Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]N)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:40](=[CH:41][CH:42]=1)[NH:43][C:22]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[C:21]2[CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:33])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 555.6 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C[O:12][C:13](=[O:28])[CH:14]([O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24]Br)[CH:17]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][CH:14]([O:26][CH3:27])[C:13]([OH:28])=[O:12])[CH:21]=[CH:20][CH:19]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Reactant: CC(C)c1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCOc2ccccc2C(C)C)c1)C(=O)O

Procedure:
The title compound was prepared from 2-isopropyl-phenol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C21H26O5 [M−H]−:357.2.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[N:4]1.C[Sn](C)(C)[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]2)=[CH:19][C:18]=1[F:34]>>[OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]4)=[CH:19][C:18]=3[F:34])=[CH:10][CH:9]=2)=[N:4]1
Reactant: OC[C@H]1COC(c2ccc(Br)cc2)=N1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(C4=N[C@@H](CO)CO4)cc3)c(F)c2)CO1

Procedure:
The same procedure as in Example 1 was conducted, except for adding 4-(4 (S)-hydroxymethyl-4,5-dihydro oxazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
Reaction SMILES: O[C:2]1([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.IC1C=C(C2CC(=O)NC3C=C(C#CC4C=CC=CC=4)C=CC=3N=2)C=CC=1.C(C1(O)CCOCC1)#C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:5]1[CH2:4][CH:3]=[C:2]([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4(O)CCOCC4)cc3NC(=O)C2)c1
Agent: C#CC1(O)CCOCC1
Agent: O=C1CC(c2cccc(I)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCOCC4)cc3NC(=O)C2)c1

Procedure:
Prepared from 3-[7-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile [prepared from 4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4)diazepin-2-one (Example 11) (387 mg, 1.0 mmol) and 4-ethynyl-tetrahydro-pyran-4-ol [CAS-No. 57385-16-7] (315 mg, 2.5 mmol) according to the general procedure F. Obtained as a yellow solid (296 mg)] (50 mg, 0.13 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (16 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[O:11][C:12]=1[C:13]#[N:14].[C:19](=[N:32][NH2:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O=[Si]=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:13]([C:12]1[O:11][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]=1[NH:33][N:32]=[C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:14]
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(Br)c(C#N)o1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NN=C(c2ccccc2)c2ccccc2)c(C#N)o1
Temperature: 102 °C
Reaction time: 45 h
Yield: 82.9 %

Procedure:
Palladium acetate (2.098 g; 9.347 mmol), DPPF (10.36 g; 18.69 mmol) and cesium carbonate (85.27 g; 0.262 mmol) were charged in a dry reaction flask under argon. A preformed dry solution of methyl 4-bromo-5-cyano-2-furoate (43.00 g, 0.187 mol) and benzophenone hydrazone (44.02 g, 0.224 mol) in 1.2 L of toluene was transferred via cannula into the reaction flask. The resulting suspension was vigorously stirred at 100-104° C. for 45 hours under argon. The reaction mixture was cooled to about 70° C., added with 65 g of Dicalite® and filtered; the panel was washed twice with hot toluene (400 mL). The filtrate was concentrated under vacuum to a small volume and kept at +4° C. for 18 hours. The solid was collected by filtration and washed with 60 mL of toluene to yield 53.52 g of yellowish product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br.O>C(Cl)Cl>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:18]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O

Procedure:
206 g (0.83 mol) of 1-(3,5-di-tert.butyl-4-hydroxyphenyl)ethanone were dissolved in 415 ml of methylene chloride while stirring, the solution was heated to boiling, and 144 g (0.9 mol) of bromine were added dropwise over the course of 30 minutes. The mixture was then refluxed for a further 2 hours and cooled, 400 ml of water were added, and the organic phase was separated off and dried over sodium sulfate. After the solvent had been removed under reduced pressure, the solid crude product obtained was recrystallized from 540 ml of methylcyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:13])=[O:12])[C:8]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CC1C=C(Cl)C(S(C)(=O)=O)=CC=1C(O)=O.OO.O=S(Cl)Cl.[NH2:39][C:40]([NH2:42])=[NH:41]>>[NH2:41][C:40]([NH2:42])=[N:39][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([S:14]([CH3:17])(=[O:16])=[O:15])[C:9]([S:11]([CH3:13])=[O:12])=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(S(C)=O)c(S(C)(=O)=O)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: OO
Solvent: O=S(Cl)Cl
Product: Cc1cc(S(C)=O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
Analogously to Example 1, by reaction of 1.3 g of 2-methyl-4-methylsulfinyl-5-methylsulfonylbenzoyl chloride [obtainable by reaction of 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with Na methanethiolate, subsequent partial oxidation with hydrogen peroxide and conversion into the acid chloride, e.g. with SOCl2 ] with guanidine, N-diaminomethylene-2-methyl-4-methylsulfinyl-5-methylsulfonylbenzamide is obtained after customary working up and recrystallization from diethyl ether.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1>>[Cl:23][C:17]1[CH:16]=[C:15]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: N#Cc1ccc(S(=O)(=O)Cl)cc1Cl

