Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>CN(C)C=O.O.ClCCl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([C:28]([N:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:11]2)=[O:29])[CH:31]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1C(=O)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (2.0 g, 10.1 mmol) in dimethylformamide (15 mL) under nitrogen was added potassium carbonate (4.1 g, 29.7 mmol). The mixture was treated dropwise with a solution of crude 5-fluoro-2-methyl benzoyl chloride of Step A (15.0 mmol) in dimethylformamide (10 mL). After stirring at room temperature for 15 minutes, the mixture was diluted with water and stirred to give a solid mass which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give a purple oil. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided 1.88 g of the title product as a foam which was crystallized by sonication from ethanol-hexane, m.p. 138-140° C.
Reaction SMILES: [NH:1]([C:8]1[C:13](I)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]([C:8]1[C:13]([C:25]#[C:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCc1ccccc1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ncc(C#CCCc2ccccc2)c(Nc2ccccc2)n1
Reaction time: 20 h
Yield: 74.9 %

Procedure:
A solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59; 662 mg, 2.0 mmol), 4-phenyl-1-butyne (260 mg, 2.0 mmol) and triethylamine (0.56 ml, 4.0 mmol) in THF (20 ml) was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (25 mg) and cuprous iodide (12.5 mg) were added and the mixture was stirred for 20 hours. Insoluble material was removed by filtration and washed with diethyl ether (50 ml). The filtrate and washings were combined and concentrated, and the residue was purified by bond elute chromatography, eluting with 25% ethyl acetate in isohexane, to give the product (0.5 g). NMR (CDCl3): 2.85 (m, 2H), 2.95 (m, 2H), 7.05 (m, 2H), 7.1-7.4 (m, 7H), 7.45 (dd, 2H), 8.2 (s, 1H); MS (MH+): 334, 336.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([C:24](Cl)=[O:25])=[N:22][CH:23]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:14]=[C:12]1[NH:11][C:10](=[O:15])/[C:9](=[CH:8]/[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:27])([F:16])[F:28])=[CH:23][N:22]=3)[N:7]=2)/[S:13]1
Reactant: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1NC(=O)/C(=C/c2ccnc(NC(=O)c3ccc(C(F)(F)F)cn3)n2)S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-5-(trifluoromethyl)picolinamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), 5-(trifluoromethyl)picolinoyl chloride (63 mg, 0.301 mmol, 3 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (4 mg, 39.5 mg theoretical, 10%). LC-MS m/z 396.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:15].N[C:17](N)=[O:18].O.Cl>CN(C=O)C>[O:18]=[C:17]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=2[O:15]1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C

Procedure:
A solution of Ethyl 2-(4-amino-3-hydroxyphenyl)propanoate (205 mg, 0.978 mmol) in DMF (5 mL) was added urea (305 mg, 5.19 mmol) and refluxed for 5 hrs. The reaction mixture was cooled to room temperature and added water (30 mL). The mixture was acidified with conc. HCl (1 ml) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:15]=[O:16])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1OC

Procedure:
600 ml of a solution of 18.3 g of 3,4,5-trimethoxyaniline in toluene was added to 140 ml of a solution of 48 ml trichloromethyl chloroformate in toluene and the mixture was refluxed for 3 h. After cooling, the solvent was distilled off and the residue was distilled under reduced pressure (115° C./1 mmHg) to obtain 15.53 g of 3,4,5-trimethoxyphenyl isocyanate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8](C(OCC)=O)[S:7][C:6]=2[CH:15]=1.[CH3:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19].[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][S:7][C:6]=2[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2ccc(Br)cc2s1
Reactant: CNS(C)(=O)=O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(Cc1csc2cc(Br)ccc12)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 11 h

