Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][C:32]=1[O:40][CH3:41].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][C:32]=3[O:40][CH3:41])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 1-[4-(6-chlorohexoxy)-3-methoxyphenyl]ethanone and sodium carbonate in butanol, the title compound is prepared.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C@H:4]1[O:9][C:8](=[O:10])[CH2:7][C@H:6]([OH:11])[CH2:5]1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:19]([O:11][C@@H:6]1[CH2:5][C@@H:4]([CH:3]([O:12][CH3:13])[O:2][CH3:1])[O:9][C:8](=[O:10])[CH2:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COC(OC)[C@@H]1C[C@@H](O)CC(=O)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(OC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 0.5 g of (4R,6S)-6-(dimethoxymethyl)-4-hydroxy-tetrahydropyran-2-one (II′) in 50 mL of dichloromethane, 280 mg of imidazole are added at 25° C. After cooling to 0° C., 400 mg of tert-butyldimethylsilyl chloride are added. The reaction mixture is then stirred for 18 hours and dichloromethane is distilled off. The residue is flash chromatographed (DIPE/acetonitrile=5/1). The solvents are distilled off to get the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11])[CH3:2].N([O-])=O.[Na+].[BrH:17]>O>[Br:17][C:6]1[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 240 ml) is added dropwise to a suspension of 4-ethyl-3-nitroaniline (20 g, 0.12 mol) in water (80 ml), and the mixture stirred until the solid is dissolved. The mixture is cooled to −5° C. and a solution of sodium nitrite (19.8 g, 0.28 mol) in water (100 ml) is added dropwise, maintaining the temperature at 0-5° C. Once the addition is complete, the cooling bath is removed and the reaction mixture is stirred for one hour at room temperature. The mixture is added dropwise to a pre-cooled solution of cuprous bromide (22.4 g, 0.16 mol) in hydrobromic acid (48% wt. in water) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature over three hours. The mixture is extracted with diethyl ether, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with hexane to give 4-bromo-1-ethyl-2-nitrobenzene (18 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.C(N(C(C)C)C(C)C)C.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.[OH-].[Na+]>C(Cl)Cl>[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40]([N:2]([CH3:1])[C:3]2[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=2)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(SC)nc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2C)n1
Reaction time: 24 h
Yield: 82.3 %

Procedure:
To a solution of 1.30 g (5.3 mmol) methyl-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-amine and 1.36 ml (7.95 mmol) N-ethyldiisopropylamine in 15 ml CH2Cl2 a solution of 1.30 g (5.3 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 5 ml CH2Cl2 were added and the reaction mixture stirred for 24 hrs. at RT. The reaction mixture was poured onto 50 ml 0.5 N NaOH-solution. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 10:1) to give 2.30 g (82%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-isobutyramide as a white solid, m.p. 124-125°, MS (ISP): 528.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([C:43]([F:46])([F:45])[F:44])[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([C:43]([F:44])([F:45])[F:46])[CH:36]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(OC)c(C(F)(F)F)c3)C2)c1
Yield: 77.4 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (58.8 mg, 0.13 mmol) in CH3CN (5 ml) was added 4-Bromomethyl-1-methoxy-2-trifluoromethyl-benzene (53.0 mg, 0.20 mmol), and diisopropylethylamine (46 μl, 0.26 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (64 mg, 77%). Calcd for C35H39F6NO3 (M+H) 635.68, Found 636.5.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:27])[C@@H:24]([NH2:26])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[C:28]([CH:31]([O:36][C:37](=[O:43])[C:38]([CH3:42])([CH3:41])[CH:39]=[CH2:40])[CH:32]1[CH2:35][O:34][CH2:33]1)(O)=[O:29].CC1(C)CCCC(C)(C)N1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:27])[C@@H:24]([NH:26][C:28]([CH:31]([O:36][C:37](=[O:43])[C:38]([CH3:42])([CH3:41])[CH:39]=[CH2:40])[CH:32]4[CH2:35][O:34][CH2:33]4)=[O:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC(C)(C)C(=O)OC(C(=O)O)C1COC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(C)(C)C(=O)OC(C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1)C1COC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.9 %

