Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:29]=1[CH:30]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:13]([O:12][C:10]([N:4]1[CH2:5][C@@H:6]([CH2:8][OH:9])[CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:33]([O:36][C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:35][C:28]=2[O:27][CH3:26])[C@@H:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H]1C[C@H](CO)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(OC(F)(F)F)cc1CN[C@H]1C[C@H](CO)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.5 %

Procedure:
To a stirred solution of (2S*,3S*,5S*)-3-amino-1-benzyloxycarbonyl-5-hydroxymethyl-2-phenylpiperidine (0.50 g, 1.36 mmol)) and 2-methoxy-5-trifluoromethoxybenzaldehyde (0.37 g, 1.70 mmol) in CH2Cl2 (20.0 ml) was added NaB(OAc)3H (0.43 g, 2.04 mmol) portionwise. The reaction mixture was stirred at room temperature for 3 hours, and then basified with sat. Na2CO3 aq. solution. The mixture was extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give a red oil (0.90 g), which solidified spontaneously on standing in a refrigerator (4 C.). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 18.0 g). Elution with CH2Cl2 --MeOH (300:1/200:1/100:1) gave title compound (0.678 g, 91.6%) as a colorless syrup. IRmax (film): 3450(s), 1698(s), 1682(s), 1670(s), 1498(s), 1230(br., s), 1160(br., s), 1030(s), 738(s), 700(s) cm31 1 ; 1H-NMR δ: 7.44-7.21(m, 9H), 7.18(br.s, 1H), 7.04(br.d, J=8.8 Hz, 1H), 7.00(br.s, 1H), 6.92(d, J=8.8 Hz, 1H), 5.40-5.27(m, 1H), 5.17(d, J=121.5 Hz, 1H), 5.05(d, J=12.5 Hz, 1H), 4.03(br.d, J=13.9 Hz, 1H), 3.74(d, J=13.9 Hz, 1H), 3.70-3.41(m, 4H), 3.62(s, 3H), 3.23-3.11(m, 1H), 2.20-1.95(m, 2H), 1.70-1.45(m, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:59]([C:63]1[CH:67]=[C:66]([CH2:68][NH2:69])[N:65]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([Cl:76])[CH:71]=2)[N:64]=1)([CH3:62])([CH3:61])[CH3:60]>C1COCC1.CN(C=O)C>[C:59]([C:63]1[CH:67]=[C:66]([CH2:68][NH:69][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][CH2:11][OH:12])=[C:2]([F:1])[CH:3]=2)[CH3:17])[N:65]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([Cl:76])[CH:71]=2)[N:64]=1)([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C(=O)O)c1ccc(COCCO)c(F)c1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(COCCO)c(F)c1
Reaction time: 36 h
Yield: 86.9 %

Procedure:
To a stirred THF/DMF (2.0 mL/0.1 mL) solution of 2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanoic acid (synthesis described for example A118) (60.0 mg, 0.25 mmol, 1.0 eq) DIPEA (0.169 mL, 0.13 mmol, 4.0 eq), TBTU (81 mg, 0.25 mmol, leg) and HOBt (33 mg, 0.25 mmol, leg) were sequentially added at RT and the mixture stirred for 15 min. (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (65 mg, 0.25 mmol, 1 eq) was then added and the mixture stirred for 36 h. After completion of the reaction the solvent was evaporated. The crude product was purified by CC using EtOAc/cyclohexane (1:1) to get N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)-propanamide (106 mg; 87%).
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:13][C@@H:12]1[CH3:45])=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:29][O:28][C:26](=[O:27])[N:25]([CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)[C@H:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[NH:11][C@@H:12]([CH3:45])[CH2:13]1
Reactant: [H][H]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc21
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)Nc2ccc(C(F)(F)F)cc21
Yield: 90 %