Procedure:
A mixture of the product from Example 76, Part D (0.100 g, 0.382 mmol), N-methylmethane-sulfonamide (45.9 mg, 0.421 mmol) and potassium carbonate (0.127 g, 0.918 mmol) in N,N-dimethylacetamide (5 mL). The mixture was stirred at 80° C. for 11 h, cooled to room temperature and partitioned between diethylether and water (3×), dried over mgSO4, filtered and concentrated in vacuo to give the title compound as a colorless waxy solid (0.128 g, quant.).
Reaction SMILES: [S:1](Cl)(Cl)=O.ClCCl.[CH3:8][N:9]1[C:16]([NH2:17])=[CH:15][C:13](=[O:14])[N:12]([CH3:18])[C:10]1=[O:11].[CH3:19][N:20]([CH3:23])[CH:21]=O>>[CH3:19][N:20]([CH3:23])[C:21]1[S:1][N:17]=[C:16]2[C:15]=1[C:13](=[O:14])[N:12]([CH3:18])[C:10](=[O:11])[N:9]2[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CN(C)c1snc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.25 h

Procedure:
To the mixture of 70 parts by volume of thionyl chloride and 125 parts by volume of dichloromethane was added 3.98 parts of N,N-dimethylformamide at 0° C. After the mixture was stirred at O° C for 15 minutes, 8.55 parts of 1.3-dimethyl-6-aminouracil was added and then refluxed for 5.5 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in 200 parts by volume of chloroform. The solution was poured in 300 parts by volume of ice-water. After the water layer was neutralized with sodium hydrogen carbonate, the chloroform layer was taken and washed twice with 200 parts by volume portions of each of water. The chloroform was distilled off under reduced pressure. The concentration residue was recrystallized from 80 parts by volume of methanol. The described procedure yielded 6.3 parts of 3-dimethylamino-5,7-dimethyl-isothiazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione as colorless needles melting at 150°-152° C.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])=[CH:3]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([C:4]3[CH:5]=[CH:6][O:2][CH:3]=3)[CH:8]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: NCc1cccc(-c2ccoc2)c1
Agent: Cl
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(furan-3-yl)benzylamine.hydrochloride was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-3-yl)benzyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 77%). Note that 3-(furan-3-yl)benzylamine.hydrochloride was neutralized in DMA by adding an equivalent amount of triethylamine, and then used in the reaction.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6](=[O:8])C)(=[O:4])=[O:3].[O:9]1[CH2:14]COOO1.C(OCOCOC(=O)C)(=O)C>>[CH3:1][S:2]([O:5][CH2:6][O:8][CH2:14][O:9][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: C1COOOO1
Reactant: CC(=O)OS(C)(=O)=O
Agent: CC(=O)OCOCOC(C)=O
Product: CS(=O)(=O)OCOCOS(C)(=O)=O
Yield: 67 %

Procedure:
Using the procedure of Example 2, acetyl methanesulfonate and tetroxane, in a molar ratio of 2:1, were reacted for 18-24 hours at 90° C. and 0.5 mm. pressure allowing the bis(acetoxymethyl) ether to distill. The residual oil was recrystallized from a small volume of dry tetrahydrofuran to give a 67% yield of CH3SO3CH2OCH2OSO2CH3.
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:7]1([C:5](=[O:6])[CH2:4][CH2:3][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]2=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: O=C1CCCCC1
Product: O=C(CCC1CCCCC1=O)c1ccccc1
Yield: 39.9 %

