Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:20])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Yield: 682.7 %

Procedure:
To a solution of 3-benzyloxybenzoic acid (22 g, 96 mmol) in toluene (200 ml) was added dropwise thionyl chloride (14.1 ml, 19 mmol). The reaction mixture was heated at 90° C. for 2 hours, cooled to ambient temperature and volatiles removed under reduced pressure to afford crude 3-benzyloxybenzoyl chloride (32 g, quant.). The crude 3-benzyloxybenzoyl chloride was dissolved in CH2Cl2 and added dropwise over 30 min., to a vigorously stirred solution of (R)-(-)-2-phenylglycinol (15.8 g, 115 mmol) and triethylamine (16 ml, 15 mmol) in CH2Cl2 (200 ml) cooled to 0° C. The reaction mixture was allowed to warm ambient temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1 L) and water (1 L). The aqueous layer was separated, extracted with ethyl acetate (2×500ml) and the combined organic phase washed with 1N HCl (500 ml), aqueous 4% NaHCO3 solution (500 ml) and brine (500 ml), dried over MgSO4 and concentrated under reduced pressure to give 2-(3-benzyloxybenzamido)-2(R)-phenylethan-1-ol (29 g, 88%) as pale yellow solids.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[N:20][CH:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([O:10]C)=[O:9])[CH:7]=1.[OH-].[Na+].O.C(O)(=O)C>CO>[Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[N:20][CH:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
Methyl 8-chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-carboxylate (0.60 g, 2.0 mmol) was stirred in methanol (40 mL) and a solution of 3 N sodium hydroxide in water (10 mL, 40 mmol) was added. The mixture was stirred for 16 hours at room temperature, and glacial acetic acid (5 mL) was added. Evaporation gave a precipitate which was filtered and washed with water to give the desired compound (0.29 g, 50%). LCMS calculated for C14H9ClFN2O2 (M+H)+: m/z=291.1. found: 290.9. 1H NMR (300 MHz, DMSO-d6): δ 7.77 (s, 1H), 7.60 (m, 2H), 7.40 (m, 4H).
Reaction SMILES: [O-:1][W:2]([O-])(=O)=O.[Na+].[Na+].[P:8](=O)(O)(O)[OH:9]>O>[OH2:1].[OH2:9].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[PH3:8].[W:2].[W:2].[W:2].[W:2].[W:2].[W:2].[W:2].[W:2].[W:2].[W:2].[W:2].[W:2]
Reactant: O=[W](=O)([O-])[O-]
Reactant: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: P
Product: [W]
Temperature: 25 °C

