Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: OCCCc1ccc(F)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CCCBr)cc1F
Yield: 84.8 %

Procedure:
Compound 53-2 (3.11 g) was dissolved in methylene chloride (60 ml), triphenylphosphine (5.21 g) and N-bromosuccinimide (3.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.6 g) as a yellow oil.
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12](OCC)=[O:13])[CH2:4]3)[CH2:8]2.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[N:26]=[C:2]3[CH:9]4[CH2:10][CH:5]5[CH2:4][C:3]3([CH2:11][CH:7]([CH2:6]5)[CH2:8]4)[C:12]2=[O:13])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C12CC3CC(CC(C3)C1=O)C2
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1N(c2cccc(Cl)c2)N=C2C3CC4CC(C3)CC12C4
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 2-oxoadamantane-1-carboxylate (5) (1.0 g, 4.5 mmol) and 3-chlorophenylhydrazine hydrochloride (3.6 g, 20 mmol) in 40 ml of ethanol is added triethylamine (2.0 g, 20 mmol). The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 20 hours, then heated to reflux for 2 hours. After cooling to ambient temperature, the solvent is removed under reduced pressure and the crude residue solid is dissolved in 30 ml of methylene chloride. The organic extract is washed with 25 ml of diluted hydrochloric acid to remove the excess of 3-chlorophenylhydrazine, then dried over anhydrous magnesium sulfate. The solvent is evaporated to leave the title compound (6) as a dark-colored, viscous oil which is flash-chromatographed on silica gel using ether-pentane (2:8) as the eluent. Subsequent recrystallization from methanol provides the pure product as pale yellow needles melting at 119.5°-120.5° C. Anal. Calcd for C17H17ClN2O: C, 67.88; H, 5.70; N, 9:31; Cl, 11.79. Found: C, 67.54; H, 5.75; N, 9.12; Cl, 11.86.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:14][C:15](=[O:29])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[Cl:28])[CH:9]=[CH:10][C:11]=1[CH2:12]O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([NH:14][C:15](=[O:29])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:19]=2[Cl:28])[CH:9]=[CH:10][C:11]=1[CH2:12][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CO)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCl)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.12 mL (16.440 mmol) thionyl chloride was added to a solution of 1.620 g (4.110 mmol) N-(3-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z32a) in 30 mL toluene and the mixture was stirred for 2 h at 80° C. The reaction mixture was evaporated down i. vac. and the residue recrystallised from ether/petroleum ether. The precipitate was filtered off, washed with petroleum ether and dried in a HV.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][CH:4]([CH2:5][CH2:6]2)[C:3]1=[O:10].C(OO)(=[O:13])C.O.O.O.C([O-])(=O)C.[Na+]>>[CH2:1]=[C:2]1[CH:7]2[CH2:6][CH2:5][CH:4]([CH2:9][CH2:8]2)[C:3](=[O:10])[O:13]1
Reactant: CC(=O)OO
Reactant: C=C1C(=O)C2CCC1CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=C1OC(=O)C2CCC1CC2
Yield: 93.9 %

