Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31]O)=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:54]>>[Cl:54][CH2:31][CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][S:14][C:3]3[N:2]([CH3:1])[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][C:9]=4[CH3:13])[N:4]=3)=[CH:17][CH:18]=2)=[O:33])=[CH:24][CH:25]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCO)cc4)cc3)n(C)c(=O)c12
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCCl)cc4)cc3)n(C)c(=O)c12

Procedure:
To a suspension of 3,5-dimethyl-2-[4-[4-(2-hydroxyethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone (651 mg) in carbon tetrachloride (15 ml) was added triphenylphosphine (476 mg) and the mixture was refluxed for 40 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane) and recrystallized from ethyl acetate to provide the title compound as colorless solid (391 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]=[CH2:15]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 106.5 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (166 g, 0.77 mol) and Et3N (214 mL) in THF (2.5 L) was added methyl chloroformate (71.2 mL, 0.93 mol) at 0-5° C. The reaction mixture was stirred for 15 min and filtered to remove TEA salt. To the filtrate was added a solution of NaBH4 (60 g, 1.54 mol) in a small amount of water at 0-5° C. The reaction was stirred at RT for 1 h and quenched with saturated NH4Cl solution. The reaction mixture was concentrated to remove most of THF and extracted with EtOAc (700 mL×3). The organic layers were washed with water, NaOH (1 N) and brine, dried over Na2SO4, and concentrated to give (S)-tert-butyl 1-hydroxypent-4-en-2-ylcarbamate (165 g), which was used without further purification. LRMS (M+H+) m/z 202.1.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH2:22][CH2:21][C:16]3([NH:20][CH2:19][CH2:18][CH2:17]3)[CH2:15]2)[CH:11]=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:25](=O)(O)[O-].[Na+]>C(O)=O>[CH3:25][N:20]1[C:16]2([CH2:21][CH2:22][N:14]([C:10]3[CH:11]=[N:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH2:15]2)[CH2:17][CH2:18][CH2:19]1
Reactant: c1ccc(Oc2cncc(N3CCC4(CCCN4)C3)c2)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCCC12CCN(c1cncc(Oc3ccccc3)c1)C2
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a stirring solution of 7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (420 mg, 1.42 mmol) in 37% aqueous solution of formaldehyde (5 mL) was added 98% formic acid (3 mL) under nitrogen. The reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature, then basified with saturated aqueous sodium bicarbonate to pH 8-9 and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford a thick brown viscous liquid. This was distilled using a Kugelrohr apparatus (2 mm, 180° C.) to give a very pale cream-colored syrup (400 mg, 90.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23](O)=O)=[O:15])=[CH:4][CH:3]=1.[C:26]1([NH2:33])[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>>[NH:32]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:33]=[C:23]1[CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: Nc1ccccc1N
Reactant: Cc1nc(C(=O)N2CCCCC2CC(=O)O)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3ccccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 52 %

