Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:19]=[C:20]([CH3:35])[S:21][C:22]=1[N:23]([C:28]([O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:29])[CH2:24][CH:25]1[CH2:27][CH2:26]1)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[CH:32]1([CH2:31][O:30][C:28](=[O:29])[N:23]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:22]2[S:21][C:20]([CH3:35])=[N:19][C:18]=2[C:16](=[O:15])[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=2)[CH2:33][CH2:34]1
Reactant: Cc1nccc(N)n1
Reactant: CCOC(=O)c1nc(C)sc1N(CC1CC1)C(=O)OCC1CC1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nccc(NC(=O)c2nc(C)sc2N(CC2CC2)C(=O)OCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A solution of 2-methyl-4-amino-pyrimidine (0.184 g, 1.68 mmol) in 10 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 0.84 ml, 1.68 mmol). The mixture was stirred at room temperature for 1 h. 5-(Cyclopropylmethoxycarbonyl-(cyclopropylmethyl)-amino)-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.135 g, 0.40 mmol) was added and the reaction mixture was refluxed for 4 h. 1 ml water and 2 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography with heptane/ethyl acetate 100:0→0:100 gradient to yield cyclopropylmethyl-[2-methyl-4-(2-methyl-pyrimidin-4-ylcarbamoyl)-thiazol-5-yl]-carbamic acid cyclopropylmethyl ester (0.101 g, 63%) as a colourless oil, MS (ISP): m/e=402.5 (M+H+).
Reaction SMILES: CN1CCCCC1.Cl.[C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH:16]([CH3:26])[CH2:17][NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])=[CH:13][CH:12]=1)#[N:10].Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C(Cl)Cl>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:26])[CH2:17][NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH:21][C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:27][CH:28]=1)#[N:10]
Reactant: CC(CNC(=O)[C@@H](N)C(C)C)Oc1ccc(C#N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(CNC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C)Oc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
0.16 g of N-methylpiperidine was added to a suspension containing 0.25 g of N1 -[2-(4-cyanophenoxy)propyl]-L-valinamide hydrochloride suspended in 20 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.13 g of phenyl chloroformate was added drop by drop to the mixture, and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 3 hours at room temperature. After the methylene chloride was removed under reduced pressure, the residue was purified by column chromatography on silica gel, thus obtaining 0.2 g of the desired product in the form of a white glutinous substance (yield: 63%).
Reaction SMILES: C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:20][C:21](=O)/[CH:22]=[C:23](\[CH3:40])/[CH2:24]/[CH:25]=[CH:26]/[C@H:27]([CH3:39])[C@@H:28]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:29][CH3:30])C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CO.C(OCC)C>[CH3:40]/[C:23](/[CH2:24]/[CH:25]=[CH:26]/[C@H:27]([CH3:39])[C@@H:28]([O:31][Si:32]([CH2:35][CH3:36])([CH2:37][CH3:38])[CH2:33][CH3:34])[CH2:29][CH3:30])=[CH:22]\[CH2:21][OH:20]
Reactant: CCOC(=O)/C=C(\C)C/C=C/[C@H](C)[C@H](CC)O[Si](CC)(CC)CC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)/C=C/C/C(C)=C/CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
1M toluene solution of diisobutylaluminum hydride (52.2 ml, 52.2 mmol) was added dropwise to an anhydrous diethyl ether (37.5 ml) solution of ethyl-(2E,5E,7S,8S)-3,7-dimethyl-8-[(triethylsilyl)oxy]deca-2,5-dienoate (8.92 g, 25.20 mmol) at −78° C. and the reaction solution was stirred at the same temperature for one hour. Methanol (1 ml) and a saturated potassium sodium tartrate tetrahydrate aqueous solution (9.3 ml) were added to the reaction solution, and the mixture was warmed to room temperature and stirred for two hours. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:diethyl ether=8:1) to obtain the title compound (3.84 g) as a colorless oil. 1H-NMR data of the title compound obtained by (2-2) is completely identical to those of the title compound obtained by (2-1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:9]([C@@:12]1([CH3:33])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:14][C:13]1=[O:32])[CH:10]=[CH2:11]>C(OCC)(=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([C@H:16]([C@H:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[OH:14])[CH2:17][C@:12]([CH3:33])([CH2:9][CH:10]=[CH2:11])[C:13]([NH:1][C@@H:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:7][OH:8])=[O:32])[CH:23]=[CH:22][CH:21]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Reactant: CC(C)(C)[C@H](N)CO
