Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:8](=O)([O:14]C(C)(C)C)[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:9][C:8]([NH:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@@H](N)CC(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
To a stirred suspension of (R)-3-aminobutanoic acid (2.415 g, 23.42 mmol) in dioxane (15 mL) and water (15.00 mL) was added TEA (4.90 mL, 35.1 mmol) dropwise. To the resulting light brown solution cooled at 0° C. was added portionwise di-tert-butyl carbonate (4.69 g, 26.9 mmol). The mixture was then stirred at rt for 16 hr. The reaction mixture was partitioned between water (80 mL) and EtOAc (80 mL). The separated aqueous layer was washed with EtOAc and acidified with 1 M aqueous KHSO4 to pH=3 and extracted with EtOAc (2×). The combined EtOAc extracts were washed with saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated to give (R)-3-(tert-butoxycarbonylamino)butanoic acid (4.301 g, 21.16 mmol, 90% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.92 (s, 1H), 4.14-3.96 (m, 2H), 2.56 (d, J=5.2 Hz, 2H), 1.45 (s, 9H), 1.25 (d, J=6.9 Hz, 3H).
Reaction SMILES: C(ON=O)(C)(C)C.[CH2:8]([Br:11])[CH:9]=[CH2:10].Br[C:13]1[CH:19]=[CH:18][C:16](N)=[CH:15][CH:14]=1.NC1C=CC=CC=1>CC#N>[CH2:15]([C:14]1[CH:13]=[CH:19][C:8]([Br:11])=[CH:9][CH:10]=1)[CH:16]=[CH2:18]
Reactant: Nc1ccc(Br)cc1
Reactant: C=CCBr
Agent: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=CCc1ccc(Br)cc1
Temperature: 32.5 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-bromoaniline (516 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 30-35° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 30° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (pentane) gave 200 mg (34%) of 4-allylbromobenzene as a clear oil. 1H NMR (CDCl3, 400 MHz) δ 7.43, (m, 2H, J=8.3 Hz), 7.08, (m, 2H, J=8.3 Hz), 6.00-5.89, (m, 1H), 5.12-5.05, (m, 2H), 3.35, (d, 2H, J 6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 139.4, 137.2, 131.9, 130.8, 120.3, 116.7, 40.0; Anal HRMS Calcd. for C9H9Br (M): 195.9888. Found: 195.9887.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]1.[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:13]12([CH2:23][C:24]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[CH:3]3)=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: Nn1cnc2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.8 %

Procedure:
3-Amino-4(3H)-quinazolinone (158.7 mg, 0.99 mmol) was dissolved in chloroform (5 mL). 1-Adamantaneacetyl chloride (204.1 mg, 0.96 mmol) and pyridine (100 μL, 1.24 mmol) were added, and the reaction was allowed to stir at ambient temperature for 22 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white solid (264.9 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.69 (m, 12H), 1.96 (br s, 3H), 7.58-7.63 (m, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.87-7.93 (m, 1H), 8.18-8.20 (m, 2H), 11.12 (s, 1H) ppm; MS (DCI/NH3) m/z 338 (M+H)+; Elemental Analysis: Calculated for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.11; H, 6.85; N, 12.43.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([I:10])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:18])=[O:19])=[CH:4][C:5]2[O:9][C:8]([I:10])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CNC(=O)c1c(I)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a suspension of 5-bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (177 mg, 90% purity, 0.34 mmol) and K2CO3 (140 mg, 1.01 mmol) in DMF (3 mL) was added dropwise CH3I (79 mg, 0.68 mol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 1 hour. After concentrated in vacuum, the residue was suspended in H2O and extracted with DCM. The residue was purified by column chromatography (eluted with DCM:EtOAc from 10:1 to 2:1) to give 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.66 (s, 1H), 6.27 (s, 1H), 3.32 (s, 3H), 3.08 (d, J=4.8 Hz, 3H), 2.89 (s, 3H). MS (M+H)+: 487/489.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CC[N:26]([CH2:29][CH3:30])CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:26][CH2:29][CH:30]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7]1)[C:6]([N:8]([CH2:14][C:15]([F:18])([F:16])[F:17])[CH2:9][C:10]([F:13])([F:11])[F:12])=[O:7])([O-:23])=[O:22]