Procedure:
(RS)-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid, D17 (110 mg, 0.3 mmol) and benzene-1,2-diamine (33 mg, 0.3 mmol) in PPA (2 g) were heated at 140° C. for 3.5 h. The cooled reaction mixture was poured onto a mixture of crushed ice and K2CO3. The basic aqueous solution was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, ethyl acetate) afforded the title compound as a dark yellow gum (72 mg, 52%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C@@:10]2([CH3:16])[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:9][O:8][C:6]1[C:5]([C@@:10]2([CH3:16])[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:4][CH:3]=[C:2]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH3:17])[CH:19]=[CH:20]3)[N:7]=1
Reactant: COc1nc(Cl)ccc1[C@@]1(C)CCNC1=O
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1nc(-c2ccc3c(ccn3C)c2)ccc1[C@@]1(C)CCNC1=O
Temperature: 110 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To a vial was added (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpyrrolidin-2-one (56.6 mg, 0.24 mmol) which was evaporated with dioxane (2.0 mL). 1-methyl-1H-indol-5-ylboronic acid (63.4 mg, 0.36 mmol) was next added followed by Pd(dppf)Cl2 (7.5 mg, 0.01 mmol). The mixture was sealed and degassed with nitrogen. Degassed dioxane (1.9 mL) and degassed 2 M Na2CO3 (0.27 mL, 2.3 equiv) were then added to the solid mixture. The reaction was stirred for 16 h at 110° C. The reaction was concentrated and partitioned between EtOAc/10% (w/v) aq. Na2CO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated to provide a crude brown glass. Purification by column chromatography (4 g RediSep Gold column) with a 40-100% EtOAc/heptane gradient provided the title compound (78 mg, 99%) as a pale yellow glass. 1H NMR (600 MHz, CDCl3) δ: 1.62 (s, 3H), 2.10 (ddd, 1H), 2.67-2.76 (m, 1H), 3.37-3.47 (m, 2H), 3.82 (s, 3H), 4.10-4.12 (m, 3H), 5.59 (br. s., 1H), 6.56 (d, 1H), 7.07 (d, 1H), 7.34-7.39 (m, 2H), 7.67 (d, 1H), 7.92-7.96 (m, 1H), 8.30 (s, 1H); MS (AP+)(M+H) 336. The absolute stereochemistry was obtained via X-ray crystallographic analysis of single crystals obtained via crystallization from a mixture of DCM and EtOH. FIG. 2 is an ORTEP drawing of (R)-3-(2-methoxy-6-(1-methyl-H-indol-5-yl)pyridin-3-yl)-3-methylpyrrolidin-2-one.
Reaction SMILES: N#N.C(OC([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20]O)[CH2:16][CH2:15]1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.II.[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[N:48]1([CH2:20][C@H:17]2[CH2:16][CH2:15][C@H:14]([NH2:13])[CH2:19][CH2:18]2)[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)OCc1ccccc1
Reactant: C1CCNC1
Agent: II
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CN2CCCC2)CC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of trans-4-benzyloxycarbonylaminocyclohexane-methanol (292 mg, 1.11 mmol), triphenylphoshine on polystyrene (3.52 mmol) and imidazole (107 mg, 1.55 mmol) in dry CH2Cl2 (40 mL) was added iodine (455 mg, 1.77 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (0.34 mL, 4.09 mmol) and K2CO3 (566 mg, 4.09 mmol). The reaction mixture was refluxed until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA, 1:0->1:1) and then the Cbz group was removed by treatment with 10% Pd/C (147 mg) in MeOH (10 mL) under a H2 atmosphere. The title compound was obtained as a colorless oil. LC-MS-conditions 07d: tR=0.97 min; [M+H]+=183.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:64]=[CH:63][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@H:20]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C@@H:19]([CH2:42][O:43]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[O:18][C@H:10]2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(O)=O>CCOCC>[CH3:1][O:2][C:3]1[CH:64]=[CH:63][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@H:20]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[C@@H:19]([CH2:42][OH:43])[O:18][C@H:10]2[S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2OCc2ccc(OC)cc2)cc1
Solvent: CCOCC
Solvent: O=CO
Product: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a solution of phenyl 2,3,4-tri-O-(4-methoxybenzyl)-6-O-triphenylmethyl-1-thio-β-D-glucopyranoside (7) (3.44 g, 3.93 mmol) in ether (8 ml) was added formic acid (8 ml), and the resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogen-carbonate solution and saturated brine, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixture of ethanol (5 ml) and 1N aqueous sodium hydroxide solution (5 ml), and the suspension was stirred overnight at room temperature. Ethanol was evaporated under reduced pressure and the resulting suspension was extracted twice with ether. The combined ether layers were washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1) to give phenyl 2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (8) (1.28 g, yield 51%) as white crystals.
Reaction SMILES: [N:1]([C@H:4]1[C@H:19](O)[CH2:18][C@@H:17](/[C:21](/[CH3:29])=[CH:22]/[C:23]2[N:24]=[C:25]([CH3:28])[S:26][CH:27]=2)[O:16][C:15](=[O:30])[CH2:14][C@H:13]([OH:31])[C:12]([CH3:33])([CH3:32])[C:11](=[O:34])[C@H:10]([CH3:35])[C@@H:9]([OH:36])[C@@H:8]([CH3:37])[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].N([C@H]1C[C@@H](/C(/C)=C/C2N=C(C)SC=2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@@H]1O)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[OH:31][C@@H:13]1[C:12]([CH3:33])([CH3:32])[C:11](=[O:34])[C@H:10]([CH3:35])[C@@H:9]([OH:36])[C@@H:8]([CH3:37])[CH2:7][CH2:6][CH2:5][C@@H:4]2[C@@H:19]([NH:1]2)[CH2:18][C@@H:17](/[C:21](/[CH3:29])=[CH:22]/[C:23]2[N:24]=[C:25]([CH3:28])[S:26][CH:27]=2)[O:16][C:15](=[O:30])[CH2:14]1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H](O)[C@H](N=[N+]=[N-])CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2N[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 30 °C
Reaction time: 29.5 h
Yield: 46 %