Procedure:
Phosphotungstic acid reagent was prepared by refluxing a solution of 4 g sodium tungstate in 30 ml of H2O with 3.2 ml of 85% by weight orthophosphoric acid for 2 hours. The solution was then cooled to room temperature and diluted to 100 cc. Then 3.2 g of Li2SO4.H2O was added and mixed well. This liquid reagent material was incorporated into pods prepared as described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(C)C=CC(C#N)=CC=1.C[O:39][C:40]1C=C(C=[CH:45][CH:46]=1)N.[O:47]1CCCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:45]=[C:46]([C:40]([OH:39])=[O:47])[N:11]=[C:10]2[C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1cccc(NC(=N)c2ccc(C)cc2)c1
Reactant: COc1cccc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(C#N)cc1
Agent: [Na+]
Product: COc1cccc(-n2cc(C(=O)O)nc2-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(3-Methoxyphenyl)-4-methylbenzenecarboxamidine To a solution of 2.5 mL (5.0 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 10 mL of tetrahydrofuran at ambient temperature was added a solution of 0.59 g (5.0 mmol) of p-tolunitrile in 20.0 mL of tetrahydrofuran and the resulting solution was stirred for 30 min. To this reaction mixture was slowly added 0.56 mL (5.0 mmol) of 3-methoxyaniline. The resulting mixture was stirred at ambient temperature overnight and then poured into ice/water (25 mL) and extracted with dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 241.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=O.[OH-].[Na+]>C(O)C.O>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:21])[C:14]=1[CH:12]=[CH:11][C:4]([C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])=[O:5]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1c(Cl)cccc1Cl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(32) To a solution of the 2,6-dichlorobenzaldehyde (438 mg, 2.50 mmol) and 2,6-dichloroacetophenone (473 mg, 2.50 mmol) in 3.7 ml of ethanol was added 0.1 ml of 40% sodium hydroxide in water at 10° C. After stirring for 2 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 465 mg (53.8%) of white, cottony needles: mp 130-130.4° C. (lit. mp 124-125° C., Kaiser, et al., Monatshefte fur Chemie, 1997, 128, 1247-1254). 1H NMR (250 MHz) δ 7.43-7.17 (m, 7H), 7.10-7.03 (d, 1H); 13C NMR (62.7 MHz) 193.0, 141.7, 137.5, 135.3 134.4, 132.1, 131.8, 131.0, 130.6, 129.0, 128.3 ppm.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]3[CH2:14][C:9]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)([CH2:10]3)[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC>COCCO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]23[CH2:10][CH:11]([CH2:14]2)[C:12](=[O:13])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]3=[O:24])=[CH:16][CH:17]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1C1CCCCC1
Agent: [Pd]
Solvent: COCCO
Solvent: CCOCC
Product: Nc1ccc(C23CC(C2)C(=O)N(C2CCCCC2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-cyclohexyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 139°-140° (from ether).
Reaction SMILES: [CH3:1][SiH:2]([CH3:7])[O:3][SiH:4]([CH3:6])[CH3:5].[CH2:8]([O:12][CH2:13][CH:14]=[CH2:15])[CH:9]1[O:11][CH2:10]1>C(OCCOCCOCC)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:11]1[CH2:10][CH:9]1[CH2:8][O:12][CH2:13][CH2:14][CH2:15][Si:2]([CH3:7])([CH3:1])[O:3][SiH:4]([CH3:6])[CH3:5]
Reactant: C=CCOCC1CO1
Reactant: C[SiH](C)O[SiH](C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCOCCOCCOCC
Product: C[SiH](C)O[Si](C)(C)CCCOCC1CO1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
An example of the synthesis of compound (5) is described in the following. 1,1,3,3-Tetramethyldisiloxane (17.5 g, 130 mmoles) is heated to the refluxing temperature and 1 mL of a 1 weight percent solution of hexachloroplatinic acid in diethylene glycol diethyl ether is added. Allyl glycidyl ether (11.4 g (100 mmoles) is added dropwise. At the same time, the temperature rises to 95° C. The reaction mixture is stirred for 2 hours at 120° C. and then fractionated with the help of a packed column. At 73° C. and 0.65 hPa, 1-(6,7-epoxy-4-oxaheptyl)-1,1,3,3-tetramethyldisiloxane (monoaddition compound) is obtained as a clear liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].CCN(CC)CC.Cl>CCOC(C)=O>[CH3:39][S:40]([O:21][CH2:20][C:18]1[CH:17]=[C:16]([O:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:15]=[C:14]([CH2:13][N:12]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[S:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[OH:38])(=[O:11])=[O:10])[CH:19]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cc(CO)cc(Oc2ccc(F)cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-(4-fluorophenoxy)-5-(hydroxymethyl)benzyl)-2-hydroxybenzenesulfonamide (1.1 g, 1.895 mmol) and methanesulfonyl chloride (0.147 mL, 1.895 mmol) in EtOAc at −30° C. was added Et3N (0.4 mL, 2.87 mmol) under Ar atm. The mixture was stirred for 1 h, but only a small amount of product was produced. Thus, additional methanesulfonyl chloride (0.25 mL) and Et3N (0.6 mL) were added at −30° C. The mixture was slowly warmed to rt, stirred at rt for 2 h and treated with 1N aq HCl and EtOAc. The EtOAc layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo to obtain the desired product as a viscous material (˜1.4 g). This material was used directly for the next step without further purification. 1H NMR (CDCl3): δ 7.61 (d, J=2.8 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.07-6.89 (m, 8H), 6.82 (d, J=1.6 Hz, 2H), 6.63 (s, 1H), 5.06 (s, 2H), 4.37 (s, 2H), 4.34 (s, 2H), 2.97 (s, 3H; MS: (M−H)−=656.1.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:18](=[O:19])[N:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]2=[N:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH2:20]([N:22]([CH2:25][CH2:26][Cl:27])[CH2:23][CH3:24])[CH3:21].[ClH:28]>CN(C)C=O.C(OCC)C>[ClH:27].[ClH:28].[CH2:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH2:24][O:3][CH2:4][C:5]1[C:18](=[O:19])[N:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]2=[N:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:21]
Reactant: O=c1c(CO)cnc2c3ccccc3ccn12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)CCOCc1cnc2c3ccccc3ccn2c1=O
Reaction time: 1 h
Yield: 28 %

Procedure:
To 0.7 g of sodium hydride (14.5 mmol) stirred in 40 ml of dry dimethylformamide under nitrogen was added dropwise over a 15 minute period a solution of 2.0 g of 3-(hydroxymethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one (8.3 mmol) in 40 ml of warm dimethylformamide. After stirring for 1 hour, 1.58 g of diethylaminoethyl chloride (11.6 mmol) was added dropwise over a 15 minute period. The reaction mixture was stirred for 3 hours, then poured onto ice-water and extracted 3 times with 500 ml of methylene chloride. The extracts were dried and concentrated in vacuo to yield a semi-solid, to which 15 ml of isopropanolic hydrochloric acid solution and diethyl ether were added. The crystalline solid which formed was collected and washed with ether to yield 3-[[2-(diethylamino)ethoxy]methyl]-4H-pyrimido[2,1-a]isoquinolin-4-one dihydrochloride (0.973 g; 28% yield) of the formula: ##STR24## having a melting point of 128.7° C. and the following elemental analysis:
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.Cl.[CH3:18][N:19](C)C=O>>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: O=C1c2cc(I)ccc2CCn2cccc21
Agent: Cl
Product: N#Cc1ccc2c(c1)C(=O)c1cccn1CC2
Reaction time: 0.5 h