Procedure:
Analogously to the procedure indicated in Example P1, 955 mg (7 mmol) of 3-methylene-bicyclo[2.2.2]octan-2-one is reacted with 1.64 g (8.4 mmol) of 32% peracetic acid in the presence of 286 mg (21 mmol) of sodium acetate trihydrate. 1 g of 4-methylene-3-oxa-bicyclo[3.2.2]nonan-2-one is isolated. After purification by column chromatography using 10% ethyl acetate in hexane, pure 4-methylene-3-oxabicyclo[3.2.2]nonan-2-one is obtained in the form of an oil.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20].Cl>CCO>[C:16]([C:17]1[CH:18]=[C:19]([NH2:20])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:13])([F:14])[F:2])=[CH:10][CH:9]=2)[N:12]=1)([CH3:23])([CH3:22])[CH3:15]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.83 g, 8.01 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.10 g, 8.81 mmol) in a mixture of conc hydrochloric acid (12 M, 2.0 mL) and EtOH (20 mL) was heated at reflux for 18 hr. The mixture was cooled to RT and was partitioned between aq. NaOH (2.0 M, 50 mL) and ether (100 mL). The organic layer was separated and was washed with brine (100 mL) and then dried and evaporated in vacuo to afford the title compound, Intermediate A27, as a yellow solid (2.22 g, 91%); Rt 2.29 min (Method 2); m/z 300 (M+H)+, (ES+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:14])[F:13])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)Cc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use (2-trifluoromethylphenyl)acetic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (78.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.97, 7.67-7.64, 7.53-7.48, 7.39-7.35, 6.96, 3.91, 3.87-3.67, 3.66-3.6, 3.58-3.51, 1.53-1.46, 0.78-0.64, 0.48-0.42, 0.10-0.06. 13C NMR (75 MHz, CDCl3) δ 168.8, 162.9, 159.9, 145.3, 133.2, 132.0, 131.5, 128.5, 128.2, 127.2, 127.0, 126.3, 126.2, 125.5, 112.3, 45.0, 44.7, 44.2, 41.2, 39.6, 37.13, 37.11, 34.4, 8.6, 4.2. MS (ES+) m/z 462.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].Cl.[F:43][C:44]([F:52])([F:51])[CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:48]3[CH2:49][CH2:50][CH:45]([C:44]([F:52])([F:51])[F:43])[CH2:46][CH2:47]3)=[O:40])=[CH:37][CH:38]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C

Procedure:
Prepare the title compound in a 51% yield by coupling procedure 1 starting from 3′,5′-dichloro-4′-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid and 4-trifluoromethyl-piperidine hydrochloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[C:8]#[N:9])[CH2:3][CH2:2]1.N>CO.[Ni]>[O:1]1[CH2:2][CH2:3][CH:4]([CH:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)[CH2:8][NH2:9])[CH2:5][CH2:6]1
Reactant: N#CC(=C1CCOCC1)c1ccc(C(F)(F)F)nc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC(c1ccc(C(F)(F)F)nc1)C1CCOCC1
Reaction time: 4 h

Procedure:
2-(Dihydro-2H-pyran-4(3H)-ylidene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.04 g, 3.88 mmol) was dissolved in methanol (50 mL) and 7 M NH3 in methanol (20 mL) was added. The solution was flushed with Ar. Raney nickel (0.033 g, 0.39 mmol) was added and mixture hydrogenated on a Parr Apparatus at room temperature for 4 hours. Then filtered through a plug of celite and concentrated in vacuo. The crude product was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(F)cc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[I-:15].[Na+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:15][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: [I-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCC(I)C(=O)O

Procedure:
To 11-bromoundecanoic acid dissolved in acetonitrile (50 ml ) were added sodium iodide (2 g) and tetra-n-butylammonium iodide (1 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give iodoundecanoic acid (0.89 g).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]2)[S:6][CH:7]=1)#[N:2].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>C(#N)C>[C:18]([S:20][C@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[S:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)[CH2:9]1)(=[O:21])[CH3:19]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc(C#N)cs2)C1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@H]1CCN(c2nc(C#N)cs2)C1
Yield: 49.2 %

Procedure:
To a solution of (3R)-1-(4-cyano-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (300 mg, 1.10 mmol) (obtained as described in Reference Example 18(7)) in acetonitrile (9 ml) was added potassium thioacetate (376 mg, 3.30 mmol) at room temperature. The mixture was heated under reflux for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (5:1→1:1) as the eluant to afford (3S)-3-acetylthio-1-(4-cyano-1,3-thiazol-2-yl)pyrrolidine (137 mg, yield 50%) as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:19])[CH3:18]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Oc1cccc(C(=O)O)c1C
Temperature: 40 °C