Procedure:
To a stirred solution of (4S,7R,8S,9S,13R,14R,16S)-13-Azido-4,8,14-trihydroxy-5,5,7,9-tetramethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)oxacyclohexadecane-2,6-dione and (4S,7R,8S,9S,13S,14S,16S)-14-Azido-4,8,13-trihydroxy-5,5,7,9-tetramethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)oxacyclohexadecane-2,6-dione mixture (12.8 g, 23.85 mmol) in anhydrous acetonitrile (90 mL) was added triphenylphosphine (9.48 g, 35.77 mmol) under nitrogen atmosphere. The clear solution was stirred at 20-40° C. for 19-40 h. The reaction mixture was cooled to 0-5° C. for 3-4 h and filtered the product. The cake was washed with heptane (64 mL) and dried at 40° C. under reduced pressure for 15-18 h to give (1S,3S,7S,10R,11S,12S16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo(14.1.0)heptadecane-5,9-dione as a white solid (5.41 g, 46%). LC-MS: Phenomenex Luna C8(2) column: 3 μm, 4.6×50 mm. Gradient: 15 min, 0% B to 100% B in 10 min, then 100% B for 5 min. Mobile phases: A=0.01 M NH4OAc in CH3CN/H2O 5:95; B=0.01 M NH4OAc in CH3CN/H2O 95:5. Flow rate: 3.0 mL/min. Wavelength: UV 250 nm. Retention time=4.43 min. MS (ESI) (M+H)+=493.68
Reaction SMILES: CO[C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])[N:15]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[C:14]=2[CH:35]=1.[CH3:37][O:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[CH3:37][O:38][CH2:39][CH2:40][CH2:41][NH:42][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:19])=[O:20])[N:15]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[C:14]=2[CH:35]=1
Reactant: COCCCN
Reactant: COC(=O)CCCCCOc1ccc2nc(S(=O)(=O)Cc3ccccc3)n(-c3ccc(C)cc3)c2c1
Product: COCCCNC(=O)CCCCCOc1ccc2nc(S(=O)(=O)Cc3ccccc3)n(-c3ccc(C)cc3)c2c1

Procedure:
100 mg of 6-[[1-(4-methylphenyl)-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 22 mg was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13]>>[Si:16]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C=O)cc1O
Product: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Yield: 100 %

Procedure:
Prepared as in Example 12-1c from 3-hydroxy-4-methoxybenzaldehyde and tert-butylchlorodimethylsilane. Yield 100%, yellowish liquid. MS 267 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH:30]1([OH:33])[CH2:32][CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:33][CH:30]2[CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Reactant: OC1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CC5)c34)cc2o1
Temperature: 25 °C
Yield: 80 %

Procedure:
6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), cyclopropanol (2 equiv), sodium tert-butoxide (2 equiv), 1,4-dioxane (0.03 M) were combined and stirred at 25° C. The reaction mixture was loaded directly onto a silica gel column and purified using flash chromatography (0-50% ethyl acetate in hexane) column, to give the title compound (80% yield) as clear oil. MS (ESI) m/z 471.5 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]([CH3:21])[CH2:5][O:4][CH2:3]1.O.NN>>[CH3:21][CH:6]1[N:7]([CH2:8][CH2:9][NH2:10])[CH:2]([CH3:1])[CH2:3][O:4][CH2:5]1
Reactant: CC1COCC(C)N1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: CC1COCC(C)N1CCN

Procedure:
The title compound was prepared by a similar method to Preparation 7 from 2-[2-(3,5-dimethylmorpholino)ethyl]-1H-isoindole-1,3(2H)-dione [see Preparation 11] and hydrazine hydrate, to afford 2-(3,5-dimethylmorpholino)ethylamine as a white solid.
Reaction SMILES: O=C(CC)CC(OCC)=O.Cl.C(NN)(C)C.[CH:17]1([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][C:21]=2[CH:28]=[O:29])C[CH2:18]1>>[CH2:17]([C:20]1[N:24]([CH:25]([CH3:26])[CH3:27])[N:23]=[CH:22][C:21]=1[CH:28]=[O:29])[CH3:18]
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: CC(C)NN
Agent: CCOC(=O)CC(=O)CC
Agent: Cl
Product: CCc1c(C=O)cnn1C(C)C

