
A mixture of CuI (263 mg) and KF (80 mg) was heated under vacuum for 30 minutes until a greenish colour was observed. The system was filled with N2 and a solution of 3-iodo-6-methylpyridazine (300 mg) in DMF (1.25 ml) and N-methylpyrrolidinone (1.25 ml) followed by trimethyl(trifluoromethyl)silane (185 μl) were subsequently added. A dark brown colour was observed. After stirring at room temperature for 5 days, the reaction was not complete. CuI (263 mg), KF (80 mg), and CF3TMS (185 μl) were added and stirring was continued overnight. Additional CuI (135 mg), KF (40 mg), and CF3TMS (90 μl) were added and after one more day at room temperature, almost no starting material was observed. Aqueous ammonia and TBME were added and the phases were separated. The aqueous one was washed with TBME. The organic extracts were combined and subsequently washed with aqueous ammonia, 1M HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated to give 70 mg (35%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]1[CH:15]([CH3:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]1=[O:19])[CH3:2].C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]1[CH:15]([CH3:16])[CH:14]([Br:28])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]1=[O:19])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C1C(=O)c2cccc(OC)c2CC1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C1C(=O)c2cccc(OC)c2C(Br)C1C
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of (5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-acetic acid ethyl ester (480 mg), NBS (420 mg), and AIBN (30 mg) in CCl4 (18 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2×). The combined organics were washed with water, dried (Na2SO4), concentrated, and purified by flash column chromatography to give a light brown solid (420 mg) LCMS-ESI+ (m/z): [M+H]+ calcd for C16H18BrO4: 353.03. Found: 352.91.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:8]=2)[N:3]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.N1C(C)=CC=CC=1C>O1CCOCC1>[CH:13]1([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH:8]=3)[N:3]=[C:2]([NH:29][C:26]3[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=3)[N:11]=2)[CH2:15][CH2:14]1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NC4CC4)c3c2)cc1
Reactant: Cn1ccc(N)n1
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: Cn1ccc(Nc2nc(NC3CC3)c3cc(-c4ccc(F)cc4)ccc3n2)n1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To a solution of [2-Chloro-6-(4-fluoro-phenyl)-quinazolin-4-yl]-cyclopropylamine (150 mg, 0.48 mmol) and 1-Methyl-1H-pyrazol-3-ylamine (70 mg, 0.72 mmol) in 1,4-dioxane (5 ml) was added 2,6-lutidine (2 equiv.; 102 mg, 0.96 mmol). The solution was heated to 100° C. for 3 hours, then cooled and purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product (140 mg, 0.287 mmol, 60% yield). The product was characterized as follows: MS (m/z): 375 ([M+H]+, 100); HPLC Rt=1.60 minutes (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18](OC)=[O:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].[Li+].[BH4-].N#N>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][C:10]([CH2:18][OH:19])([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:6]
Reactant: COC(=O)C12CC3CC(CC(NC(=O)c4cccc(Cl)c4)(C3)C1)C2
Agent: N#N
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC12CC3CC(CC(CO)(C3)C1)C2)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a solution of methyl 3-[(3-chlorobenzoyl)amino]adamantane-1-carboxylate (220 mg, 0.63 mmol) in THF (15 mL) at 0° C. was added LiBH4 (2.0M in THF, 0.6 mL, 1.2 mmol) dropwise under N2. After stirring at 0° C. for 30 min, the reaction mixture was allowed to warm up to room temperature overnight. The reaction was quenched with Sat. NH4Cl, and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 200 mg (99%) of the title compound, 3-chloro-N-[3-(hydroxymethyl)-1-adamantyl]benzamide, as a colorless oil, which was used in the next step without further purification. ESI-MS m/z: 320 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10])([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:38]12([CH2:48][CH2:49][NH2:50])[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH2:39]1)[CH2:45]2.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][CH2:12]2)=[CH:5][C:4]=1[C:1]([NH:50][CH2:49][CH2:48][C:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH2:39]1)[CH2:45]2)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Reaction time: 14 h
Yield: 49.2 %