Procedure:
Acetic acid (8750 mL), 3-hydroxy-2-methylbenzoic acid (3500 g), and sulfuric acid (70 mL) were charged into a 22 liter reactor. The reactor contents were stirred to give a homogeneous mixture. The mixture exothermed to 36° C. Acetic anhydride (2390 mL) was added to the mixture in the 22 L reactor. An exotherm warmed the reactor contents from 36 to 44° C. The reaction mixture was stirred at ambient temperature for two hours (reactor contents allowed to cool slowly). The reaction was tested for complete conversion of the starting material by TLC. The reaction mixture was generally a tan slurry at the completion of the reaction.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:27]=2)[N:19]=[C:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:17]=1>CN(C=O)C>[CH2:7]([O:14][C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:27]=2)[N:19]=[C:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(-c2cncc(-c3cc(Cl)nc(-c4ccccn4)n3)c2)c1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cncc(-c3cc(OCc4ccccc4)nc(-c4ccccn4)n3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium tert-butoxide (2 eq, 18.6 mg) in DMF (1 ml) is added benzyl alcohol (2 eq, 7.2 μl) under an inert atmosphere of argon. After stirring at RT for 15 minutes, the mixture is treated dropwise with a solution of 4-chloro-6-[5-(3-methoxy-phenyl)-pyridin-3-yl]-2-pyridin-2-yl-pyrimidine (1 eq, 31 mg) and then allowed to stir at RT for 5 hours. The reaction is quenched with water (4 ml) and the mixture is extracted with EtOAc. The organic extracts are combined, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is loaded onto a SCX-2 cartridge (1 g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum overnight to afford the title compound [M+H]+=447 as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl.[Cl:20]C1C=CC(Cl)=CC=1C1(CC(N)=[NH:35])CCCC1>>[ClH:20].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][C:17]([NH2:35])=[NH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#CCC1(c2ccc3ccccc3c2)CCCC1
Reactant: N=C(N)CC1(c2cc(Cl)ccc2Cl)CCCC1
Agent: Cl
Product: N=C(N)CC1(c2ccc3ccccc3c2)CCCC1