Procedure:
A stirred mixture of 1 gm. of 9-iodo-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one, 1 gm. of cuprous cyanide and 5 ml. of dimethylformamide is heated to reflux for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2N hydrochloric acid. After stirring the resulting mixture at 60° for 30 min., it is extracted with 3 × 50 ml. of ethyl acetate, the organic extracts washed with 3 × 100 ml. of water and dried over Na2SO4. Evaporation of the dried solution yields 9-cyano-6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one, m.p. 127°-128° C.
Reaction SMILES: CO[C:3]1[C:8]([C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)=[CH:7][N:6]([C:15]2[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[C:5](=O)[C:4]=1[C:24]#[N:25].[OH2:26].[NH2:27][NH2:28].C(O)C>O1CCCC1>[NH2:25][C:24]1[C:4]2[C:5](=[O:26])[N:6]([C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]#[N:22])[CH:7]=[C:8]([C:9]3[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=3)[C:3]=2[NH:28][N:27]=1
Reactant: COc1c(-c2ccn(C)n2)cn(-c2ncccc2C#N)c(=O)c1C#N
Reactant: NN
Reactant: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccc(-c2cn(-c3ncccc3C#N)c(=O)c3c(N)n[nH]c23)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A mixture of 4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-2H-[1,2′-bipyridine]-3,3′-dicarbonitrile obtained in Step E (0.12 g), hydrazine monohydrate (0.087 g), ethanol (10 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 2 hr. The solvent was evaporated under reduced pressure, to the residue was added a mixed solvent (5 mL) of ethanol/ethyl acetate=1/1, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (0.069 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]([CH3:33])[CH3:32])[CH:26]=C3)[CH:21]=1)=[O:16])[CH3:13]>ClCCl>[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:30]=[C:29]3[C:28](=[CH:24][CH:23]=2)[N:27]([CH:31]([CH3:32])[CH3:33])[CH:26]=[C:2]3[CH:1]=[O:5])[CH:21]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cn(-c2ccc3c(ccn3C(C)C)c2)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)c(C=O)cn3C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To anhydrous dichloromethane (30 mL) was added oxalyl chloride (0.03 mL, 0.36 mmol). N,N-dimethylformamide (0.03 mL, 0.36 mmol) was added at 0° C., which was then stirred for 30 min at 0° C. To this solution was added 1-(1-isopropylindol-5-yl)-imidazole-4-carboxylic acid ethyl ester (0.09 g, 0.3 mmol) obtained in Preparation 27, and the mixture was stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (30 mL) and 20% aqueous ammonium acetate solution (30 mL) were added to the residue, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.09 g, 92% Yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]#[CH:12])=O)=[CH:4][CH:3]=1.[BrH:13]>C(OCCC)(=O)C>[Br:13][CH2:12][C:11]1[C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:8][CH:10]=1
Reactant: C#CCS(=O)c1ccc(C)cc1
Reactant: Br
Solvent: CCCOC(C)=O
Product: Cc1ccc2scc(CBr)c2c1
Temperature: 100 °C
Yield: 88 %

Procedure:
In 445 mL of propyl acetate, was dissolved the compound obtained in Example 11 (29.7 g, 167 mmol). The resulting solution was heated at 100° C. for 1 hour. The solution was then cooled with ice to keep the internal temperature of the reaction system at 10° C. To the cooled solution, was added 22.8 mL of a 48% hydrobromic acid. The obtained mixture was allowed to stand under cooling with ice for 1 hour and 30 minutes. The aqueous layer was separated, and the organic layer was washed with 50 mL of water, dried with magnesium sulfate, vacuum concentrated and dried to obtain 35.3 g of a brown transparent oil 3-(bromomethyl)-5-methylbenzo[b]thiophene. (yield=88%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH2:19][C:20]3=[O:25])[CH:13]=[CH:14][CH:15]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH:19]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[C:20]3=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCc2c1cccc2-c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2Cc3c(cccc3-c3cccc(Cl)c3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.49 mL, 0.98 mmol) was added to a solution of 4-(3-chlorophenyl)-2,3-dihydro-1H-inden-1-one (235 mg, 0.97 mmol) in THF (3.3 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (229 mg, 1.0 mmol) in THF (1.7 mL) was added via cannula. After 1 h at −78° C., the mixture was allowed to slowly warm to 0° C. After 1 h at 0° C., the reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→30% EtOAc/hexanes, gradient) to afford 20 mg (5%) of methyl 4-((4-(3-chlorophenyl)-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.C[N:19](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:54])=[C:40]([C@@:42]2([CH3:53])[NH:47][C:46](=S)[C@:45]([F:50])([CH3:49])[CH2:44][C:43]2([F:52])[F:51])[CH:41]=1.C(N(CC)C(C)C)(C)C.N>CN(C=O)C.C(OCC)(=O)C>[NH2:19][C:46]1[C@:45]([F:50])([CH3:49])[CH2:44][C:43]([F:52])([F:51])[C@:42]([C:40]2[CH:41]=[C:36]([NH:35][C:8](=[O:10])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:37]=[CH:38][C:39]=2[F:54])([CH3:53])[N:47]=1
Reactant: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=S
Reactant: O=C(O)c1ccc(F)cn1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.6 %