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-amino-2-chloro-benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])/[C:24]#[N:25])=[C:19]([F:35])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:35])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(F)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 44.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(2,3-difluoro-phenyl)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 62a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 44%).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH3:22])=O.O.[NH2:24][NH2:25]>CN(C1C=CN=CC=1)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:25][N:24]=2)=[C:15]([CH3:22])[CH:16]=1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(C)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Yield: 41.3 %

Procedure:
Prepared as in Example 104 from [2-fluoro-3-(trifluoromethyl)phenyl](4-methoxy-2-methylphenyl)methanone (1.34 g, 4.90 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.620 g) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Solvent: ClCCl
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.58 h
Yield: 69.9 %

Procedure:
(2R,5R)-2-Hydroxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (25 g, 68 mmol) in DCM (823 mL) was cooled to 4° C. (ice bath). 1,8-bis(dimethylamino)naphthalene (72 g, 337 mmol) was added in one portion followed by trimethyl oxonium tetrifluoroborate (50 g, 337 mmol) portionwise over 5 min. The mixture was stirred for 35 min at 5° C., the ice bath removed, then warmed from 5-17° C. over 1 h. After stirring for a further 20 min., saturated aqueous ammonium chloride (300 mL) was added slowly and reaction stirred for 10 min. The organic layer was separated and the aqueous phase extracted with DCM (2×300 mL). The combined organic extracts were washed with 1.0 M HCl (3×1.5 L), saturated sodium bicarbonate solution (3×1.5 L), dried over sodium sulfate, filtered and concentrated. The oil was dissolved in DCM and petrol added until precipitation of 1,8-bis(dimethylamino)naphthalene occurred. Purification by column chromatography (silica gel, 0-0%, 0-100%, EtOAc/petrol) gave an oil which contained 1,8-bis(dimethylamino)naphthalene as a contaminant. The remaining 1,8-bis(dimethylamino)naphthalene was captured during filtration through a SCX-2 column eluting with MeOH, to give the title compound (18 g, 52% over two steps) as a pale yellow oil. 1H NMR (Me-d3-OD): 7.46-7.26 (5H, m), 5.26-5.07 (2H, m), 4.31 (2H, d), 4.04-3.85 (1H, m), 3.79 (1H, d), 3.46 (2H, s), 3.28-3.09 (2H, m), 1.48 (9H, s), 1.15 (3H, dd).
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=O)C>Cl>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Br:14])=[CH:7][C:6]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Yield: 72.8 %