Procedure:
2-(1-Naphthalen-2-yl-cyclopentyl)-acetamidine hydrochloride (216) (5.0 g, crude) was synthesized as a white solid from (1-naphthalen-2-yl-cyclopentyl)-acetonitrile (215) (5.0 g, 21.27 mmol) following the procedure described for the HCl-salt of 2-[1-(2,5-dichlorophenyl)-cyclopentyl]-acetamidine hydrochloride (203).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:19])[C:11]([CH3:18])=[CH:12][C:13]=2[CH3:17])[O:8]1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:24]([O:23][C:21]([CH2:20][C:7]1([CH3:6])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:19])[C:11]([CH3:18])=[C:12]([S:2]([Cl:1])(=[O:5])=[O:3])[C:13]=2[CH3:17])[O:8]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC1(C)CCc2c(C)cc(C)c(C)c2O1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)Cl)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of chlorosulfonic acid (2.79 ml) in dichloromethane (CH2Cl2) (15 ml) was added dropwise to a solution of ethyl (2,5,7,8-tetramethylchroman-2-yl)acetate (2.90 g) in CH2Cl2 (100 ml) at 0-10° C. over an hour. After stirring at room temperature for 5 hours, the reaction mixture was poured into chilled saturated aqueous sodium hydrogen carbonate (sat. aq. NaHCO3). The separated organic phase was washed with sat. aq. NaHCO3, water, and brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl chloride as a syrup (3.29 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.CCCCC.[I:25]I>O1CCCC1>[I:25][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1I
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of Example 17A (2.16 g, 11.12 mmol) in anhydrous tetrahydrofuran (50 mL) under N2 was cooled to −78° C. and treated dropwise with 1.7 M tert-butyl lithium in pentane (16.35 mL, 27.8 mmol). The mixture was stirred at −78° C. for 15 minutes, warmed to −30° C. and stirred for 2.5 hours. The dark brick-red solution was re-cooled to −78° C. and a solution of iodine (7.06 g, 27.8 mmol) in anhydrous tetrahydrofuran (18.5 mL) was added dropwise over 20 minutes to give a thick reaction mixture that was difficult to stir. The mixture was swirled at −78° C. for 15 minutes, warmed to −30° C., stirred for 40 minutes and warmed to 0° C. The mixture was quenched by addition of H2O (100 mL) and treated with solid Na2SO3 until a constant yellow color was achieved. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated by rotary evaporation. Purification by chromatography on silica eluting with 10%-20% ethyl acetate in dichloromethane afforded the title compound as an amber oil which crystallized upon standing (2.32 g, 65%). MS (DCI+) m/z 321 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[CH:8]=[CH:7]2.[Li]CCCC.CON(C)[C:21](=[O:23])[CH3:22]>C1COCC1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:21](=[O:23])[CH3:22])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CON(C)C(C)=O
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cccc2ccc(Cl)nc12
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
To a solution of 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 10.0 g, 41.2 mmol) in 200 mL THF in a dry ice/acetone bath was added nBuLi solution (2.5 M in hexanes; 18.14 ml, 45.4 mmol) slowly (dropwise) via addition funnel such that the internal temperature did not exceed −72° C. After 15 min, N-methoxy-N-methylacetamide (Aldrich; 5.05 ml, 49.5 mmol) was added via syringe such that the internal temperature did not exceed −72° C. The dry ice/acetone bath was removed and the reaction was quenched with 200 mL saturated aq. NH4Cl and diluted with 300 mL Et2O. The organic layer was washed 1× brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (240 g column) using 0-20% EtOAc/hexanes until less polar impurities elute, then 20-40% EtOAc/hexanes to elute desired material. Fractions were combined and concentrated to give 1-(2-chloroquinolin-8-yl)ethanone (3.63 g, 17.65 mmol, 43% yield) as a peach-colored solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (1H, d, J=8.6 Hz), 8.06 (1H, dd, J=7.2, 1.6 Hz), 7.96 (1H, dd, J=8.0, 1.6 Hz), 7.59-7.66 (1H, m), 7.46 (1H, d, J=8.6 Hz), 2.98 (3H, s). m/z (ESI, +ve) 206.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34](Cl)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:18]=[C:19]([F:26])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:26][C:19]1[CH:18]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:16]=[C:15]([F:14])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(C(F)(F)F)cc2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 23.6 %

Procedure:
4-Trifluoromethylbenzeneboronic acid (50 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (15 mg, 24%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[C@@H:7]([NH:8][C:9](=[O:10])[O:11][CH3:12])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H]1CCNC[C@H]1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 140 %

Procedure:
(3R,4S)-tert-butyl 3-fluoro-4-((methoxycarbonyl)amino)piperidine-1-carboxylate (127 mg, 0.460 mmol) was taken up in DCM (5 mL) and TFA (0.708 mL, 9.19 mmol) was added. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was dissolved in MeOH. The solution was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and the column was rinsed with MeOH, followed by 7N NH3/MeOH to obtain the product. The solvent was removed in vacuo to obtain methyl ((3R,4S)-3-fluoropiperidin-4-yl)carbamate (113.5 mg) as a colorless gum. The crude material was taken onto the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:10](=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:10](=[S:44])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Product: COc1ccc(CCC(=S)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Yield: 94 %

Procedure:
A mixture of N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-(4-methoxyphenylmethyl) acetamide (20 mg, 0.045 mmol) and Lawesson's reagent (25 mg, 0.062 mmol), was taken in a glass vial and mixed thoroughly with magnetic stirbars. The glass vial was then irradiated in a microwave oven (900 W, Whirlpool M401) for 8 min. Upon completion of the reaction, the yellow-colored material was transferred to an ion-exchange column with the aid of methanol (2 ml). The ion-exchange column was subsequently washed with CH2Cl2 (2 ml) and methanol (2 ml) and the product was thereafter eluted from the ion-exchange column (10% NH3 in methanol, 2 ml) to give N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylmethyl thioacetamide (20 mg, 97%) as a white solid; LC-MS: (M+H)+ 459, tr 9.60 min; TLC (CH2Cl2/methanol 20:1) Rf=0.38.