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)C(C)(C)C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
(S)-tert-leucinol (0.937 g, 7.99 mmol) and (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (1 g, 2.66 mmol; Example 261, Step F) were combined in a reaction flask and heated to 100° C. After 2 d, the reaction mixture was cooled to RT and dissolved in ethyl acetate. The organic phase was washed with 3×10 mL 1N HCl and 1×10 mL brine, dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.O1CCOCC1.[ClH:31]>>[ClH:31].[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(CN)cc1
Reaction time: 3 h

Procedure:
4-cyanobenzylamine hydrochloride (EX-59A) was prepared from 10 g (0.030 moles) of 4-{N,N-bis-(tert-butoxycarbonyl)aminomethyl}benzonitrile, prepared following Synthetic Communication, 28(23), 4419-4429 (1998), by stirring it in 4N HCl Dioxane (75 ml). After 3 h, the solution was concentraed in vacuo and triturated with ether. The solid was collected by filtration and vacuum dried to yield 5 g (98%) of EX-59A as a white solid: 1H NMR (DMSO) d 8.68 (br s, 2H) 7.84 (m, 2H), 7.67 (m, 2H), 4.06 (s, 2H); HRMS (EI) calcd for C8H8N2 133.0766, found 133.0807.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[N:31]=2)=[C:26]([CH:29]=1)[CH:27]=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[C:30]1[O:34][N:33]=[C:32]([CH3:35])[N:31]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc(-c2nc(C)no2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C)no2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.1 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (155 mg, 0.60 mmol) and 5-methoxy-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (155 mg, 0.60 mmol) in DMF (10.0 mL) is added Oxone (155 mg, 0.71 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 5% MeOH in CH2Cl2 as the eluent to afford the title compound (25 mg, 9%) as a white solid. LCMS (ESMS): m/z 456.20 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1.[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1
Reactant: O=Cc1cc2cc(F)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2cc(F)ccc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
Compound 13 (180 mg, 1.10 mmol) was dissolved in EtOH (12 mL). NaBH4 (45 mg, 1.21 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvents were evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). The solvent was evaporated off in vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (3:1) to give 14 (150 mg, 91%) as a white solid. 1H NMR (500 MHz, CDCl3): δ: 7.36 (1H, d, J=8.35 Hz, H-7), 7.19 (1H, d, J=7.80, H-4), 7.00 (1H, t, J=8.75H-6), 6.60 (1H, s, H-3), 4.75 (2H, s, CH2).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])=[C:5]([CH3:19])[O:4][N:3]=1.[CH3:20]S(O)(=O)=O>CO>[CH3:1][C:2]1[C:6]([CH:7]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH2:8][C:9]([O:11][CH3:20])=[O:10])=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1C(CC(=O)O)c1ccc(O)cc1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CC(c1ccc(O)cc1)c1c(C)noc1C
Temperature: 65 °C
Reaction time: 1 h
Yield: 18.72 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 20 mL of methanol. To the stirred solvent was added 3-(3,5-Dimethyl-1,2-oxazol-4-yl)-3-(4-hydroxyphenyl)propanoic acid (1.0 g, 6.1 mmol), followed by methanesulfonic acid (1.16 g, 12.0 mmol). After addition, the RM was refluxed at 65° C. for 1 h. After 1 h, the solvent was evaporated, water (20 mL) was added and the organic layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.2 g, yield: 18.72%).
Reaction SMILES: CC(CC(C)C)=O.[CH2:8]([C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:34]=[N:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].[OH-].[K+:58].C>C(O)C>[CH3:11][CH2:10][CH2:9][CH2:8][C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]=[N:36][N-:35][N:34]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1.[K+:58]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)CC(C)C
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
In a 500 ml flask a mixture of 200 ml of dry ethanol, 20 g (0.026 mol) of 2-n-butyl-4-chloro-1-[(2′-(2-triphenylmethyl -2H-tetrazol-5-yl)-1,1′-biphenyl-4-yl)-methyl]1H-imidazol-5-methanol methyl-isobutyl ketone solvate and 1.45 g (0.026 mol) of potassium hydroxide was refluxed for 9 h, treated with 0.5 g of charcoal and filtered. The filtrate was concentrated to a volume of 30 ml under diminished pressure, and after addition of 150 ml of acetonitrile again to a volume: of 60 ml. The suspension was stirred at 0° C. for 1 h, the precipitated crystals were filtered, washed twice with 25 ml of cold acetonitrile and dried at 70° C. to give 10.6 g (88%) of the title compound.