Procedure:
A solution of 4-(3-carboxy-4-chlorophenyl)hexahydro-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (0.075 g, Example 5b) and 1,140 -carbonyldiimidazole (0.034 g) in dimethylformamide (3 ml) was stirred at room temperature of 2.5 h. Tricyclo[3.3.1.13,7]decane-1-ethanamine, hydrochloride salt (0.045 g) and N,N-diisopropylethylamine (0.037 ml) were then added and stirring continued for 14 h. The reaction mixture was poured into water and extracted with ethyl acetate three times. The ethyl acetate layers were combined and washed with 2M hydrochloric acid, 10% aqueous sodium hydroxide and brine, then dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel eluting with 20% ethyl acetate in iso-hexane gave the subtitle compound as a yellow oil (0.053 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([NH:35]C(=O)C)[CH:13]=[C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[Si](C(C)C)(C(C)C)C(C)C)[CH:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:39][O-:40].[Na+]>CO>[NH2:35][C:12]1[CH:11]=[C:10]([C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:40][CH3:39])[CH:7]=2)=[O:9])[CH:15]=[C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)[CH:13]=1
Reactant: C[O-]
Reactant: CC(=O)Nc1cc(C(=O)c2ccnc(Cl)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)c2cc(N)cc(-c3cccc4[nH]ccc34)c2)ccn1
Yield: 12.9 %

Procedure:
To N-[3-(2-Chloro-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-acetamide (Example 83, 0.150 g, 0.27 mmol) in 25 mL of anhydrous methanol was added 0.022 g (0.41 mmol) NaOMe. The reaction mixture was refluxed overnight. The methanol was removed under vacuum and water was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. The crude product was purifed by preparative TLC using 10:1 methylene chloride:methanol to give 12 mg [3-amino-5-(1H-indol-4-yl)-phenyl]-(2-methoxy-pyridin-4-yl)-methanone. 1H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 8.22 (s, 1H), 7.38 (t, J=1.5 Hz, 1H), 7.34 (t, J=1.0 Hz, 1H), 7.32 (t, J=0.9 Hz, 1H), 7.21-7.16 (m, 4H), 7.13 (dd, J=5.1, 1.3 Hz, 1H), 7.10-7.07 (m, 2H), 7.00 (s, 1H), 6.62-6.59 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:20][F:21])([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]#[C:5][C:6](O)=[O:7].C(N(CC)CC)C.ClC(OCC)=O.[NH2:35][CH2:36][CH2:37][C:38]#[N:39]>ClCCl.CCCCCC.C(OCC)(=O)C>[C:36]([CH2:37][CH2:38][NH:39][C:6](=[O:7])[C:5]#[C:4][C:3]([CH2:2][F:1])([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:20][F:21])#[N:35]
Reactant: N#CCCN
Reactant: O=C(O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#CCCNC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Yield: 93.3 %

Procedure:
An amount (1.1 g) of 5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-2-pentynoic acid and triethylamine (903 mg) were dissolved in dichloromethane (20 ml); to the solution under stirring at −10° C., ethyl chloroformate (464 mg) was added dropwise and the mixture was stirred at −10° C. for another one hour. Subsequently, 3-aminopropionitrile (500 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. To the reaction mixture, a hexane/ethyl acetate mixed solvent (1/1) was added and the resulting mixture was washed with 0.1 N HCl, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=3/2) to give the titled compound (1.2 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[C:3]=1[N+:15]([O-:17])=[O:16].ClCCl.C(N(CC)CC)C.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH2:40])[CH:29]=1>C(O)C>[N+:15]([C:3]1[C:4]2[N:5]([N:12]=[N:13][N:14]=2)[C:6]2[C:11]([C:2]=1[NH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][CH2:34][C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1c(Cl)c2ccccc2n2nnnc12
Reactant: NCCOCCCc1cccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
5-Chloro-4-nitrotetrazolo[1,5-a]quinoline (28.86 g, 0.11 mol), dichloromethane (600 ml), and triethylamine (21.14 ml, 0.11 mol) were combined and the resulting solution was chilled to 0° C. 2-(3-Pyridin-3-ylpropoxy)ethylamine (22.9 g, 0.13 mol) was added dropwise. The reaction was allowed to slowly warm to room temperature, then stirred at room temperature for 1 hour and finally at reflux for 2 hours. The reaction was cooled to room temperature and then quenched with water (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic fractions were washed with brine (100 ml), dried (Na2SO4), filtered and concentrated to yield a yellow solid. The solid was slurried in ethanol (150 ml) and filtered to provide 34.3 g of 4-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinolin-5-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[CH3:14][N:15]1[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[C:16]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-]>C1COCC1>[C:20]([C:19]1[N:15]([CH3:14])[C:16]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=2)=[CH:17][CH:18]=1)#[N:21]
Reactant: CC(C)c1cc(Br)ccc1NC#N
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2ccc(C#N)n2C)ccc1NC#N
Yield: 18.9 %