Procedure:
5-fluoropicolinic acid (269 mg, 1.906 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo-[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (797 mg, 2.10 mmol) were placed in a round bottom flask, dissolved in DMF (5.2 mL), and stirred at room temperature for 5 min. (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (292 mg, 0.953 mmol) was added followed by N,N-diisopropylethylamine (830 μl, 4.77 mmol) and the reaction was stirred at room temperature for 5 min. The reaction was diluted with ethyl acetate (50 mL) and washed with a mixture of water (25 mL) and saturated aqueous NH4Cl (25 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The intermediate 5-fluoro-N-(4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)picolinamide was purified using a CombiFlash system (40 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40). The intermediate (225 mg, 0.523 mmol) was split in two equal portions and placed in two separate reaction vials. Ammonia (14.6 mL, 102 mmol, 7 M in methanol) was also split in two equal portions and added to the two vials. The vials were capped and heated to 65° C. using an oil bath. After 6 h stirring at this temperature the reactions were allowed to cool to room temperature, the mixtures were combined and concentrated under reduced pressure. The crude material was subjected to silica-gel chromatography (eluent; heptane:ethyl acetate=50:50→0:100) to afford N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-fluoropico linamide (124 mg, 57% yield).
Reaction SMILES: C(OC)(OC)OC.[CH2:8]([C@H:11]([NH2:15])[C:12]([OH:14])=[O:13])[CH2:9][NH2:10].Cl.[C:17](#N)[CH3:18]>CO>[CH3:17][C:18]1[NH:10][CH2:9][CH2:8][C@@H:11]([C:12]([OH:14])=[O:13])[N:15]=1
Reactant: CC#N
Reactant: NCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CO
Solvent: COC(OC)OC
Product: CC1=N[C@H](C(=O)O)CCN1

Procedure:
60 ml of trimethyl orthoformate are dissolved in 400 ml of methanol, and reacted with 30 g of L-diaminobutyric acid×2 HCl at 55° C. with constant stirring. After a reaction time of 2 hours, the solvent is evaporated under reduced pressure, the crude product which remains is dissolved in 50 ml of demineralized water, and the solution is neutralized using NaOH. The compound is subsequently purified on an ion retardation column type BIORAD® AG11A8 (Bio-Rad Laboratories GmbH, Munich, Germany) using demineralized water as the eluent, and the product is dried and recrystallized from methanol. The compound obtained can be identified by means of high-pressure liquid chromatography (HPLC); (for example E. Merck, Darmstadt, Germany, LiChroCART® 125-NH2 5μ, eluent: 80% acetonitrile), and is characterized by the following 13C-NMR data:
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13][C:14]([O:23][OH:24])([CH2:16][CH2:17][C:18]([CH3:22])([O:20]O)[CH3:19])[CH3:15].S([O-])([O-])=O.[Na+].[Na+]>>[C:1]([O:24][O:23][C:14]([CH3:15])([CH3:13])[CH2:16][CH2:17][C:18]([OH:20])([CH3:22])[CH3:19])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(CCC(C)(C)OO)OO
Reactant: CC(C)(C)CCCCCC(=O)Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)CCCCCC(=O)OOC(C)(C)CCC(C)(C)O
Yield: 55.1 %

Procedure:
Reacting neodecanoyl chloride with 2,5-dimethyl-2,5-dihydroperoxyhexane followed by reducing the intermediate product with a buffered sodium sulfite solution employing the same procedure as used in preparation of C-5 resulted in the preparation of 4-hydroxy-1,1,4,4-tetramethylbutyl peroxyneodecanoate. The liquid product had an assay of 91.7% and was obtained in a corrected yield of 55.1%. An infrared spectrum of the product showed a broad OH band centered at 3300 to 3500 cm-1.