Reaction SMILES: N.[Na].Cl[C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH:6]=[CH:7][C:8]#[N:9].[N+]([O-])([O-])=O.[NH4+]>[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[C:8]([CH:7]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:4]=[C:5]2[CH2:6]1)#[N:9]
Reactant: N#CC=Cc1ccccc1Cl
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Product: N#CC1Cc2ccccc21
Reaction time: 3 h
Yield: 50 %

Procedure:
A 3-liter, three-necked flask equipped with a dry ice condenser, mechanical stirrer and Claisen adapter fitted with an ammonia gas inlet and nitrogen inlet is rinsed with acetone, dried in an oven at 125° C., and heated with an air gun while flushing with nitrogen. The apparatus is cooled in a dry ice-acetone bath and the condenser is filled with a dry ice-acetone mixture. Ammonia gas flow is initiated and 600 ml is condensed out. The ammonia inlet tube is replaced by a stopper, and 0.4 g of powdered iron (III) nitrate is added. Sodium metal, 51.52 g (2.24 moles) is added in small portions over 1 hour. After all the sodium is added, the dry ice bath is removed and cooling is left to the dry ice condenser. Complete conversion of the sodium/ammonia solution to sodamide is indicated by a color change from deep blue to gray. Next, 92.82 g (0.56 mole) of o-chlorocinnamonitrile is added over a period of 10 minutes. The last traces of the nitrile are washed into the flask with small amounts of anhydrous ethyl ether. The dark green reaction mixture is stirred vigorously for 3 hours and then is treated with 134.4 g (1.68 moles) of solid ammonium nitrate. The ammonia is allowed to evaporate overnight at room temperature. Water (420 ml) is cautiously added to the residue. The organic layer is taken up in two 224-ml portions of chloroform, and the solutions are combined and washed twice with 140 ml of aqueous 5 percent hydrochloric acid and once with 140 ml of water. The chloroform solution is dried over anhydrous magnesium sulfate, filtered, and evaporated on a rotary evaporator. The residual liquid is distilled under reduced pressure through an insulated 12-inch Vigreux column. The product is collected at 59° C.-69° C./0.2 mm Hg. The infrared, 'H and 13C nuclear magnetic resonance are run to identify the product. The yield is 50 percent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH:12]1([CH:17]([OH:20])[CH:18]=[CH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([C:17](=[O:20])[CH2:18][CH2:19][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C=CC(O)C1CCCC1
Reactant: CCc1cc(Br)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1cc(CCC(=O)C2CCCC2)ccc1OC
Temperature: 140 °C
Yield: 47.2 %

Procedure:
A mixture of bromide (1.3 g, 6.02 mmol, from step 1), 1-Cyclopentyl-2-propen-1-ol (1.14 g, 9.07 mmol), dichlorobis(triphenylphosphine)palladium (II) (85 mg, 0.12 mmol), sodium bicarbonate (0.61 g, 7.25 mmol) in N-methylpyrrolidinone (12 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. The oil was purifed by silica gel chromatography to give the title compound as a yellow oil (0.74 g, 47%). 1H NMR (CDCl3): δ ?1.17 (t, 3H, J=7.6 Hz), 1.54-1.80 (m, 9H), 1.17 (q, 2H, J=7.6 Hz), 2.73 (m, 2H), 2.84 (m, 2H), 3.80 (s, 3H), 6.75 (d, 1H, J=8.0 Hz), 6.97 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])(CC)C.[C:26](=O)([O:30]CC)[O:27][CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[C:26]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:7]=[CH:6]2)([O:27][CH2:28][CH3:29])=[O:30]
Reactant: CCOC(=O)OCC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of 760 mg (2.61 mmol) of 6-fluoro-1-triisopropylsilylindole dissolved in 6 ml of anhydrous tetrahydrofuran are added dropwise at −78° C. under argon 2.01 ml of a sec-butyllithium solution (1.3M in cyclohexane, 2.01 mmol). The reaction mixture is stirred for 2 h at −78° C. then 500 μL (3.15 mmol) of diethyl carbonate are added dropwise at −78° C. to the reaction mixture. This mixture is stirred for 5 h with a gentle temperature rise then an ammonium chloride saturated aqueous solution is added. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 97:3) to yield 445 mg (46%) of 5-carboethoxy-6-fluoro-1-triisopropylsilylindole in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[F:18][C:19]1[C:24]([CH:25]=[O:26])=[C:23]([F:27])[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(OCC)(=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[F:18][C:19]1[C:20]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[CH:10]=[C:4]3[CH:3]=2)=[CH:21][CH:22]=[C:23]([F:27])[C:24]=1[CH:25]=[O:26]