Procedure:
2-(3'-Phenyl-3'-oxopropyl)cyclohexanone was prepared according to the method of W. Hahn and J. Epsztain (Roczniki Chem. 1963, 37, 403-12): A mixture of β-dimethylaminopropiophenone (27 gm.) and cyclohexanone (37.5 g.) were heated at reflux for 5 hours under nitrogen and the solvent removed in vacuo. The residual oil was distilled giving 2-(3'-phenyl-3'-oxopropyl)cyclohexanone (14 g.) which was cyclised to the title compound according to the method of Hahn and Epsztain by dissolving the diketone (12 g.) in ethanol (65 ml.), treating with hydroxylamine hydrochloride (9 g.) and heating under reflux for 1 hour. The cooled reaction mixture was poured onto water (300 ml.), extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was made basic with K2CO3 and extracted with ether (3 × 50 ml.). The combined ether extracts were dried and the solvent removed in vacuo. The residual oil was distilled to give the title compound as a colourless oil (7 g.) b.p. 134-8° C/15 mm. Found: C, 85.40; H, 7.5; N, 6.9%, C15H15N requires: C, 86.00; H, 7.2; N, 6.7%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[N:12]=[N:13][C:14]([NH:17][NH2:18])=[CH:15][CH:16]=1.[CH:19](=O)[C:20]([CH3:23])([CH3:22])[CH3:21].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[C:20]([C:23]1[N:13]2[N:12]=[C:11]([C:10]#[C:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:16]=[CH:15][C:14]2=[N:17][N:18]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)C=O
Reactant: NNc1ccc(C#Cc2ccc(F)cc2F)nn1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
A mixture of 3-((2,4-difluorophenyl)ethynyl)-6-hydrazinylpyridazine (0.60 g, 2.4 mmol) and pivalaldehyde (0.31 g, 3.7 mmol) were dissolved in DCM (8 mL) and were stirred at ambient temperature for about 2 h. Iodobenzene diacetate (0.86 g, 2.7 mmol) was added and was stirred for about 2 h at ambient temperature. The reaction mixture was concentrated in vacuo and was purified by silica gel chromatography using DCM/MeOH (gradient, 0-2% MeOH) to afford the title compound (0.49 g, 64%): LC/MS (Table 1, Method a) Rt=2.50 min; MS m/z: 313.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:21]1[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])=[O:7].[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49]([C@H:51]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52]1)=[O:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49]([C@H:51]1[CH2:56][CH2:55][CH2:54][N:53]([CH2:2][C:3]2[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=2)[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]2[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=2)[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:25])=[O:7])[CH2:52]1)=[O:50]
Reactant: COCCNC(=O)[C@H]1CCCNC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCNC(=O)[C@H]1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 20 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a, 8.8 mg of (S)—N-(2-methoxyethyl)piperidine-3-carboxamide and 13.7 mg of K2CO3 in 0.33 mL of DMF was stirred for 2 h. The product was isolate by preparative reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 23 mg of product. MS (ES, m/z) 757.3 [M+H]+
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:10]/[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 4′-(trifluoromethyl)acetophenone (9.60 g, 50 mmol) in 25 ml of N,N-dimethylformamide dimethyl acetal (DMF-DMA) is stirred at 105 to 110° C. for 20 hrs. It is then cooled to room temperature, and diluted with hexanes. The resulting suspension is filtered, and the precipitate washed with hexanes to give 10.93 g of a yellow solid; mp 96.5-98° C.; MS (ESI) m/z 244.1 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[K+].CCOCC.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:21]([O:20][C:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Yield: 71 %

Procedure:
To L-penicillamine (15.75 g; 105.8 mmol) was added a solution of KOH (12.4 g; 222.2 mmol) in water (250 ml). When the solution was complete, Et2O (100 ml) was added and the solution cooled to 0° C. Benzyl chloroformate (14.9 ml; 105.8 mmol) was added dropwise and the stirred reaction mixture allowed to warm to RT. The layers were separated, the aqueous layer acidified to pH 1-1.5 with 1N hydrochloric acid, extracted with CH2Cl2 (×3) and dried (MgSO4). The solvent was removed in vacuo to yield N-benzyloxycarbonyl-L-penicillamine (21.27 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[O:18][C:13]([O:19][CH2:20][CH3:21])=[CH:14][CH:15]([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=CC(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 197.3 %