Procedure:
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester. (Example 56) (2.8 g, 4.3 mmol), ethanol (50 mL), and 10% palladium on carbon (280 mg) were combined in a Parr bottle and agitated under 50 psi of hydrogen gas on a Parr shaker for 0.5 h. The mixture was then filtered through a bed of Celite®, eluting with ethyl acetate, and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography using 5% ethyl acetate/hexanes as eluent to afford 2.0 g of the title product (90%): MS m/z 516 (M+ +2); 1H NMR (CDCl3) δ 1.18 (C2-Me, d, 3H, J=5.8 Hz), 6.50 (C8, d, 1H, J=8.3 Hz), 7.21 (C7, d, 1H, J=8.5).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: Nc1nc2c(Br)cccn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2nc3c(Br)cccn3n2)cc1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A suspension of 8-bromo-[1,2,4]triazolo[1, 5-a]pyridin-2-amine (2.8 g, 13.2 mmol, 1 equiv), methyl 4-iodobenzoate (3.4 g, 13 mmol, 1.0 equiv), cesium carbonate (8.4 g, 26 mmol, 2.0 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (763 mg, 1.32 mmol, 0.10 equiv), and palladium (II) acetate (300 mg, 1.32 mmol, 0.10 equiv) in dioxane (100 mL) was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane (100 mL). The resulting solids were filtered and sequentially rinsed with water (3×50 mL) and methanol (2×20 mL). The solids were dried in vacuo to afford methyl 4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate (3.1 g). 1H NMR (400 MHz, DMSO-d6), δ: 10.42 (s, 1H), 8.87 (m, 1H), 7.93 (m, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.00 (dd, J=7.4, 6.9 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:6]1[C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3][C:2]1([CH3:10])[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)NC(=O)C(C)(C)N1
Reactant: ClCc1ccccc1
Product: CC1(C)NC(C)(C)N(Cc2ccccc2)C1=O

Procedure:
If, instead of 7,14-diaza-15-oxo-dispiro[5.1.5.2]pentadecane, 2,2,5,5-tetramethyl-4-oxo-imidazolidine is used, and this alkylated with benzyl chloride as described in Example 1, then 3-benzyl-2,2,5,5-tetramethyl-4-oxo-imidazolidine (VII), M.P. 210°C, is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C@H:18]([NH:25]C(=O)OC(C)(C)C)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:25][C@H:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[CH:10][C:4]=23)[CH2:12][CH2:13]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)C1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
(R)-tert-Butyl 2-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-cyclohexyl-2-oxoethylcarbamate (0.010 g, 0.019 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (R)-2-amino-1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-2-cyclohexylethanone (0.005 g, 62% yield) as the dihydrochloride salt. MS ESI (+) m/z 421 detected.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:29]([OH:30])[CH2:28][NH:27][C@H:26]2[C@H:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[CH:24][C:25]=32)OC[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([N:33]([CH3:43])[S:34]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])(=[O:36])=[O:35])[C:10](=[O:44])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](O)(C(F)(F)F)=[O:46]>>[CH2:1]([C@@H:8]1[NH:9][C:10](=[O:44])[C@@H:11]([N:33]([CH3:43])[S:34]([CH2:37][CH2:38][C:39]([F:42])([F:40])[F:41])(=[O:35])=[O:36])[CH2:12][CH:13]=[CH:14][CH2:15][O:46][CH2:45][C@@H:19]2[CH2:18][C@@H:26]([C:21]3[CH:22]=[C:23]([O:31][CH3:32])[CH:24]=[CH:25][C:20]=32)[NH:27][CH2:28][C@H:29]1[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)[C@H]1NC[C@@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N(C)S(=O)(=O)CCC(F)(F)F)CCCCCO[C@H]1C2
Reactant: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@@H]1C[C@H]2COCC=CC[C@H](N(C)S(=O)(=O)CCC(F)(F)F)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN1

