Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[NH:12][C:11]1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[NH:12][C:11]1=[S:42])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=S
Yield: 57.1 %

Procedure:
2,2-Bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (7.8 g) and Lawesson's reagent (7.8 g, 1.2 eq.) were suspended in toluene (100 ml). The reaction mixture was refluxed for four hours. The mixture was then evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=0-80%) to give 2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (4.6 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:33]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:33][N:19]([CH:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1CCC2N(C)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.18 g) and methyl iodide (85 mg) in DMF (3 ml) was added K2CO3 (0.12 g). After being stirred for 16 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.13 g). MS (m/z): (M+ +1) NMR (CDCl3, δ): 2.02-2.28 (1H, m), 2.44 (3H, s), 2.64-3.17 (3H, m), 3.82 (5H, s), 4.60 (1H, br), 6.73 (1H, d, J=7.9 Hz), 7.08-7.32 (2H, m), 7.32-7.48 (6H, m), 7.58-7.72 (4H, m)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[CH:16]1([NH:21][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1Cl
Yield: 59 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.6 g, 5.5 mmol), cyclopentylamine (0.54 mL, 5.5 mmol) and triethylamine (1.1 mL, 7.8 mmol) were reacted to form the desired product (1.1 g, 59%). LC-MS m/z 339(M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([C:19]([OH:21])=[O:20])[C:17]=1[OH:18])[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].S(=O)(=O)(O)O.[OH-].[Na+].[CH2:29](O)[CH2:30][CH3:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([C:19]([O:21][CH2:29][CH2:30][CH3:31])=[O:20])[C:17]=1[OH:18])[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]
Reactant: CCCO
Reactant: O=C(Nc1cc(Br)c(O)c(C(=O)O)c1)c1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCOC(=O)c1cc(NC(=O)c2ccccc2O)cc(Br)c1O
Yield: 54.5 %

Procedure:
3'-Bromo-5'-carboxy-2,4'-dihydroxybenzanilide (1.0 g.) described in Example 4 was dissolved in n-propanol (50 ml.), and after adding conc. sulfuric acid (1 ml.) the solution was refluxed for 8 hours. After neutralizing with sodium hydroxide solution, the reaction solution was evaporated to dryness and the residue was washed with 5% sodium bicarbonate solution and recrystallized from aqueous acetone to give 3'-bromo-2,4'-dihydroxy-5'-n-propyloxycarbonylbenzanilide (0.61 g.). Yield: 54.5% Melting point 198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:15][C:4]1[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 500 mg, 1.6 mmol) in CH2Cl2 (10.0 ml) was added triethylamine (0.7 ml, 4.0 mmol) followed by isonicotinoyl chloride hydrochloride (707.7 mg, 4.8 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-{4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-yl}isonicotinamide (11, 392.5 mg) as white solids in 59% yield: 1H NMR (500 MHz, DMSO-d) δ 13.1 (s, 1 H), 8.81 (d, J=5.7 Hz, 2 H), 8.50 (s, 1 H), 8.41 (s, 1 H), 8.36 (s, 1H), 8.00 (d, J=5.7 Hz, 2 H), 7.41 (s, 2 H), 7.30 (s, 1 H), 2.13 (s, 6 H). ESI-MS: m/z 420.2 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Pb+2:5].[C:6]([O-:9])(=[O:8])[CH3:7].[CH:10]1[CH:15]=[C:14]2[CH:16]=C[CH:18]=[C:19](C([O-])=O)[C:13]2=[CH:12][CH:11]=1.[K+]>O>[CH:11]1[CH:12]=[C:13]2[C:14]([CH:16]=[C:2]([C:1]([O-:4])=[O:3])[CH:18]=[CH:19]2)=[CH:15][CH:10]=1.[CH:11]1[CH:12]=[C:13]2[C:14]([CH:16]=[C:7]([C:6]([O-:9])=[O:8])[CH:18]=[CH:19]2)=[CH:15][CH:10]=1.[Pb+2:5]
Reactant: O=C([O-])c1cccc2ccccc12
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Pb+2]
Solvent: O
Product: O=C([O-])c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