Procedure:
5-Ethyl-1-isopropyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl 3-oxopentanoate and isopropyl hydrazine hydrochloride in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>CN(C=O)C.O>[ClH:28].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirring solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (150 mg, 0.371 mmol) in dry DMF (7.4 mL) under nitrogen was added triethylamine (0.31 mL, 2.23 mmol) to give a white slurry. 4-Chlorobenzoyl chloride (0.106 mL, 0.835 mmol) was added dropwise to the slurry, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×20 mL), and the organic phase was back-extracted with 1 N HCl (15 mL). The organic layer was discarded, and all aqueous layers were combined and washed with ethyl acetate (2×15 mL). The aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 5% to 50% A over 24 min, then 50% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (3 mL)/acetonitrile (6 mL) and concentrated. The residue was once again treated with 0.5N HCl (3 mL)/acetonitrile (6 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-[1-(4-chlorobenzoyl)piperidin-4-yl]hexanoic acid hydrochloride (75 mg, 47%) as a faint yellow solid. 1H NMR (MeOH-d6, 400 MHz) δ 7.51 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 4.77 (m, 1H), 3.82 (m, 1H), 3.19 (m, 1H), 2.85 (m, 1H), 2.25 (m, 1H), 2.10-1.40 (m, 8H), 1.28 (m, 2H), 0.85 (bt, J=7.2 Hz, 2H). ESI+ MS found for C18H26BClN2O5 m/z 379.3 (M−18+H); ESI+ MS m/z 395.4 (M−H), 377.4 (M−18−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[CH:4][C:3]=1[O:14][CH3:15].C[Si](I)(C)C.[OH-].[Na+].Br[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[CH:4][C:3]=1[O:14][C:15]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1ccccc1
Reactant: COc1cc(C(=O)C(F)(F)F)ccc1F
Agent: C[Si](C)(C)I
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccc(F)c(Oc2ccccc2)c1)C(F)(F)F

Procedure:
Trifluoromethyl 4-fluoro-3-phenoxyphenyl ketone may be prepared using the following procedure. Bromination of 2-fluoroanisole yields a mixture of bromo-2-fluoroanisole isomers from which 5-bromo-2-fluoroanisole is isolated. The Grignard reagent of 5-bromo-2-fluoroanisole is then prepared and is in turn reacted with N-methoxy-N-methyl-2,2,2-trifluoroacetamide in tetrahydrofuran, yielding trifluoromethyl 4-fluoro-3-methoxyphenyl ketone. This ketone is protected by formation of the corresponding ketal, which is in turn treated with trimethylsilyl iodide, sodium hydroxide, bromobenzene, and acid, yielding trifluoromethyl (4-fluoro-3-phenoxyphenyl) ketone.
Reaction SMILES: [C:1](=[O:24])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.Cl.Cl.[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:47][C:48]1[CH:49]=[CH:50][C:51]([N:54]2[CH2:59][CH2:58][N:57]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]3)=[O:24])[CH2:56][CH2:55]2)=[CH:52][CH:53]=1
Reactant: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCN1CCC(COC(=O)N2CCN(c3ccc(C)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
(1-(2-methoxyethyl)piperidin-4-yl)methanol (Intermediate 3, step 2; 1.73 g, 10.0 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. NMM (1.21 mL, 11.0 mmol) and 4-nitrophenyl chloroformate (2.02 g, 10.0 mmol) were added. The reaction mixture was stirred at 0° C. for 15 minutes and then added to a solution of 4-(4-methylphenyl)piperazine dihydrochloride (2.62 g, 10.5 mmol) and DIPEA (6.10 mL, 35.0 mmol) in DMF (75 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1M aq NaOH solution (6×100 mL), brine (100 mL), and then dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [1-(2-methoxyethyl)piperidin-4-yl]-methyl 4-(4-methylphenyl)piperazine-1-carboxylate (0.95 g, 25.4%) as a pale yellow oil.
Reaction SMILES: [OH2:1].[NH2:2][C:3]1[C:30]([Cl:31])=[CH:29][C:6]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:12][C@H:11]2[O:27][CH3:28])=[O:8])=[C:5]([O:32][CH3:33])[CH:4]=1>CO>[NH2:2][C:3]1[C:30]([Cl:31])=[CH:29][C:6]([C:7]([NH:2][C:3]2[CH:4]=[C:5]([O:32][CH3:33])[C:6]([C:7]([NH:9][C@H:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:12][C@H:11]3[O:27][CH3:28])=[O:8])=[CH:29][C:30]=2[Cl:31])=[O:1])=[C:5]([O:32][CH3:33])[CH:4]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Reactant: O
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)Nc1cc(OC)c(C(=O)N[C@H]2CCN(CCCOc3ccc(F)cc3)C[C@H]2OC)cc1Cl

Procedure:
40 Parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate was boiled in 160 parts of methanol. The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane. The product was filtered off, dried and recrystallized from 4-methyl-2-pentanone. The product was filtered off and dried (water-separator) yielding 18.5 parts of cis-4-amino-5-chloro-N-[2-chloro-4-[[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]aminocarbonyl]-5-methoxyphenyl]-2-methoxybenzamide; mp. 181.5° C. (compound 239).