Procedure:
A stirred solution of (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (141 mg, 0.618 mmol) and 2,2-dimethyl-but-3-enoic acid carboxy-oxetan-3-yl-methyl ester (315 mg, 0.725 mmol) in anhydrous N,N-dimethylformamide (10 mL) was cooled to 0° C. under nitrogen. 2,2,6,6-Tetramethylpiperidine (261 mg, 313 μL, 1.85 mmol) was added, rapidly followed by (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (371 mg, 0.865 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was diluted with dichloromethane and washed with saturated ammonium chloride solution (2×), saturated sodium bicarbonate solution (2×), the organic layer was filtered through a phase-separator and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:0 to 0:1 to give the title compound (167 mg, 42%) as a yellow/brown foam and as an approximate 1:1 mixture of diastereoisomers. LCMS (m/z) 644.2, 646.1[M+H], Tr=2.63 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11])=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)Cc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
To a mixture of ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (2 g, 6.91 mmol) in THF (200 mL) was added LAH (0.525 g, 13.83 mmol) in portions. The mixture was stirred at 25° C. for 10 h. The mixture was quenched with 15% NaOH (aq, 10 mL). The mixture was dried over Na2SO4. The mixture was filtered and the filtrate was concentrated. The residue was purified on silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.35) were combined and concentrated to yield a light yellow oil of 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (1.1 g, 4.45 mmol, 64.4% yield): 1H NMR (400 MHz, MeOD) δ: 7.17 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.84 (dd, J=2.4, 8.0 Hz, 1H), 3.31 (s, 2H), 2.67 (d, J=1.2 Hz, 2H), 0.84 (s, 6H); ES-LCMS m/z 248 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([OH:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[N-:67]=[N+:68]=[N-:69].[Na+].O>CN(C)C=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:67]=[N+:68]=[N-:69])[CH:46]([OH:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(S(=O)(=O)c4ccccc4[N+](=O)[O-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 80 °C

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-{2'-[4"-(o-nitrobenzenesulfonyl)-3"-hydroxycyclohexyl]-1'-methylvinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (87 mg) in dry dimethylformamide (1 ml) is added sodium azide (16.7 mg) in one portion. The reaction is heated at 80° C. under nitrogen atmosphere for 3 hr. The reaction mixture is cooled, poured into water (5 ml) and extracted with ethyl acetate. Normal work-up followed by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:18])([C:13]#[C:14][CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[C:6]([F:19])[C:5]([F:20])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:28][C:29](Br)=[O:30]>CCOCC>[F:19][C:6]1[C:7]2[C:8]([C:13]#[C:14][CH:15]([CH3:17])[CH3:16])([C:9]([F:10])([F:11])[F:12])[O:18][CH2:28][C:29](=[O:30])[NH:1][C:2]=2[CH:3]=[CH:4][C:5]=1[F:20]
Reactant: CC(C)C#CC(O)(c1c(N)ccc(F)c1F)C(F)(F)F
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)C#CC1(C(F)(F)F)OCC(=O)Nc2ccc(F)c(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled soliution of 81 mg of 6-Amino-2,3-difluoro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 8 mL of dry ether was added 0.55 mL of dry pyridine and 0.032 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 10 mg of 100% sodium hydride for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1 h. The reaction was quenched with one drop of acetic acid and then the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and this solution vas washed with water and brine, dried and evaporated to a solid which was crystallized from ethyl acetate/hexanes affording 28 mg of the title compound as colorless crystals: mp 192.5-193.5°; HRMS: Calcd. for C15H13NO2F5 (M+H)+ : 334.086645. Found: 334.084917.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CCO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2]/[N:3]=[C:4](/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(-c2ccc(CCC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-(4′-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}biphenyl-4-yl)propanoate (0.25 g, 0.6 mmol) in THF was added ethanol and aqueous solution of NaOH and stirred at RT for 2 h, reaction mass was concentrated to remove solvents and diluted with water and neutralized with 1 N HCl and extracted with ethyl acetate, organic layer was washed with water and brine solutions dried over anhydrous Na2SO4 and concentrated to white solid (0.2 g, 83.3%); purity: 99.5%
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:27]([O:29]C)=[O:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>O1CCOCC1.O>[C:1]([NH:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COCc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)O)cc2)cc1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Methyl N-isobutyryl-O-{2-[4-(methoxymethyl)phenyl]ethyl}tyrosinate (0.7 g, 1.69 mmol) was dissolved in dioxane (6 ml). Lithium hydroxide monohydrate (0.25 g, 5.95 mmol) in water (6 ml) was added. The mixture was stirred overnight and then diluted with water and evaporated in vacuum to remove dioxane. The residue was acidified with 1M hydrochloric acid, pH ˜3 and then extracted twice with dichloromethane. The organic phase was washed with brine and dried with sodium sulfate. The solvent was then evaporated. 0.67 g desired product was obtained, yield 99%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:17]([O:19][CH3:20])=[O:18])[CH2:3]1.[CH3:21]I.[H-].[Na+]>C1COCC1>[CH3:21][O:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH:4]([C:17]([O:19][CH3:20])=[O:18])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(OC)CN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (500 mg, 1.79 mmol) in THF (6 mL) was added methyl iodide (0.385 mL) followed by sodium hydride (95 mg, 3.94 mmol). The reaction was stirred for 1 hour, then quenched with ice and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-benzyl 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate. MS ESI calc'd. for C15H19NO5 [M+H]+ 294. found 294.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH3:24])[C:19]([CH:22]=O)=[N:20][CH:21]=1>>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:22][C:19]1[C:18]([CH3:24])=[CH:17][C:16]([Cl:15])=[CH:21][N:20]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)cnc1C=O
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Product: Cc1cc(Cl)cnc1CNCCCCN(C)C(=O)OC(C)(C)C