On the other hand, 38 g of stannous chloride, 26 g of lead acetate and 200 g of water were charged into a 500 ml beaker equipped with a stirrer and the metal salts were dissolved into the water with stirring. This aqueous solution of the metal salts was added to the aforesaid aqueous solution of potassium naphthenate and a double decomposition reaction was then carried out for 1 hour at 30° C. The reaction mixture was dehydrated, dried and then extracted with toluene. The residue was heated under a reduced pressure of 10 mm Hg to distill off the toluene whereby stannous and lead naphthenates were obtained which had a tin content of 13.2% by weight and a lead content of 9.2% by weight.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:25])[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[O:15][CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:29][CH2:30][OH:31]>O1CCOCC1>[CH2:1]([C:5]1[C:6](=[O:25])[N:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:8]2[C:13]([C:14]=1[O:15][CH2:16][CH2:17][O:18][CH2:29][CH2:30][OH:31])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(OCCO)c2cccnc2n(-c2ccccc2)c1=O
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCc1c(OCCOCCO)c2cccnc2n(-c2ccccc2)c1=O

Procedure:
To a mixture of 6.8 g. of 3-(n-Butyl)-4-(2-hydroxyethoxy)-1-phenyl-1,8-naphthyridin-2(1H)one and 150 ml of anhydrous dioxane is added 0.8 g. of sodium hydride (60% oil dispersion) with stirring. The reaction mixture is stirred and warmed on a steam bath for 30 minutes, followed by dropwise addition of 2.6 g. of 95% 2-bromoethanol. The reaction mixture is stirred and refluxed for 24 hours, the solvent is removed in vacuo and the residual solid is dissolved in chloroform. The chloroform solution is successively washed with water, 0.5N sodium hydroxide and water, the organic layer is dried over magnesium sulfate, filtered and concentrated to dryness to yield the product of this example.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=2)[O:10][C:9]=1[CH3:21].O.[NH2:23][NH2:24]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:16]2[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=2[OH:10])=[N:23][NH:24][C:9]=1[CH3:21]
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccccc1Br
Reactant: NN
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccccc1Br

Procedure:
This compounds was synthesised in the same manner as described above. 3-(2-Bromo-phenyl)-6-chloro-7-hydroxy-2-methyl-chromen-4-one (2.5 g, 6.9 mmol), Hydrazine hydrate (10 ml). 4-[4-(2-Bromo-phenyl)-5-methyl-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol precipitated out as an off white solid (0.53 g, 20.2%); Rf 0.5 cf SM 0.85 [ethyl acetate/petroleum ether 40–60° C. (80/20)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1>[CH3:30][O:31][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: CO
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(-c4ccccc4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and methanol in dioxane. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13](=N)N)=[CH:7][CH:6]=1.BrC[CH2:18][CH2:19][Cl:20]>O>[Cl:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:8]1[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=1
Reactant: N=C(N)SCc1ccncc1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1ccncc1
Temperature: 83 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (97 cc) is added dropwise, in the course of 15 minutes and whilst keeping the temperature below 14° C., to a solution of 2-(pyrid-4-yl-methyl)-isothiourea dihydrochloride (116.5 g) in distilled water (240 cc). After heating for 20 minutes at 83° C. and then cooling to 12° C., a 10 N aqueous solution of sodium hydroxide (60 cc) and then 1-bromo-3-chloropropane (81.5 g) are added, whilst stirring, and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (430 cc in total); the organic extracts are combined, washed with distilled water (250 cc) and dried over anhydrous sodium sulphate. After filtration, the solution obtained is poured onto neutral silica gel (125 g) contained in a column of diameter 3.2 cm; the column is then eluted with methylene chloride (1600 cc). The first fraction (400 cc) is discarded; the second fraction (1200 cc) is collected and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. Pyrid-4-yl-methyl 3-chloropropyl sulphide (81 g) is thus obtained in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)[C:13]([Cl:27])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionic acid (240 mg, 0.65 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 376 μL, 0.75 mmol) which produced gas evolution and was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 2 mL and then another portion of methylene chloride (˜2 mL) was added to produce a roughly 0.16 M solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride which was used.