Reactant: CCN(CC)CC
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCCO2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (83 mg, 0.238 mmol) and R/S-2-aminomethyl-tetrahydropyran hydrochloride (40 mg, 0.262 mmol) in 3 mL of EtOH containing Et3N (0.070 mL, 0.476 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 100 mg (95%); 1H NMR (CDCl3) 1.48 (m, 1H), 1.58 (m, 3H), 1.68 (m, 1H), 1.95 (m, 1H), 3.35 (m, 1H), 3.41 (m, 1H), 3.52 (m, 1H), 3.64 (m, 1H), 4.07 (m, 1H), 4.26 (m, 4H), 6.96 (d, J=8.98 Hz, 1H), 7.54 (d, J=8.98 Hz, 1H), 8.31 (s, 1H), 8.55 (brs, 1H); MS (ESI) 530.21 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][CH3:30])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].[I-:31].[Na+]>C(C(C)=O)C>[CH2:13]([O:12][CH2:11][CH:10]([O:29][CH3:30])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:31])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCCl)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCI)OC
Yield: 77 %

Procedure:
To a solution of 3.845 (8.18 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecyloxy-2-methoxypropane IIIa3 in 30 ml of methyl ethyl ketone is added 2.45 g (16.36 mM) of sodium iodide and the mixture is refluxed for 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent. The product is recrystallied from methanol to give 3.556 g (6.332 mM) of 1-hexadecyloxy-3-(3-iodopropylsulfonylamino)-2-methoxypropane IIa3 in 77% yield.
Reaction SMILES: CN1CCCC1.[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29](=O)[O:30]C(C)=C.Cl.[F:36][C:37]([F:45])([F:44])[C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29]([NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[C:37]([F:45])([F:44])[F:36])=[O:30]
Reactant: CC(C)(CCN)C(F)(F)F
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C(F)(F)F)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 75.1 %

Procedure:
Add 1-methylpyrrolidine (1.214 mL, 11.54 mmol) in a mixture of prop-1-en-2-yl (2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (0.92 g, 2.31 mmol) and 4,4,4-trifluoro-3,3-dimethylbutan-1-amine hydrochloride (0.487 g, 2.54 mmol) in THF (23 mL) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (0-50% EtOAc/Hexanes) to afford the title compound (860 mg, 75% yield). MS (m/z): 496.2 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].CN([CH:31]=[O:32])C>C1COCC1>[Cl:15][C:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([F:27])[C:24]([CH:31]=[O:32])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(F)cccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was added nBuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at −78° C. and the reaction mixture was warmed to 0° C. over a period of 1 h. Then the reaction mixture was cooled to −78° C. and a solution of ethyl 2-chloro-6-fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at −78° C. for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h and then gradually warmed to 0° C. over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-formylbenzoate. 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.05-8.00 (t, J=7.8 Hz, 1H), 7.72-7.69 (d, J=8.4 Hz, 1H), 4.53-4.46 (q, J=6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J=6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq, solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55° C. for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. 1H NMR (300 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, J=8.1 Hz, 1H), 7.49-7.46 (d, J=8.4 Hz, 1H), 4.44-4.37 (q, J=7.5, 14.1 Hz, 2H), 1.34-1.29 (t, J=7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HCl in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3 h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of NaHCO3. The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. 1H NMR (300 MHz, CDCl3): δ 7.54 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 4.45 (q, J=7.5, 14.1 Hz, 2H), 4.11 (d, J=3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[N:8][CH:9]=1.[CH3:13]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[N:8][CH:9]=1
Reactant: CI