Procedure:
4-bromo-2-isopropylphenylcyanamide (0.132 g, 0.5 mmol) tris (dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL) was added with stirring. Then tri-tert-butylphosphine (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir until starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate and filtered through a plug of silica gel, solvent evaporated and the residue was flash chromatographed using 4/1 Hexane/THF to give (0.025 g, 18%) [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-isopropylphenyl]cyanamide.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>O1CCCC1.CCOCC.CC(C)=O>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[C:1]1([CH:7]([C:32]2[CH:31]=[CH:3][CH:2]=[CH:1][CH:6]=2)[O:8][CH2:9][CH2:10][N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(COCc1ccccc1)N1CCCC(c2ccccc2)C1
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(C2CCCN(CCOC(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 8 h

Procedure:
A solution of 3 g (7.78 mmole) of 1-[(phenylmethoxy)acetyl]-3-phenylpiperidine in 30 cm3 of tetrahydrofuran was added dropwise to a solution of 0.5 g (12.4 mmole) of lithium aluminum hydride in 50 cm3 of tetrahydrofuran. The mixture was heated to reflux for 4 hours, left overnight, and then hydrolyzed by the addition of 2.5 cm3 of water. It was diluted with 100 cm3 of ether. The alkaline sediments are separated and washed with ether. The ethereal phases were collected, dried on sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 20 cm3 of acetone. A solution of 0.75 g (8.3 mmole) of oxalic acid in 30 cm3 of acetone was added. The oxalate precipitate was filtered, and recrystallized from acetone.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[BH4-].[Na+].O>CO.C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13]
Reactant: C=C1N(C)c2ccccc2C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC1N(C)c2ccccc2C1(C)C

Procedure:
To a stirred solution of 3.46 g of 1,3,3-trimethyl-2-methyleneindoline (VIII, R2 =R8 =R9 =Me) in 50 ml methanol was added at room temperature in three portions at about five-minute intervals a total of 1.14 g of sodium borohydride (conveniently, as three 7/16-inch pellets, a commercially available form). The initial deep red color of the solution gradually changed to a light orange during the reaction. The mixture was then diluted first with 20 ml of ethyl ether, and then with 50 ml of water. The ether layer was separated, and the lower aqueous layer was again extracted with ether. The combined ether layers were washed with 10% aqueous sodium hydroxide solution and then water, and dried over anhydrous magnesium sulfate. Removal of solvent from the filtered extracts left 3.10 g (88.6%) of an orange oil. This oil was distilled in vacuum to give 2.52 g (72.0% of the theoretical amount of 3.50 g) of pale yellow oil boiling at 80°-81° C. at 2.3 mm Hg pressure.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:9][C:10]1[CH:11]=[C:12]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][SiH:23](Cl)[CH2:22][CH2:21]2)[CH:13]=[C:14]([F:17])[C:15]=1[F:16]>>[F:17][C:14]1[CH:13]=[C:12]([O:18][CH2:19][C@H:20]2[CH2:21][CH2:22][Si@H:23]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:24][CH2:25]2)[CH:11]=[C:10]([F:9])[C:15]=1[F:16]
Reactant: CCCCCCCBr
Reactant: Fc1cc(OCC2CC[SiH](Cl)CC2)cc(F)c1F
Product: CCCCCCC[Si@H]1CC[C@H](COc2cc(F)c(F)c(F)c2)CC1