Procedure:
Step DE (3): The product isomers A and B from Step DE (2) were individually converted to isomers A and B of the TFA salts of the title compound (4 mg of isomer A, and 4 mg of isomer B, colorless oils) by a procedure analogous to Step CX (3). Data for isomer A: LC-MS Rt 1.70 min (method A), (M+H)+ 614.16. Data for isomer B: LC-MS Rt 1.71 min (method A), (M+H)+ 614.30.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.O.C(=O)([O-])[O-].[K+].[K+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[C:22]1([C:2]2[CH:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: c1ccc(-c2ccc3[nH]c4ccccc4c3c2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 3-bromo-9H-carbazole (0.4 g, 1.6 mmol) in DMF:H2O (15 mL:2 mL) are added tetrakis(triphenylphosphine)-palladium (0.184 g, 0.1 eq), potassium carbonate (0.66 g, 3 eq) and phenyl boronic acid (0.58 g, 3 eq). The resulting mixture is stirred at 80° C. for 4 hr. After cooling to rt, DCM (10 mL) is added and the reaction mixture is quenched with brine. After extraction, drying over MgSO4 and concentration in vacuo, the residue is purified via flash chromatography using PetEther:EtOAc 10:1 as eluting solvent to give the title compound (0.35 g, 1.44 mmol) as a white powder in a 90% yield. M.p.: 221° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[NH4+].[OH-].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:16]#[N:17])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 90 °C

Procedure:
A mixture of (3-bromo-phenyl)-acetic acid ethyl ester (12.38 g, 54.05 mmol), zinc cyanide (4.33 g, 36.9 mmol), and DMF (150 mL) was deoxygenated with nitrogen and Pd(PPh3)4 (3.10 g, 2.68 mmol) was added. The mixture was heated in a 90° C. oil bath for 2.5 h and was cooled to room temperature. Aqueous NH4OH (5%) was added and the product was extracted into Et2O (3×). The combined organic extracts were washed with 5% NH4OH followed by brine. The organic solution was dried over MgSO4, filtered and concentrated. Flash chromatography (9:1 hexanes:EtOAc) provided (3-cyano-phenyl)-acetic acid ethyl ester (9.08 g) as a pale yellow liquid which was identical spectroscopically to that obtained using Method A above.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[N:18]([CH3:43])[C:19]3[C:24]([N:25]=2)=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:22]=[C:21]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH2:41][CH3:42])[N:20]=3)([OH:16])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:33]1[N:32]([C:21]2[N:20]=[C:19]3[C:24]([N:25]=[C:17]([C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)([OH:16])[CH3:15])[N:18]3[CH3:43])=[C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:22]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=1)[CH3:42]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCNCC3)n(C)c2n1
Reaction time: 1 h

Procedure:
To a solution of 4-{1-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-hydroxyethyl}piperidine-1-carboxylic acid tert-butyl ester (104 mg, 0.18 mmol) in DCM (1 mL) was added TFA (1 mL) and the resulting mixture stirred for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM affording 1-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-piperidin-4-ylethanol. LCMS (method A): RT 1.88 min, [M+H]+ 491.2
Reaction SMILES: [C:1](=[O:39])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]3[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24][C:11]=3[N:12]=[C:13]([C:15]3[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=3[F:23])[N:14]=2)[CH2:5][CH2:4]1.[CH3:40][NH:41][CH2:42][CH2:43][OH:44].C(=O)(O)[O-].[Na+].Cl.O1CCOCC1>C1COCC1.CN(C=O)C>[ClH:22].[OH:44][CH2:43][CH2:42][N:41]([CH3:40])[C:1](=[O:39])[O:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:10]3[CH2:26][S:25](=[O:27])(=[O:28])[CH2:24][C:11]=3[N:12]=[C:13]([C:15]3[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=3[F:23])[N:14]=2)[CH2:7][CH2:8]1
Reactant: CNCCO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)OC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 84 %

Procedure:
A mixture of 300 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl 4-nitrophenyl carbonate, 43 mg of 2-(methylamino)ethanol, and 5 ml of DMF was stirred at ambient temperature for 19.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the mixture was extracted twice with chloroform. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The yellow oil obtained was dissolved in THF, here was added 4M HCl-dioxane solution, and the solution was concentrated under reduced pressure to give solid, which was recrystallized from acetonitrile-ether to yield 120 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl (2-hydroxyethyl)methylcarbamate hydrochloride as colorless solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36](O)=[O:37])[C:26]1=[O:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:37])[C:26]1=[O:27]
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2ccccc2oc1=O
Yield: 43.5 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), coumarin-3-carboxylic acid (2.7 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.0 g, 43%) as an oily product.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[C@H:22]([CH3:28])[C@@H:21]([O:29][Si](C(C)(C)C)(C)C)[C@@H:20]([CH3:37])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][C@@H:13](/[C:38](/[CH3:46])=[CH:39]/[C:40]2[N:41]=[C:42]([CH3:45])[S:43][CH:44]=2)[O:12][C:11](=[O:47])[CH2:10]1)(C(C)(C)C)(C)C>C1COCC1.C(Cl)Cl>[CH3:45][C:42]1[S:43][CH:44]=[C:40](/[CH:39]=[C:38](/[C@H:13]2[O:12][C:11](=[O:47])[CH2:10][C@H:9]([OH:8])[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[C@H:22]([CH3:28])[C@@H:21]([OH:29])[C@@H:20]([CH3:37])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]2)\[CH3:46])[N:41]=1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\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=C\CCC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 22 °C
Reaction time: 36 h