Procedure:
A mixture of 2-acetamido-5-bromo-3-nitrobenzotrifluoride (400 mg, 1.258 mmol) in concentrated HCl (3.5 mL) was refluxed overnight, then it was extracted by ethyl acetate (2×3 mL). The extract was dried over Mg2SO4 and evaporated to give 261 mg (75.6%) of 2-amino-5-bromo-3-nitrobenzotrifluoride. 1H NMR (CDCl3): δ 6.663 (S, 2H); 7.825 (d, 1H, J=1.2 Hz); 8.487 (d, 1H, J=1.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[P:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P:18](Cl)Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([P:11]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[P:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)c1ccccc1P(Cl)Cl
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Fc1ccc(P(c2ccc(F)cc2)c2ccccc2P(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A THF solution (26.6 mL, 1.03 M, 27.40 mmol) of p-fluorophenylmagnesium bromide was added to a mixture of 1,2-bis(dichlorophosphino)benzene (0.96 g, 3.43 mmol) and THF (20 mL) in an argon atmosphere at −78° C. After warming to room temperature, the mixture was allowed to react overnight at 60° C. The reaction mixture was cooled to ambient temperature, and the solvent was removed under reduced pressure; subsequently, CH2Cl2 (30 mL) was added. 1N aqueous solution of hydrochloric acid (20 mL) was added to the reaction mixture, and the aqueous layer was extracted three times with CH2Cl2. The moisture contained in the combined organic extract was removed with magnesium sulfate, and the extract was filtered. After removing the solvent under reduced pressure, the resulting yellow oily substance was triturated with methanol to give a white powder, and the white powder was washed two times with methanol, giving the title compound as a white powder (1.10 g, yield 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1B(O)O.[OH:12]O.[OH-].[Na+]>O1CCCC1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:12]
Reactant: OO
Reactant: OB(O)c1cc(I)ccc1F
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: C1CCOC1
Product: Oc1cc(I)ccc1F
Reaction time: 0.17 h

Procedure:
To a cooled solution of 2-fluoro-5-iodophenylboronic acid in tetrahydrofuran (200 mL) at 0° C. add an aqueous solution of 30% hydrogen peroxide (9.92 mL, 103 mmol) dropwise, stir 10 min, and add an aqueous 4 N solution of sodium hydroxide (1.78 mL, 7.12 mmol). Warm the reaction to room temperature and stir overnight. Add manganese dioxide (250 mg) to the reaction, stir 90 min and filter through fluted filter paper. Concentrate and partition the residue between diethyl ether and water. Separate the layers and sequentially wash the organic layer with water and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Purify the resulting tan oil by silica gel chromatography, eluting with a gradient of 0:100 to 30:70 ethyl acetate:hexanes, to give the title compound as a yellow waxy solid (18.1 g, 65%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([OH:13])[CH:6]=1.C[O:16][C:17](=O)[CH2:18][C:19]1[O:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[N:22][N:23]=1.N1CCCCC1>C1C=CC=CC=1.C(#N)C>[F:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]2[C:8]([CH:9]=[C:18]([C:19]3[O:20][C:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[N:22][N:23]=3)[C:17](=[O:16])[O:13]2)=[CH:11][CH:12]=1
Reactant: CN(CCF)c1ccc(C=O)c(O)c1
Reactant: COC(=O)Cc1nnc(-c2cccs2)o1
Solvent: C1CCNCC1
Solvent: CC#N
Solvent: c1ccccc1
Product: CN(CCF)c1ccc2cc(-c3nnc(-c4cccs4)o3)c(=O)oc2c1
Yield: 18.6 %

Procedure:
40 mg (ca. 0.2 mmol) crude 4-[(2-Fluoro-ethyl)-methyl-amino]-2-hydroxy-benzaldehyde and 30 mg (0.13 mmol) (5-thiophen-2-yl-[1,3,4]oxadiazol-2-yl)-acetic acid methyl ester are dissolved under argon in 4 mL benzene and 2 mL acetonitrile, treated with 0.03 mL (2 eq.) piperidine and heated to reflux for 1 h. The reaction mixture is allowed to reach room temperature, evaporated, and the residue column chromatographed (silica gel, AcOEt/petroleum ether 1:1). The fluorescent, yellow product is triturated in diisopropylether, then dried under high vacuum to yield 9 mg (19%) desired product as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH:9]=[CH:10][O:11][C:6]=2[CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])([CH3:35])[CH3:34]>C(Cl)Cl>[O:8]1[C:7]2[CH:12]=[CH:13][C:4]([C:2]3[O:3][C:44](=[O:45])[C:43]([S:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[CH:33]([CH3:34])[CH3:35])=[C:47]([OH:48])[CH:1]=3)=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc2c(c1)OC=CO2
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc3c(c2)OCCO3)oc1=O