Procedure:
The general procedure of Example 1 was repeated using n-heptyl bromide and 4-(3,4,5-trifluorophenyloxymethyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: C([O:9][CH:10]([C:12]1[N:17]2[N:18]=[CH:19][N:20]=[C:16]2[N:15]=[CH:14][CH:13]=1)[CH3:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[N:18]1[N:17]2[C:12]([CH:10]([OH:9])[CH3:11])=[CH:13][CH:14]=[N:15][C:16]2=[N:20][CH:19]=1
Reactant: CC(OC(=O)c1ccccc1)c1ccnc2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethyl benzoate (1 g), potassium carbonate (2 g), methanol (25 ml) and water (20 ml) was stirred at ambient temperature for 1 hour 30 minutes. The methanol was removed from the mixture under reduced pressure and the mixture was then diluted with brine (20 ml) before being continuously extracted with dichloromethane overnight. The extracts were dried over magnesium sulphate and the solvent evaporated under reduced pressure to give 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol. Yield 0.39 g.
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][O:43][C:44]1[N:49]=[C:48]([N:50]([CH3:54])[CH2:51][CH2:52][NH2:53])[CH:47]=[C:46]([CH3:55])[N:45]=1>CN(C=O)C>[CH:1]1(/[CH:4]=[CH:5]/[C:6]([NH:53][CH2:52][CH2:51][N:50]([C:48]2[CH:47]=[C:46]([CH3:55])[N:45]=[C:44]([O:43][CH3:42])[N:49]=2)[CH3:54])=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/C1CC1
Reactant: COc1nc(C)cc(N(C)CCN)n1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COc1nc(C)cc(N(C)CCNC(=O)/C=C/C2CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-3-Cyclopropylprop-2-enoic acid (11.2 mg, 0.1 mmol) and diisopropylethylamine (17.4 μl, 1 mmol) were dissolved in anhydrous DMF (0.5 ml), HBTU (39 mg, 0.1 mmol) was added and the mixture was stirred for 15 minutes at room temperature. N-(2-methoxy-6-methyl-pyrimidin-4-yl)-N-methyl-ethane-1,2-diamine (19.6 mg, 0.1 mmol) and diisopropylethylamine (17.4 μl, 0.1 mmol), dissolved in anhydrous DMF (0.5 ml) were added and the mixture was stirred at room temperature overnight. The mixture was purified directly by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 13.7 mg (0.047 mmol, 47.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:43][CH2:44][C:45]([NH:47][C@@H:48]([C:52]([O:54]C(C)(C)C)=[O:53])[CH:49]([CH3:51])[CH3:50])=[O:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:43][CH2:44][C:45]([NH:47][C@@H:48]([C:52]([OH:54])=[O:53])[CH:49]([CH3:50])[CH3:51])=[O:46])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reactant: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (15.3 mg, 0.03 mmol), N-methylmorpholine (10 μl, 0.091 mmol) and tert-butyl glycyl-D-valinate hydrochloride, (10.4 mg, 0.039 mmol) were dissolved in DCM (2 ml). After 10 minutes, TBTU (11.9 mg, 0.037 mmol) was added and the mixture was stirred overnight. The intermediate tert-butylester was confirmed. M/z: 727.8 (M−H). The reaction mixture was extracted between water (10 ml, acidified to pH of 3 with KHSO4 (2M)) and DCM (3×10 ml). The combined organic phases were washed with water (2×20 ml), dried over Na2SO4, filtered and concentrated. The oily residue was dissolved in DCM (2 ml) and TFA (1.3 ml) was added. The mixture was stirred overnight. The solvent was evaporated and co-evaporation with toluene was performed to assist the removal of TFA. The residue was dissolved in methanol (2 ml) and sodium borohydride (12.3 mg, 0.33 mmol) was added. After 15 minutes, ammonium acetate (17 mg) was added and the solvent was removed under reduced pressure. The residue was purified on preparative HPLC on C8 column. A gradient from 20% to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (15.1 mg, 77%). H-NMR (400 MHz, DMSO-d6): 0.78 (d, 3H), 0.80 (d, 3H), 0.95-1.03 (m, 1H), 2.83-3.00 (m, 2H), 3.75-3.80 (m, 2H), 3.93-4-00 (t, 1H), 4.30 (d, 0.5H), 4.36-4.38 (brs, 0.5H), 4.52 (s, 2H), 4.69-4.77 (m, 1H), 5.02 (d, 0.5H), 5.06 (d, 0.5H), 6.96-7.00 (m, 2H), 7.18-7.22 (m, 2H), 7.31-7.38 (m, 8H), 7.60-7.74 (m, 1H), 8.28 (t, 1H). M/z: 671.9 (M+H).