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:42](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:42])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(N)=O)cc3OC)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-156), 0.05 g (0.13 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.03 mL (0.16 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes, 0.010 g (0.16 mmole) of ammonium chloride was added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 0.012 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl-amino)-3-methoxy-benzamide (I-157).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[NH:11][C:10]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH3:25])[C:10]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1[nH]c2ccc(C)cc2c1Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Sc2ccc(Cl)cc2)c2cc(C)ccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Compound 7 (200 mg, 0.6 mmol) was added in portions to a mixture of sodium hydride (60 mg, 1.2 mmol) in DMF (5 mL) at 0° C. After 15 min, methyl iodide (50 μL, 0.9 mmol) was added and the mixture was stirred for 1 h. The reaction was allowed to warm to rt and stirred overnight under N2. The reaction mixture was then quenched with ice water and extracted with EtOAc. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 50% EtOAc-hexanes to provide 166 mg (63%) of product 4 as an off white solid, mp 110-111° C. 1H NMR (300 MHz, DMSO-d6) δ 2.35 (s, 3H), 3.83 (s, 3H), 4.00 (s, 3H), 7.06 (d, J=9 Hz, 2H), 7.23-7.29 (m, 4H), 7.63 (d, J=9 Hz, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.79; H, 4.64; N, 3.98; S, 9.05; Cl, 10.03.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH2:13][C@H:14]([CH2:19][NH2:20])[CH2:15][C:16]([OH:18])=[O:17])[CH3:12]>C1COCC1>[C:1]([NH:20][CH2:19][C@@H:14]([CH2:13][CH:11]([CH3:12])[CH3:10])[CH2:15][C:16]([OH:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C[C@H](CN)CC(=O)O
Solvent: C1CCOC1
Product: CC(C)C[C@H](CNC(=O)c1ccccc1)CC(=O)O
Reaction time: 18 h
Yield: 47 %

Procedure:
Benzoyl chloride (0.88 ml, 7.6 mmol) was added to a stirred suspension of pregabalin (1.0 g, 6.3 mmol) in THF (80 ml) at room temperature under argon and the reaction mixture was stirred for 18 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was chromatographed (SiO2, heptane-ethyl acetate, 1:1 to 3:7) to give 4 (0.78 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:13][C:12](=O)[CH2:11][C@H:10]1[C:15](OCC1C=CC=CC=1)=O)=[O:8])=[O:4].Cl.Cl.Cl.[F:31][C:32]1([F:83])[C:44]2[CH:43]=[C:42]([C:45]3[CH:46]=[CH:47][C:48]4[N:52]=[C:51]([C@@H:53]5[CH2:57][CH2:56][CH2:55][N:54]5[C:58](=[O:71])[C@@H:59]([NH:66][C:67](=[O:70])[O:68][CH3:69])[CH:60]5[CH2:65][CH2:64][O:63][CH2:62][CH2:61]5)[NH:50][C:49]=4[CH:72]=3)[CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][C:35]([C:73]1[NH:77]C([C@@H]3CCCN3)=[N:75][CH:74]=1)=[CH:36][CH:37]=2>>[CH3:69][O:68][C:67](=[O:70])[NH:66][C@@H:59]([CH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1)[C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]1[NH:50][C:49]2[CH:72]=[C:45]([C:42]3[CH:41]=[CH:40][C:39]4[C:38]5[C:33](=[CH:34][C:35]([C:73]6[NH:77][C:15]([C@@H:10]7[CH2:11][CH2:12][CH2:13][N:9]7[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:25]([CH3:26])[CH3:27])=[N:75][CH:74]=6)=[CH:36][CH:37]=5)[C:32]([F:83])([F:31])[C:44]=4[CH:43]=3)[CH:46]=[CH:47][C:48]=2[N:52]=1)=[O:71]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate, except that methyl (S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride. MS (ESI) m/z 879.88 [M+H]+. (122 mg, 52%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=1.O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccnc1-n1cc(I)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 243 mg, 6.07 mmol) was suspended in 4 mL anhydrous N,N-dimethylformamide. To this solution was added 4-iodo-1H-pyrazole (982 mg, 5.06 mmol) in 4 mL anhydrous N,N-dimethylformamide at 0° C. under nitrogen. The mixture was stirred at 0° C. for 15 min, and then allowed to warm to ambient temperature and stirred at the same temperature for 2 hrs. After this period of time, a solution of 2-chloro-3-trifluoromethyl-pyridine (1.01 g, 5.56 mmol) in 4 mL N,N-dimethylformamide was added and the mixture was heated at 90° C. for 5 hrs. After cooling off, the mixture was poured into water and extracted with ethyl acetate three times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-(4-iodo-pyrazol-1-yl)-3-trifluoromethyl-pyridine as a white solid (1.406 g, 74% yield). The product was used for the next step without purification. 1H-NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H, J=4.80, J=8.08), 7.79 (s, 1H), 8.21 (dd, 1H, J=1.52, J=8.08), 8.27 (s, 1H), 8.67 (dd, 1H, J=1.52, J=4.80).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH3:22][C:23]1([CH3:31])[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][C:24]1=[O:30].CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O.CN(C)C=O.ClCCl>[OH:30][C:24]1[C:23]([CH3:31])([CH3:22])[CH2:28][CH2:27][C:26](=[O:29])[C:25]=1[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:6]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
The resulting 2-methyl-6-trifluoromethylnicotinic acid (1.026 g, 0.005 mol) is dissolved in 20 ml of oxalyl chloride. Three drops of dimethylformamide are added and the mixture is refluxed for 1 hour. The mixture is then concentrated on a rotary evaporator and the residue (2-methyl-6-trifluoromethylnicotinoyl chloride) is taken up in 100 ml of methylene chloride. At a temperature of 0° C., 1.6 ml (0.0115 mol) of triethylamine and 0.7 g (0.005 mol) of 4,4-dimethylcyclohexane-1,3-dione are added. After 2 hours at a temperature of 22° C., the solvent is removed on a vacuum rotary evaporator, the residue which remains is dissolved in 55 ml of acetonitrile, and 0.15 ml (0.0016 mol) of acetone cyanohydrin and 0.79 ml (0.0057 mol) of triethylamine are added in order to subject the intermediate to a rearrangement reaction. After the reaction solution has been stirred for 4 hours at room temperature, it is evaporated. The syrup which remains is chromatographed on silica gel. Elution with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) gives a pale yellow viscous oil (Rf 0.39 on the abovementioned mixture as mobile phase), which is dissolved in dichloromethane and washed in succession with 75 ml of 5% hydrochloric acid and 75 ml of water. Evaporation to dryness of the organic solution which has been dried with Na2SO4 yields 1.05 g (63%) of pure 3-hydroxy-4,4-dimethyl-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-2-enone in the form of white crystals of melting point 75-77° C.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:8]=[O:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.CCOCC>[CH3:1][C:2]([CH3:10])([CH:8]1[O:13][CH2:12][CH2:11][O:9]1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: OCCO
Reactant: COC(=O)CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CC(C)(C)C1OCCO1
Yield: 94 %

Procedure:
Methyl 3,3-dimethyl-4-oxobutanoate (10 g, 70 mmol), prepared according to the procedure of Hudlicky et al., Synth. Commun., 16 169 (1986), was dissolved in 40 mL of benzene, followed by addition of ethylene glycol (20 mL), and p-toluenesulfonic acid monohydrate (1.3 g). The reaction was refluxed with azeotropic removal of water for 1 hour. The reaction was poured into 200 mL of ether, washed with saturated sodium bicarbonate, water and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4 g (94%) of the title compound.