Procedure:
The title compound was prepared by Method A using 1,4-benzodioxin-6-yl methyl ketone (2 g, 11.22 mmol), trimethylsilyl triflate (2.5 g, 11.22 mmol), triethylamine (2.27 g, 22.44 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.73 g, 5.61 mmol). m.p. 246-248° C.; 1H NMR (400 MHz, DMSO-d6) δ1.25 (d, 6H), 3.4 (m, 1H), 4.32 (m, 4H), 6.72 (s, 1H), 6.89 (d, 1H), 7.01 (d, 1H), 7.06 (t, 1H), 7.11 (t, 1H), 7.26 (d,1H), 7.31 (d, 1H), 7.35 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH2:9][CH2:10]O)[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.S(Cl)(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>C1COCC1.C(#N)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][N:35]3[CH2:36][CH2:37][CH2:38][CH:34]3[CH3:33])[S:8][C:4]=2[CH:3]=1
Reactant: OCCc1nc2ccc(Br)cc2s1
Reactant: C[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CCCN1CCc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of 2-(6-bromo-benzothiazol-2-yl)-ethanol (2.23 g, 8.6 mmol) and triethylamine (2.19 g, 21.6 mmol) in THF (45 mL) was cooled to −20° C., and mesyl chloride (1.58 g, 13.8 mmol) was added at −20 to −10° C. The mixture was warmed to room temperature and stirred for 2 hr. Potassium carbonate (1.79 g, 13 mmol), 2-(R)-methylpyrrolidine hydrochloride (2.1 g, 17.2 mmol) and acetonitrile (40 mL) were added to the mixture, and the mixture was stirred at 60° C. for 18 hr. Solvents were removed and the residue was dissolved in 45 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride was concentrated to oil and purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give 6-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (2.48 g, 88.3% yield). H NMR (CDCl3, 400 MHz) δ 1.12 (d, 3H, J=7 Hz), 1.41–1.50 (m, 1H), 1.68–1.87 (m, 2H), 1.91–1.99 (m, 1H), 2.24 (q, 1H, J=7 Hz), 2.39–2.48 (m, 1H), 2.56–2.64 (m, 1H), 3.19–3.33 (m, 4H), 7.52 (dd, 1H, J=8, 4 Hz), 7.79 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=4 Hz); 13C NMR(CDCl3, 400 MHz) δ19.3, 22.1, 33.1, 33.9, 52.5, 53.7, 59.9, 117.9, 123.3, 123.7, 128.9, 136.9, 151.3, 170.4; (DCI/NH3) m/z 325, 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][N:21]([CH2:32][CH2:33]O)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:33][CH2:32][N:21]([CH2:20][CH2:19][OH:18])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:15])[CH:7]=[CH:6]2
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)OCCN(CCO)S(=O)(=O)c3ccc(C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.0 g, 21.7 mmol), N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide (16.89 g, 65.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.530 g, 4.34 mmol) in CH2Cl2 (250 mL) and DMF (3 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 4.99 g, 26.05 mmol). The reaction mixture was stirred overnight at room temperature, and then partitioned between CH2Cl2 and HCl (1N). The aqueous layer was washed with CH2Cl2 and the combined organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAC/hexane (1:1) to give the title compound as a thick oil (7.15 g, 15.16 mmol, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.6 Hz, 2H), 7.66 (m, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=2.5, 8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 3.88 (q, J=7.2 Hz, 1H), 3.38 (m, 2H), 3.09 (t, J=5.1 Hz, 2H), 2.44 (s, 3H), 2.18 (t, J=6.0 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 472 (MH+), 489 (M+18+).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C@@:24]([CH3:39])([S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[C:18](=[O:40])[CH:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1>O1CCOCC1>[OH:28][NH:27][C:25](=[O:26])[C@:24]([CH3:39])([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:23][CH2:22][N:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH:6]3[CH2:5][CH2:4][CH:3]([OH:2])[CH2:8][CH2:7]3)=[CH:15][CH:14]=2)=[CH:17][C:18]1=[O:40]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC3CCC(O)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(OC3CCC(O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Yield: 53.8 %

Procedure:
HCl (1.0 N in water, 2.37 mL) was added to a solution of the (2R)-4-[4-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (444 mg, 0.789 mmol) in 1,4-dioxane (5 mL). After 1 hour the reaction was concentrated to give a brown solid. The solid was triturated with ethanol at 50° C., for 30 minutes. After cooling, filtration afforded the title compound as a white solid (203 mg, 54%). LCMS m/z 479.7 (M+1)