Reactant: N#CCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a suspension of NaH (95%, 113 mg, 4.70 mmol) in DMF was added a solution of 2-(5-bromopyridin-3-yl)acetonitrile (from example 199, 0.8 g, 4 mmol) in DMF. Upon completion of addition, the reaction mixture was stirred at RT for 30 min. After this time, methyl iodide (0.3 mL, 4 mmol) was added and the stirring continued for an additional 4 h. At the conclusion of this period, the reaction mixture was quenched by addition of saturated ammonium chloride solution and then extracted into ethyl acetate. The combined organic portions were concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (30% EtOAc in hexanes) to yield racemic 2-(5-bromopyridin-3-yl)propanenitrile (200 mg, 24%). 1H NMR (400 MHz, CDCL3) δ (ppm): 8.67 (d, 1H, J=2 Hz); 8.53 (d, 1H, J=5 Hz); 7.88 (t, 1H, J=5 Hz); 3.94 (q, 1H, J=7.6 Hz); 1.69 (d, 3H, J=7.6 Hz). LCMS Method Y: retention time 1.54 min; [M+1]=212.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:13][C:14](=O)[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(O)(O)(=O)=O.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:13][C:14](=[N:23][OH:24])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: CCC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCC(CC1(c2ccc(Cl)c(Cl)c2)CCC1)=NO
Temperature: 25 °C

Procedure:
A mixture of 1-[1-(3,4-dichlorophenyl)cyclobutyl]butan-2-one (4.3 g) prepared as described above, hydroxylamine sulphate (2.65 g), sodium acetate (4.0 g), industrial methylated spirit (56 ml) and water (23 ml) was stirred at ambient temperature for sixteen hours. The reaction mixture was extracted with ether. The ether extract was washed with water, dried and evaporated to give a solid which was recrystallised from petroleum ether (b.p. 80°-100° C.) to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]butan-2-one oxime (m.p. 106°-110° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[CH:12](O)[CH3:13])=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:64]([CH:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)[CH3:13])=[N+:65]=[N-:66]
Reactant: CC(O)c1ccccc1-c1noc2ccccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(N=[N+]=[N-])c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 0.6 g of 2-[2-(1,2-benzisoxazol-3-yl]-a-methylbenzyl alcohol and 0.65 g of triphenylphosphine in 10 ml tetrahydrofuran at 0° C. was added 0.39 ml of diethyl azodicarboxylate followed by a solution of 0.54 ml of diphenylphosphoryl azide in 5 ml of tetrahydrofuran. The solution was warmed to room temperature and stirred for 1.5 h. The reaction was evaporated and purified by flash chromatography eluting with 1:1 toluene-heptane to yield 0.27 g of 3-[2-(1-azidoethyl)-phenyl]-1,2-benzisoxazole as a colourless gum, 1H-NMR (200 MHz, CDCl3) dH 5.10 (CHN3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:22](Cl)[O:23][CH2:24][CH2:25][O:26][CH3:27]>C(Cl)Cl>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][CH:6]=1
Reactant: COCCOCCl
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-hydroxyphenylacetate (200 mg, 1.20 mmol) in DCM (5 ml) is added DIPEA (0.315 ml, 1.81 mmol), and then MEMCl (0.204 ml, 1.81 mmol), and the resulting reaction mixture is stirred for 2 hours at room temperature. An additional portion of MEMCl (0.102 ml, 1 mmol) and of DIPEA (0.158 ml, 1 mmol) are added, and the reaction mixture is stirred for a further 16 hours. An additional portion of MEMCl (0.102 ml, 1 mmol) and of DIPEA (0.158 ml, 1 mmol) are added and the reaction mixture is stirred for 3 hours. The reaction mixture is diluted with DCM and washed with 0.5 M HCl, 1 M NaOH and then 0.5 M HCl, dried (MgSO4) and concentrated in vacuo to afford [4-(2-Methoxy-ethoxymethoxy)-phenyl]-acetic acid methyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[CH:10]1.C1C(=O)N([Br:33])C(=O)C1.O>CN(C=O)C>[Br:33][C:10]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:13](=[O:24])[C:12]=2[C:11]=1[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(-c2ccc(Cl)cc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Reaction time: 1 h
Yield: 40 %

Procedure:
To as solution of 1-(2,4-dichlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (0.93 g, 2.46 mmol) in DMF (25 ml) was added NBS (0.48, 2.71 mmol) at 0° C. The reaction mixture was stirred at this temperature for one hour and then water was added. The mixture was extracted with ether (×3). The combined ether extracts were dried (Na2SO4), filtered and concentrated to give 0.45 g (40%) of the title compound after flash chromatography (heptane:EtOAc gradient).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:6]([NH:8][O:9][CH3:10])=[O:7])[NH2:2].[I:15][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=1)[C:19]([C:21](=[CH:24]NC1C=CC=CC=1)[C:22]#[N:23])=[O:20].CCOC(C)=O>CCO>[NH2:23][C:22]1[N:1]([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=2[CH3:14])[C:6]([NH:8][O:9][CH3:10])=[O:7])[N:2]=[CH:24][C:21]=1[C:19](=[O:20])[C:18]1[CH:32]=[CH:33][CH:34]=[C:16]([I:15])[CH:17]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Reactant: CONC(=O)c1ccc(C)c(NN)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(I)c3)c2N)c1
Temperature: 67.5 °C
Yield: 55 %

Procedure:
To a stirred solution 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (116 mg, estimated 0.14 mmol) in EtOH (10 ml) was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 3 (59 mg, 0.14 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) and mixture was heated (bath T=65-70° C.) for 4 hr, when additional 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (80 mg, 0.11 mmol) was added and the mixture was heated at the same temperature for 27 hr. It was cooled to room temperature, concentrated and redissolved in EtOAc before it was washed with water and brine, dried over Na2SO4, concentrated to give a crude semisolid. The mixture was then purified by flash chromatography, eluting with 1:1 EtOAc/hexanes to remove impurities then 100% EtOAc give 3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide 4 as an off-white solid (38 mg, 0.08 mmol, 55%). HPLC (6 minute gradient) tR 3.49 min; MS m/z 476.96 [M+H]+; 1H NMR (CD3OD, 300 MHz) δ 8.10 (s, 1H), 7.95 (d, J=8.0, 1H), 7.88 (d, J=8.0, 1H), 7.82 (m, 2H), 7.78 (s, 1H), 7.58 (d, J=8.0, 1H), 7.33 (t, J=7.8, 1H), 5.02 (s. 3H), 2.33 (s, 3H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 189.3, 154.3, 143.5, 143.3, 142.0, 138.3, 137.4, 133.5, 132.9, 132.0, 130.4, 128.8, 128.4, 104.8, 95.4, 64.8, 18.2 ppm.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:28])[C:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH3:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:10]([O:12][C:13](=[O:28])[C:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: CCOC(=O)C(C)(C)CCC(Br)c1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine (0.65 g, 4.61 mmol) and 5-bromo-5-(2-chlorophenyl)-2,2-dimethylpentanoic acid ethyl ester (1.42 g, 4.08 mmol) were dissolved in THF (5 mL) and triethylamine (3 mL) with a few crystals of DMAP. The solution was heated overnight to 85° C. using an oil bath. After 20 hours, the solution was cooled to room temperature and sodium bicarbonate solution (20 mL) was added. After mixing, the product was extracted with dichloromethane (2×25 mL). The combined dichloromethane fractions were dried over sodium sulfate, filtered, and concentrated. The remaining yellow oil was purified by MPLC on a Companion Chromatography station using silica gel (40 g), eluting with a gradient of 100% heptane to 10% ethyl acetate over 20 minutes followed by a second gradient to 100% ethyl acetate at 40 minutes. The second broad fraction was collected and concentrated to produce 5-(2-chlorophenyl)-5-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylpentanoic acid ethyl ester (Compound Ib, 1.11 g, 67.2% yield) as a light, yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ=7.46 (dd, 1H, J=7.80, 1.5 Hz), 7.38 (dd, 1H, J=7.80, 1.5 Hz), 7.30-7.15 (m, 2H), 7.04 (d, 1H, J=5.1 Hz), 6.70 (d, 1H, J=5.1 Hz), 4.18 (dd, 1H, J=8.7, 4.5 Hz), 4.08 (q, 2H, J=7.2 Hz), 3.79 (d, 1H, J=14.4 Hz), 3.45 (d, 1H, J=14.4 Hz), 2.90-2.62 (m, 4H), 2.0-1.85 (m, 1H), 1.82-1.68 (m, 1H), 1.49 (dt, 1H, J=13.5, 4.2 Hz), 1.30 (dt, 1H, J=13.5, 4.5 Hz), 1.20 (t, 3H, J=7.2 Hz), 1.10 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=177.59, 138.99, 134.95, 134.25, 133.59, 129.64, 129.11, 128.07, 126.73, 125.43, 122.61, 63.81, 60.38, 50.63, 47.95, 42.22, 36.43, 28.22, 26.17, 25.52, 25.38, 14.47. MS (MMI-TOF): Calculated for C22H28NO2ClS (MH+): 406.1602; found 406.1576.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CSCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 48, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl mercaptan.