Procedure:
A 2 liter flask was equipped with a mechanical stirrer, addition funnel, reflux condenser, nitrogen inlet and thermometer. The flask was dried with external heat and then charged with 563 milliliters of dry tetrahydrofuran, 75.9 grams (0.75 mol) of diisopropylamine and cooled to 0° C. Over a 30 minute period 523 milliliters of 1.6 M n-butyl lithium (0.94 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 minutes, then cooled to -76° C. in a dry ice-acetone bath and 97.65 grams (0.75 mol) of ethyl isovalerate was added dropwise over about 30 minutes. When this addition was complete, the reaction mixture was stirred for 15 minutes at -76° C., then 205 milliliters (2.20 mol) of chlorotrimethylsilane was added dropwise. When this addition was complete, the dry ice-acetone bath was removed and the reaction mixture allowed to come to room temperature. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue which was triturated with ether and filtered. The filtrate was concentrated under vacuum to give a residue and the residue was vacuum distilled through a vigreux column to give 136.44 grams (1.48 mol) of 1-trimethylsilyloxy-1-ethoxy-3-methylbutene having a boiling point of 78°-88° C. at 30 millimeters pressure.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:25]1([CH2:31][O:32][CH2:33][CH2:34][Br:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC#N>[Br-:35].[OH:10][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:34][CH2:33][O:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: Cc1ccc(C(O)(c2ccc(C)cc2)C23CCN(CC2)CC3)cc1
Reactant: BrCCOCc1ccccc1
Solvent: CC#N
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C23CC[N+](CCOCc4ccccc4)(CC2)CC3)cc1
Product: [Br-]
Yield: 53.2 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl[bis(4-methylphenyl)]methanol (0.0525 g, 0.163 mmol) and 2-bromoethyl phenylmethyl ether (0.0387 mL, 0.245 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0465 g, 53.1%). EI-MS m/z 456(M+) Rt (2.09 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[N:19]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([C:18]1[CH:23]=[CH:22][C:21]([CH:34]=[O:35])=[C:20]([F:25])[N:19]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(Br)c(F)n2)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1F
Temperature: -45 °C
Yield: 70.4 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (60, 2.90 g, 6.74 mmol) in 25.0 mL of tetrahydrofuran at −35° C. under nitrogen, isopropylmagnesium chloride (3.54 mL, 2.00 M in tetrahydrofuran, 7.08 mmol) was added and the reaction was allowed to come to 0° C. over an hour. The reaction was cooled to −45° C. and N,N-dimethylformamide (1.0 mL, 13.0 mmol) was added. The reaction was allowed to warm to room temperature over 2 hours, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (61, 1.80 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Br:26][CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[O:29]>CCOC(C)=O>[Br-:26].[F:25][C:21]1[CH:20]=[C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[O:10][C:8]([CH:5]2[CH2:4][CH2:3][N+:2]([CH3:1])([CH2:27][C:28](=[O:29])[C:30]3[S:31][CH:32]=[CH:33][N:34]=3)[CH2:7][CH2:6]2)=[O:9])[CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Reactant: O=C(CBr)c1nccs1
Solvent: CCOC(C)=O
Product: C[N+]1(CC(=O)c2nccs2)CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 27 h
Yield: 70.2 %

Procedure:
To a solution of bis(3-fluorophenyl)methyl 1-methylpiperidine-4-carboxylate (106 mg, 0.31 mmol, prepared as in example 40) in EtOAc (3 ml), 2-bromo-1-(thiazol-2-yl)ethanone (63.2 mg, 0.31 mmol) was added. The mixture was stirred at room temperature for 27 hours. The solvent was evaporated, and the crude was triturated with Et2O and collected by filtration. The compound was purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain 4-((bis(3-fluorophenyl)methoxy)carbonyl)-1-methyl-1-(2-oxo-2-(thiazol-2-yl)ethyl)piperidinium bromide (120 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])=[CH2:8])[CH3:2].II.I[CH2:27]I>CCOCC.CCOC(C)=O.[Cu].[Zn]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH2:6][C:7]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[CH2:27][CH2:8]1)([OH:22])[C:18]([F:19])([F:20])[F:21])[CH3:2]
Reactant: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cc(F)ccc1OC
Reactant: ICI
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)(CC1(c2cc(F)ccc2OC)CC1)C(F)(F)F
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of 620 mg (1.84 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester, 475 mg zinc copper couple, and an iodine crystal in anhydrous ether in a sealed tube warmed to 55° C. was added dropwise 500 μL (6.20 mmol) of diiodomethane. The reaction was monitored by TLC in dichloromethane-hexanes (1:1) or ether-hexanes (2:8). After 18 hours, the mixture was cooled, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was washed with three 10 mL portions of 1 N aqueous HCl, 10 mL of brine, three 10 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The crude material was adsorbed onto silica gel and chromatographed on silica gel using ether-hexanes (0:100, then 1:99, then 2:98) to afford 494 mg (76%) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]-2-hydroxypropionic acid ethyl ester.