Procedure:
Yellow oil prepared from (4-amino-butyl)-methyl-carbamic acid tert-butyl ester and 5-chloro-3-methyl-pyridine-2-carbaldehyde. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.50-1.60 (m, 4H), 2.27 (s, 3H), 2.30-2.36 (m, 2H), 2.83 (s, 3H), 3.20-3.26 (m, 2H), 3.83 (s, 2H), 8.34 (d, 1H, J=1.5 Hz), 7.4 (d, 1H, J=1.9 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1COCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCN(Cc2ccccc2)C1
Yield: 100.2 %

Procedure:
A solution of 10.0 g (52.9 mmol) of 1-benzyl-4-piperidone and 4.61 g (52.9 mmol) of morpholine in 100 ml of toluene was subjected to azeotropic dehydration for 5 hours under heating and reflux by using a water separator. After the completion of the reaction, the solvent was distilled off under reduced pressure, whereby 13.7 g of 1-benzyl-4-morpholino-1,2,5,6-tetrahydropyridine were obtained in a quantitative yield. A solution of 1.52 g (34.6 mmol) of acetaldehyde in 20 ml of methylene chloride was cooled to -40° C. under an argon atmosphere, followed by the dropwise addition of 5.3 ml (43 mmol) of a boron trifluoride--ether complex and 7.44 g (28.8 mmol) of 1-benzyl-4-morpholino-1,2,5,6-tetrahydropyridine obtained above. After the completion of the dropwise addition, the temperature was raised gradually and the reaction mixture was allowed to stand overnight at room temperature. After the addition of water to terminate the reaction, the reaction mixture was extracted with methylene chloride. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=4/1), whereby 4.68 g (yield: 69.7%) of 1-benzyl-3-(1-hydroxyethyl)-4-piperidone were obtained as a yellowish brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:10]=2)[CH:7]=1.C1C(=O)N([I:27])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:9][C:10]=2[I:27])[CH:7]=1
Reactant: FC(F)(F)C(F)(F)CCc1ncc2ccc(Cl)cn12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)CCc1nc(I)c2ccc(Cl)cn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from Step G (3.64 g, 12.19 mmol) in anhydrous DCM (50 mL) was added NIS (5.48 g, 24.4 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated. The residue was suspended in ethyl acetate and washed with saturated sodium thiosulfate (2×). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give a bright white solid. m/z=424.7 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccncc2)C1

Procedure:
The title compound is synthesized by coupling of (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloromethyl-pyridine HCl salt analogously to the preparation of Intermediate 193.2 as a white solid; ES-MS: M+=279.2: AtRet=2.84.
Reaction SMILES: [C:1]1([C:7]2([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCC1(c2ccccc2)CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A solution of 1.15 g (6.04 mmol) of (1-phenylcyclopentyl)carboxylic acid in 10 ml of tetrahydrofuran was added dropwise over a period of 20 minutes to a suspension of 344 mg (9.06 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran, whilst ice-cooling, and the resulting mixture was stirred for 30 minutes at 60° C. At the end of this time, the reaction mixture was again ice-cooled, and then 0.3 ml of water, 10 ml of a 2N aqueous solution of sodium hydroxide and 1 ml of water were added, in that order, and the resulting mixture was diluted with diethyl ether. The white gel material which appeared was filtered off, and then the filtrate was washed with water, with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using methylene chloride as the eluent, to give 1.06 g (yield 99%) of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)O)[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:19])CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[F:19])[CH:5]=[CH:4][N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(c1ccnc(Cl)n1)C1CC1
Solvent: ClCCl
Product: FC(c1ccnc(Cl)n1)C1CC1
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanol (75 mg, 0.406 mmol) in dichloromethane (2 mL) at 0° C. was added diethylaminosulfur trifluoride (66 mg, 0.410 mmol) and stirred for 30 min. The solution was concentrated to dryness and purified by flash chromatography on silica gel (0-100% EtOAc/hexanes) to afford 2-chloro-4-[cyclopropyl(fluoro)methyl]pyrimidine (20 mg, 0.107 mmol, 26% yield) as a colorless oil. MS ESI: [M+H]+ m/z 187.1. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=5.0, 1H), 7.43 (d, J=5.0, 1H), 4.93 (dd, J=7.4, 47.5, 1H), 1.13 (m, 1H), 0.70-0.60 (m, 4H).