Reactant: Fc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Reactant: O=Cc1c(F)ccc(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1c(F)ccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1F
Yield: 76.6 %

Procedure:
The procedure described in stage 2.4 is followed, starting with 0.300 g (1.03 mmol) of 5-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine obtained in stage 2.3, 0.210 g (1.13 mmol) of 2,4-difluoro-3-formylphenylboronic acid, 1.00 g (3.09 mmol) of caesium carbonate and 0.084 g (0.10 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) in 5 ml of a 9/1 mixture of tetrahydrofuran and water. After chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.278 g (76%) of the expected product is obtained in the fowl of a beige powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16]>C(O)C>[CH2:16]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH:15]=[CH2:14]
Reactant: OC1CCNCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCN1CCC(O)CC1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
Into a mixture of 4-hydroxypiperidine (75 g, 0.74 mol) and potassium carbonate (104 g, 0.75 mol) in ethanol (250 ml) is added allyl bromide (65 ml, 0.74 mol) in four equal portions over a three-hour period. After the addition is complete, the reaction mixture is stirred at ambient temperature until the disappearance of the reactants, as determined by TLC analysis (approximately six hours). The insoluble solids formed are then removed by filtration and the filtrate is concentrated in vacuo. The residue is purified by flash chromatography on silica gel with a mixture of 25% (vol.) methanol in ethyl acetate as the solvent to give 53.2 g (51% yield) of the title compound as a yellow oil.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH:16]([CH3:18])[CH3:17])C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O1CCCC1.O>O1CCCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][OH:30])=[CH:25][CH:24]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)[C@@H](Cc1ccc(C(C)(C)C)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 4(R)-benzyl-3-[2(R)-(p-tert-butyl-benzyl)-3-methyl-butyryl]-oxazolidin-2-one (8.63 g) in tetrahydrofuran (40 ml) is added dropwise at 0° C., with stirring, to a suspension of lithium aluminium hydride (2.41 g) in tetrahydrofuran (160 ml). The reaction mixture is stirred for 4 hours at 0° C. and then, at 0° C., ethyl acetate (5 ml), 30 ml of a (1:1) mixture of tetrahydrofuran/water and 2N sulfudc acid (80 ml) are added in succession thereto. The supension is extracted with ethyl acetate and the crude product is purified by FC (700 g of silica gel, eluant dichloromethane). The title compound is obtained: Rf (dichloromethane)=0.34; m.p. 49°-51° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C:24](=[O:26])[N:23]([CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[S:22]2(=[O:34])=[O:33])=[C:17]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:16]=1)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[S:22](=[O:33])(=[O:34])[N:23]([CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:24](=[O:26])[CH2:25]2)=[C:17]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:16]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3N)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-phenyl)-carbamic acid tert-butyl ester (1.7 g, 2.73 mmol) in methylene chloride (10 mL) is added TFA (5 mL) and the mixture is stirred at RT for 20 min. The solvent is removed under reduced pressure and methylene chloride is added to the residue and evaporated (6×) to give the title compound as its TFA salt.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[N:15]=[N:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:18]=2[CH3:19])=O)[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1>C(#N)C>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][N:17]2[C:18]([CH3:19])=[C:14]([CH2:12][NH:11][C:5]3[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=3)[N:15]=[N:16]2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: Cc1c(C(=O)Nc2cc(CO)cc(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: Cc1c(CNc2cc(CO)cc(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Yield: 5 %

Procedure:
This compound was obtained as a by product of the reduction of dimethyl 5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-benzenedicarboxylate (Intermediate 14) in the preparation of N-[3,5-bis(hydroxymethyl)phenyl]-1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 52). It was obtained as a white solid (5%) via recrystallisation from acetonitrile. HRMS calculated for C19H20Cl2N4O2 (M+H)+407.1042, found: 407.1022, Rt: 2.40 min. MP: 120° C.