Procedure:
A solution of (4S,7R,8S,9S,16S,Z)-4,8-Bis((tert-butyldimethylsilyl)oxy)-5,5,7,9-tetramethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)oxacyclohexadec-13-ene-2,6-dione (26.2 mg, 37.1 μmol) in THF (3.6 ml) in a plastic vial was treated with HF-pyridine complex (70% HF, 1.09 mL). The reaction mixture was stirred at 22° C. for 36 h, diluted with DCM and quenched by NaHCO3 (sat.). The aqueous layer was extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification on SiO2 (hexanes: diethyl ether 2:1 to 1:1) afforded 15.2 mg (81%, Z:E=95:5) of epothilone C as a colorless solid together with 2.6 mg of mono-desilylated product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32](=[O:34])[CH3:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:10]=12.N1C=CC=CC=1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl.C(OCC)(=O)C>[CH3:51][C:41]1[CH:46]=[CH:45][C:44]([S:47]([O:20][CH2:19][CH2:18][C:17]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:31][C:32](=[O:34])[CH3:33])=[CH:3][C:2]=3[F:1])[N:15]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:16]=2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCO)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCOS(=O)(=O)c2ccc(C)cc2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.10 mmol) of N-[3-fluoro-4-({3-(2-hydroxyethyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo-[2,3-b]pyridin-4-yl}oxy)phenyl]acetamide are initially charged in 2.0 ml of dichloromethane. 25 μl (0.31 mmol) of pyridine and 19.7 mg (0.10 mmol) of p-toluenesulfonyl chloride are added, and the mixture is stirred at RT overnight. Two more times, the same amounts of pyridine and p-toluenesulfonyl chloride are added, at intervals of 2 hours. After the reaction has come to completion, the reaction solution is diluted with ethyl acetate and extracted twice with saturated ammonium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][O:10][CH:9]([O:12][CH3:13])[O:8]1)=[O:4].[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1CCCCC1>[F:15][C:2]([F:14])([F:1])[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][O:10][CH:9]([O:12][CH2:13][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[O:8]1)=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC1OCC(CNC(=O)C(F)(F)F)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCCCOC1OCC(CNC(=O)C(F)(F)F)O1
Reaction time: 2 h

Procedure:
3 g of 2,2,2-trifluoro-N-(2-methoxy-[1,3]dioxolan-4-ylmethyl)acetamide (Ortho 1, 13.09 mmol) were mixed with 3.54 g of octadecanol (13.09 mmol). The mixture was melted at 80° C. and left for 2 hours after the addition of 32 mg of pyridinium para-toluenesulfonate (0.13 mmol). The crude reaction product was then dissolved in cyclohexane, washed with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution, dried over magnesium. sulfate and then concentrated to dryness. This crude product was used as it was for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.C1(C)C=CC=CC=1>[CH2:22]([O:29][C:2]1[CH:3]=[N:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Reactant: OCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: c1ccc(COc2cnc(-c3nc4ccc(OCC5CC5)cc4o3)nc2)cc1
Temperature: 110 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
Under an argon atmosphere, a mixture of 2-(5-bromopyrimidin-2-yl)-6-(cyclopropylmethoxy)-1,3-benzoxazole (260 mg), benzyl alcohol (812 mg), cesium carbonate (368 mg), copper(I) iodide (14.3 mg), 1,10-phenanthroline (27.0 mg) and toluene (5 mL) was stirred at 110° C. for 3 days. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow solid (205 mg).